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Current Drug Discovery Technologies

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ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

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Research Article

Long-term Stabilization of Aqueous Doxycycline Formulations, in Mucoadhesive Hydrogels for Treatment of Oral Mucosal Conditions

Author(s): Venu G.R. Patlolla, William P. Holbrook, Sveinbjorn Gizurarson* and Thordis Kristmundsdottir

Volume 17, Issue 3, 2020

Page: [376 - 386] Pages: 11

DOI: 10.2174/1570163816666190222193902

Price: $65

Abstract

Background: The main aim of this work was to develop stable (>2 years) doxycycline formulation, at clinically relevant concentrations and using clinically relevant formulation. Doxycycline has a MMP- inhibitory effects that is important for the treatment of various oral mucosal conditions. Therefore, protecting doxycycline from degradation in aqueous formulation requires halting or prevention of oxidation and epimerisation of the active compound.

Methods: Stabilizing excipients were intuitively put together to enhance the stability as a cumulative effort. A total of 30 hydrogels were compared with different types and concentrations of stability enhancing excipients, pH, storage temperatures (4, 25 and 40°C) and mucoadhesive polymers. The duration of the study was from day 1 and up to 58 months. The gelation temperature was adjusted below the actual body temperature. The complexation efficiency between the doxycycline and HPβCD was studied using the DSC, FTIR and XRPD.

Results: The majority of formulations at 4°C were highly stable by the end of 58 months and their stabilities were improved at all 3 temperatures.

Conclusion: In conclusion, it is possible to prevent doxycycline from both oxidation and epimerization in an aqueous formulation, for up to 5 years.

Keywords: Stability, doxycycline, in situ, oral mucosal, drug delivery, mucoadhesive hydrogels.

Graphical Abstract

[1]
Scully C, Porter S. Recurrent aphthous stomatitis: current concepts of etiology, pathogenesis and management Journal of oral pathology & medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 1989; 18: 21-7.
[2]
Niharika Swain JPLSPYP. Niharika Swain, Etiological Factors of Recurrent Aphthous Stomatitis: A Common Perplexity - Review Articles 2012.
[3]
Wray D, Ferguson MM, Mason DK, Hutcheon AW, Dagg JH. Recurrent aphthae: treatment with vitamin B12, folic acid, and iron. BMJ 1975; 2(5969): 490-3.
[http://dx.doi.org/10.1136/bmj.2.5969.490] [PMID: 1148667]
[4]
Baert JH, Veys RJ, Ampe K, De Boever JA. The effect of sodium lauryl sulphate and triclosan on hamster cheek pouch mucosa. Int J Exp Pathol 1996; 77(2): 73-8.
[http://dx.doi.org/10.1046/j.1365-2613.1996.00965.x] [PMID: 8762865]
[5]
Herlofson BB, Brodin P, Aars H. Increased human gingival blood flow induced by sodium lauryl sulfate. J Clin Periodontol 1996; 23(11): 1004-7.
[http://dx.doi.org/10.1111/j.1600-051X.1996.tb00528.x] [PMID: 8951628]
[6]
Lehner T, Lavery E, Smith R, van der Zee R, Mizushima Y, Shinnick T. Association between the 65-kilodalton heat shock protein, Streptococcus sanguis, and the corresponding antibodies in Behçet’s syndrome. Infect Immun 1991; 59(4): 1434-41.
[http://dx.doi.org/10.1128/IAI.59.4.1434-1441.1991] [PMID: 2004821]
[7]
Cimen MY, Kaya TI, Eskandari G, Tursen U, Ikizoglu G, Atik U. Oxidant/antioxidant status in patients with recurrent aphthous stomatitis. Clin Exp Dermatol 2003; 28(6): 647-50.
[http://dx.doi.org/10.1046/j.1365-2230.2003.01415.x] [PMID: 14616834]
[8]
Brice SL. Clinical evaluation of the use of low-intensity ultrasound in the treatment of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83(1): 14-20.
[http://dx.doi.org/10.1016/S1079-2104(97)90084-6] [PMID: 9007917]
[9]
Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: a study of the comparative therapeutic effects of systemic prednisone and systemic sulodexide. Int J Dermatol 2003; 42(5): 394-7.
[http://dx.doi.org/10.1046/j.1365-4362.2003.01853.x] [PMID: 12755982]
[10]
Chadwick B, Addy M, Walker DM. Hexetidine mouthrinse in the management of minor aphthous ulceration and as an adjunct to oral hygiene. Br Dent J 1991; 171(3-4): 83-7.
[http://dx.doi.org/10.1038/sj.bdj.4807615] [PMID: 1888587]
[11]
Eisen D, Lynch DP. Selecting topical and systemic agents for recurrent aphthous stomatitis. Cutis 2001; 68(3): 201-6.
[PMID: 11579786]
[12]
Abdulrahman Hani Sabbagh MFF. Therapeutic management of recurrent aphthous stomatitis: A review of the growing knowledge. Annals of International Medical and Dental Research 2016; 2
[13]
Häyrinen-Immonen R, Sorsa T, Nordström D, Malmström M, Konttinen YT. Collagenase and stromelysin in recurrent aphthous ulcers (RAU). Int J Oral Maxillofac Surg 1993; 22(1): 46-9.
[http://dx.doi.org/10.1016/S0901-5027(05)80357-1] [PMID: 8459124]
[14]
Hayrinen-Immonen R, Sorsa T, Pettila J, Konttinen YT, Teronen O, Malmstrom M. Malmstrom, Effect of tetracyclines on collagenase activity in patients with recurrent aphthous ulcers Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 1994; 23: 269-72.
[15]
Ingman T, Tervahartiala T, Ding Y, et al. Matrix metalloproteinases and their inhibitors in gingival crevicular fluid and saliva of periodontitis patients. J Clin Periodontol 1996; 23(12): 1127-32.
[http://dx.doi.org/10.1111/j.1600-051X.1996.tb01814.x] [PMID: 8997658]
[16]
Kivelä-Rajamäki M, Maisi P, Srinivas R, et al. Levels and molecular forms of MMP-7 (matrilysin-1) and MMP-8 (collagenase-2) in diseased human peri-implant sulcular fluid. J Periodontal Res 2003; 38(6): 583-90.
[http://dx.doi.org/10.1034/j.1600-0765.2003.00688.x] [PMID: 14632921]
[17]
Skulason S, Holbrook WP, Kristmundsdottir T. Clinical assessment of the effect of a matrix metalloproteinase inhibitor on aphthous ulcers. Acta Odontol Scand 2009; 67(1): 25-9.
[http://dx.doi.org/10.1080/00016350802526559] [PMID: 18991147]
[18]
Skulason S, Holbrook WP, Thormar H, Gunnarsson GB, Kristmundsdottir T. A study of the clinical activity of a gel combining monocaprin and doxycycline: a novel treatment for herpes labialis, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 2012; 41: 61-7.
[19]
Preshaw PM, Hefti AF, Jepsen S, Etienne D, Walker C, Bradshaw MH. Subantimicrobial dose doxycycline as adjunctive treatment for periodontitis. A review. J Clin Periodontol 2004; 31(9): 697-707.
[http://dx.doi.org/10.1111/j.1600-051X.2004.00558.x] [PMID: 15312090]
[20]
Shinwari MS, Tanwir F, Hyder PR, Bin Saeed MH. Host modulation therapeutics in periodontics: role as an adjunctive periodontal therapy. J Coll Physicians Surg Pak 2014; 24(9): 676-84.
[PMID: 25233975]
[21]
Abernethy J. A randomized, double-blind study to evaluate the safety and efficacy of NanoDOX™ 10% doxycycline monohydrate hydrogel in diabetic adult subjects with lower extremity ulcers compared to placebo hydrogel, Clinical connection, 2014.
[22]
Gu Y, Lee H-M, Sorsa T, Simon SR, Golub LM. Doxycycline [corrected] inhibits mononuclear cell-mediated connective tissue breakdown. FEMS Immunol Med Microbiol 2010; 58(2): 218-25.
[http://dx.doi.org/10.1111/j.1574-695X.2009.00625.x] [PMID: 19909341]
[23]
Meli DN, Coimbra RS, Erhart DG, et al. Doxycycline reduces mortality and injury to the brain and cochlea in experimental pneumococcal meningitis. Infect Immun 2006; 74(7): 3890-6.
[http://dx.doi.org/10.1128/IAI.01949-05] [PMID: 16790761]
[24]
Burns FR, Stack MS, Gray RD, Paterson CA. Inhibition of purified collagenase from alkali-burned rabbit corneas. Invest Ophthalmol Vis Sci 1989; 30(7): 1569-75.
[PMID: 2545645]
[25]
Benjamin MM, Khalil RA. Matrix metalloproteinase inhibitors as investigative tools in the pathogenesis and management of vascular disease. Exp Suppl 2012; 103: 209-79.
[http://dx.doi.org/10.1007/978-3-0348-0364-9_7] [PMID: 22642194]
[26]
Solomon A, Rosenblatt M, Li DQ, et al. Doxycycline inhibition of interleukin-1 in the corneal epithelium. Invest Ophthalmol Vis Sci 2000; 41(9): 2544-57.
[PMID: 10937565]
[27]
Shlopov BV, Stuart JM, Gumanovskaya ML, Hasty KA. Regulation of cartilage collagenase by doxycycline. J Rheumatol 2001; 28(4): 835-42.
[PMID: 11327259]
[28]
Pisal SS, Paradkar AR, Mahadik KR, Kadam SS. Pluronic gels for nasal delivery of Vitamin B12. Part I: preformulation study. Int J Pharm 2004; 270(1-2): 37-45.
[http://dx.doi.org/10.1016/j.ijpharm.2003.10.005] [PMID: 14726120]
[29]
Cho HJ, Balakrishnan P, Park EK, et al. Poloxamer/cyclodextrin/chitosan-based thermoreversible gel for intranasal delivery of fexofenadine hydrochloride. J Pharm Sci 2011; 100(2): 681-91.
[http://dx.doi.org/10.1002/jps.22314] [PMID: 20803575]
[30]
Nalluri BN, Chowdary KPR, Murthy KVR, Satyanarayana V, Hayman AR, Becket G. Inclusion Complexation and Dissolution Properties of Nimesulideand Meloxicam–hydroxypropyl-β-cyclodextrin Binary Systems. J Incl Phenom Macrocycl Chem 2005; 53: 103-10.
[http://dx.doi.org/10.1007/s10847-005-1676-9]
[31]
Su W, Li Z, Lin M, et al. The effect of doxycycline temperature-sensitive hydrogel on inhibiting the corneal neovascularization induced by BFGF in rats. Graefes Arch Clin Exp Ophthalmol 2011; 249(3): 421-7.
[http://dx.doi.org/10.1007/s00417-010-1539-y] [PMID: 20953876]
[32]
Friedrich H, Nada A, Bodmeier R. Solid state and dissolution rate characterization of co-ground mixtures of nifedipine and hydrophilic carriers. Drug Dev Ind Pharm 2005; 31(8): 719-28.
[http://dx.doi.org/10.1080/03639040500216097] [PMID: 16221606]
[33]
Adriaens E, Remon JP. Mucosal irritation potential of personal lubricants relates to product osmolality as detected by the slug mucosal irritation assay. Sex Transm Dis 2008; 35(5): 512-6.
[http://dx.doi.org/10.1097/OLQ.0b013e3181644669] [PMID: 18356773]
[34]
Begay O, Jean-Pierre N, Abraham CJ, et al. Identification of personal lubricants that can cause rectal epithelial cell damage and enhance HIV type 1 replication in vitro. AIDS Res Hum Retroviruses 2011; 27(9): 1019-24.
[http://dx.doi.org/10.1089/aid.2010.0252] [PMID: 21309617]
[35]
Swati Rawat SW. Swaroop Lahoti In Situ Gel Formulation of Ornidazole for the Treatment of Periodontal Disease Current Pharma Research 2010; 1
[36]
Zhang H, Chen M, He Z, et al. Molecular modeling-based inclusion mechanism and stability studies of doxycycline and hydroxypropyl-β-cyclodextrin complex for ophthalmic delivery. AAPS PharmSciTech 2013; 14(1): 10-8.
[http://dx.doi.org/10.1208/s12249-012-9877-1] [PMID: 23160918]
[37]
Chang Y. Tetracycline stabilizing formulations. US Patent WO2010033800A22010.
[38]
Granatek AP. Tetracycline formulations stabilized by bisulfites. US Patent 3132993 1964.
[39]
Loftsson TÓ B, Fridriksdottir H, Jonsdottir S. Cyclodextrin complexation of NSAIDSs: physicochemical characteristics. Eur J Pharm Sci 1993; 1: 95-101.
[http://dx.doi.org/10.1016/0928-0987(93)90023-4]
[40]
Baboota S, Dhaliwal M, Kohli K. Physicochemical characterization, in vitro dissolution behavior, and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. preparation and properties of rofecoxib hydroxypropyl β-cyclodextrin inclusion complex: a technical note. AAPS PharmSciTech 2005; 6(1): E83-90.
[http://dx.doi.org/10.1208/pt060114] [PMID: 16353967]
[41]
Pourmokhtar M, Jacobson GA. Enhanced stability of sulfamethoxazole and trimethoprim against oxidation using hydroxypropyl-beta-cyclodextrin. Pharmazie 2005; 60(11): 837-9.
[PMID: 16320945]
[42]
Cappello B, Maio CD, Iervolino M, Miro A. Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin. J Incl Phenom Macrocycl Chem 2005; 54: 289.
[http://dx.doi.org/10.1007/s10847-005-9004-y]
[43]
Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: an updated review. AAPS PharmSciTech 2005; 6(2): E329-57.
[http://dx.doi.org/10.1208/pt060243] [PMID: 16353992]
[44]
Liu YR, Luhua YM. Qu, Yunzhi, Study on antiageing of doxycycline hydrochloride dropping pills. Heilongjiang Yiyao 2009; 22: 785-8.
[45]
Jawad R, Drake AF, Elleman C, et al. Stability of sugar solutions: a novel study of the epimerization kinetics of lactose in water. Mol Pharm 2014; 11(7): 2224-38.
[http://dx.doi.org/10.1021/mp400509t] [PMID: 24815988]
[46]
Hudson CS. Further studies on the forms of milk-sugar. J Am Chem Soc 1908; 30: 1767-83.
[http://dx.doi.org/10.1021/ja01953a015]
[47]
Jenness R, Marth EH, Wong NP, Keeney M. Fundamentals of Dairy Chemistry. Springer 1988.
[48]
Vijayabala GS, Kalappanavar AN, Annigeri RG, Sudarshan R, Shettar SS. Single application of topical doxycycline hyclate in the management of recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 116(4): 440-6.
[http://dx.doi.org/10.1016/j.oooo.2013.06.015] [PMID: 24035110]

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