A new enhancer-coenhancer system to increase skin permeation of morphine hydrochloride in vitro

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Although the transdermal drug delivery system, used as non-oral alternative systemic drug delivery system, is a convenient system form for primary and intensive home care (since it does not involve direct injection through the skin), the skin barrier prevents the passage of most drugs. To overcome the skin barrier function temporarily, various physical (iontophoresis, ultrasound, electoporation) and chemical (penetration enhancers, prodrugs) method or their combinations have been used to achieve enhanced transdermal drug transport.1) Among these methods, the most widely used to enhance permeation of stratum corneum barrier are the chemical penetration enhancers.2) Despite the large amount of research and the many different chemical enhancers identified, few have yet reached the market place, because in most of cases, there is a linear correlation between the enhancement effects and skin toxicity.3) This has stimulated research into the combined use of two or more safe and known types of additives. [4][5][6] We have reported a greatly increased effect of l-menthol-ethanol-water (MEW) system on the skin permeation of morphine and several cardiovascular agents compared with their use as single agents. 7,8) The MEW system has a non-selective enhancing effect on a range of both hydrophilic and hydrophobic drugs, and this unselective effect is due to the delipidation of the stratum corneum. This produces skin irritation.9) This result suggests that, if a drug-selective enhancer can be found, it should be possible to minimize the skin irritation. We have found that a lipophilic multicomponent system consisted of L-lactic acid (1%), ethanol (10%) and isopropyl myristate (LEI) system selectively enhances the skin permeation of basic drugs and causes very little skin irritation. [10][11][12] On the other hand, there are many acidic drugs such as NSAIDs which are potentially effective and used routinely in clinical situations. Therefore, it is worthwhile developing a skin permeation enhancer, which would be selective for acidic drugs. In the present study, we have studied a lipophilic multicomponent system consisted of triethanolamine, ethanol and isopropyl myristate (TEI) system, based on our earlier LEI system. MATERIALS AND METHODS MaterialsMefenamic acid (MA), monoethanolamine (M), diethanolamine (D), triethanolamine (T) diethylamine (De), triethylamine (Te), propanolamine (P) and aminopyrine, were purchased from Wako Pure Chemical Ind., Ltd. (Osaka, Japan). Ketoprofen was supplied by Nissan Chemical Ind., Ltd. (Tokyo, Japan). Isosorbide dinitrate (ISDN) was supplied by Toko Pharmaceutical Ind. Co., Ltd. (Tokyo, Japan). Ibuprofen and ketotifen fumarate were obtained from Nissei Chemical Co., Ltd. (Tokyo, Japan). Diclofenac sodium, antipyrine and isopropyl myristate (IPM) were obtained from Tokyo Kasei Kogyo Co., Ltd. (Tokyo, Japan). Dehydrated ethanol (E) (JP grade) was purchased from Imazu Yakuhin Kogyo K. K. (Tokyo, Japan). All other chemicals and solvents were of reagent grade.Animals Male hairless rats (WBN/ILA-Ht)...

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confidence: 99%

The Enhancing Effect of a Triethanolamine-Ethanol-Isopropyl Myristate Mixed System on the Skin Permeation of Acidic Drugs.

Fang

Kobayashi²,

Numajiri

et al. 2002

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“…15) Enhancement effects of mixed solvents such as IPM/NMP 16,17) and l-menthol/ethanol 18) have already been reported. Table 2 shows the results of pretreatment of skin with mixed solvent systems for subsequent skin permeation of FF.…”

Section: Effects Of Solvents On Skin Permeation Of Formoterol Fumaratementioning

confidence: 99%

Effects of Solvents on Skin Permeation of Formoterol Fumarate

Kakubari

Nakamura

Takayasu

et al. 2006

Transdermal drug delivery is recognized as a desirable route for administration of systemically active drugs but the skin permeation of drugs is generally poor. Therefore, various methods for enhancing transfer have been examined using penetration enhancers, iontophoresis, 1) and sonophoresis. 2,3) In particular, many studies have been performed using terpenes, 4,5) pyrrolidones, 6,7) polyunsaturated fatty acids, 8) and fatty acid esters. 9)Formoterol is a catecholamine analogue possessing b 2 -adreoceptor agonist potential, with high potency and prolonged efficacy. 10,11) Clinical studies have revealed that it causes bronchodilation for at least 12 h after a single oral administration. However, dosing is needed twice a day to maintain inhibition of bronchoconstriction in many asthma patients and in order to maintain effective plasma concentrations and suppress asthmatic fits, transdermal drug delivery has decided advantages.In the present study, various chemicals were tested for their ability to enhance permeation of formoterol fumarate (FF) across excised rat skin. MATERIALS AND METHODSMaterials FF was obtained from Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan). All other chemicals and solvents were of reagent grade quality and obtained commercially and employed without further purification.In Vitro Skin Permeation Study Hair on the abdominal skin of male Wistar strain rats (Nihon SLC, body weight, 170-200 g) was shaved, and full-thickness skin was excised and preserved at Ϫ40°C until mounted in horizontal diffusion cells (available diffusion area, 0.785 cm 2 ; volume of each half-cell, 4.0 ml) with a water jacket (37°C) for assessing skin permeability with 4.0 ml of chemicals containing 50 mg FF and 10 ml ethanol as a solubilizer in solution. Modified Frantz diffusion cells (available diffusion area, 0.950 cm 2 ; volume of receiver cell, 4.0 ml) were also used in a manner similar to in vivo exposure for evaluation of 135 ml aliquots of mixed solvents containing 54 mg FF in solution. The receiver cells were filled with saline and solutions in both cells were stirred using magnetic stirrers. At appropriate intervals, 0.5 or 0.3 ml samples were taken from the receiver solution and replaced by the same volume of fresh saline to maintain a constant volume.Samples collected were made alkaline by the addition of 1.0 ml of 0.5 M phosphate buffer (pH 9.0) and extracted with 3.0 ml of ethyl acetate. After vigorous shaking for 10 min, the organic layer was separated by centrifugation at 3000 rpm for 10 min, and 2.5 ml of the organic layer was transferred to a centrifuge tube, and evaporated in a nitrogen stream at 40°C. The residue was redissolved in 0.3 ml of 0.1 M of phosphate buffer (pH 3.5), and the concentration of formoterol was determined by HPLC using ECD. Determination of FF ConcentrationsThe HPLC system consisted of a Model AS-950 autosampler, a Model PU-980 pump (JASCO Co., Tokyo, Japan), and an ECD-100 glassy carbon electrochemical detector (Eicom Co., Kyoto, Japan). Detector potential was set at ϩ650 m...

“…The cumulative amount of morphine permeated through hairless rat skin over 10 h was 5-fold times higher than the sum of those with 40% ethanol alone and l-menthol alone. 9) In the present study, therefore, we tried to improve the percutaneous absorption of PTZ using a combination of various enhancers. The skin permeation of PTZ through hairless mouse skin as a model membrane was determined using Franz diffusion cells and to select an appropriate enhancer for developing a new transdermal system.…”

mentioning

confidence: 99%

Effect of Permeation Enhancers on the in Vitro Percutaneous Absorption of Pentazocine1)

Furuishi

Oda

Saito

et al. 2007

The transdermal drug delivery system (TDDS) has some advantages as an alternative dosage form (i) avoiding firstpass metabolism, (ii) easy discontinuation of administration, and (iii) reduced side effects; however, the stratum corneum, which is the outermost layer of skin, provides a primary barrier to transdermal drug delivery.Pentazocine (PTZ), a relatively short-acting narcotic-antagonist analgesic, is used clinically for the relief of cancerrelated or postoperative pain, and PTZ shows an analgesic effect, a third as strong as morphine. As PTZ has a short halflife of 2 to 3 h 2) and undergoes extensive first-pass metabolism in the liver, conventional therapy with tablets or injection may result in unstable plasma concentration of the drug, which results in the induction of unexpected side effects. Long-term delivery of PTZ is thus needed at a controlled rate in the body for chronic pain management.3) Mandal et al. have reported the percutaneous absorption of PTZ together with isopropyl myristate (IPM) as an enhancer, 4,5) however, the enhanced skin permeation of PTZ is considered limited when IPM is used alone, and increased concentration of the enhancer would cause skin irritation.6) It is well known that the combination of various enhancers improved the percutaneous absorption of drugs much greater than either enhancer alone. 7,8) Regarding opioid analgesics, Morimoto et al. have reported that the percutaneous absorption of morphine hydrochloride was improved with a combination of l-menthol and ethanol. The cumulative amount of morphine permeated through hairless rat skin over 10 h was 5-fold times higher than the sum of those with 40% ethanol alone and l-menthol alone. 9)In the present study, therefore, we tried to improve the percutaneous absorption of PTZ using a combination of various enhancers. The skin permeation of PTZ through hairless mouse skin as a model membrane was determined using Franz diffusion cells and to select an appropriate enhancer for developing a new transdermal system. The flux, lag time and cumulative amount of permeated PTZ were measured as indicators of skin permeation improvement. Moreover, the effects of the structure of enhancers and hydrophiliclipophilic balance (HLB) on permeation rates of PTZ were discussed. MATERIALS AND METHODSMaterials PTZ was purchased from Kobayashi Kako Co., Ltd. (Fukui, Japan). IPM, citric acid, urea, and 1-octadecanol were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). N-Methyl-2-pyrrolidone (Pharmasolve ® , Japanese Pharmaceutical Excipient grade) was a gift from ISP Japan (Tokyo, Japan). Glyceryl monocaprylate (GEFA-C 8 , Sunsoft ® 700P-2), glyceryl monocaprate (GEFA-C 10 , Sunsoft ® 760), glyceryl monolaurate (GEFA-C 12 , Sunsoft ® 750), gylceryl monostearete (GEFA-C 18 , Sunsoft ® 8000V) and glyceryl dicaprylate (GEFA-DiC 8 , Sunsoft ® GDC-S) were a gift from Taiyo Kagaku Co., Ltd. (Mie, Japan). Glyceryl tricaprylate (GEFA-TriC8, Panacate ® 800) and polyoxyethylene laurylether (NONION K-204) were a gift from NOF Corporation (T...