DEVELOPMENT AND EVALUATION OF BIOADHESIVE MUCOSAL DOSAGE FORMS OF PILOCARPINE HCL FOR XEROSTOMIA THERAPY

Abstract

Objective: Saliva maintains vital mouth functions and acts as a barrier to dental health. Xerostomia, which is characterised as a feeling of dry mouth, adversely affects the patient’s quality of life. Palliative therapies, such as sialagogues, form the based on treatment of xerostomia. The FDAapproved sialagogue pilocarpine is currently recommended as the firstline medication for patients. Owing to its wide range of action, oral pilocarpine users may experience several negative side effects. The purpose of this study was to increase the duration of action and prevent systemic side effects of pilocarpine hydrochloride by designing and evaluating prolonged-release formulations of the drug using either xanthan gum, hydroxyethyl cellulose, or a combination of these two natural polymers buccal bioadhesive films. Material and Methods: The films were analysed for their physicochemical, mechanical, bioadhesive, swelling, in vitro release, and in vitro cytotoxicity. Results: Physicochemical and mechanical feature examinations revealed that the Xanthan-HEC combinations showed better results compared to the single polymer-used formulations. The in vitro dissolving profiles of all the optimal formulations showed a sustained release pattern with a steady-state plateau after an initial fast release. Using various release kinetic models to assess drug release kinetics revealed that the Higuchi and Korsmeyer-Peppas correlations are primarily followed by drug release from buccal films. Conclusion: The findings show that the mucoadhesive buccal formulation is a viable method for pilocarpine localised distribution that is both safe and effective in treating xerostomia. Further in vivo studies are planned to assess the pharmacokinetic and histopathological effects of the formulation.

Keywords

• Buccal delivery
• buccal film
• pilocarpine hydrochloride
• sialogogues
• xerostomia

KSEROSTOMİ TEDAVİSİ İÇİN PİLOKARPİN HCL’NİN BİYOADEZİF MUKOZAL DOZAJ FORMLARININ GELİŞTİRİLMESİ VE DEĞERLENDİRİLMESİ

Abstract

Amaç: Tükürük salgısı hem ağız içi fonksiyonları hem de diş sağlığını koru maktadır. Bu nedenle ağız kuruluğu hissi ile karakterize olan kserostomi durumu hastanın yaşam kalitesini olumsuz yönde etkilemektedir. Sialagoglar gibi palyatif tedaviler, kserostominin tedavisinin temelini oluş turmaktadır. Mevcut hastalar için birinci basamak ilaç tedavisi olarak, Amerikan ilaç ve Gıda Dairesi tarafından onaylı pilokarpin HCl önerilmek tedir. Oral yoldan pilokarpin kullanımı, geniş etki yelpazesi nedeniyle çeşitli olumsuz yan etkinin ortaya çıkmasına neden olabilmektedir. Çalışmanın amacı, pilokarpin hidroklorürün etki süresini arttırmak ve siste mik yan etkilerini önlemek için; ksantan sakızı, hidroksietil selüloz veya bu iki doğal polimerin kombinasyonunun kullanıldığı bukkal biyoadhezif film lerinin hazırlanması ve ilacın uzun süreli salınımını sağlayan formülasyon larının tasarlanıp değerlendirilmesidir. Gereç ve Yöntemler: Bukkal filmler; fizikokimyasal, mekanik, biyoadheziflik, şişme, in vitro salım ve in vitro sitotoksisite açısından analiz edimiştir. Bulgular: Fizikokimyasal ve mekanik özellikler Ksantan-HEC kombinasyonlarının tek polimerin kullanıldığı formülasyonlara göre daha iyi sonuçlar verdiğini göstermiştir. Tüm optimal formülasyonların in vitro çözünürlük profilleri, başlangıçtaki hızlı salımdan sonra kararlı durum platosuyla birlikte sürekli salım modeli göstermiştir. İlaç salım kinetiğini değerlendirmek için kullanılan çeşitli salım kinetik modelleri öncelikli Higuchi ve KorsmeyerPeppas korelasyonlarının gerçekleştiğini bukkal filmlerden ilaç salımının takip ettiğini göstermiştir. Sonuç: Bulgular mukoadezif bukkal formülasyonun lokalize dağılımı için pilokarpinin kserostomi tedavisinde hem güvenli hem de etkili olarak uygulanabilir bir yöntem olduğunu göstermektedir. İleri çalışmalar olarak formülasyonun farmakokinetik ve histopatolojik etkilerini değerlendirmek için in vivo deneyler planlanmaktadır.

Keywords

• Bukkal uygulama
• bukkal film
• pilokarpin hidroklorür
• sialagog
• kserostomi

References

1. Salum FG, Medella-Junior FAC, Figueiredo MAZ, Cherubini K. Salivary hypofunction: An update on therapeutic strategies. Gerodontology 2018;35(4):305-16. google scholar
2. Nakagawa Y. Management of dry mouth in Sjögren’s syndrome. Japanese Dental Science Review 2011;47(2):115-23. google scholar
3. Malallah OS, Garcia CMA, Proctor GB, Forbes B, Royall PG. Buccal drug delivery technologies for patient-centred treatment of radiation-induced xerostomia (dry mouth). Int J Pharm 2018;541(1-2):157-66. google scholar
4. Shipp L, Liu F, Kerai-Varsani L, Okwuosa TC. Buccal films: A review of therapeutic opportunities, formulations & relevant evaluation approaches. J Controlled Release 2022;352:1071-92. google scholar
5. Yildiz Pekoz A, Sedef Erdal M, Okyar A, Ocak M, Tekeli F, Kaptan E, et al. Preparation and in-vivo evaluation of dimenhydrinate buccal mucoadhesive films with enhanced bioavailability. Drug Dev Ind Pharm 2016;42(6):916-25. google scholar
6. Dinte E, Muntean DM, Andrei V, Boşca BA, Dudescu CM, Barbu-Tudoran L, et al. In Vitro and In Vivo Characterisation of a Mucoadhesive Buccal Film Loaded with Doxycycline Hyclate for Topical Application in Periodontitis. Pharmaceutics 2023;15(2):580. google scholar
7. Rençber S, Karavana SY, Yilmaz FF, Eraç B, Nenni M, Gurer-Orhan H, et al. Formulation and evaluation of fluconazole loaded oral strips for local treatment of oral candidiasis. J Drug Delivery Sci Tech 2019;49:615-21. google scholar
8. Nafee NA, Ismail FA, Boraie NA, Mortada LM. Mucoadhesive buccal patches of miconazole nitrate: in vitro/in vivo performance and effect of ageing. Int J Pharmaceutics 2003;264(1):1-14. google scholar

9. Nair AB, Al-Dhubiab BE, Shah J, Vimal P, Attimarad M, Harsha S. Development and evaluation of palonosetron loaded mucoadhesive buccal films. J Drug Delivery Sci Tech 2018;47:351-8. google scholar
10. Desai SD, Blanchard J. A Simplified and Rapid High-Performance Liquid Chromatographic Assay for Pilocarpine Hydrochloride*. J Chromatographic Sci 1992;30(4):149-52. google scholar
11. Kalapathy U, Proctor A, Shultz J. Production and properties of flexible sodium silicate films from rice hull ash silica. Bioresource Tech 2000;72(2):99-106. google scholar
12. Coşkunmeriç N, Üstündağ Okur N, Okur ME, Ayla Ş, Yoltaş A, Karavana SY. Promising nanogels loaded with usnic acid for oral ulcer treatment: development, characterization, and in vivo evaluation in rabbits. Pharmaceutical Development Tech 2021;26(4):431-43. google scholar
13. Peh KK, Wong CF. Polymeric films as vehicle for buccal delivery: swelling, mechanical, and bioadhesive properties. J Pharm Pharm Sci 1999;2(2):53-61. google scholar
14. Arslan D, Akbal Dağıstan Ö, Sagirli O, Mulazimoglu L, Cevher E, Yildiz-Pekoz A. Development and Evaluation of Combined Effect Buccal Films for Treatment of Oral Candidiasis. AAPS PharmSciTech 2022;24(1):23. google scholar
15. Higuchi T. Rate of Release of Medicaments from Ointment Bases Containing Drugs in Suspension. J Pharmaceutical Sci 1961;50(10):874-5. google scholar
16. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of potassium chloride release from compressed, hydrophilic, polymeric matrices: effect of entrapped air. J Pharm Sci 1983;72(10):1189-91. google scholar
17. Peppas NA. Analysis of Fickian and non-Fickian drug release from polymers. Pharm Acta Helv 1985;60(4):110-1. google scholar
18. Nazlı H, Mesut B, Akbal-Dağıstan Ö, Özsoy Y. A Novel Semi-Solid Self-Emulsifying Formulation of Aprepitant for Oral Delivery: An In Vitro Evaluation. Pharmaceutics 2023;15(5). google scholar
19. Abu-Huwaij R, Assaf S, Salem M, Sallam A. Mucoadhesive Dosage form of Lidocaine Hydrochloride: I. Mucoadhesive and Physicochemical Characterization. Drug Development and Industrial Pharmacy 2007;33(8):855-64. google scholar
20. Nair AB, Kumria R, Harsha S, Attimarad M, Al-Dhubiab BE, Alhaider IA. In vitro techniques to evaluate buccal films. J Control Release 2013;166(1):10-21. google scholar
21. Nair AB, Al-ghannam AA, Al-dhubiab BE, Hasan AA. Mucoadhesive Film Embedded with Acyclovir Loaded Biopolymeric Nanoparticles: In vitro Studies. J Young Pharmacists 2017;9:100-5. google scholar
22. Khan S, Trivedi V, Boateng J. Functional physico-chemical, ex vivo permeation and cell viability characterization of omeprazole loaded buccal films for paediatric drug delivery. Int J Pharmaceutics 2016;500(1):217-26. google scholar
23. Weyermann J, Lochmann D, Zimmer A. A practical note on the use of cytotoxicity assays. Int J Pharm 2005;288(2):369-76. google scholar
24. Singh M, Tiwary AK, Kaur G. Investigations on interpolymer complexes of cationic guar gum and xanthan gum for formulation of bioadhesive films. Res Pharm Sci 2010;5(2):79-87. google scholar
25. Kapoor D, Maheshwari R, Verma K, Sharma S, Ghode P, Tekade RK. Chapter 14 - Coating technologies in pharmaceutical product development. In: Tekade RK, editor. Drug Delivery Systems: Academic Press; 2020. p. 665-719. google scholar
26. Pamlenyi K, Kristo K, Sovany T, Regdon G, Jr. Development and evaluation of bioadhesive buccal films based on sodium alginate for allergy therapy. Heliyon 2022;8(8):10364. google scholar
27. Ghosh S, Seelbinder B, Henderson JT, Watts RD, Scott AK, Veress AI, et al. Deformation Microscopy for Dynamic Intracellular and Intranuclear Mapping of Mechanics with High Spatiotemporal Resolution. Cell Rep 2019;27(5):1607-20.4. google scholar
28. Akash MSH, Khan IU, Shah SNH, Asghar S, Massud A, Qadir M, et al. Sustained release hydrophilic matrices based on xanthan gum and hydroxypropyl methylcellulose: development, optimization, in vitro and in vivo evaluation. J Applied Pharm 2010;2:89-103. google scholar
29. Jadav M, Pooja D, Adams DJ, Kulhari H. Advances in Xanthan Gum-Based Systems for the Delivery of Therapeutic Agents. Pharmaceutics 2023;15(2). google scholar
30. Perioli L, Ambrogi V, Angelici F, Ricci M, Giovagnoli S, Capuccella M, et al. Development of mucoadhesive patches for buccal administration of ibuprofen. J Control Release 2004;99(1):73-82. google scholar