Absorption, Distribution and Excretion
Azone (1-dodecylazacycloheptan-2-one) is a substance that has been shown to enhance the transdermal absorption of drugs. The mechanism of action of azone is believed to be through entry into the skin lipid bilayer, thereby disrupting its structure. An open-label study enrolled 9 volunteers (2 men, 7 women; age 51–76 years) who applied azone cream (1.6%; 100 mg) topically to a 5 × 10 cm area on the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the azone cream contained 47 microcuries of 14C-labeled azone. The skin application site was washed with soap and water 24 hours after each administration. Transdermal absorption was determined by urinary radioactive excretion. (14)C Azone is cyclolabeled [14C-2-cycloheptan]. Radiochemical purity >98.6%, cold Azone purity 99%. The dermal absorption rate on the first dose (day 1) was 1.84 ± 1.56% (standard deviation) of the administered dose, lasting 24 hours. Following repeated dosing, the dermal absorption rate significantly increased on day 8 (p<0.002) to 2.76 ± 1.91%. With continued repeated dosing, the dermal absorption rate remained constant on day 15 at 2.72 ± 1.21%. In humans, repeated application of Azone leads to an initial enhanced autoresorption, likely due to its mechanism of action. However, steady-state dermal absorption of Azone is established after the initial change. Therefore, Azone can enhance its own absorption as well as the absorption of other compounds. This should be considered in any pharmacological or toxicological evaluation. Washing the skin at the application site with soap and water recovers only 1-2% of the radioactive material. Previous published studies have shown that washing with ethanol can recover the Azone dose. Therefore, Azone may accumulate in the skin.

Interactions
This study explored the feasibility of using novel topical sprays to enhance the transdermal delivery of sex hormones testosterone (Tes), estradiol (E2), progesterone (Prog), and norethindrone acetate (NA). Novel penetration enhancers palidimal ester O (PadO) and octyl salicylate (OSal) were used and compared with lauryl capplan (AZ) and oleic acid (OA). A limited dose (5 μL/cm²) of each carrier was applied in vitro to molted snake or pig skin, and penetration was measured using a flow-through diffusion cell. Distribution in pig skin was determined 1 minute after exposure. Tes and PadO rapidly partitioned into pig skin after 1 minute; after rinsing with anhydrous ethanol to remove unabsorbed doses, 70% and 60% of the administered dose, respectively, remained in the skin. Compared with the control group, the 24-hour cumulative amount of testosterone (Tes) permeated through snake skin was significantly enhanced (p<0.05), with an increase of up to 6 times in the OSal group, 3 times in the OA and AZ groups, and 2 times in the PadO group. When using PadO or AZ, the Q24 hr values of estradiol (E2), progesterone (Prog), and norepinephrine (NA) were 3 to 13 times higher than in the control group (p<0.05). Extrapolating these data to humans suggests that clinically relevant doses of sex hormones should be achievable with once-daily administration. This study aims to determine the effects of carriers and penetration enhancers on the transdermal absorption of methotrexate (MTX) and its analogue edarax (EDAM), and to develop a transdermal drug delivery (TD) system for the treatment of rheumatoid arthritis (RA). Based on previously published pharmacokinetic parameters of low-dose methotrexate (MTX) treatment and considering a diffusion area of 50 cm², the target steady-state in vitro transdermal (TD) throughput of MTX was calculated to be 35 μg/cm²/h. In vitro skin penetration studies were conducted using a modified Franz diffusion chamber and hairless mouse skin. In vivo studies were performed using hairless mice. The delivery amounts of MTX and edemycin (EDAM) in the receiver phase liquid (or blood) were determined by a validated reversed-phase high-performance liquid chromatography (HPLC). The intrinsic partition coefficient of MTX was low (log P = -1.2). A target MTX throughput of ≥35 μg/cm²/h was only achievable using a 1–15% (v/v) Azone solution in propylene glycol (PG). In an isopropanol (IPA)-5% (v/v) Azone system, the throughput of EDAM (85 μg/cm²/h) was higher than that of MTX. Clinically meaningful steady-state plasma concentrations of MTX and EDAM were achieved in vivo using a PG delivery system containing ≥2.5% Azone. The area under the drug concentration-time curve (AUC0-24 hr) for MTX in the PG-2.5% Azone and PG-7.5% Azone systems were 2379 and 3534 ng·hr/mL, respectively. The AUC0-24 hr for EDAM in the PG-2.5% Azone system was 6893 ng·hr/mL. The permeability of naproxen through isolated human skin and isolated perfused rabbit ear skin was determined. The results showed that Azone enhanced permeability by up to 4-fold. The degree of this enhancement was similar in human and rabbit skin. In Azone-pretreated skin, the permeability of saturated naproxen solution was similar to that of the commercially available formulation (Naprosyn).

Laurocapram belongs to the caprolactam class of compounds. Laurocapram is a transdermal absorption enhancer. After application to the skin, Laurocapram interacts with lipids in the stratum corneum, enhancing the skin's ability to absorb hydrophilic chemicals. Mechanism of Action: Absorption enhancers are substances used to temporarily increase the permeability of membranes (e.g., skin and mucous membranes). Their mechanisms of action include interaction with membrane components (lipids or proteins) or increasing the membrane/carrier partition coefficient. ... The enhancing effect of Laurocapram (Azone) is attributed to various mechanisms, such as its dodecyl insertion into the intercellular lipid bilayer, increased movement of lipid alkyl chains, and fluidity of the hydrophobic regions of the layered structure. ... Therapeutic Uses: 1-Dodecylazacycloheptan-2-one (Azone) is a novel drug that enhances the transdermal absorption of a variety of chemicals. This report describes its penetration-enhancing effects on clindamycin phosphate, erythromycin base, fusidic acid sodium, fluorouracil, desonide, ansilonide, and triamcinolone. Therefore, the concentration of 1-dodecylazacycloheptan-2-one can be as low as 1%. It is colorless, odorless, and non-toxic, and can be applied directly to human skin without causing any irritation.
/Therapeutic Trial/ To evaluate the safety and tolerability of a combined topical gel formulation of methotrexate and lolocapram, and to obtain preliminary information on the treatment potential of methotrexate-lolocapram in patients with early-stage mycosis fungoides (stage IA or IB). An open-label phase 1/2 pilot study has been completed. …Ten patients aged ≥18 years with histologically confirmed stage IA or IB mycosis fungoides were included. …Methotrexate-lolocapram gel was applied to the entire body skin, excluding the genitals, perianal area, nipples, face, and submammary skin, every other day for 24 weeks. This study assessed the safety of methotrexate-lolocapram by retrospectively analyzing adverse events and laboratory data. Efficacy endpoints included changes in lesion condition and severity, reduction in lesion area, and investigator's overall assessment. Adverse events were primarily mild skin reactions. No clinically significant laboratory abnormalities were observed. Based on the investigator's overall assessment at the end of the treatment phase (week 24), 7 out of 9 patients (78%) showed mild to moderate efficacy with methotrexate-lorocapram. Induration and pruritus symptoms reached statistical significance (P = 0.049), erythema symptoms trended towards improvement (P = 0.10), while scaling symptoms remained unchanged (P = 0.37). These results indicate that topical methotrexate-lorocapram is safe and generally well-tolerated. This therapy may provide a new treatment option 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.)