Skin Toxicity of propranolol in guinea pigs.

Kobayashi, Ichiro; Hosaka, Kyoko; Maruo, Hiroki; Saeki, Yuji; Kamiyama, Masashi; Konno, Chohachi; Gemba, Munekazu

doi:10.2131/jts.24.103

Cited by 7 publications

(2 citation statements)

References 9 publications

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“…Mishra et al (20) showed that in vivo, in rats, maximum plasma concentrations of propranolol hydrochloride were low (25 ± 5.0 ng/mL) 24 hours after topical administration of 200 μL of 0.4% drug solution on 1 cm² of the dorsal skin. Cumulative skin irritation studies in guinea pigs indicated that propranolol caused skin irritation but no sensitization, phototoxicity, or photosensitization (21). Skin irritation increased with increasing propranolol dosage and application times.…”

Section: Discussionmentioning

confidence: 99%

Topical Propranolol Therapy for Infantile Hemangiomas

Kunzi‐Rapp

2011

Pediatric Dermatology

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The nonselective beta-adrenergic receptor antagonist propranolol is an effective therapy for infantile hemangiomas. Systemic propranolol therapy shows a rapid therapeutic effect with good drug tolerability. We report on the efficacy of local application of propranolol ointment in superficial hemangiomas of the skin. In our outpatient department, 45 children with 65 hemangiomas were treated with 1% propranolol in a hydrophilic ointment topically applied twice a day. Before start of treatment and at each visit, clinical photographs were taken. If ultrasound did not confirm occult deeper components, children were included in the study. Treatment in the proliferative phase within the first 6 months of life (including seven preterm infants) induced regression in 59% and cessation of growth in 26% of the hemangiomas. No response or proliferation of subcutaneous components was observed in 15%. Clinically, no side effects caused by the beta-receptor blocker were noticed. Treatment of two ulcerated hemangiomas of the perineal region twice using a flash lamp pulsed-dye laser and propranolol ointment in the surrounding lesion led to healing of the ulcers in 3 and 6 weeks, respectively. In six patients, topical therapy was started between the ages of 7 and 33 months. Even in these hemangiomas, improvement was obvious after 2 or 3 months. Propranolol administered topically in 1% ointment could have a beneficial effect on superficial hemangiomas of the skin. The treatment was well tolerated without side effects even in preterm infants and in children with numerous or large lesions.

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Section: Discussionmentioning

confidence: 99%

Topical Propranolol Therapy for Infantile Hemangiomas

Kunzi‐Rapp

2011

Pediatric Dermatology

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“…[22][23][24][25] Moreover, adhesive plasters with low tensile stress and removal force and short stress relaxation time have lowest levels of skin irritation.…”

Section: Evaluation Of Skin Irritation With Eva Matrix Patchesmentioning

confidence: 99%

Effects of Ethylcellulose and 2-Octyldodecanol Additives on Skin Permeation and Irritation with Ethylene-Vinyl Acetate Copolymer Matrix Patches Containing Formoterol Fumarate

Kakubari

Sasaki

Takayasu

et al. 2006

Biological & Pharmaceutical Bulletin

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Formoterol is a catecholamine analogue possessing highly potent, long-lasting b 2 -adreoceptor agonist effects.1,2) Clinical studies have revealed that it induces bronchodilation for at least 12 h after a single oral administration. 3,4) However, in order to maintain effective plasma concentrations and suppress asthmatic fits, there is considerable interest in development of transdermal drug delivery systems.Transdermal drug delivery is well recognized as an alternative to oral delivery and has many advantages, including the avoidance of metabolism in the gastrointestinal tract and the liver, long-term maintenance of therapeutic plasma levels of drugs and ready discontinuation of drug input if side effects arise.However, without the use of skin permeation enhancers, systemic delivery of most drugs through the skin is limited due to the barrier function of the stratum corneum. Such agents increase drug transport through the skin by elevating partition and diffusion coefficients. Ideally enhancers should increase drug transport by reversibly altering the skin barrier function without sensitization or irritation. We have already reported effects of l-menthol and N-methyl-2-pyrrolidone (NMP) on skin permeability and stability of formoterol fumarate (FF) in matrix patches. 5) Furthermore, efficacy under simulated conditions relevant to asthma in experimental animals was demonstrated. However, no significant effects were observed with 2-octyldodecanol (OD) on rat skin permeability of FF in solution. 6) In the present study, we evaluated the skin permeability of FF and irritation of EVA matrix patches containing ethylcellulose (EC) and OD using different species of experimental animal. MATERIALS AND METHODSMaterials FF and bromo-formoterol were obtained from Yamanouchi Pharmaceutical Co., Ltd. (Tokyo, Japan) and ethylene-vinyl acetate copolymer (MW: 396000) of 45% (w/w) vinyl acetate content (EVA), hydrogenated rosin glycerol ester (Ester Gum H), EC, OD, l-menthol, and NMP were purchased from Bayer AG (Tokyo, Japan), Arakawa Chemical Co., Ltd. (Osaka, Japan), Dow Chemical Co. (Tokyo, Japan), Kokyu Alcohol Kogyo Co., Ltd. (Chiba, Japan), Takasago International Co. (Tokyo, Japan) and ISP Japan Ltd. (Tokyo, Japan), respectively. All other chemicals and solvents were of reagent grade quality, obtained commercially and used without further purification.Preparation of EVA Matrix Patches EVA matrix patches were prepared by a casting method. 7,8) An adhesive solution was made by adding EVA, Ester Gum H, EC and OD to toluene as a coating solvent and mixing with a magnetic stirrer at room temperature. FF was dissolved at NMP followed by addition of l-menthol. The drug solution was then mixed with the adhesive solution and the mixture applied to a baking sheet of polyethylene terephthalate film. After drying at 50°C for 10 min, a release liner was placed on the dry adhesive. The compositions of the matrix patches on prescription are shown Table 1. The adhesive layer of the EVA matrix patch without EC was adjusted to 68 mm thickne...

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Formulating propranolol as an amorphous melt affords reduced skin irritation potential for transdermal drug delivery

2015

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Oral propranolol is commonly the first-line treatment of infantile hemangioma. However, oral delivery of propranolol is limited by systemic side effects, particularly in infants. Topical application may be a more patient friendly alternative while concurrently affording targeted delivery to the site of the skin lesion. Unfortunately, dose-dependent skin irritation is typically observed when propranolol is applied topically. Of additional concern, irritation is often exacerbated by organic solvents required to formulate propranolol. To address these concerns, we present novel formulations of propranolol as amorphous melts. Propranolol melts were successfully synthesized, and their physicochemical properties were tuned suitably for transdermal delivery using dialkyl sulfosuccinates as the counter species. Melts used in this study possessed the ability to penetrate skin when applied neat, without the need of any addition of solvent. Moreover, skin irritation potential of the lead melt was reduced compared to that of the propranolol free base (PFB). This reduction may be due to association of propranolol with the counter species in amorphous melts. The results presented here suggest amorphous melt formulations may open up the possibility to topically deliver drugs that traditionally elicit skin irritation.

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Skin Toxicity of propranolol in guinea pigs.

Cited by 7 publications

References 9 publications

Topical Propranolol Therapy for Infantile Hemangiomas

Topical Propranolol Therapy for Infantile Hemangiomas

Effects of Ethylcellulose and 2-Octyldodecanol Additives on Skin Permeation and Irritation with Ethylene-Vinyl Acetate Copolymer Matrix Patches Containing Formoterol Fumarate

Formulating propranolol as an amorphous melt affords reduced skin irritation potential for transdermal drug delivery

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