Absorption, Distribution and Excretion
Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 uCi of (14)C Azone. The skin application site was washed with soap and water after each 24-hr dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The (14)C Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was >98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-hr skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p<0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.

Interactions
The feasibility of using some novel topical spray vehicles for enhanced transdermal delivery of the sex hormones, testosterone (Tes), estradiol (E2), progesterone (Prog), and norethindrone acetate (NA) has been investigated. The new penetration enhancers, padimate O (PadO) and octyl salicylate (OSal) were used and compared with laurocapram (AZ) and oleic acid (OA). A finite dose (5 uL/sq cm) of each vehicle was applied to either shed snake skin or swine skin in vitro, and the amount penetrated was measured with flow-through diffusion cells. Partitioning into swine skin was determined after an exposure time of 1 min. Rapid partitioning of Tes and PadO into swine skin occurred after 1 min with 70% and 60% of the applied dose, respectively, remaining in the skin after the unabsorbed dose was removed by rinsing with absolute ethanol. The cumulative amount at 24 hr (Q24 hr) of Tes penetrating across the snake skin was significantly enhanced (p less than 0.05) up to 6-fold for OSal, 3-fold for OA and AZ, and 2-fold for PadO compared to control. Using PadO or AZ, the Q24 hr ranged from three- to thirteen-fold over control (p less than 0.05) for E2, Prog, and NA. Extrapolation of these data to predict what would happen in humans suggests that it should be possible to deliver clinically relevant amounts of sex hormones in this manner with once daily dosing.
... The objective of this study was to determine the effect of vehicles and penetration enhancers on the percutaneous absorption of methotrexate (MTX) and its analog edatrexate (EDAM), and develop transdermal (TD) delivery systems of the drugs for the treatment of rheumatoid arthritis (RA). ... From previously published pharmacokinetic parameters with low-dose MTX therapy, and considering a 50 sq cm diffusional area, the target steady state in vitro TD flux for MTX was calculated to be 35 micrograms/cm2/hr. Modified Franz diffusion chambers and hairless mouse skin were used for in vitro skin permeation studies. Hairless mice were used for in vivo studies. Delivered amounts of MTX and EDAM were determined by assaying the receiver phase fluid (or blood) with validated reversed phase HPLC methods. Intrinsic partition coefficient of MTX was low (log P = -1.2). Target MTX fluxes of greater than or = 35 ug/sq cm/hr were achievable only with 1-15% (v/v) Azone in propylene glycol (PG). Flux of EDAM (85 ug/sq cm/hr) was higher than MTX from an isopropyl alcohol (IPA)-5% (v/v) Azone system. Clinically significant steady state in vivo blood concentration of MTX and EDAM was achieved using delivery systems containing greater than or = 2.5% Azone in PG. Area under the drug concentration-time curves (AUC0-24 hr) for MTX were 2379 and 3534 ng hr/mL from PG-2.5% Azone and PG-7.5% Azone systems respectively. AUC0-24 hr of EDAM was 6893 ng hr/mL using a PG-2.5% Azone system.
The permeation of naproxen through excised human skin and isolated perfused rabbit ear skin has been determined. It was found that ... Azone ... enhanced the permeation with an enhancement ratio of up to 4-fold. The magnitudes of the effect were similar in human and rabbit skin. The permeation of naproxen from a saturated solution of the drug through skin pre-treated with Azone was similar to that from a commercial preparation (Naprosyn)...

Laurocapram is a member of caprolactams.
Laurocapram is a percutaneous enhancer. Upon application to the skin, laurocapram interacts with lipids in the stratum corneum and may enhance the ability of the skin to absorb a hydrophilic chemical.

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Mechanism of Action
Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. ... The enhancing effect of Laurocapram (Azone) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. ...

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Therapeutic Uses
1-Dodecylazacycloheptan-2-one (Azone) is a new agent that enhances the percutaneous absorption of a number of different chemicals. This report delineates the enhancement of penetration of clindamycin phosphate, erythromycin base, fusidate sodium, fluorouracil, desonide, amcinonide, and triamcinolone acetonide. For this purpose 1-dodecylazacycloheptan-2-one can be used in concentrations as low as 1%. It is colorless, relatively odorless, nontoxic, and can be applied neat to human skin without any irritation.
/EXP THER/ To assess the safety and tolerability of a topical gel formulation combining methotrexate and laurocapram and to obtain preliminary information on the therapeutic potential of methotrexate-laurocapram in patients with early-stage mycosis fungoides (stage IA or IB). An open-label, phase 1/2 pilot study /was conducted/. ...Ten patients 18 years or older with histologically confirmed stage IA or IB mycosis fungoides. ... The gel formulation of methotrexate-laurocapram was applied to the total body surface, excluding genital, perianal areas, nipples, face, and skin under the breasts, on an every-other-day basis for 24 consecutive weeks. The safety of methotrexate-laurocapram was assessed in this study by reviewing adverse events and laboratory data. Efficacy outcomes included changes in lesion condition and severity assessments, reduction in area of sample lesions, and the investigator's global evaluation. Adverse events consisted of skin reactions of mild severity. No clinically significant laboratory abnormalities were observed. Based on the investigator's global evaluation at the end of the treatment phase (week 24), 7 (78%) of 9 patients demonstrated a slight-to-moderate response to treatment with methotrexate-laurocapram. Statistical significance (P =.049) was reached for induration and pruritus, a trend (P =.10) was observed for erythema, and no change was found for scaling (P =.37). These findings indicate that the topical administration of methotrexate-laurocapram is safe and in general well tolerated. This treatment may represent a new therapeutic potential for patients with mycosis fungoides.

C18H35NO

281.484

281.271

59227-89-3

42981

Clear, colorless liquid

0.9±0.1 g/cm3

404.9±14.0 °C at 760 mmHg

-7ºC

165.2±10.7 °C

0.0±0.9 mmHg at 25°C

1.466

6.57

0

1

11

20

240

0

O=C1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H]

AXTGDCSMTYGJND-UHFFFAOYSA-N

InChI=1S/C18H35NO/c1-2-3-4-5-6-7-8-9-10-13-16-19-17-14-11-12-15-18(19)20/h2-17H2,1H3

1-dodecylazepan-2-one

N 0252; Azone; Laurocapram

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~355.27 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)