Use of hollow microneedles for targeted delivery of phenylephrine to treat fecal incontinence.

A hollow microneedle (HM) was prepared to deliver a phenylephrine (PE) solution into the anal sphincter muscle as a method for treating fecal incontinence. The goal of this study was the local targeted delivery of PE into the sphincter muscle through the perianal skin with minimal pain using hollow microneedles, resulting in the increase of resting anal sphincter pressure. PE was administered on the left and the right sides of the anus of a rat through the perianal skin using 1.5mm long HM. An in vivo imaging system study was conducted after injection of Rhodamine B, and a histological study was performed after injection of gentian violet. The resting anal sphincter pressure in response to various drug doses was measured by using an air-charged catheter. Anal pressure change produced by HM administration was compared with change produced by intravenous injection (IV), subcutaneous (SC) injection and intramuscular (IM) injection. The change in mean blood pressure produced by HM administration as a function of PE dose was compared with change produced by PBS injection. A pharmacokinetic study of the new HM administration method was performed. A model drug solution was localized in the muscle layer under the perianal skin at the injection site and then diffused out over time. HM administration of PE induced significant contraction of internal anal sphincter pressure over 12h after injection, and the maximum anal pressure was obtained between 5 and 6h. Compared to IV, SC and IM treatments, HM treatment produced greater anal pressure. There was no increase in blood pressure after HM administration of PE within the range of predetermined concentration. Administration of 800μg/kg of PE using HM produced 0.81±0.38h of tmax. Our study suggests that HM administration enables local delivery of a therapeutic dose of PE to the anal sphincter muscle layer with less pain. This new treatment has great potential as a clinical application because of the ease of the procedure, minimal pain, and dose-dependent response.

[1]  Mark R Prausnitz,et al.  Infusion pressure and pain during microneedle injection into skin of human subjects. , 2011, Biomaterials.

[2]  H. Andreyev,et al.  Topical phenylephrine in the treatment of radiation-induced faecal incontinence. , 2005, Clinical oncology (Royal College of Radiologists (Great Britain)).

[3]  P. Bossuyt,et al.  Impact of faecal incontinence severity on health domains , 2005, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[4]  Wijaya Martanto,et al.  Mechanism of fluid infusion during microneedle insertion and retraction. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[5]  M. A. Kamm,et al.  Randomized controlled trial of topical phenylephrine in the treatment of faecal incontinence , 2000, The British journal of surgery.

[6]  M. Crowell,et al.  Impact of Anal Incontinence on Psychosocial Function and Health-Related Quality of Life , 2007, Digestive Diseases and Sciences.

[7]  William Simon,et al.  Mathematical Techniques for Biology and Medicine , 1978 .

[8]  R. Nelson.  Epidemiology of fecal incontinence. , 2004, Gastroenterology.

[9]  Jung Ho Park,et al.  Local transdermal delivery of phenylephrine to the anal sphincter muscle using microneedles. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[10]  M. Cuesta,et al.  Anal sphincter repair improves anorectal function and endosonographic image , 1996, Diseases of the colon and rectum.

[11]  R. Allman,et al.  Prevalence and Correlates of Fecal Incontinence in Community‐Dwelling Older Adults , 2005, Journal of the American Geriatrics Society.

[12]  Duck-Woo Kim,et al.  The efficacy and adverse effects of topical phenylephrine for anal incontinence after low anterior resection in patients with rectal cancer , 2007, International Journal of Colorectal Disease.

[13]  J. R. Roberts,et al.  Epinephrine absorption in children with a history of anaphylaxis. , 1998, The Journal of allergy and clinical immunology.

[14]  F. Pesce,et al.  Prevalence of urinary incontinence among institutionalized patients: a cross-sectional epidemiologic study in a midsized city in northern Italy. , 2000, Urology.

[15]  S. Whitesall,et al.  Comparison of simultaneous measurement of mouse systolic arterial blood pressure by radiotelemetry and tail-cuff methods. , 2004, American journal of physiology. Heart and circulatory physiology.

[16]  M. Prausnitz,et al.  Minimally invasive insulin delivery in subjects with type 1 diabetes using hollow microneedles. , 2009, Diabetes technology & therapeutics.

[17]  Roger J Marshall,et al.  The Prevalence of Fecal Incontinence in Community-Dwelling Adults: A Systematic Review of the Literature , 2004, Diseases of the colon and rectum.

[18]  A. Wald.  Fecal Incontinence in Adults , 2007 .

[19]  S. Furner,et al.  Community-based prevalence of anal incontinence. , 1995, JAMA.

[20]  E. Ehrenpreis,et al.  Pharmacotherapy for Fecal Incontinence: A Review , 2007, Diseases of the colon and rectum.

[21]  Y. Scarlett.  Medical management of fecal incontinence. , 2004, Gastroenterology.

[22]  Mark R. Prausnitz,et al.  Effect of Microneedle Design on Pain in Human Volunteers , 2008, The Clinical journal of pain.