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The Development of Transdermal Ketamine Patch Rie Kubota1, Yoshimichi Maruyama1, Yoshio Wada1, Ayuko Okamoto1, Aya Tsukamoto1, Takako Komiyama1

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The Development of Transdermal Ketamine Patch Rie Kubota1, Yoshimichi Maruyama1, Yoshio Wada1, Ayuko Okamoto1, Aya Tsukamoto1, Takako Komiyama1 Kubota R. et al. Medical Research Archives, vol. 6, issue 4, April 2018 issue Page 1 of 9 RESEARCH ARTICLE The Development of Transdermal Ketamine Patch Rie Kubota1, Yoshimichi Maruyama1, Yoshio Wada1, Ayuko Okamoto1, Aya Tsukamoto1, Takako Komiyama1 Authors’ affiliations: 1. Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan Corresponding Author: Rie Kubota, Pharm.D., Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan, Address: 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan, E-mail: [email protected], Telephone & Fax number: 81-3-3440-3055 Abstract Objective We prepared the transdermal ketamine patch, determined the size of the patch to yield proper plasma ketamine level due to human skin permeability and the amount of residual ketamine in the patch, and estimated the utility of this ketamine transdermal patch when it will be applied to patients. Methods A ketamine patch was prepared with ketamine hydrochloride intramuscular solution (3.0mg/cm2). The ketamine patch was put on the skin samples taken from the human. The solutions of the diffusion cell were examined every two hours after the application until 30 hours. The amount of ketamine that has penetrated into the skin was measured by using HPLC system, and Flux of transdermal ketamine patch was defined. Results The cumulative ketamine permeation amount was found to be 785.6 g/cm2 at the 30-hour sampling, showing a stable Flux of 30.1 g/cm2/hr during the period from 10 to 30 hours of sampling. Conclusion We have been attempting to formulate transdermal ketamine patches at a size of 155 cm2 to yield a plasma ketamine level of 50 ng/mL for use in the clinical practice setting. The patch may become a formulation of choice as an analgesic adjuvant for combined use with opioids. Key words: ketamine, transdermal patch, skin permeability, flux Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Kubota R. et al. Medical Research Archives, vol. 6, issue 4, April 2018 issue Page 2 of 9 Introduction expected to become a novel, clinically applicable dosage form of ketamine. Ketamine is a dissociative anesthetic en- Although Azevedo et al. indicated that dowed with both analgesic and anesthetic transdermal ketamine was effective as an effects. It exerts its analgesic effect by adjuvant of epidural lidocaine for acting as a non-competitive antagonist of postoperative analgesia, and prolonged the the N-methyl D-aspartate (NMDA) duration of analgesia, the appropriate receptor. At low doses, ketamine exerts an dosage and pharmacokinetics of ketamine obvious analgesic effect against neuro- was not determined (6). Therefore, we pathic pain refractory to morphine. prepared the transdermal ketamine patch, Ketamine has been administered by the IV determined the size of the patch to yield and IM routes for obtaining analgesia. proper plasma ketamine level due to There are no commercially available human skin permeability and the amount formulations except for injection, so liquid of residual ketamine in the patch, and formulation is prepared for in-hospital use estimated the utility of this ketamine (1). The efficacy of ketamine administered transdermal patch when it will be applied alone or in combination with opioids is to patients. anticipated, particularly in patients with terminal-stage cancer in whom opioid medication alone fails to provide Methods satisfactory relief. Recently, it is also 1. Preparation of the Transdermal Keta- said that ketamine might be effective in the mine Patch treatment of depression.(2-3) However, the pharmacokinetic profile of ketamine in Partially neutralized polyacrylate (0.60 g), humans, has not yet been clarified, nor has aluminum stearate (0.48 g) and ketamine the appropriate dosage schedule been hydrochloride (0.48 g) were mixed by established. Further, there exist problems slow stirring. Concentrated glycerin (2.10 inherent to the use of injectable g), 1,3-butylene glycol (2.10 g), isopropyl preparations, which can hardly be myristate (0.30 g), diisopropanolamine prescribed to patients wishing home care, (0.96 g), lactic acid (0.06 g) were added to and liquid formulations, which are the mixture and stirred until it equalized. unsuitable for patients incapable of oral 10% Methyl vinyl ether maleic anhydride intake. copolymer dissolved in ethanol solution (6.00 g) added to the mixture and stirred We have investigated and confirmed the until it equalized. The mixed suspension pharmacokinetics of ketamine and its removed air was spread on the release active metabolite, norketamine after oral layer of polyethylene terephthalate using a administration of liquid formulation of knife coater (Kodaira Seisakusho Co., Ltd. ketamine (4). We formulated a ketamine Japan) to contain about 3.0 mg of ketamine transdermal patch and applied it to hairless hydrochloride per cm2. The film was dried rats, and demonstrated that the at 60C for 1 hour and covered with the pharmacokinetic profile of this formulation backing layer of polyethylene terephthalate, was similar to that of ketamine intravenous and heated at 100C for 1hour. The infusion (5). The transdermal patch is Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Kubota R. et al. Medical Research Archives, vol. 6, issue 4, April 2018 issue Page 3 of 9 ketamine hydrochloride used in the above internal standard, and the resultant mixture formulation was lyophilized hydrochloride was stirred in a vortex mixer and analyzed ketamine (Ketalar ) for Intramuscular In- by a high performance liquid jection (Daiichi-Sankyo Co., Ltd, Tokyo). chromatography (HPLC) system to determine the amount of ketamine that had 2. In vitro Human Skin Permeability penetrated the skin. The HPLC conditions Study were as follows: pump, LC-10AD; detector, SPD-10A; auto injector, 2.1. Materials SIL-10AXL; column oven, CTO-10AC Caucasian human abdominal skin (Shimadzu Co. Ltd., Japan); column, (BIOPREDIC International, France) was Purospher RP-18e (125 mm×4 mm, 5m; used. The skin specimens were surgically Merk Co. Ltd., Germany); column collected skin sections, preserved at 80C temperature, 40C. The mobile phase until use in the test. Six pieces of skin were consisted of acetonitrile and 0.03 mol/L cut out of two 12-cm2 skin specimens from phosphate buffer at rations of 1 : 1. The the same individual and used for the tests flow rate was 1mL/min. The absorption on normal skin and tape-stripped skin. The wavelength was determined at 210 nm (7). dermal stripping for removal of the stratum After completion of the permeability study, corneum was carried out by repeatedly the skin was processed with 20 mL of applying surgical tape to the skin surface methanol solution to extract ketamine, about 30 times. followed by analysis performed in the same manner as that in the permeability 2.2. Sampling and analysis study, to verify the amount of residual ketamine in the skin. The rate of ketamine A human skin specimen with a round patch, residue in the skin was calculated from the 1 cm in diameter, containing 2.49 mg of amount of residual ketamine to the amount ketamine hydrochloride was mounted in a of ketamine content in the patch. diffusion cell (available diffusion area, 0.785 cm2; volume of receiver cell, 2.8 mL). The receiver cell was filled with 2.3. Indicator of skin permeability phosphate buffered saline. During the The amount of drug that has penetrated the experiments the solution in receptor side skin (stratum corneum, epidermis, and was maintained at 37C and stirred using a dermis) per unit area of the patch per unit magnetic stirrer. At each of all the 15 time was defined as the percutaneous drug time-points (2, 4, 6, 8, 10, 12, 14, 16, 18, permeability rate (Flux). This variable was 20, 22, 24, 26, 28, and 30 hrs) after the calculated from the gradient of the start of the stirring, 500 L of the receiver steady-state cumulative permeation solution was sampled and the same volume amount of drug determined from the of fresh receiver solution was pipetted to permeability study. fill up the complement. To 200 L of the sampled solution, the same volume of a 0.05-mg/mL tulobuterol hydrochloride solution in methanol was added as the Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Kubota R. et al. Medical Research Archives, vol. 6, issue 4, April 2018 issue Page 4 of 9 3. Verification of the Amount of of residual ketamine in an unused patch. Residual Ketamine in the Patch after The ketamine content of a test patch used the Human Skin Permeability Study in the skin permeability study was estimated from the weight of the drug 3.1. Materials reservoir of the test patch prior to use. The Six ketamine hydrochloride patches (1 cm ketamine residual rate (%) at 30 hours of in diam., 0.785 cm2) that had been applied application was calculated from the to test human skin specimens for 30 hours estimated ketamine content and the in the human skin permeability study and residual amount in the used patch. three unused ketamine hydrochloride Weight of drug reservoir (g) = Weight of patches (1 cm in diam., 0.785 cm2) were drug product (g) Mean weight of used. All these patch preparations were liner/support (g) weighed prior to use and those that were still unused were checked for the weight of Ketamine concentration (%) = Ketamine the drug-containing plaster base material content (mg)/Weight of drug reservoir (g) (drug reservoir) (g) [Weight of drug Estimated ketamine content (mg) = Weight product (g) Mean weight of liner/support of drug reservoir (g) Ketamine (g)].
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