JPH0813757B2 - Novel transdermal absorption enhancer and composition containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of the Invention The present invention is directed to 1,3-dioxacyclopentanes and 1,3
-Methods of using dioxacyclohexanes to enhance skin penetration of therapeutic agents, and compositions containing compounds of this type, as well as novel penetration enhancing compounds within these chemical classes.

(Prior Art) The reasons why the delivery of a physiologically active agent from the skin (that is, transdermal delivery) is more promising than that of other parenteral administration methods or administration from a fire extinguisher system is based on many factors.
Large surface area of skin (more than 3000 square inches for the average adult) and extensive circulatory system (1/3 of whole blood) available near skin, lymphoid network, topical application and those from skin The generally non-invasive nature of drug delivery, convenience, safety, greater controllability of the drug to be delivered, and minimal side effects are some of the advantages found in this technique.

While not all drugs are suitable for transdermal delivery due to local irritation, allergic reactions, etc., most drugs have been suggested to be suitable. Unfortunately, however, the greatest challenge lies in overcoming the general barriers to skin drug penetration (actually any substance). The drug must pass through the outer layer of the skin or epidermis and through the entire dermis layer as absorbed into the bloodstream. The epidermis consists of two main parts, the stratum corneum and the germ layer. The stratum corneum forms the outermost layer of the epidermis and is composed of a layer of compacted, flat, keratinized cells (nucleus free). This outermost layer serves as a physical barrier to light, heat, microbes and most chemicals. Furthermore, it acts as a primary barrier to transdermal absorption. Due to its skin barrier effect, it has hitherto only been possible to deliver up to 10 mg / day of "low dose" or low molecular weight drugs. Furthermore, they must have a proper lipophilic-hydrophilic balance to allow adequate absorption. It was as early as early in the century that fat-soluble substances (eg non-electrolytes) were found to have a relatively greater skin permeability than water-soluble substances (eg electrolytes).

The phenomenon of percutaneous absorption or permeation is followed by absorption of osmotic molecules at the surface of the stratum corneum, diffusion through that surface and the living epidermis, and finally through the papillary dermis into the microcirculatory system. It is considered as a complex of a series of steps consisting of The large diffusion resistance of the stratum corneum was demonstrated in the comparative absorption of drugs such as hydrocortisone. The rectal and vaginal mucosa absorbs 26-29% of the applied steroid, whereas the skin absorbs less than 2% of the applied amount.

Compounds known or reported to facilitate transdermal delivery of drugs include dimethyl sulfoxide (DMSO), polyethylene glycol monolaurate,
Included are alkyl lactams, and long chain amides.
Prior art patents related to penetration enhancers for bioactive agents include: US Pat. No. 3,551,554 discloses dimethyl sulfoxide; 3989.
No. 816 discloses 1-substituted azacycloheptan-2-ones; No. 4132781 discloses topical antibiotics and 2-pyrrolidone or n-lower alkyl-2-pyrrolidone; No. 4017641 is also 2
-Pyrrolidone (but including propylene glycol); other interesting disclosures are the following U.S. patent specifications: 3,903,256; 4,343,798; 4,046,886
No. 3,934,013; 4,070,462; 4,130,643;
No. 4,130,667; No. 4,289,764; No. 4,070,462; No. 3,5
No. 27,864; No. 3,535,422; No. 3,598,123; No. 3,952,09
No. 9; 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. 3,5
98,122; 4,405,616; 3,896,238; and 3,
No. 472,931. U.S. Pat. No. 4,557,934 is also worth noting. None of the cited references has previously disclosed 1,3-dioxolane or 1,3 dioxane, especially its substituted forms, for use as percutaneous absorption enhancers for bioactive substances.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to certain compounds that are effective in promoting the transport of a number of high dose, low absorption drugs through the skin.

The 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 I: [In the formula, R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently a hydrogen atom and a C _{1 to} C ₁₈ aliphatic group (preferably an alkyl group or an alkenyl group. , Halo, hydroxy group, carboxy group, carboxamido group and / or carboalkoxy group-substituted C ₁ -C ₁₈ aliphatic group); R, R ₀ , R ₁ , R ₂ , R ₃ , R _At least one of ₄ , R ₅ and R ₆ is a C ₄ -C ₁₈ alkyl group or alkenyl group; n is 0 or 1; R, R ₀ , R ₁ , R ₂ , R ₃ , R The total number of all carbon atoms of ₄ , R ₅ and 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 Of these, 1 or 0 contains 18 or more carbon atoms. Suitable compounds of general formula I are those in which R is C ₄ -C ₁₈ , preferably C
_{6 to} C ₁₂ , more preferably C _{7 to} C ₁₀ . Another preferred class is where R and R ₀ are hydrogen and _one of R ₁ , R ₂ , R ₅ and R ₆
One is C ₄ -C _18, preferably C ₆ -C _12, more preferably C ₇ ~
Cyclopentane (ie dioxolane) which is C ₁₀ . Suitable groups for the R group include alkyl groups, alkenyl groups, carboalkoxy groups (eg Or a -CH ₂ OR.

The general formula for the optimum accelerator is Formula II: (Wherein R C ₄ -C _18, preferably C ₆ -C _12, more preferably a C ₇ -C _10, and the other R Motogun a lower group (C ₁ ~
C ₄ ) or hydrogen, halo, carboxy group, hydroxy group,
Any of the other groups, such as an amide group, and n =
0 or 1); and Formula III: (Wherein one of the R groups is C _{4 to} C ₁₈ , preferably C _{6 to} C ₁₂ , more preferably C _{7 to} C ₁₀ and the other R groups are as defined in formula II). And Formula IV: [Wherein R ₄ is C _{4 to} C ₁₈ , preferably C _{6 to} C ₁₂ , more preferably C _{7 to} C ₁₀ , and R ₁ , R ₂ and R ₃ are of formulas II and II
As defined for the other R groups in I, n = 0 or 1, and when n = X is a carbonyl It is]. In formulas II and III, R ₀ is preferably hydrogen. In formula III, R is also preferably hydrogen.

The compounds contained herein are applied, for example, as a mixture therewith, together with a drug desired to be transdermally administered to humans or animals. Immediately before (eg several minutes or more, ie 15 minutes, 30 minutes, 1 hour etc.) or after (eg immediately or 15 minutes, 30 minutes, 1 hour, 10
Pretreatment after hours or 24 hours is also often desirable. Dioxane or dioxolane with or without therapeutic agents or other additives can be loaded onto a suitable support such as by coating or impregnation. It is mixed with a hydrophilic or hydrophobic substance and in this form is coated on a suitable support or (eg polyethylene, nylon, polyester, polyurethane, hydrolyzed (eg 85%)
Molded into films (using hydrophilic or hydrophobic film-forming resins such as polyvinyl acetate, cellulose acetate, regenerated cellulose) and used as self-supporting films, or paper, metal, resin binders Laminated or otherwise bonded to other substrates such as non-woven fabrics, with or without, woven fabrics (eg, cotton, rayon, nylon, polyester, etc.). The accelerator is dissolved or dispersed alone or with agents and / or additives in one or other of the above thermoplastics and melt spun or calendered or molded into the desired shape or structure. A very useful support for the promoter itself or the promoter in combination with the bioactive agent is a pressure sensitive adhesive coated support (eg, plastic, paper, cloth, metal, foil, etc.). It is, of course, apparent that many of the conventional auxiliaries commonly and otherwise utilized and / or administered with a given bioactive agent can be used in the various compositions, articles and methods described herein. .

Auxiliaries of this kind are usually used in solvents (eg water, ethanol etc.), lipids, colorants, fragrances, antioxidants, thickeners, UV stabilizers, preservatives, and compositions of this kind. Others are included.

Example I Preparation of 2-n-pentyl-1,3-dioxolane (1) In a 250 ml round bottom flask equipped with a Dean Stark trap, condenser and mechanical stirrer, 30 g of hexanal (0.29 mol) in 100 ml of benzene, 31 g of ethylene glycol.
(0.5 mol), p-toluenesulfonic acid (p-Ts) 100 mg
I put it in. The mixture was heated under reflux until no more water separated from the benzene phase. The mixture was then cooled to room temperature, 100 ml of 5% sodium hydrogen carbonate, saturated NaCl.
100 ml of solution, finally washed with water. The solution was dried over sodium sulfate, the solvent was removed, and the crude oily substance was fractionally distilled.
19.6 g of colorless oil was obtained. ▲ n ²⁰ _D ▼ = 1.4554.

Example II Preparation of 2-n-heptyl-1,3-dioxolane (2) According to the production method of compound 1, octyl aldehyde 30 g (0.23 mol), ethylene glycol 31 g in 70 ml of benzene
(0.5 mol), and 20.5 g of colorless oily substance from 100 mg of p-Ts
(50.9%) was obtained. ▲ n ²⁰ _D ▼ 1.4336.

Example III Preparation of 2-n-nonyl-1,3-dioxolane (3) According to Example I, 78.77 g (0.5 mol) decylaldehyde, 37.22 g ethylene glycol in 100 ml toluene.
78 g (77.4%) of a colorless product were obtained from (0.6 mol) and 0.5 g of p-toluenesulfonic acid. Boiling point 80 ° ~ 81 ° C /
0.5mmHg; ▲ n ²⁰ _D ▼ = 1.4392.

Example IV Preparation of 2-n-undecyl-1,3-dioxolane (4) 45.56 g of dodecyl aldehyde (0.25 mol), 17.85 g of ethylene glycol in 140 ml of tolue according to Example I
(0.288 mol) and 0.02 g of p-toluenesulfonic acid were reacted to obtain 30 g (55%) of a colorless product. Boiling point 112 ° ~
^{116 ℃ / 1.5mmHg; ▲ n 20} D ▼ = 1.9999.

Example V Preparation of Pentylene-1,5-bis-1,3-dioxolane (5) According to the preparation method of compound 1, glutaraldehyde 32 g (0.31 mol), ethylene glycol 52.
01 g (0.83 mol) and 200 mg of p-Ts were reacted to obtain 46.03 g (67%) of colorless oil. ▲ n ²⁰ _D ▼ ＝ 1.4559; Boiling point 78
゜ 〜82 ℃ / 0.1mmHg.

Example VI Preparation of 2- (2 ', 6'-dimethyl-2', 6'-heptadienyl) -1,3-dioxolane (6) According to Example I, 50 g citral in 75 ml benzene
(0.32 mol), ethylene glycol 24.8 g (0.4 mol) and p-toluenesulfonic acid 0.02 g from pale yellow oil 18.
2 g were obtained. ▲ n ²⁰ _D ▼ ＝ 1.4940; Boiling point = 0.5mmHg / 34〜
36 ° C.

Example VII 2- (2 ', 6'-Dimethyl-2'-heptaenyl) -1,
Production of 3-dioxolane (7) 80% citronellal in a 500 ml flask equipped with a distillation receiver, condenser with drying tube, and magnetic stirrer
0.58 g (0.158 mol was added. Next, 100 ml of dry benzene was added.
Ethylene glycol 14.59 g (0.23 mol) and p- in
0.02 g of toluenesulfonic acid was added and the mixture was heated under reflux with stirring until water no longer separated in the distillation receiver (about 6 hours). Upon completion of the reaction, the mixture was washed with 2 x 10 ml of 5% sodium hydrogen carbonate solution and water and dried over sodium sulfate. The reaction mixture was passed and the liquid was concentrated to give a yellow oil. Distillation gave 17.57 g (41%) of colorless product. Boiling point 65 ° -70 ° C
/0.5mmHg; ▲ n ²⁰ _D ▼ = 1.4645.

Example VIII Preparation of 2-n-nonyl-5-chloromethyl-1,3-dioxolane (8) According to the preparation of compound 1, 24.95 g (0.16 mol) of decyl aldehyde, 17.6 g (0.16 mol) of 3-chloro-1,2-propanediol and 0.2 g of p-Ts in 100 ml of toluene give 30.49 g (77%) of colorless oil. )was gotten. Boiling point = 0.14 mm
Hg / 91-100 ° C; ▲ n ²⁰ _D ▼ = 1.4533.

Example IX 2- (2 ', 6'-Dimethyl-2'-heptaenyl) -5
-Chloromethyl-1,3-dioxolane (9) According to the preparation method of compound 1, 15 g (0.097 mol) of 3-chloro-1,2-propanediol, 10 g (0.06 mol) of citronellal and 150 mg of p-Ts in 75 ml of benzene gave 12.56 g of crude product (oil).

Example X Preparation of 2- (2 ', 6'-dimethyl-2', 6'-heptadienyl) -5-chloromethyl-1,3-dioxolane According to the preparation method of compound 1, 12.77 g (0.08 mol) of citral, 10 g (0.09 mol) of 3-chloro-1,2-propanediol and 60 mg of p-Ts in 50 ml of benzene were used to obtain crude oil 1
0.7 g (54.7 mol) was obtained.

Example XI Preparation of 2- (2 ', 6'-dimethyl-2', 6'-heptadienyl) -5-hydroxymethyl-1,3-dioxolane Citral 51. in 150 ml benzene according to Example I.
4 g (0.33 mol) glycerol 46 g (0.5 mol) and p-
Toluenesulfonic acid 0.04 g was reacted to give a colorless oil 31.
Obtained 45 g (41.11%). ▲ n ²⁰ _D ▼ = 1.4693.

Example XII 2- (2 ', 6'-Dimethyl-2'-heptaenyl) -5
-Hydroxymethyl-1,3-dioxolane According to the preparation method of compound 1, 27.62 g (0.3 mol) of glycerol in 150 ml of toluene, 17.2 ml of citronellal (0.1 mol)
Mol) and p-Ts 400 mg to give 9.69 g of an oil.

Example XIII Preparation of 2-n-nonyl-1,3-dioxane According to Example I, in 100 ml of toluene 78.77 g (0.5 mol) decylaldehyde, 45.65 g 1,3-propanediol
(0.6 mol) and 0.5 g of p-toluenesulfonic acid were reacted to give 67.69 g (62.65%) of a colorless product. Boiling point 7
0 ° -74 ° C / 0.1mmHg; ▲ n ²⁰ _D ▼ = 1.4448.

Example XIV Preparation of 2-n-undecyl-1,3-dioxane A colorless oil was obtained from 11.19 g (0.064 mol) of dodecyl aldehyde, 7.5 g (0.098 mol) of 1,3-propanediol and 50 mg of p-Ts in 50 ml of benzene according to the preparation method of compound 1.
7.46 g (48%) was obtained. ▲ n ²⁰ _D ▼ = 1.4477; Boiling point =
0.065mmHg / 89 ℃.

Example XV 2- (2 ', 6'-Dimethyl-2'-heptaenyl) -1,
3-dioxane manufacturing method A 250 ml flask equipped with a distillation receiver, a condenser with a drying tube, and a magnetic stirrer was charged with 10 g (64 mol) of 80% citronellal. Then in 50 ml of dry benzene
7.5 g (0.098 mol) of 1,3-propanediol and 0.05 g of p-toluenesulfonic acid are added and the mixture is heated under reflux with stirring until no more water separates in the distillation receiver (about 6 hours). did. When the reaction is complete, add 2
Wash with × 10 ml of 5% sodium bicarbonate solution and water,
It was dried over sodium sulfate. The reaction mixture was passed and the liquid was concentrated to give a yellow oil. Colorless product after distillation 1
7.57 g (72.6%) was obtained. Boiling point 65 ° ~ 70 ° C / 0.5mmHg; ▲ n ²⁰
_D ▼ = 1.4609.

Example XVI 2- (2 ', 6'-Dimethyl-2', 6'-heptadienyl) -5- (bis-ethylcarboxylate) -1,3-
Manufacturing method of dioxane (18) According to the preparation method of compound XV, 9.13 g (0.06 mol) of citral, 20 g (0.09 mol) of ethyl (bis-hydroxymethyl) malonate and 0.3 g of p-toluenesulfonic acid in 60 ml of benzene gave a pale yellow oil. Boiling point = 0.5 mmH
g / 140 ° C; ▲ n ²⁰ _D ▼ = 1.4761.

Example XVII 2-n-nonyl-5- (bis-5-carboxylate)
Production method of -1,3-dioxane Decylaldehyde 5.2 in a 100 ml flask equipped with a distillation receiver, condenser with drying tube and magnetic stirrer.
g (0.33 mol) was added. Then 8.53 g of ethyl (bis-hydroxymethyl) malonate in 50 ml of dry benzene (0.0
387 mol) and 0.2 g of p-toluenesulfonic acid,
The mixture was heated under reflux with stirring until no more water separated in the distillation receiver (about 6 hours). Upon completion of the reaction, the mixture was washed with 2 x 10 ml of 5% sodium hydrogen carbonate solution and water and dried over sodium sulfate. The reaction mixture was passed and the liquid was concentrated to give a yellow oil. After distillation The following properties: Boiling point = 0.22mmHg / 150
° C; ▲ n ²⁰ _D ▼ = 1.4490 colorless product 8.96 g (7
4.1%) was obtained.

Example XVIII Preparation of 2-n-pentyl-5- (bis-ethylcarboxylate) -1,3-dioxane 6 g of hexyl aldehyde in a 100 ml flask equipped with distillation receiver, condenser with drying tube and magnetic stirrer
(0.06 mol) was added. Then 20 g (0.09 mol) of ethyl (bis-hydroxymethyl) malonate in 60 ml of dry toluene and 0.2 g of p-toluenesulphonic acid are added until the mixture no longer separates water in the distillation receiver (about 6 hours. ) Heated under reflux with stirring. Upon completion of the reaction, the mixture was washed with 2 x 10 ml of 5% sodium hydrogen carbonate solution and water and dried over sodium sulfate.
The reaction mixture was passed and the liquid was concentrated to give a yellow oil. After distillation 11.19 g (62%) of a colorless product was obtained. Boiling point = 0.2 mmHg / 100-118 ° C .; ▲ n ²⁰ _D ▼ = 1.4453.

Example XIX According to the preparation method of compound XV, from citronellal 9.25 g (0.06 mol), ethyl (bis-hydroxymethyl) malonate 20 g (0.09 mol) and p-toluenesulfonic acid 0.3 g in 60 ml of benzene, the following properties: boiling point = 0.3 mmHg / 135 ° C
3.5 g of a colorless oil with n ²⁰ _D = 1.4751 was obtained.

(Effect of the invention) Compounds of Examples III, IV, V, VI, VIII, XIII, XIV and XV are hairless rat skin and diffusion cell method (a method that mimics the in vivo situation because the skin is exposed to ambient conditions). Using in
Tested in vitro. The flow diffusion cell uses perfusion on the dermal side of the skin. The test collection is simplified by automatically collecting the liquid continuously throughout the day. The cell is equipped with a water jacket to provide temperature control and equilibration of skin and dermal fluids.

The general method is as follows. The skin is fixed in a cell 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% w / v) diluted with saline. The constituents are added to the bath to avoid the development of bacteria. Test drug in ethanol / water (95/5 weight / volume) mixed solvent
Apply 500 mg to the epidermis. After application, the solvent is allowed to develop for 1-2 hours and leave a solid drug deposit on the skin. The drug to be tested is a radioactive compound and its absorption rate is followed after application of the radioactive mixture by measuring the radioactivity in the dermal fluid sample every hour for 48 hours.
Twenty-four hours after drug application, 0.1 ml of accelerator is applied to the treated surface.

In accordance with the above method, the compound of Example III showed significantly increased skin diffusion when tested with progesterone, caffeine and indomethacin and when the accelerator of Example III was applied to the skin after drug application. Thus
For example, the% diffused indomethacin was 1.47% / cm ² during the first 24 hours (drug alone-without accelerator application), but 12.85% / cm ² after 48 hours (24 hours with accelerator application only).
It was cm ² . In the case of progesterone, Example I
The compound of II was found to be 10 times more effective than the alcohol of N-dodecyl caprolactam, a known accelerator.

In a similar manner, Examples IV, V, VI, VIII, XIII, XIV and X
The compound of V was also found to be significantly effective.

In another study, the total% of transdermal absorption after 48 hours (drug only for the first 24 hours, followed by application of enhancer) was as follows:

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Claims (15)

[Claims] 1. A 1,3-dioxacyclopentane containing at least one pharmaceutically acceptable aliphatic group having 4 to 18 carbon atoms as a physiologically active agent and an effective skin penetration enhancer, or A therapeutic composition containing 1,3-dioxacyclohexane suitable for transdermal administration to humans and animals. 2. A bioactive agent and the following formula: [In the formula, R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are each independently a hydrogen atom and a C _{1 to} C ₁₈ aliphatic group (preferably an alkyl group or an alkenyl group. , Halo, hydroxy group, carboxy group, carboxamido group and / or carboalkoxy group-substituted C ₁ -C ₁₈ aliphatic group); R, R ₀ , R ₁ , R ₂ , R ₃ , R _At least one of ₄ , R ₅ and R ₆ is C
_{4 to} C ₁₈ alkyl group or alkenyl group; n is 0 or 1; sum of all carbon atoms of R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ The number is 40 or less (preferably less than 20); among R, R ₀ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ , one containing 18 or more carbon atoms is 1 Or 0. ] A therapeutic composition suitable for transdermal administration to humans and animals, which comprises an effective skin permeation 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 ₁₀ 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 third claim, wherein R is undecyl.
A therapeutic composition according to item. 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. The therapeutic composition according to claim 7, wherein R ₁ , R ₂ and R ₅ are hydrogen atoms and R ₆ is hydroxymethyl. 12. A support and a pharmaceutically acceptable 4-18.
For facilitating transdermal administration of bioactive agents consisting of 1,3-dioxacyclopentane or 1,3-dioxacyclohexane containing one aliphatic group having one carbon atom to humans and animals Suitable therapeutic article. 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 of claim 13 wherein the film is a pressure sensitive adhesive.