Comparative permeability of various chemical markers through human vaginal and buccal mucosa as well as porcine buccal and mouth floor mucosa

doi:10.1016/j.archoralbio.2003.12.002

Archives of Oral Biology

Volume 49, Issue 5, May 2004, Pages 387-392

https://doi.org/10.1016/j.archoralbio.2003.12.002 Get rights and content

Abstract

A number of drugs undergo extensive first-pass metabolism after oral administration, necessitating large doses for effective therapeutic responses in the body. Buccal administration of drugs is becoming more popular because the drugs diffuse into the systemic circulation directly, circumventing the first-pass metabolism. Lower concentrations thus need to be administered and side effects may be minimized. In this study, one of the classic models for human buccal permeability, i.e. the porcine buccal mucosal model, is compared with the more recent human vaginal model and both these are in turn further compared to porcine mouth floor mucosa. To determine the permeability of the different markers (arecoline, 17β-estradiol, water and vasopressin), a continuous flow-through perfusion system was used (20 °C, 24 h). Mean steady state flux values were compared statistically using a t-test at a significance level of 5%. Porcine buccal mucosa showed a consistently lower permeability towards all the markers than the other mucosae tested. Porcine mouth floor mucosa was found to be more permeable than porcine buccal mucosa. From these studies we concluded that human vaginal and porcine mouth floor mucosae were superior models for human buccal mucosa than porcine buccal mucosa, using in vitro permeability studies with various chemical markers.

Introduction

Over the last decade, interest in delivering drugs via the oral mucosa has increased. When therapeutic agents are administered via the buccal route, hepatic first-pass metabolism and degradation in the gastrointestinal tract are circumvented and the drugs are made available directly to the systemic circulation. Other advantages of this route of drug administration include termination of drug delivery when this is required and ease of administration.1., 2., 3., 4.

Because human buccal mucosa is difficult to obtain in sufficient quantities for in vitro permeability studies, we developed the human vaginal/buccal mucosal model.⁵ The use of human vaginal mucosa as an in vitro permeability model has shown to be, in our laboratory, very successful with respect to various chemical compounds.5., 6., 7., 8., 9., 10., 11. The advantages of using human vaginal mucosa, are that sufficient quantities can be obtained on an ongoing basis following standard hysterectomy procedures and that the permeability and histological characteristics are very similar to human buccal mucosa.¹²

Buccal mucosa from various animals e.g. rabbits,13., 14. dogs,¹⁵ monkeys,¹⁶ hamsters17., 18. and pigs19., 20., 21., 22., 23., 24., 25., 26., 27. as well as cells grown in culture (TR 146)28., 29., 30., 31., 32., 33. have been used as models for human buccal mucosa in in vitro permeability experiments. Porcine buccal mucosa, however, has been used as a representative model for human buccal mucosa most frequently by various leading research groups throughout the world,19., 20., 21., 22., 23., 24., 25., 26., 27. when compared to the other animal models. Porcine buccal and mouth floor mucosa as well as human buccal mucosa are all non-keratinised tissue2., 18., 27., 28., 29., 30., 31., 32., 33., 34., 35., 36. while human vaginal mucosa may sometimes be keratinised to a limited degree.¹² Concern has been raised as to whether the human vaginal/buccal permeability model is as representative a model as the porcine buccal/human buccal permeability model. To address this concern, it was decided to compare the permeabilities of the two models to various chemical compounds (water, 17β-estradiol, arecoline and vasopressin) of differing molecular size and lipophilicity. Water is a standard marker used in these studies. Estradiol, a hormone that is rapidly broken down by first-pass metabolism, was chosen specifically because buccal absorption ensures direct entry into the blood with minimal gastrointestinal/hepatic degradation. Arecoline is a potentially deleterious compound found in various substances (betel nut) chewed by specific populations all over the world. Vasopressin is a small peptide, degraded easily by gastrointestinal enzymes when it is administered via the oral route.

Because previous studies have shown that porcine mouth floor mucosa is more permeable than porcine buccal mucosa,2., 37. the possibility of using porcine mouth floor mucosa as a representative model for human buccal mucosa was also investigated.

The aim of the present study was therefore to compare the in vitro permeability characteristics of the four mucosae to water, 17β-estradiol, arecoline and vasopressin and to determine whether the use of human vaginal mucosa was as effective and as representative a model for human buccal mucosa, as porcine buccal mucosa.

Section snippets

Vaginal mucosa

Specimens were obtained from excess tissue removed from two postmenopausal patients, ages 60 and 68 years, following vaginal hysterectomies at the Louis Leipoldt and Panorama Mediclinic Hospitals, Bellville, South Africa.

Human buccal mucosa

Specimens were obtained from excess tissue removed from 13 patients, mean age 30±13 S.D. (range: 17–66) year, after trimming of tissue during open reduction of mandibular fractures at the Oral and Dental Teaching Hospital of the University of Stellenbosch.

Porcine buccal and mouth floor mucosa

Specimens were

Results

The mean steady state flux values of water and arecoline versus time across human vaginal, human buccal, porcine buccal and porcine mouth floor mucosa are shown in Figure 1, Figure 2, respectively. The mean estimated steady state flux values of 17β-estradiol and vasopressin through the above mucosae versus time are shown in Figure 3, Figure 4, respectively. Water steady-state fluxes were obtained after approximately 12 h across human vaginal, human buccal and porcine mouth floor mucosae and 20 h

Discussion

Oral drug administration may lead to decreased bioavailability because of poor dissolution of the formulation, large scale first-pass metabolism in the liver or the gut wall, as well as possible acid degradation in the stomach.1., 2., 3., 4. Another method of administration of drugs that is becoming popular is that via the oral mucosal route. When drugs are administered by this route, many problems of the oral route are circumvented and drugs gain direct access to the systemic circulation.1., 2.

Acknowledgements

This material is based upon work supported by the National Research Foundation (NRF) under Grant number 2053880. The authors would also like to thank the University of Stellenbosch for their financial support. Special thanks are extended to the Maitland Abattoir, Maitland, Western Cape, South Africa, for the provision of porcine mucosa.

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^☆: Disclaimer: Any opinion, findings and conclusions or recommendations expressed in this material are those of the author(s) and therefore the NRF does not accept any liability thereto.

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Comparative permeability of various chemical markers through human vaginal and buccal mucosa as well as porcine buccal and mouth floor mucosa☆

Abstract

Introduction

Section snippets

Vaginal mucosa

Human buccal mucosa

Porcine buccal and mouth floor mucosa

Results

Discussion

Acknowledgements

J. Pharm. Sci.

J. Control Release

Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod.

Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod.

Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod.

Arch. Oral. Biol.

Toxicol. Lett.

Int. J. Pharm.

Comp. Biochem. Physiol. B

J. Invest Dermatol.

Arch. Oral. Biol.

J. Pharm. Sci.

J. Control Release

Int. J. Pharm.

Int. J. Pharm.

Eur. J. Pharm. Sci.

Int. J. Pharm.

Developments in buccal drug delivery

Crit. Rev. Ther. Drug Carrier Syst.

Buccal mucosa as a route for systemic drug delivery: a review

J. Pharm. Pharm. Sci.