Interpolymer Complexes Based on Carbopol^® and Poly(2-ethyl-2-oxazoline) as Carriers for Buccal Delivery of Metformin

Introduction. Buccal drug delivery has a number of advantages over oral administration: ease of application, good blood supply to the buccal mucosa, drug can enter the systemic circulation directly, avoiding the "first pass effect through the liver", and are not exposed to the acidic environment of the gastric juice and the destructive action of digestive enzymes. The use of interpolymer complexes (IPCs) makes it possible not only to ensure adhesion to the mucosal membranes of the oral cavity, but also to achieve a prolonged release of drugs.

Aim. Development of carriers based on interpolymer complexes using Carbopol^® 971 NF (C971) and poly(2-ethyl-2-oxazoline) (POZ) of different molecular weights for buccal delivery of metformin (MF).

Materials and methods. The study of IPC adhesion was carried out using a TA.XTplus texture analyzer (Stable Micro Systems, UK); mucin compacts with a diameter of 13 mm were used as a substrate; these were prepared by compressing porcine gastric mucin powder using a manual hydraulic press for IR spectroscopy (PerkinElmer, USA) at a pressure of 2.45 MPa. The study of the swelling capacity was carried out by placing polymer matrices in an artificial saliva medium, with constant thermostating at a temperature of 37.0 ± 0.5 °C for 5 hours. The study of the release of MF from the matrices based on IPC was carried out using a DFZ II apparatus (Erweka, Germany) according to the Flow Through Cell method (USP IV) with cells for tablets (22.6 mm) and adaptors for ointments, creams and gels in a medium simulating saliva. The concentration of MF in the samples from the dissolution tests was determined with UV-spectrophotometry (Lambda, PerkinElmer, USA) at 232.8 nm.

Results and discussion. In a comparative study of the mucoadhesive properties of polymer samples, IPC compacts showed a mucoadhesion capacity comparable to that of poly(2-ethyl-2-oxazoline); at the same time, compacts from physical mixtures (PM) and C971 are inferior in terms of the separation force to IPC samples, however, POZes dissolve in an artificial saliva medium, that is, they are not suitable as dosage forms for buccal delivery. For 5 hours of the experiment to assess the swelling capacity, the IPC matrices did not change significantly, which can ensure their comfortable use as carriers for buccal delivery. When evaluating the release of metformin from polymer matrices (with weight ratio MF/IPC 1: 0.5), the most complete release (more than 90 %) is observed from both IPC matrices compared to matrices of PM and individual polymers.

Conclusion. Polycomplex matrix systems based on C971-POZ (50 kDa) and C971-POZ (500 kDa) are suitable for buccal delivery of metformin.

1. Pather S. I., Rathbone M. J., Senel S. Current status and the future of buccal drug delivery systems. Expert Opinion on Drug Delivery. 2008;5(5):531–542.

2. Khutoryanskiy V. V. Advances in Mucoadhesion and Mucoadhesive Polymers. Macromolecular Bioscience. 2011;11:748–764.

3. Tan Y. T., Peh K. K., Al-Hanba O. Investigation of interpolymer complexation between Carbopol and various grades of polyvinylpyrrolidone and effects on adhesion strength and swelling properties. Journal of Pharmacy & Pharmaceutical Sciences. 2001;4:7–14.

4. Nguyen H. V., Nguyen V. H., Lee B.-J. Dual release and molecular mechanism of bilayered aceclofenac tablet using polymer mixture. International Journal of Pharmaceutics. 2016;515:233–244.

5. Satoh K., Takayama K., Machida Y., Suzuki Y., Nakagaki M., Nagai T. Factors affecting the bioadhesive properties property of tablets consisting of hydroxypropyl cellulose and carboxyvinyl polymer. Chemical and Pharmaceutical Bulletin. 1989;37:1366–1368.

6. Takayama K., Nagai T. Application of interpolymer complexation of polyvinylpyrrolidone/carboxyvinyl polymer to control of drug release. Chemical and Pharmaceutical Bulletin. 1987;35(12):4921–4927.

7. Nurkeeva Z. S., Mun G. A., Dubolazov A. V., Khutoryanskiy V. V. pH-effects on the complexation, miscibility and radiation-induced cross-linking in poly(acrylic acid)-poly(vinyl alcohol) blends. Macromolecular Bioscience. 2005;5:424–432.

8. Nurkeeva Z. S., Mun G. A., Khutoryanskiy V. V., Bitekenova A. B., Dubolazov A.V., Esirkegenova S.Zh. pH effects in the formation of interpolymer complexes between poly(N-vinylpyrrolidone) and poly(acrylic acid) in aqueous solutions. The European Physical Journal E. 2003;10:65-68.

9. Mustafin R. I., Semina I. I., Garipova V. A., Bukhovets A. V., Sitenkov Y. A., Salakhova A. R., Gennari C. G. M., Cilurzo F. Comparative study of polycomplex oral drug delivery systems based on CarbopolTM and oppositely charged polyelectrolytes. Himiko-farmacevticheskij zhurnal = Pharmaceutical Chemistry Journal. 2015;49(1):3–8. (In Russ.). DOI: 10.30906/0023-1134-2015-49-1-3-8.

10. Garipova V. R., Gennari C. G. M., Selmin F., Cilurzo F., Moustafine R. I. Mucoadhesive Interpolyelectrolyte Complexes for the Buccal Delivery of Clobetasol. Polymers. 2018;10(2):85. DOI:10.3390/polym10010085.

11. Gordeeva D. S., Sitenkova (Bukhovets) A. V., Moustafine R. I. Interpolyelectrolyte complexes based on Eudragit® copolymers as carriers for bioadhesive gastroretentive metronidazole delivery system. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2020;9(2):72–76. (In Russ.). DOI: 10.33380/2305-2066-2020-9-2-72-76.

12. Moustafine R. I., Budnikov V. V., Abdullina S. G., Nasibullin S. F., Saleev R. A. Polycomplex carrier for buccal mucoadhesion delivery of metronidazole. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2020;9(2):83–90. (In Russ.). DOI: 10.33380/2305-2066-2020-9-2-83-90.

13. Moustafine R. I., Viktorova A. S., Khutoryanskiy V. V. Interpolymer complexes of Carbopol® 971 and poly(2-ethyl-2-oxazoline): Physicochemical studies of complexation and formulations for oral drug delivery. International Journal of Pharmaceutics. 2019;558;53– 62. DOI: 10.1016/j.ijpharm.2019.01.002.

14. Ruiz-Rubio L., Alonso M. L., Pérez-Álvarez L., Alonso R. M., Vilas J. L., Khutoryanskiy V. V., Formulation of Carbopol®/Poly(2-ethyl-2-oxazoline)s mucoadhesive tablets for buccal delivery of hydrocortisone. Polymers. 2018;10(2):175. DOI: 10.3390/polym10020175.

15. Kharenko E. A., Larionova N. I., Demina N. B. Mucoadhesive drug delivery systems. Himiko-farmacevticheskij zhurnal = Pharmaceutical Chemistry Journal. 2009;43(4):21–29. (In Russ.). DOI: 10.30906/0023-1134-2009-43-4-21-29.

16. Hoogenboom R. Poly(2-oxazoline)s: A polymer class with numerous potential applications. Angewandte Chemie International Edition. 2009;48:7978–7994. DOI: 10.1002/anie.200901607.

17. Khutoryanskiy V. V. Beyond PEGylation: alternative surface-modification of nanoparticles with mucus-inert biomaterials. Advanced Drug Delivery Reviews. 2018;124:140–149. DOI: 10.1016/j.addr.2017.07.015.

18. Claeys B., Vervaeck A., Vervaet C., Remon J. P., Hoogenboom R., De Geest B. G. Poly(2-ethyl-2-oxazoline) as matrix excipient for drug formulation by hot melt extrusion and injection molding. Macromolecular Rapid Communications. 2012;33:1701–1707. DOI: 10.1002/marc.201200332.

19. Fael H., Rafols C., Demirel A. L. Poly(2-ethyl-2-oxazoline) as an alternative to poly(vinylpyrrolidone) in solid dispersions for solubility and dissolution rate enhancement of drugs. Journal of Pharmaceutical Sciences. 2018;107:2428–2438. DOI: 10.1016/j.xphs.2018.05.015.

20. Shan X., Williams A. C., Khutoryanskiy V. V. Polymer structure and property effects on solid dispersions with haloperidol: poly(N-vinyl pyrrolidone) and poly(2-oxazolines) studies. International Journal of Pharmaceutics. 2020;590:119884.

21. Morales J. O., McConville J. T. Manufacture and characterization of mucoadhesive buccal films. European Journal of Pharmaceutics and Biopharmaceutics. 2011;77:187–199.

22. Kamel R., Mahmoud A., El-Feky G. Double-phase hydrogel for buccal delivery of tramadol. Drug Development and Industrial Pharmacy. 2012;38(4):468–483.

23. Abruzzo A., Bigucci F., Cerchiara T., Cruciani F., Vitali B., Luppi B. Mucoadhesive chitosan/gelatin films for buccal delivery of propranolol hydrochloride. Carbohydrate Polymers. 2012;87:581–588.

24. Kianfar F., Ayensu I., Boateng J. S. Development and physico-mechanical characterization of carrageenan and poloxamer-based lyophilized matrix as a potential buccal drug delivery system. Drug Development and Industrial Pharmacy. 2013. DOI: 10.3109/03639045.2012.762655

25. Mustafin R. I., Bukhovets A. V., Protasova A. A., Shaykhramova R. N., Sitenkov A. Y., Semina I. I. Comparative investigation of polycomplex systems for gastroretentive metformin delivery. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2015;1(10):48–51. (in Russ.).

26. Çelik B. Resperidone mucoadhesive buccal tablets: formulation design, optimization and evaluation. Drug Design, Development and Therapy. 2017;11:3355–3365. DOI: 10.2147/DDDT.S150774.

27. Esim O., Savaser A., Ozkan C. K., Bayrak Z., Tas C., Ozkan Y. Effect of polymer type on characteristics of buccal tablets using factorial design. Saudi Pharmaceutical Journal. 2018;26:53–63. DOI: 10.1016/j.jsps.2017.10.013

28. Ambrogi V., Rubini D., Giovagnoli S., Ricci M., Blasi P., Rossi C. Novel mucoadhesive buccal formulation containing metronidazole for the treatment of periodontal disease. Journal of Controlled Release. 2004;95(3):521–533. DOI:10.1016/j.jconrel.2003.12.018.

29. Peddapalli H., Bakshi V., Boggula N. Formulation, in vitro and ex vivo characterization of mucoadhesive buccal tablets for antihypertensive drug. Asian Journal of Pharmaceutical and Clinical Research. 2018;11(8):402–411. DOI: 10.22159/ajpcr.2018.v11i8.26126.

30. Wang K., Liu T., Lin R., Liu B., Yang G., Bu X., Wang W., Zhang P., Zhou L., Zhang J. Preparation and in vitro release of buccal tablets of naringenin-loaded MPEG-PCL nanoparticles. RSC Advances. 2014;4:33672–33679. DOI: 10.1039/c4ra04920a.

31. Kirzhanova E. A., Khutoryanskiy V. V., Balabushevich N. G., Kharenko A. V., Demina N. B. Methods for analysis of mucoadhesion: from basic research to practical applications in dosage forms development. Razrabotka i registratsiya lekarstvennykh sredstv = Drug development & registration. 2014;3(8):66–80. (In Russ.).