JPS62230732A - Composition for exodermal administration - Google Patents

Abstract

PURPOSE:A composition for exodermal administration, obtained by containing a prolinol ester to enhance the skin permeability and percutaneous absorbing action of a drug and further blending a polar substance to synergistically enhance the percutaneous absorbability. CONSTITUTION:A composition obtained by containing a prolinol ester expressed by formula I (Ra is H or aliphatic hydrocarbon residue; Rb is aliphatic hydrocarbon residue; Ra + Rb is <=18C) and having high percuteaneous absorbability of a drug, e.g. local aneasthetic, antibiotic substance, antihistaminic agent, etc. The compound expressed by formula I is further used together with a polar compound, e.g. cyclic urea expressed by formula II (R1 and R2 are H or lower alkyl), lower alcohol, glycerol, etc., to synergistically enhance skin permeability and percutaneous absorbing action of the drug. The compound expressed by formula I is preferably blended in an amount of 1-50wt% based on the total weight of the polar compound and the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a composition for dermal administration that can enhance transdermal absorption of drugs, and a method for promoting transdermal absorption of drugs.

[Prior Art/Problems to be Solved by the Invention] Conventionally, when administering drugs to the outer skin, drugs have been administered locally for the purpose of acting locally on the outer skin or the subcutaneous tissue directly beneath it, such as sterilization, disinfection, analgesia, antipruritic, and antiinflammatory. It was something to do. Furthermore, when the purpose is to have a systemic effect, oral preparations or injections have traditionally been used; however, oral preparations are more susceptible to hepatic metabolism after absorption and have a long-lasting effect. However, there is a problem in that in order to achieve this, the concentration in the body will temporarily become higher than necessary, and there are concerns about side effects.

In addition, some drugs, such as indomethacin, cause gastrointestinal disorders when administered orally.

On the other hand, administration by injection allows rapid absorption, but requires a specialist such as a doctor.

In recent years, transdermal administration methods aiming at systemic effects have been proposed in order to improve the above-mentioned side effects and drawbacks.

When a drug is administered transdermally, it is easy to maintain the drug;
It has advantages such as being able to control the concentration of the drug in the body and being less susceptible to hepatic metabolism because it enters the bloodstream directly through the skin tissue.

However, since normal skin inherently has a barrier function to prevent foreign substances from entering the body, the purpose of administering medicines through the skin has been limited to local use. Therefore, when a systemic effect is intended, a transdermal absorption promoting aid is necessary, and various kinds of aids have been proposed in recent years. For example, US Pat. No. 3,551,554 discloses dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methyldecyl sulfoxide, and the like.

In addition, as an absorption promoting agent in combination with a lower alkylamide, dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl palmitate (U.S. Pat. No. 3,472,431), 2-pyrrolidone and a suitable oil, or a straight chain fatty acid can be used. There are examples of combinations of alcohol and alcohol esters (US Pat. No. 4,017,641), but these absorption promoting aids are still not satisfactory in terms of effectiveness, safety, and usability.

Under these circumstances, the present inventors have conducted intensive research and have obtained the following findings. That is, the specific prolinol ester (1) described below increases the skin permeability and transdermal absorption of the drug, and furthermore, the effect is synergistically enhanced by using the prolinol ester H) in combination with a polar compound. I discovered that.

The present invention was completed based on the above-mentioned new findings, and its first purpose is to provide a composition for dermal administration that can enhance the skin permeability and percutaneous absorption of drugs.

A second object of the present invention is to provide a method for increasing skin permeability and percutaneous absorption of drugs.

[Means for solving problems]

The present invention is based on the general formula: (wherein, Ra represents a hydrogen atom or an aliphatic hydrocarbon residue,
Rb represents an aliphatic hydrocarbon residue, and the total number of carbon atoms of Ra and Rh is 18 or less. It is.

Still, the present invention, in addition to prolinol ester (1),
The composition further contains a polar compound for dermal administration.

Furthermore, the present invention provides that in the presence of prolinol ester (1),
The present invention relates to a method for increasing the transdermal transitivity and transdermal absorption of a drug, which preferably further comprises administering the drug transdermally in the presence of a polar compound.

In the present specification, lower alkyl may be linear or branched, and includes those having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, 1so-propyl, n-butyl, and 1so-butyl. This is exemplified as a preferable example.

Regarding the general formula (2), the aliphatic hydrocarbon residues represented by Ra and Rb refer to groups in which one hydrogen atom has been removed from a hydrocarbon, and it may be either saturated or unsaturated, or linear or branched. It may be either shaped or cyclic. The aliphatic hydrocarbon residue preferably has about 1 to 18 carbon atoms, and the total number of carbon atoms of Ra and Rb is preferably 18 or less. When the aliphatic hydrocarbon residue is an unsaturated group, the unsaturated bonds contained are preferably double bonds, and the number of unsaturated bonds is preferably 1 to 2. In addition, in the case of a cyclic group, those having 6 to 12 carbon atoms are preferred, and the number of rings is preferably 1, and 5 to 12.
A seven-membered ring is preferred.

Aliphatic hydrocarbon residues in Ra include methyl, ethyl, n-propyl, 1so-propyl, n-butyl,
5ec-butyl, Lert-butyl, n-amyl, 1s
Alkyl having 1 to 5 carbon atoms such as o-amyl is preferred.

The aliphatic hydrocarbon residue associated with Rb may be either saturated or unsaturated, and may be chain (either linear or branched) or cyclic. Specific examples of such substances include, for example, n-hexyl, n-heptyl,
n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-)lysosyl, n-tetradecyl, n-hexadecyl, n-octadecyl, 2-ethylhexyl, 2-ethylhexyl, 3.7- Saturated chains such as methyloctyl, 2-hexynrudecyl, 234.4-trimethyl-pentyl, cis-3-hexenyl,
Unsaturated compounds such as oleyl and geranyl with 6 carbon atoms
-18 chain-like ones, 6-1 carbon atoms such as 2-cyclohexylethyl, cycloheptyl, schifhexylmethyl, 4-cyclohexylbutyl, 3-cyclopentylpropyl, etc.
Examples include two saturated rings.

Prolinol ester ([) is substantially a known compound, and can be produced by a known method or a method analogous thereto. For example, a compound (VT
) and a compound (■) represented by the general formula (wherein Ra has the same meaning as above)
It is produced by reacting with.

At that time, the compound (■) is an acid halide (acid chloride),
Acid anhydrides, mixed acids 41! ! The reactive v and R forms of carboxylic acids such as hydrates and active esters are used in this reaction. Known conditions may be used as the reaction conditions. General formula (
(2) In general formula (1), Ra is a hydrogen atom.
When producing prolinol ester (1), which is a hydrogen atom, the amino group in the compound (■) is protected, the esterification reaction is carried out, and after the esterification reaction is completed, the protecting group is removed. It is preferable. Protection 3 at that time
The i group is not particularly limited as long as it is not removed during the esterification reaction but can be removed after the esterification reaction, and examples thereof include a carbobenzoxy group and a t-butoxycarbonyl group. In addition, in the general formula (■), Ra
A compound (■) in which is an aliphatic hydrocarbon residue is, for example, a compound (■) in which Ra is a hydrogen atom in the general formula (■) to Chavdarian.

Charles G.; 5anders, Edw.
ard B, (Org, Prep.

Proced, Int,), 13 (6), 3
89-393 (1981) or a method similar thereto.

It is preferred that the composition for dermal administration of the present invention further contains a polar compound. The transdermal absorption of the drug is thus synergistically enhanced.

The polar compound can also be used as a solvent, and examples of preferable polar compounds include the following compounds: lower alcohol, glycerin, glycerin ester, thioglycerol, lactic acid ester, general formula [in the formula , R1,
R2 each represents a hydrogen atom or a lower alkyl (preferably one having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, 1so-propyl, n-butyl)] A raw urea (■) represented by General formula [wherein R3, R4 and R5 are each a hydrogen atom or lower alkyl (preferably 1 carbon number such as methyl, ethyl, n-propyl, 1so-propyl, n-butyl, etc.]
~4)] An amide compound (■) represented by alkylene glycol, monoalkyl ether of mono- or diethylene glycol, lactone, general formula [wherein R6 is a hydrogen atom or lower alkyl (preferably methyl, ethyl , n-propyl, 1so-propyl, n-butyl, etc.)] A pyrrolidone compound (IV) represented by the general formula [wherein R7 is lower alkyl (preferably methyl , ethyl, n-propyl, 1so-propyl, n-butyl, etc.) having 1 to 4 carbon atoms, n represents 4 or 5], and is a lactam compound (V) represented by the above-mentioned suitable polar compound. A specific example is as follows.

■Lower alcohol Methyl alcohol, ethyl alcohol, n-propyl alcohol% 150-propyl alcohol, n-butyl alcohol, 1so-butyl alcohol, 5eC-butyl alcohol, [-butyl alcohol, n-amyl alcohol, 1so-amyl alcohol, low Preferred examples include aliphatic monohydric alcohols having 1 to 6 carbon atoms, such as hexyl alcohol and cis-3-hexenol.

(2) Glycerin and its ester The ester may be mono-, di- or triester, and the acid component is preferably a fatty acid having 2 to 6 carbon atoms, particularly acetic acid. Specifically, glycerin monoacetate, glycerin diacetate, etc. are listed.

(2) Thioglycerol may be mono-, di- or triglycerol, such as α-monothioglycerol.

(2) Lactic acid ester Among the esters, lower alkyl esters having 1 to 4 carbon atoms are particularly preferred, and specific examples include methyl lactate, ethyl lactate, propyl lactate, and butyl lactate.

(iii) Cyclic urea (U) A 5-membered ring is preferred, and may be substituted with lower alkyl. Specifically, N,N'-dimethylethyleneurea, ethyleneurea, N,N'-diethylethyleneurea and the like are listed.

■Amide compounds (I[[) Specifically, formamide, N-methylformamide,
N,N-dimethylformamide, N,N-diethylformamide, acetamide, N-methylacetamide, N,N-dimethylacetamide, N,N-diethylacetamide, propionamide, N-methylpropionamide, N,N-dimethylpropion Amide, N, N-
Diethylpropionamide and the like are listed.

■Alkylene glycol Alkylene preferably has 2 to 8 carbon atoms,
Specifically, ethylene glycol, 1,3-propanediol, 2-propanediol, butanediol, bentanediol, 2-methyl-2□4-bentanediol, 2-ethyl-1°3-hexanediol, etc. Enumerated.

(2) Monoalkyl ether of mono- or diethylene glycol The alkyl in the monoalkyl ether preferably has 1 to 2 carbon atoms. Specific examples include ethylene glycol monomethyl ether and ethylene glycol monoethyl ether.

(2) Lactone A 4-membered or 5-membered ring is preferred, and specific examples include propiolactone and butyrolactone.

[Phase] Pyrrolidone compound (rV) Specifically, 2-pyrrolidone, N-methylpyrrolidone, etc. are listed.

(2) Lactam compound (V) Specific examples include N-methylpiperidone and N-methylcaprolactam.

The amount of prolinol ester (+) is preferably 0.5 to 0.5 to the total amount of the polar compound and prolinol ester (1).
It is blended at a ratio of 70 double stars, more preferably 1 to 50 double stars.

The composition for external administration of the present invention has the effect of effectively promoting transdermal absorption of a drug, and a drug is blended with it to form an external preparation! ! ! Or, if the drug is administered dermally in the presence of the composition, the drug is easily absorbed into the body. Preferably, the drug is previously incorporated into the composition of the present invention.

There are no particular restrictions on the drug as long as it can be administered through the skin.
It may be a drug intended for local or systemic action. According to the present invention, if the drug is intended for local action, the drug is allowed to penetrate deep into the body, and if the drug is intended for systemic action, the drug is quickly transferred into the blood.

The drug is preferably less than or equal to 500 molecules, more preferably less than 500 molecules.

Specifically, local drugs include local anesthetics (e.g., brocaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, lidocaine, lidocaine hydrochloride, piperolyne acetate), antihistamines (e.g., diphenhydramine hydrochloride, chlorpheniramine maleate). , prompheniramine maleate,
diphenylimidazole, clemizole hydrochloride), antibiotics (e.g. lincomycin, penicillin G1 erythromycin, tetracycline hydrochloride, clindamycin, kanamycin, oxytetracycline, chloramphenicol, fradiomycin, nyscutin, gramicidin hydrochloride, bacitracin), antifungal agents Example C, griseofulvin, N-methyl-N-(3-tolyl)thiocarbamic acid-2-naphthyl ester, siametazole hydrochloride, oleothricin, trichomycin, pyrrolnidoline, 5-fluorocytosine] and the like.

Specifically, as systemic drugs, benzodiazepines (
e.g. diazepam, nitrazepam, fludiazepam, lorazepam, prazepam, fludiazepam, clonazepam)
, diuretics [e.g., thiazides (e.g., pendroflumethiazide, polythiazide, methyclothiazide, trichlormethiazide, cyclopenthiazide, pentyldrochlorothiazide, hydrochlorothiazide, bumetanide)],
Antihypertensive agents (e.g., clonidine), antihistamines [e.g., aminoethers (e.g., diphenhydramine, carbinoxamine, diphenylbilarin), ethylenediamines (e.g., fenbenzamine), monoamines (e.g., chlorpheniramine)], Nonsteroidal anti-inflammatory agents (e.g., indomethacin, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen), sodium salicylate, antineoplastic agents [e.g., 5-fluorouracil, 1- (2-tetrahydrofuryl)-5-fluorouracil, cytarabine, proxuridine], steroid anti-inflammatory agents (e.g., cortisone, hydrocortisone, prednisolone, prednisone, triamcinolone, dexamethasone, hetamethasone), antiepileptic agents (e.g., ethosuximide), arrhythmia treatment drugs (e.g., ajmaline, brassimarin, pindolol, propranolol, quinidine), neuropsychiatric drugs (e.g., clofluperiol, trifluberidol, haloperidol, moperon), scopolamines (
e.g., methylscopolamine, butylscopolamine), metoclopramide hydrochloride, chloropromacine, atropine (
e.g., methylatropine bromide, methylanisotropine bromide), vasodilators (e.g., isosorbitcinitrate,
nitroglycerin, pentaerythritol tetraborate, propanyl nitrate, dipyridamole), antibiotics [e.g.
Tetracycline M (e.g., tetracycline, oxytetracycline, minocycline, doxycycline,
minocycline), chloramphenicols, and erythromycins].

The amount of the drug to be mixed may be an amount sufficient to achieve the desired medicinal effect, and it varies depending on the type of drug, patient's weight, symptoms, etc., and may be appropriately selected depending on these conditions. Generally, it is preferably 0.01 to 20% by weight, particularly 0.2 to 10% by weight, based on the total amount of prolinol ester (+) and polar compound.

Note that the amount of the drug to be used can be adjusted by increasing or decreasing the area of the drug-containing composition applied to the skin, so it is not necessarily limited to the above-mentioned amount.

The composition for external administration according to the present invention can be used as it is or with the addition of additives (carriers, etc.) required for the formulation to form external preparations such as ointments, plasters, lotions, adhesive tapes, impregnating agents, and gels. It is administered to the integument as a. As an impregnating agent, for example, the composition for external administration or a composition containing known additives may be applied to a suitable adsorbent (gauze, etc.).
Examples include those adsorbed onto filter paper, porous membranes, etc.), which are generally applied to the outer skin by fixing with adhesive tape. In addition, as a gel agent, for example, dibenzylidene sorbitol [e.g., Gelol D■ (manufactured by Shin Nihon Rika Co., Ltd.)
) and made into a gel form and spread on a support. In addition, examples of the adhesive base for the adhesive tape include those known per se, such as acrylic copolymers, polyvinyl ether compounds, and rubber adhesive mixtures. Other external preparations can also be easily prepared by means known per se.

[Action/Effect]

The prolinol ester (I) used in the present invention is
It has the effect of increasing the skin i3 absorption and transdermal absorption of drugs. Therefore, by incorporating the prolinol ester into a composition for dermal administration, the skin ItJ permeability and transdermal absorption of the drug can be increased.Also, the prolinol ester ([) and a polar substance can be used in combination. This synergistically enhances the skin i3 transit and transdermal absorption effects of the drug.

Therefore, by further incorporating a polar substance into the above composition, more efficient transdermal absorption of the drug can be achieved.

〔Example〕

The present invention will be explained in more detail below using Reference Examples, Examples, and Experimental Examples, but the present invention is not limited thereto.

Reference Examples 1 to 5 Prolinol esters (1) in which Ra and Rh were groups listed in Table 1 were produced.

Since the manufacturing method is almost the same for all compounds, the manufacturing method of the compound of Reference Example 1 is shown below as a representative example.

Table 1 (Production method of compound of Reference Example I) In general formula (1), Ra = If, I? b --(C
I+2) Production of uCH3 ester [25 g of thionyl chloride was added to a benzene solution containing 5.0 g (0,023 mol) of lysocanoic acid, and the mixture was refluxed for 5 hours.

Excess thionyl chloride and benzene were distilled off to obtain tridecanoic acid chloride.

Next, 1.8 g of pyridine was added to 5.4 g of N-carpohenzoxyprolinol in benzene/8v&, the above tridecanoic acid chloride was added dropwise under water cooling, and the mixture was stirred at room temperature for 2 hours. Thereafter, it was poured into saturated sodium bicarbonate solution, extracted with benzene, the benzene layer was washed with water and saturated brine, dried over sodium sulfate, distilled off, and purified by column to obtain tridecane 1% tN-carpobenzene. Kin-2
-7.1g of pyrrolidine methyl ester was obtained.

This was dissolved in methanol and catalytically hydrogenated using Pd-C as a hornworm medium for 3 hours at room temperature and normal pressure. Thereafter, the reaction solution was filtered through Celite II to remove Pd-C, methanol was distilled off, and 3.4 g of the desired ester was purified by column purification.
Obtained. Yield: 49% (from tridecanoic acid).

Reference Examples 6-1O Prolinol esters ([) in which Ra and Rb are the groups listed in Table 2 were produced. Since the manufacturing method is almost the same for all compounds, the manufacturing method of the compound of Reference Example 6 is shown below as a representative example.

(The following is a blank space) (Production method of the compound of Reference Example 6) In the general formula (1), Ra = CIh, Rb --(C1
)2) Preparation of ester of ++01)3 5 g (0,050 mol) of prolinol was added to Tli
treatment with 2 equivalents of n-butyllithium at -70°C in
7.0 g of methyl iodide was added dropwise at -70°C and stirred for 2 hours. After gradually raising the temperature and reacting for 2 hours with water cooling, 1.8
g of water was added, the resulting precipitate was filtered off, the filtrate was concentrated and purified by column to obtain 3.0 g of N-methylprolinol.

Next, 5.6 g (0,026 mol) of tridecanoic acid
and N-methylprolinol 3.0 g (0,02
61Iol) was added with PI luenesulfonic acid as a catalyst, and azeotropically dehydrated in benzene for 3 hours. Saturated sodium bicarbonate solution was poured into the reaction solution, extracted with benzene, washed with water and saturated brine, dried over sodium sulfate, distilled off benzene, and purified by column to obtain 6.1 g of the desired ester. .

Yield: 39% (from prolinol).

Examples 1-30 Basic formulation (1) Drug 1% by weight (2)
Polar compound 89% by weight (3) Prolinol ester (+) 10% by weight (1), (2)
Using each of the items shown in Table 3 as (3) and (3),
A liquid composition having the above basic formulation was prepared by first mixing (3) with (2) and then dissolving (1).

Control formulation (1) Drug 1% by weight (2
) Dimethyl sulfoxide 99% by weight (1) was dissolved in (2) to prepare two rounds.

Comparative Examples 1 to 10 (1) Drug 1% by weight (2)
Polar compound 99% (1) to (2
).

As +1) and (2), those listed in Table 4 were used.

Experimental Examples The amount of drug permeated through the skin in the compositions of Examples 1 to 30, control formulations, and comparative examples 1 to 10 was measured using excised rat abdominal skin, and the results are shown in Tables 3 and 4. Ta.

Note that the Q values in Tables 3 and 4 mean the following.

Q=C/D C: Amount of drug permeated through the skin in Examples or Comparative Examples D: Amount of drug permeated through the skin in the control formulation (Measurement method) The rat skin was attached to a glass filter cell so that the corresponding part was in contact with physiological saline, and the drug that had permeated into the physiological saline was determined by high-performance liquid chromatography. This experiment was conducted in a 1.1 container.

(Margin below)

Claims (7)

[Claims] (1) General formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, Ra represents a hydrogen atom or an aliphatic hydrocarbon residue,
Rb represents an aliphatic hydrocarbon residue, and the total number of carbon atoms of Ra and Rb is 18 or less. . (2) The composition according to claim (1), wherein Ra is a hydrogen atom or an aliphatic hydrocarbon residue having 1 to 5 carbon atoms, and Rb is an aliphatic hydrocarbon residue having 6 to 18 carbon atoms. . (3) The composition according to claim (1) or (2), further comprising a polar compound. (4) Polar compounds include lower alcohols, glycerin, glycerin esters, thioglycerol, lactic acid esters, general formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 and R_2 each represent a hydrogen atom or a lower alkyl Cyclic urea (II) represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (wherein R_3, R_4 and R_5 each represent a hydrogen atom or lower alkyl) Compound (III), alkylene glycol, monoalkyl ether of mono- or diethylene glycol, lactone, represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (In the formula, R_6 represents a hydrogen atom or lower alkyl) Pyrrolidone compound (IV), general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (V) (In the formula, R_7 represents lower alkyl, n represents 4 or 5) The composition according to claim (3), which is at least one type of composition. (5) Claims (2) to (2) wherein the amount of prolinol ester (I) is 0.5 to 70% by weight based on the total amount of prolinol ester (I) and the polar compound.
The composition according to any one of item 4). (6) Claim No. 1 further comprising a drug.
) to (5). (7) The composition according to claim (6), wherein the amount of prolinol ester (I) is 0.5 to 70% by weight based on the total amount of prolinol ester (I) and the polar compound. .