JP2886972B2 - Polyorganosiloxane having phosphoric acid amide group at one terminal and transdermal absorption enhancer - Google Patents

Description

The present invention relates to a novel polyorganosiloxane having a phosphoric acid amide group at one terminal and a transdermal absorption enhancer for promoting the penetration and absorption of the drug through the skin. As for the use as.

(Prior art)

The polyorganosiloxane having a phosphoric acid amide group at one end of the present invention is a novel compound, and it is completely known that the polyorganosiloxane having a phosphoric acid amide group at one end is useful as a transdermal absorption enhancer. I didn't.

Research on drug delivery systems (DDS) has been actively conducted in order to more efficiently reach drugs at target sites and suppress side effects. Among them, in recent years, a transdermal absorption system using skin as a site to which a drug is applied has attracted attention. The advantage of this system is that the skin permeation rate of the drug is controlled and a sustained and constant blood concentration can be maintained, which can avoid the first-pass effect in the liver. Dosing is not affected by food or vomiting. Easy to control dosing,
It can be administered near the target site. But,
At present, there are disadvantages such as a limited amount of a drug to be administered in a relatively small amount, limitation of a drug that can be used, deterioration of the stratum corneum and promotion of a skin allergic reaction, and short-term efficacy. Therefore, in order to improve these points, the combined use of a transdermal absorption enhancer has been studied.

So far, dimethyl sulfoxide, 1-dodecyl-
2-pyrrolidone, 1-dodecylazacycloheptane-2
-Use of on, urea, etc. has been proposed (supervised by Isao Kaetsu,
Drug Delivery System, pp. 213-237, CMC).

[Problems to be solved by the invention]

However, these accelerators are not always satisfactory in the promoting effect, and the promoting effect may be drastically reduced depending on the kind of the drug medium. Therefore, a more effective accelerator has been desired. Further, even if a good accelerating effect is exhibited, the conventional accelerating agent has problems in practical use in that it has toxicity and irritation to the skin.

[Means for solving the problem]

The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that a specific polyorganosiloxane exhibits an extremely excellent transdermal absorption promoting action, and have completed the present invention.

That is, the present invention relates to the general formula (Wherein, R ¹ and R ² may be the same or different and may have 1 to 6 carbon atoms or a phenyl group; R ^{3 to} R ⁷ may be the same or different and have 1 to 6 carbon atoms or an alkyl group; Is 2
An integer from 1 to 7, and n is an integer of 1 or more. However, R ³ and R ⁴ may be the same or arbitrarily different for each repeating unit. The present invention relates to a polyorganosiloxane having a phosphoric acid amide group at one end represented by the formula (1) and a percutaneous absorption enhancer for a drug comprising this compound.

The polyorganosiloxane of the present invention can be produced, for example, by the following method. That is, the general formula (Wherein, R ^{3 to} R ⁷ may be the same or different and have 1 to 1 carbon atoms)
6, an alkyl group, p is an integer of 2 to 7, and n is an integer of 1 or more. However, R ³ and R ⁴ may be the same or arbitrarily different for each repeating unit. A) a polyorganosiloxane having an aminoalkyl group at one end represented by the general formula (Wherein, R ¹ and R ² may be the same or different and each is an alkyl group having 1 to 6 carbon atoms or a phenyl group). A polyorganosiloxane having a phosphoric acid amide group at one terminal represented by the formula [I] can be produced.

In this amidation reaction, it is preferable to use a solvent, such as hexane, benzene, toluene,
Diethyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, chloroform, methylene chloride, N, N
-Dimethylformamide (DMF), N-methylpyrrolidone and the like. The reaction is carried out at 0-100 ° C, preferably 20-8
It proceeds smoothly in the range of 0 ° C. This reaction proceeds more smoothly by coexisting with an organic base such as trimethylamine, triethylamine, N, N-dimethylaniline, and pyridine.

The chlorophosphate diester represented by the general formula [III] used in the amidation reaction includes dimethyl chlorophosphate, diethyl chlorophosphate, dipropyl chlorophosphate, diisopropyl chlorophosphate,
Dibutyl chlorophosphate, diisobutyl chlorophosphate, di-t-butyl chlorophosphate, dipentyl chlorophosphate,
Dihexyl chlorophosphate, methyl ethyl chlorophosphate,
Examples thereof include methylpropyl chlorophosphate, methylbutyl chlorophosphate, methylhexyl chlorophosphate, ethylhexyl chlorophosphate, diphenyl chlorophosphate, and methylphenyl chlorophosphate. Some of these compounds are commercially available, and those not commercially available can be easily synthesized by a condensation reaction between phosphorus oxychloride and corresponding alcohols.

The polyorganosiloxane having an aminoalkyl group at one terminal represented by the general formula [II] is, for example, a compound represented by the general formula: (Wherein, R ^{5 to} R ⁷ may be the same or different and have 1 to 1 carbon atoms)
6 alkyl groups. ) Is reacted with a strong base to form a silanolate anion. (Wherein, R ³ and R ⁴ may be the same or different and are an alkyl group having 1 to 6 carbon atoms, and q is an integer of 3 to 6). (In the formula, R ³ ′ and R ⁴ ′ may be the same or different and may be an alkyl group having 1 to 6 carbon atoms, and p is an integer of 2 to 7, provided that R ³ ′ and R ⁴ ′ shown here.) Is the general formula [V]
And may be the same as or different from R ³ ′ and R ⁴ ′. By stopping the reaction using the chlorosilane compound represented by (Wherein, R ^{3 to} R ⁷ may be the same or different and have 1 to 1 carbon atoms)
6, an alkyl group, p is an integer of 2 to 7, and n is an integer of 1 or more. However, R ³ and R ⁴ may be the same or arbitrarily different for each repeating unit. Can be produced by synthesizing a polyorganosiloxane having a cyanoalkyl group at one end represented by the formula (1), and then reducing the cyanoalkyl group at one end of the polyorganosiloxane by an ordinary method.

As the strong base used in the above reaction, methyl lithium, n-butyl lithium, sec-butyl lithium,
Organolithium compounds such as t-butyllithium, phenyllithium, lithium diisopropylamide, bistrimethylsilyllithium amide, alkali metal hydrides such as sodium hydride and potassium hydride, methylmagnesium iodide, ethylmagnesium bromide, phenylmagnesium bromide Grignard compounds and the like can be exemplified. These strong bases are usually used as raw materials in the above general formula [VII].
Approximately one equivalent is used for the silanol compound represented by The reaction is preferably performed at a relatively low temperature from -70 ° C to room temperature from the viewpoint of suppressing side reactions. In addition, this reaction
The reaction is preferably performed in an organic solvent, and as the solvent used here, tetrahydrofuran, benzene, toluene, n-hexane, chloroform, carbon tetrachloride and the like are suitably used. Further, this reaction is desirably performed in an atmosphere of an inert gas such as argon or nitrogen.

On the other hand, without using the silanol compound represented by the general formula [IV] in the above reaction, methyl lithium, n
-Butyl lithium, sec-butyl lithium, alkyl lithium compounds such as t-butyl lithium as an initiator,
Similarly, the cyclosiloxane compound represented by the general formula [V] and the chlorosilane compound represented by the general formula [VI] are reacted to form the compound represented by the general formula [VI]
The polyorganosiloxane having a cyanoalkyl group at one end represented by the formula [I] can also be synthesized more easily. In this case, of the alkyl groups represented by R ^{5 to} R ⁷ in the general formula [VII], two are the same as R ³ and R ⁴ in the general formula [V], and one is used herein. It is the same as the alkyl group of the alkyl lithium compound.

Examples of the silanol compound represented by the general formula [IV] include trimethylsilanol, triethylsilanol, tripropylsilanol, triisopropylsilanol, tributylsilanol, tripentylsilanol, trihexylsilanol, methyldiethylsilanol, dimethylethylsilanol, and dimethylsilanol. Examples thereof include propylsilanol, dimethylisopropylsilanol, dimethylbrilsilanol, dimethylisobutylsilanol, dimethyl-t-butylsilanol, and dimethylhexylsilanol.

As the cyclosiloxane compound represented by the general formula [V], (In the above formula, q is an integer of 3 to 6) and the like. Further, a mixture of two or more of these cyclosiloxane compounds may be used.

Examples of the chlorosilane compound represented by the general formula [VI] used as a terminator include cyanomethyldimethylchlorosilane, 2-cyanoethyldimethylchlorosilane,
-Cyanopropyldimethylchlorosilane, 4-cyanobutyldimethylchlorosilane, 5-cyanopentyldimethylchlorosilane, 6-cyanohexyldimethylchlorosilane, 3-cyanopropyldiethylchlorosilane, 3-
Examples include cyanopropyldiethylchlorosilane, 3-cyanopropylmethylethylchlorosilane, 4-cyanobutyldihexylchlorosilane, and 6-cyanohexylmethylethylchlorosilane.

The reduction reaction from the polyorganosiloxane having a cyanoalkyl group at one end represented by the general formula [VII] to the polyorganosiloxane having an aminoalkyl group at one end represented by the general formula [II] is carried out by diborane,
The desired product can be easily obtained by reacting with a commonly used reducing agent such as lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium aluminum hydride, sodium dialkoxyaluminum hydride, and sodium diethylaluminum hydride. Can be. It is preferable to carry out any of the reactions in a solvent, and any solvent may be used as long as it does not participate in the reaction, and examples thereof include diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, benzene, and toluene. The reaction can be carried out at a temperature of -60 ° C to 100 ° C, preferably -10 ° C to 80 ° C.

According to the method described above, the polyorganosiloxane having an aminoalkyl group at one terminal represented by the general formula [II] can be obtained by continuously adding each of the reaction reagents in the same container to the general formula [VII] Can be easily synthesized via a polyorganosiloxane having a cyanoalkyl group at one end represented by the following formula: Further, by adjusting the amount of the cyclosiloxane compound represented by the general formula [V] used in the reaction, a polyorganosiloxane having a cyanoalkyl group at one terminal represented by the general formula [VII], Formula [II]
The polymerization degree n of the polyorganosiloxane having an aminoalkyl group at one terminal represented by the formula (I) and the polyorganosiloxane having a phosphoric acid amide group at one terminal represented by the formula [I] of the present invention can be controlled. However, in this case, the polyorganosiloxanes represented by the general formulas [VII], [II] and [I] are actually measured because they are mixtures of polyorganosiloxanes having different degrees of polymerization n. The degree of polymerization is expressed as an average value (real number of 1 or more). Also,
When particularly synthesizing the organosiloxane represented by the general formula [VII], the general formula [II], or the general formula [I] wherein n and 1 are represented by the aforementioned general formula [VII] In a reaction for synthesizing a polyorganosiloxane having a cyanoalkyl group at one end, the silanol compound represented by the general formula [IV] and the silanol compound represented by the general formula [IV] are used without using the cyclosiloxane compound represented by the general formula [V]. It can be obtained by directly reacting with the chlorosilane compound represented by [VI].

Since the polyorganosiloxane having a phosphoric acid amide group at one end represented by the general formula [I] of the present invention is a compound having a phosphoric acid amide group as a polar group and a polyorganosiloxane chain as a hydrophobic group, it has a surfactant. It has properties as an agent. Therefore, in addition to the use of the drug of the present invention as a transdermal absorption enhancer, it can be applied to detergents, bactericides, preservatives, cosmetics, and the like. When this is used as a drug for percutaneous absorption of a drug, the average degree of polymerization has a large effect on the promotion effect, and the average degree of polymerization is 1 It is preferably in the range of 100 to 100, and more preferably in the range of 1 to 40.

The percutaneous absorption enhancer of a drug comprising a polyorganosiloxane having a phosphoric acid amide group at one terminal represented by the general formula [I] of the present invention is dissolved in a solvent such as water or alcohol together with the drug to be administered. Tincture or ointment,
It can be used in any form such as an ointment or cream mixed in a cream base, or a tape preparation mixed in a polymer film or an adhesive.

The content of the percutaneous absorption enhancer of the present invention varies depending on the form of use, 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 remarkable, and on the contrary, 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, choline salicylate,
1-menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, planoprofen, fenoprofen, fenprofen, flurbiprofen, indofurofen,
Fenthiazac, trimethine, suprofen, benzadac, bufexamac, piroxicam, phenylbutazone, oxyfenbutazone, clofezone, pentazozine, mepyrizole, etc .; steroidal anti-inflammatory agents include hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, Fluocinolone acetonide, fludrocortisone acetate, etc .; chlorpheniramine, glycyrrhizinate, diphenhydramine, periactin, etc. as antihistamines or antiallergic agents; benzocaine, procaine, dibucaine, lidocaine, etc. as local anesthetics; antibacterial agents, etc. ,
Tetracyclines such as chlortetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin, macrolides such as erythromycin, chloramphenicol, iodine compounds, nitrofurantoin,
Nystatin, amphotericin, fradiomycin, sulfonamides, pyrrolnitrin, clotrimazole, nitrofurazone, etc .; as antihypertensive agents, clonidine, α-methyldopa, reserpine, syrosingopine,
Resinamine, cinnarizine, hydrazine, prazosin, etc .; antihypertensive diuretics such as theophylline, trichloromethiazide, furosemide, tribuamide, meticlothiazide,
Penfluzide, hydrothiazide, spironolactone, metrazone, etc .; digitalis, ubidecarenone, dopamine, etc. as cardiotonic agents; nitroglycerin, isosorbitol-dinitrate, erythose tetranitrate, pentaerythol tetranitrate, dipyridamole as coronary vasodilators , Dilazeb, trapidil, trimetazidine, etc .; vasoconstrictors such as dihydroergotamine, dihydroergotoxin, etc .; β-blockers or antiarrhythmic therapeutics such as pindol, propralol, etc .; calcium antagonists such as diltiazem, nifedipine, nicardipine, verapamil, benpicran. , Dilazeb, etc .; antiepileptic drugs such as nitrazepam, meprobamate, phenytoin, etc .; Phosphorus, betahistine, scopolamine, etc .; tranquilizers such as diazepam, lorazepam, flunitrazepam, flufenadine, etc .; hypnotic sedatives, such as phenobarbital, amobarpital, cyclobarbital; etc .; muscle relaxants, such as triperizone, baclofen, tantrolene sodium, Benzapyrin, etc .; agents for autonomic nerves, such as atropine and levodopa; agents for respiratory organs, such as codeine, ephedrine, isoproterenol, dextromethorphan, oresiprenaline, ipratropium bromide, cromoglycic acid, etc .; Is corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, salivary gland hormone, thyroid hormone, adrenal hormone, Kallikrein, insulin, oxendrone, etc .; vitamins such as vitamins A, B, C, D, E, K and their derivatives, calciferols, mecobalamin, etc .;
-Fluorouracil and its derivatives, adriamycin, krestin, picibanil, ancitabine, cytarabine and the like; enzymes and the like; urokinase and the like; herbal medicines and herbal extracts as licorice, aloe, purple roots and the like; Other examples include prostaglandins, agents for treating diabetes, and the like. If necessary, two or more of these drugs can be used in combination.

The preparation of the drug containing the transdermal absorption enhancer of the present invention can be applied by applying a necessary amount to the skin and mucous membrane (oral cavity, nasal cavity, rectum, vagina) of each part of the human body according to the purpose. For example, for the local treatment of trauma, skin ulcer, myalgia, arthritis, etc., directly at or near the affected area, or for the systemic treatment of internal organs, etc., the site where the drug is easily absorbed ( Example: Undeveloped area of keratin)
It is preferably applied to In addition, when used for cosmetics, the above preparations are used as they are or selected from the above drugs or those containing known cosmetic ingredients, and are used for skin washing, packing, measures against sunburn and rough skin, moisturizing, etc. Can be used.

Hereinafter, the present invention will be described in more detail by reference examples, examples, and comparative examples. However, it goes without saying that the present invention is not limited to these. Incidentally, represented in the reaction formula shown below, D ₃ is hexamethylcyclotrisiloxane, n-BuLi is n- butyllithium, respectively.

Reference Examples 1-3 Synthesis of polyorganosiloxane having a cyanopropyl group at one end Trimethylsilanol in the amount shown in Table 1 was dissolved in 100 ml of tetrahydrofuran, and a hexane solution of n-butyl lithium (1.6 mol
/ l) in equimolar amount to trimethylsilanol and add about 1
Stirred for hours. To these solutions were added solutions of hexamethylcyclotrisiloxane (D ₃ ) in the amount shown in Table 1 in 180 ml of tetrahydrofuran, and the mixture was further stirred at room temperature for 12 hours. Next, the reaction is stopped by adding the amount of 3-cyanopropyldimethylchlorosilane shown in Table 1. After distilling off the solvent, the formed salt was filtered off and dried under reduced pressure.
After heating and stirring at 2 ° C. for 2 hours, a colorless, transparent and viscous oil was obtained. From the results of the ¹ H-NMR spectrum and IR spectrum shown below, each of these products is a polydimethylsiloxane having a 3-cyanopropyl group represented by the above structure at one end and a trimethylsilyl group at one end. I found it. In the above structure, the average degree of polymerization of the polydimethylsiloxane chain was determined from the integral ratio between the proton peak of the methyl group and the proton peak of the 3-cyanopropyl group on the silyl group in the ¹ H-NMR spectrum. Table 1 shows the results. ¹ H-NMR _{spectrum, δ (CDCl 3, ppm)} ; 0.07 (S, proton peaks of the methyl groups on _{silicon), 0.07 (m, -CH 2} CH 2 CH 2 CN), 1.71 (m, -CH 2 CH ₂ CH ₂ CN), 2.37 (t, −CH ₂ CH ₂ CH ₂ CN). IR spectrum (cm- ¹ ); 2980, 2250 (characteristic absorption of cyano group), 1450, 1420, 1350, 1260 (characteristic absorption of Si-C bond), 1
100 to 1020 (characteristic absorption of siloxane bond), 800,700. Reference Examples 4 to 6 Synthesis of polyorganosiloxane having aminobutyl group at one terminal The polydimethylsiloxane having a 3-cyanopropyl group at one end obtained in Reference Examples 1 to 3 was measured in the amount shown in Table 2, and each was dissolved in 10 ml of tetrahydrofuran. Was slowly added dropwise at 0 ° C. to 20 ml of tetrahydrofuran in which lithium aluminum hydride was dispersed, and after the addition was completed, the solution was further refluxed overnight. After the completion of the reaction, the solution was poured into 100 ml of ice water, the solid was separated by filtration, the obtained filtrate was washed with water, extracted with ether, and the solvent was distilled off. When the mixture was further heated and stirred at 120 ° C. for 2 hours under reduced pressure, a yellow viscous oil was obtained. From the results of the ¹ H-NMR spectrum and IR spectrum shown below, all of these products are 4-aminobutyl groups represented by the above structure and polydimethylsiloxane having a trimethylsilyl group at one end and one end at one end. I found it. In the above structure, the average degree of polymerization of the polydimethylsiloxane chain is ¹ H-NM
It was determined from the integral ratio between the proton peak of the methyl group on the silyl group and the proton peak of the 4-aminobutyl group in the R spectrum. Table 2 shows the results. ¹ H-NMR spectrum, δ (CDCl ₃ , ppm); 0.05 (S, proton peak of methyl group on silicon), 0.40 to 0.70 (m, —CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ), 1.25 (m , −CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ), 1.30 to 1.65 (m, −CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ), 2.37 (m, −CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ ) IR Spectra (cm- ¹ ): 3600-3100 (characteristic absorption of amino group), 2980, 2130, 1730, 1600, 1450, 1420, 1260 (Si-C
Characteristic absorption of bond), 1180-950 (characteristic absorption of siloxane bond), 950-720,700. Reference Example 7 Synthesis of 4-aminobutylpentamethyldisiloxane 5.50 ml (49.4 mmol) of trimethylsilanol was dissolved in 60 ml of tetrahydrofuran, and 4.11 ml (29.7 mmol) of triethylamine and 4.04 ml (29.4 mmol) of 3-cyanopropyldimethylchlorosilane were added to this solution at 0 ° C. under an argon gas atmosphere.
4.7 mmol) and further stirred at room temperature overnight. After distilling off the solvent, the formed salt was separated by filtration and dried under reduced pressure to obtain 4.2 g of a colorless transparent liquid. From the results of the ¹ H-NMR spectrum and IR spectrum shown below, this product was 3-cyanopropylpentamethyldisiloxane represented by the above structure. (Yield 78.9%) ¹ H-NMR spectrum, δ (CDCl ₃ , ppm); 0.05 (S, proton peak of methyl group on silicon, 15
H), 0.76 (m, −CH ₂ CH ₂ CH ₂ CN, 2H), 1.68 (m, −CH ₂ CH ₂ CH ₂ CN, 2H), 2.35 (t, −CH ₂ CH ₂ CH ₂ CN, 2H) . IR spectrum (cm- ¹ ): 3000, 2250 (characteristic absorption of cyano group), 1730, 1430, 1350, 1260 (characteristic absorption of Si-C bond), 1
180,114-1000 (characteristic absorption of siloxane bond), 845,81
Next, 1.0 g (4.6 mmol) of the obtained 3-cyanopropylpentamethyldisiloxane was slowly added dropwise to 10 ml of diethyl ether in which 0.26 g (7.0 mmol) of lithium aluminum hydride was dispersed at 0 ° C. The solution was further refluxed overnight after the addition was completed. After the completion of the reaction, the solution was poured into 100 ml of ice water, the solid was separated by filtration, the obtained filtrate was washed with water, extracted with ether, the solvent was distilled off, and the residue was dried under reduced pressure to obtain a yellow liquid. It is shown below
^From the results of the ¹ H-NMR spectrum and the IR spectrum, this product was 4-aminobutylpentamethyldisiloxane represented by the above structure. (Yield 61.5%) ¹ H-NMR spectrum, δ (CDCl ₃ , ppm); 0.05 (S, proton peak of methyl group on silicon, 15
H), 0.50 (m, −CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ , 2H), 1.25 (s, −CH ₂ CH ₂ CH ₂ CH ₂ NH ₂ , 2H), 1.38 (m, −CH ₂ CH _{2 CH 2 CH 2 NH 2, 4H} ), 2.66 (m, -CH 2 CH 2 CH 2 CH 2 NH 2, 2H). IR spectrum (cm- ¹ ); 3600-3100 (characteristic absorption of amino group), 2960, 2930, 2850, 1720, 1410, 1250 (characteristic absorption of Si-C bond), 1060 (characteristic absorption of siloxane bond), 840 , 80
Examples 1 to 4 Synthesis of polyorganosiloxane having a phosphoric amide group at one end Table 3 shows the polydimethylsiloxane having a 4-aminobutyl group at one end obtained in Reference Examples 4 to 6 or the 4-aminobutylpentamethyldisiloxane obtained in Reference Example 7.
And dissolved in 8 ml of diethyl ether. To these solutions, diethyl chlorophosphate in an amount described in Table 3 and 1.2 equivalents of triethylamine based on diethyl chlorophosphate were added, and the mixture was allowed to stand at room temperature overnight. Stirred. After completion of the reaction, the resulting salt was filtered off, the filtrate was washed with water, extracted with ether, and purified by silica gel column chromatography to obtain a yellow solid. From the results of the ¹ H-NMR spectrum and IR spectrum shown below,
All of these products were found to be polydimethylsiloxane or disiloxane having a diethylphosphoramide group at one end represented by the above structure. In the above structure, the average degree of polymerization of the polydimethylsiloxane chain was determined from the integral ratio between the proton peak of the methyl group on the silyl group and the proton peak of the diethylphosphoramide group at one end in the ¹ H-NMR spectrum. . Table 3 shows the results. ¹ H-NMR spectrum, δ (CDCl ₃ , ppm); 0.05 (S, proton peak of methyl group on silicon), 0.60 (m, -CH ₂ CH ₂ CH ₂ CH ₂ NH-), 1.30 (t,- PO (OCH ₂ C
_{H 3) 2), 1.45 (} m, -CH 2 CH 2 CH 2 CH 2 NH-), 2.50 (m, -CH 2 CH 2 CH 2 CH 2 NH -), 2.90 (m, -CH 2 CH 2 CH _{Two
CH 2 NH -), 4.08 (} m, -PO (OCH 2 CH 3) 2). IR spectrum (cm- ¹ ); 3600-3100 (characteristic absorption of amino group), 3000,1740 (characteristic absorption of amide group), 1450, 1420,1
260 (characteristic absorption of Si-C bond), 1170-950 (characteristic absorption of siloxane bond), 920,850,800,700,670. Examples 5 to 8 Rabbit abdominal exfoliated skin was sandwiched between ^two -chamber diffusion cells (effective cross-sectional area 0.95 cm ² ), the anti-inflammatory agent indomethacin (1 wt.%) Was used as a donor, and one end obtained in Examples 1 to 4 A polydimethylsiloxane or disiloxane having a diethylphosphoric acid amide group (transdermal absorption enhancer) (2 wt.%) And a nonionic surfactant Tween 20 (0.5 wt.%),
2 ml of 50 wt.% Aqueous solution of ethanol is added, and the receptor
2 ml of phosphate buffer adjusted to 7.4
The sample was immersed in a constant temperature bath at ℃. After 6 hours and 12 hours, both chambers were sampled from the receptor after stirring, and the amount of permeated indomethacin was determined by high performance liquid chromatography. Table 4 shows the results of the transmission measurement. Also,
Table 4 shows the case where these polydimethylsiloxanes were not added.
This is shown as Comparative Example 1. As can be seen from Table 4, it was clarified that both polydimethylsiloxane and disiloxane having a diethylphosphoric acid amide group at one terminal show an excellent transdermal absorption promoting effect.

Examples 9 and 10 Using the polydimethylsiloxane having a diethylphosphoramide group at one end (= 4.3) obtained in Example 1 as a percutaneous absorption enhancer, permeation of the drug through the skin in the same manner as in Examples 5 to 8 An experiment was performed. However, the same procedure as in Examples 5 to 8 was carried out except that the concentration of the aqueous ethanol solution used as the base in the donor portion was adjusted to 70 wt.% And 80 wt.%.
The accumulated permeation amount of indomethacin after 6 hours and 12 hours was measured. Table 5 shows the results of each transmission measurement. Table 5 shows the case where this polydimethylsiloxane was not added.
The results are shown as Comparative Examples 2 and 3. As can be seen from Table 5, the polydimethylsiloxane having a diethylphosphoric acid amide group at one end of the present invention exhibited an excellent transdermal absorption promoting effect even when the base composition of the donor portion was changed.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07F 9/24 C08G 77/26 C08G 77/395 A61K 47/34 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) General formula (Wherein, R ¹ and R ² may be the same or different and may have 1 to 6 carbon atoms or a phenyl group; R ^{3 to} R ⁷ may be the same or different and have 1 to 6 carbon atoms or an alkyl group; Is 2
An integer from 1 to 7, and n is an integer of 1 or more. However, R ³ and R ⁴ may be the same or arbitrarily different for each repeating unit. A) a polyorganosiloxane having a phosphoric amide group at one end represented by the formula: 2. The general formula (Wherein, R ¹ and R ² may be the same or different and may have 1 to 6 carbon atoms or a phenyl group; R ^{3 to} R ⁷ may be the same or different and have 1 to 6 carbon atoms or an alkyl group; Is 2
An integer from 1 to 7, and n is an integer of 1 or more. However, R ³ and R ⁴ may be the same or arbitrarily different for each repeating unit. A) a percutaneous absorption enhancer of a drug comprising a polyorganosiloxane having a phosphoric acid amide group at one end represented by the formula (1):