JPH01135727A - Novel percutaneous absorption promoter and composition containing the same - Google Patents

Abstract

PURPOSE: To obtain an absorption promoter effective for promoting transportation of a large amount of a great number of medicines low in absorption through skin, comprising a substituted 1,3-dioxanecyclopentane or a substituted 1,3-dioxacyclopentane. CONSTITUTION: This composition comprises a compound of the formula [R, R0 and R1 to R6 are each H or a 1-18C aliphatic group (preferably substituted with an alkyl, an alkenyl, a halo, OH, carboxy, carboxyamido and/or carboalkoxy) and at least one of R, R0 and R1 to R6 is a 4-18C alkyl or a 4-18C alkenyl; (n) is 0 or 1; the number of the total of carbons in R, R0 and R1 to R6 is <=40 (preferably <20) and a physiological activator.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 1,3-dioxacyclopentanes and 1,3-dioxacyclopentanes.
, 3-dioxacyclohexanes to enhance skin penetration of therapeutic agents, and compositions containing such compounds, as well as novel penetration-enhancing compounds within these chemical classes.

BACKGROUND OF THE INVENTION The reason why delivery of bioactive agents through the skin (i.e., transdermal delivery) is more promising than other parenteral administration methods or administration through the gastrointestinal system is based on a number of factors. There is.

The large surface area of the skin (more than 3000 square inches for the average adult) and the extensive circulatory system (173 of the total blood) and lymphatic network available in the vicinity of the skin, their local application and their delivery to the skin. The generally non-invasive nature of -, simplicity, safety, relatively greater controllability of the drug to be delivered, and minimal side effects are some of the advantages seen with this technology.

Although not all drugs are suitable for transdermal delivery due to local irritation, allergic reactions, etc., it has been suggested that most drugs are suitable.

Unfortunately, however, the greatest challenge remains in overcoming the general barrier to drug penetration of the skin (indeed, of any substance). Drugs must pass through the outer layer of the skin or epidermis and through the dermal layer before being absorbed into the bloodstream.9 The epidermis consists of two main parts: the stratum corneum and the stratum germinatum. The stratum corneum forms the outermost layer of the epidermis and is compressed,
It consists of a layer of flat, keratinized cells (containing no nucleus). This outermost layer serves as a physical barrier to light, heat, microorganisms, and most chemicals. Furthermore, it acts as a primary barrier to percutaneous absorption. Because of their skin barrier action, it has been until now only possible to deliver low-dose or low-molecular-weight drugs of less than 10 mg/day. As early as the beginning of this century, it was recognized that lipophilic substances (e.g. non-electrolytes) have a relatively greater skin permeability than water-soluble substances (e.g. electrolytes), and a suitable balance of lipophilicity-hydrophilicity must be maintained. confirmed.

The phenomenon of transdermal absorption or transdermal penetration involves sequentially the absorption of permeable molecules at the surface of the stratum corneum, their diffusion through that surface and the living epidermis, and finally through the papillary dermis into the microcirculatory system. It can be thought of as a complex of a series of steps.

The great diffusion resistance of the stratum corneum has been demonstrated in the comparative absorption of drugs such as hydrocortisone. The mucous membranes of the rectum and shins absorb 26-29% of the applied steroid, whereas less than 2% of the applied dose is absorbed through the skin.

Compounds known or reported to enhance transdermal delivery of drugs include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate, alkyl lactams, and long chain amides. Prior art patents related to penetration enhancers for bioactive agents include: U.S. Patent No. 35515
No. 54 discloses dimethyl sulfoxide;
No. 3,989,816 discloses 1-substituted azacyclohebutan-2-ones; No. 4,132,781 discloses topical antibiotics and 2-pyrrolidone or n-
Discloses lower alkyl-2-pyrrolidone;
No. 017,641 also discloses 2-pyrrolidone (but includes propylene glycol); other interesting disclosures are the following U.S. patent specifications: No. 3,90
No. 3,256; No. 4,343,798; No. 4,046
, No. 886; No. 3,934,013; No. 4,070,
No. 462; No. 4,130,643; No. 4,130,6
No. 67; No. 4,289,764; No. 4,070,46
No. 2; No. 3,527,864; No. 3,535,422
No. 3,598,123; No. 3,952,099; No. 4,379,454; No. 4,286,592;
No. 4,299,826; No. 4,314,557; No. 4,343,798; No. 4,335,115; No. 3
, 598, 122; No. 4.405.616: No. 3,
No. 896,238; and No. 3,472,931. Also worth noting is US Pat. No. 4,557,934. None of the cited documents has previously disclosed 1,3-dioxolane or 1,3-dioxane, particularly the substituted forms thereof, as described hereinafter, for use as transdermal absorption enhancers for bioactive substances. .

SUMMARY OF THE INVENTION The present invention relates to certain compounds that are effective in facilitating the transport of many high-dose, poorly absorbed drugs through the skin.

Compounds provided by and used in the present invention are substituted 1,3-dioxacyclopentanes and substituted 1,3-dioxacyclohexanes.

The compound has the general formula t: [wherein R, R0, R+, Rz, R3, R4,
Rs and R6 are each independently a hydrogen atom and C3~
selected from C11 aliphatic groups (preferably C1-C11 aliphatic groups substituted with alkyl groups, alkenyl groups, halo, hydroxy groups, carboxy groups, carboxamide groups and/or carbalkoxy groups); R, Ro,
At least one of Rr, Rx, R3, R4, Rs and R is a C1 to cps alkyl group or alkenyl group; n is 0 or 1; R, Ro, Rl, R2, R2, R4, The total number of all carbon atoms in Rs and R6 is 40 or less (preferably less than 20); R, Ro, RI, R2, Rs, R4, Rs and R6 contain 18 or more carbon atoms; There are 1f1Ml or 0 items. -m Preferred compounds of formula 1 are those in which R is C1-C18, preferably 06-C1□, more preferably 07-C9°;
Another preferred type is where R and Ro are hydrogen, and R+
, one of R2, Rs and R6 is a cyclopentane (i.e. dioxolane) in which one of R2, Rs and R6 is C4-C+a, preferably C, -C12, more preferably 07-CIO;
Suitable groups for the group are alkyl groups, alkenyl groups, carbalkoxy groups (e.g. -CH20C-4> or -C
It is H20R.

The general formula representing a suitable accelerator is the formula ■: is either a lower group (C+ to C1) or another group such as hydrogen, halo, carboxy group, hydroxy group, amide group, and n=o or 1): and 2): [wherein R4 is C4 to C4, preferably C6 to C+Z, as shown, n=o or 1, and n.

When =1, X is carbonyl (-C-)].

In formulas (1) and (2), Ro is preferably hydrogen. In 2), R is also preferably hydrogen.

The compounds contained herein are applied, for example, as a mixture with a drug that is desired to be administered transdermally to humans or animals. Skin treatment immediately before (e.g. several minutes or more, i.e. 15 minutes, 30 minutes, 1 hour, etc.) or after (e.g. immediately after or after 15 minutes, 30 minutes, 1 hour, 10 hours or 24 hours) The dioxane or dioxolane, with or without therapeutic agents or other additives, which may also often be desirable to be pretreated (e.g.), can be supported on a suitable support, such as by coating or impregnation. It can be mixed with hydrophilic or hydrophobic substances and coated in this form on a suitable support (e.g. polyethylene, nylon, polyester, polyurethane, hydrolyzed (e.g. 85%) polyacetic acid). (using hydrophilic or hydrophobic film-forming resins such as vinyl, cellulose acetate, regenerated cellulose) and used as self-supporting films, or using paper, metal, or resin binders. The substrate may be laminated or otherwise bonded to other substrates, such as non-woven or woven fabrics (eg, cotton, rayon, nylon, polyester, etc.), with or without use.

The accelerator alone or together with drugs and/or additives is dissolved or dispersed in one or other of the thermoplastic resins mentioned above and melt spun or calendered or molded into the desired shape or structure. Very useful supports for promoters on their own or in combination with bioactive agents are those coated with pressure-sensitive adhesives (e.g., plastic, paper, cloth, metal, foil, etc.) for a given bioactive agent. It will, of course, be apparent that many of the conventional adjuncts commonly utilized and/or administered in conjunction with agents can be used in the various compositions, articles and methods described herein.

Auxiliary agents of this type include, inter alia, solvents (e.g. water, ethanol, etc.), lipids, colorants, fragrances, antioxidants, thickeners,
Included are ultraviolet light stabilizers, preservatives, and others commonly used in compositions of this type.

2-n-benzene 13-diosolane (1) in a 250 ml round bottom flask equipped with a Dean-Stark trap, condenser and mechanical stirrer.
30 g (0.29 mol) of hexanal in M1, 311 ? of ethylene glycol? (0.5 mol), p-toluenesulfonic acid (p Ts > 100 mFI) was charged. The mixture was heated under reflux until no more water separated from the benzene phase. Then the mixture was cooled to room temperature, 5
% Sodium bicarbonate 100 companies, saturated NaCl 1 solution 7? !
1ooa/, and finally washed with water. The solution was dried over sodium sulfate and the crude oil was fractionated after removing the solvent.

19.6 g of a colorless oil was obtained. n20; 1.455
According to the method for preparing compound 1 of 4゜2-n-heple 13-disone 2, 30 y (0.23 mol) of octylaldehyde, 31 ethylene glycol in 70 ml of benzene.
g<0.5 mol), and p-Tsl OOml? From colorless oil 20.51? (50.9%) was obtained.

n201.433B.

According to Example I, 78 fI (77 ,4
%)was gotten.

Boiling point 80° to 81°C 10.5 mmHg; n” □1.
4392゜Blood According to Example I, 45゜56 g (0.25 mol) of dodecylaldehyde, 17.851? of ethylene glycol in toluene 1401? (0,288 mol) and p-)luenesulfonic acid 0.02. React to produce colorless product 3
0 g (55%) was obtained. Boiling point 112° to 116°C/1.
5sa+Hg;n''=1.9999°(t)-LL According to the preparation of compound 1, 32 g (0.31 mol) of glutaraldehyde, 52.01y (0.83 mol) of ethylene glycol and p-Ts in 150xl of benzene
200-9 to form a colorless oil 46.031F (6
7%).

n20=1.4559; boiling point 78@~82℃10.1m
s+Hg.

Citral 5 in benzene 7511 according to Example I
0 y (0.32 mol), ethylene glycol 24.8
゜(0.4 mol) and I)-toluenesulfone 10.
Light yellow oil from 02g 18.2. was gotten. ■2°
・1.4940. Boiling point: 0.5mmt1g/34-36℃.

13 - Gen 7 1 A 500 ml flask equipped with a distillation receiver, a condenser containing a drying tube, and a magnetic stirrer was charged with 30.58 g (0,158 mol) of 80% citronellal.
Then 1 ethylene glycol in 1 oose of dry benzene
4.59 g (0.23 mol) and 0.02. Upon completion of the reaction, the mixture was heated to reflux with stirring until no more water separated during distillation (approximately 6 hours).
Washed with 10 m/ml of 5% sodium bicarbonate solution and water and dried over sodium sulfate. The reaction mixture was filtered and the liquid was concentrated to give a yellow oil. Distillation yielded 17.57 g (41%) of colorless product. Boiling point 65°~
70 ° C / 0.5 mm 11 g; n2 ° · 1.4645 ° According to the preparation of compound 1, 24.95 g (0.16 mol) of decylaldehyde, 17.6 g of 3-chloro-1,2-propanediol ( 0.16 mol) and p-Ts 0.2y to colorless oil 30.4
9y (77%) was obtained. Boiling point = 0.14mm1g7
91-100℃; n20; 1.4533゜3-chloro-1,
2-propanediol 15 g (0,097 mol), citronellal 10y (0,06 mol) and 9 Ts1
50B to crude product (oil) 12.561? was gotten.

α1 According to the preparation of compound 1, 12.77 g (0.08 mol) of citral, 3-chloro-1,
2-propanediol 10f (0,09 mol) and p
-10.7y (54.7 mol) of crude oil cannot be obtained from 60my of Ts.

According to Example I, 51.4 g (0.33 mol) of citral and 46 g (0.33 mol) of glycerol (
0.5 mol) and p-)luenesulfonic acid 0.049
was reacted to form a colorless oil of 31.45 fI (41,11
1) Obtained n 26 = 1.4693°Ten l [According to the manufacturing method of Compound 1, toluene 150j! 27.62g (0.3 mol) of glycerol, 17.2zz of citronellal! (0.1 mol) and p-Ts 400
From B, 9.69 g of oil was obtained.

According to Example 1, 78.77 g (0.5 mol) of decylaldehyde, 45.65 y (0.6 mol) of 1,3-propanediol and 0.5 g of p-toluenesulfonic acid are reacted in 100 ii' of toluene. , colorless product 6
7.691F (62,65g) was obtained, boiling point 70° ~ 7
11.19 g (0,064 mol) of dodecyl aldehyde in benzene 50R1, 1.3
- 7.5 g (0,098 mol) of propanediol and p-Ts! 50mg to 7.48ti (48
%)was gotten.

n20=1.4477; boiling point=0.065mmHir
/ 89℃.

80% citronellal 10y (64 moles) was placed in a 250z1 flask equipped with a distillation receiver, a condenser with a soot tube, and a magnetic stirrer.

Then 7.5 g (0,098 mol) of 1,3-propanediol in dry benzene 5011 and 0.05 g of p-toluenesulfonic acid. On completion of the reaction, the mixture was heated to reflux with stirring until no more water separated during distillation (approximately 6 hours).
Washed with +1 5% sodium bicarbonate solution and water and dried over sodium sulfate. The reaction mixture was filtered and the r liquid was concentrated to give a yellow oil.

After distillation, 17.5711 ($72.6) of colorless product was obtained. Boiling point 65°~70°C/0.5mmHg; n”=1
．． 4609゜13-Dine 18- According to the preparation of compound A pale yellow oil was obtained from 0.3 g of toluenesulfonic acid. Boiling point・0.5mm1g/140℃;n”1
．． 4761° In a 10011 flask equipped with a distillation receiver, a condenser with a drying tube and a magnetic stirrer, 5.2 g (0.33 mol) of decylaldehyde were placed in a solution of (bis-hydroxy) in 50 M1 of dry benzene. methyl)
Ethyl malonate 8.5 h (0,0387 mol) and p
-) Add 0.2 g of toluenesulfonic acid and heat the mixture under reflux with stirring until no more water separates during distillation (approximately 6 hours). At the completion of the reaction, the mixture is heated to reflux. Washed with 2×10 11 5% sodium bicarbonate solution and water and dried over sodium sulfate. The reaction mixture was filtered and the liquid was concentrated to give a yellow oil. Distillation raft-like properties: Boiling point = 0.22 + @mHg/
A colorless product 8.9b (74.1$) with n20: 1.4490 was obtained at 150°C.

100zz equipped with distillation vessel, cooler with drying tube and electric stirrer! Hexylaldehyde Og (o, oe mole) was placed in a flask, then dried toluene 6
20 g (0,09 mol) of ethyl (bis-hydroxymethyl)malonate and p-toluenesulfone [0,2,0. At the completion of the reaction, the mixture was heated to reflux with stirring (approximately 6 hours), and the mixture was heated to 2X
Washed with 10 z1 of 5% sodium bicarbonate solution and water and dried over sodium sulfate. The reaction mixture was filtered and the P solution was concentrated to give a yellow oil. After distillation a colorless product 11.29y (62%) was obtained. Boiling point = 0
．． 2mmHg/100~118℃-02°=1.44
53° and 1 salmon 1 According to the preparation of compound go, 3. ．． The following properties: boiling point = 0.3 + n + Hg / 135°C; n'' = 1
．． 3.5 g of a colorless oil having a molecular weight of 4751 were obtained.

(Effect of the invention) The compounds of Examples m, rv, v, vt, Tested in vitro using the following method.

Flow diffusion cells use perfusion of the dermal side of the skin. Sampling is facilitated by automatic collection of fluids continuously throughout the day. The cell is equipped with a water jacket to provide temperature control and equilibration of skin and dermal fluids.

-a method is as follows. The skin is fixed in cells and allowed to equilibrate with environmental conditions for 5 hours (20±1° C.).

The temperature of the water jacket is 37 °C, and the liquid in the dermal chamber is bovine albumin (1,5% by weight/volume) diluted with saline, the constituents are added to the bath liquid to avoid the generation of bacteria. Add. Ethanol/water (9515 weight/volume Ji)
500 mg of the test drug in a mixed solvent is applied to the epidermal surface.

After application, the solvent is allowed to evolve for 1-2 hours and leaves a solid drug deposit on the skin. The drug to be tested is a radioactive compound, the rate of absorption of which is followed after application of the radioactive mixture by measuring the radioactivity in dermal fluid samples hourly for 48 hours. 24 hours after drug application, 0.1 t1 of accelerator is applied to the treated surface.

In accordance with the above method, the compound of Example 1 was tested with progesterone, caffeine and indomethacin and showed significantly increased skin diffusion when the enhancer of Example 2 was applied to the skin after drug application. Thus, for example, the % of indomethacin diffused was 1.47%/C12 during the first 24 hours (drug alone - no accelerator application), but after 48 hours (accelerator application only after 24 hours). 1
It was 2.85%/CI+12. Also, in the case of progesterone, the compound of Example 1 was found to be 10 times more effective than the alcohol of N-dodecylcaprolactam (a known promoter).

In a similar manner, Examples IV, V, V1. ■, x m,
The compounds x rv and x■ were also found to be effective against sinus.

In other studies, the total percent transdermal absorption after 48 hours (first 24 hours drug only, then enhancer applied) was as follows:

Medicine-'1 Prog India' j
Sterone 67.4> Metaradio 1, drug only 4.9 7.7 1.72, compound of Example ■ 11.98 52.4 5.33,
Compound of Example ■ 9.55 54.4 7.0
4. Compound of Example ■ 14.3 47.6 14
．． 35, Compound of Example ■ 11.0 11.4
1.8 (4 others)

Claims (16)

[Claims] (1) 1,3-dioxacyclopentane or 1,3-dioxacyclopentane containing at least one pharmaceutically acceptable aliphatic group having 4 to 18 carbon atoms as a bioactive agent and effective skin penetration enhancer; A therapeutic composition suitable for transdermal administration to humans and animals, containing 3-dioxacyclohexane. (2) Physiologically active agent and the following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R, R_0, R_1, R_2, R_3, R_4
, R_5 and R_6 each independently represent a hydrogen atom and a C_1 to C_1_8 aliphatic group (preferably an alkyl group, an alkenyl group, a halo, a hydroxy group, a carboxy group,
R, R_0, R_1, R_2, R_3, R_4, R
At least one of _5 and R_6 is C_4 to C_
1_8 alkyl group or alkenyl group; n is 0 or 1; R, R_0, R_1, R_2, R_3, R_4, R_5
and the total number of all carbon atoms in R_6 is 40 or less (
preferably less than 20); R, R_0, R_1, R_2, R_3, R_4, R_5
and R_6, 1 or 0 contain 18 or more carbon atoms. ] A therapeutic composition suitable for transdermal administration to humans and animals, containing an effective skin penetration enhancer as defined in claim 1. (3) The therapeutic composition according to claim 2, wherein n=0. (4) The therapeutic composition according to claim 2, wherein n=1. (5) The therapeutic composition according to claim 3, wherein R is a C_5 to C_1_0 aliphatic group. (6) The therapeutic composition according to claim 5, wherein R is n-pentyl. (7) The therapeutic composition according to claim 5, wherein R is nonyl. (8) The therapeutic composition according to claim 3, wherein R is undecyl. (9) The therapeutic composition according to claim 5, wherein R is 2,6-dimethyl-2,6-heptadienyl. (10) The therapeutic composition according to claim 7, wherein R_1, R_2 and R_5 are hydrogen atoms, and R_6 is chloromethyl. (11) R_1, R_2 and R_5 are hydrogen atoms, and R_6 is hydroxymethyl Claim 7
Therapeutic compositions described in Section. (12) A bioactive agent consisting of a support and 1,3-dioxacyclopentane or 1,3-dioxacyclohexane containing one pharmaceutically acceptable aliphatic group having 4 to 18 carbon atoms. A therapeutic article suitable for facilitating the transdermal administration of to humans and animals. (13) The therapeutic article according to claim 12, wherein the support is a hydrophilic or hydrophobic film. (14) The therapeutic article according to claim 13, wherein the film is a hydrogel. (15) The therapeutic article according to claim 13, wherein the film is a pressure-sensitive adhesive. (16) Pre-administering or post-administering 1,3-dioxacyclopentane or 1,3-dioxacyclohexane containing at least one pharmaceutically acceptable aliphatic group having 4 to 18 carbon atoms. , a method of facilitating transdermal administration of bioactive agents to humans and animals.