Table 1.

Drug delivery systems for treatment of bacterial infection-related conditions in the oral cavity

Drug	Target	Delivery system	Ingredients	In vitro studies	In vivo studies	Results	Reference
Antimicrobials
Ampicillin and metronidazole	Oral mucosa	Fiber	Polylactide	- Antibacterial activity agar diffusion assay - Cytocompatibility human gingival fibroblasts	-	- Antibacterial effect against A. actinomycetemcomitans, F. nucleatum, P. gingivalis and E. Faecalis - No cytotoxic effect	[183]
Cefuroxime axetil	Oral mucosa	Mono and bilayered film and wafer	Chitosan and HPMC	- Drug release Franz diffusion cells - Antimicrobial activity agar disk diffusion method	-	- Prolonged release adhesive chitosan backing layer and HPMC based drug loaded layer with suitable mucoadhesion - Increased antimicrobial activity against E. coli and S. aureus	[182]
Chlorhexidine digluconate	Oral mucosa Periodontal pocket	Film, gel	Chitosan, TPP, glycerin, lactic acid	- Mucoadhesion Texture analyzer (porcine buccal mucosa) - Antimicrobial activity blood agar plates	-	- Suitable mucoadhesion - Enhanced antimicrobial activity against Porphyromonas gingivalis in presence of chitosan	[87]
Chlorhexidine	Oral cavity	Mouthwash	Chitosan	-	Healthy volunteers - Plaque index, gingival index Quickley–Hein plaque index (QPI), probing depth -Antimicrobial activity on dental plaques Agar diffusion	- Significant reduction in clinical parameters in presence of chitosan - Enhanced antimicrobial effect against S. mutans or enterococci in presence of chitosan -	[184]
Chlorhexidine	Tooth surface	Varnish	- Ethyl cellulose and poly ethylene glycol in ethanol	-	Orthodontic patients (10 -16 year-old) - Antimicrobial activity in sputum samples of orthodontic patients	- A significant decrease in S mutans levels for 3 weeks - No significant change in Actinomyces viscosus levels	[185]
Chlorhexidine/thymol	Tooth root surface	Varnish	Vinyl acetate co-polymer and acrylate co-polymer Ethanol or ethyl acetate as solvents	- Antibacterial activity (agar difussion assay)	- Patients (35 and 55 year-old) with one tooth with buccal gingival recession of 1–2 mm and initial root caries (between)	- Significant reduction in Streptococci and Lactobacilli in supragingival plaque - Stronger antibacterial activity against A.actinomycetemcomitans with ethyl acetate when compared to ethanol as a solvent - Highest activity against strains: P. gingivalis and Fusobacterium Nucleatum	[186]
Chlorhexidine and diclofenac sodium Chlorhexidine and Betamethasone Chlorhexidine and Lidocaine	Buccal mucosa	Film	HPMC, PEG 400 and Carbopol 917	- Anti-inflammatory activity prostaglandin E2 levels - Antibacterial activity - Cytotoxicity test HaCaT keratinocyte cell line	-	- Anti-inflammatory activity by reducing prostaglandin E2 levels - Antibacterial activity against planktonic and biofilm bacteria - No cytotoxic effect	[176]
Doxycycline	Periodontal pocket	Nanoparticle loaded gel	Nanoparticles: chitosan Gel: PVA, PVP, glycerol and PEG 400	-	- Patients with moderate chronic periodontitis - IL-6 and TNF-a levels in gingival crevicular fluid	- Reduced probing pocket depth - Decreased levels of IL6 and TNF-a	[156]
Doxycycline	Subgingival placement	Strip	Methylcellulose	-	- Patients with inflammatory periodontal disease - Gingival index, probing depth, attachment loss, and gingival shrinkage - Microbiological evaluation in subgingival fluid	- Significant decrease in clinical parameters at week 8 - Marked decrease in anaerobic count by week 10	[167]
Metronidazole	Periodontal pocket	Microcapsuleloaded hydrogel	Chitosan, PVA	- Drug release Dialysis diffusion method - Bacteriostasis activity	Ligation induced periodontitis in Wistar rats	- Prolonged drug release - Prolonged in vitro antibacterial activity - Enhanced in vivo antibacterial activity - Reduced probing depth of the periodontal pocket	[104]
Metronidazole	Periodontal pocket	Fiber	Polylactide	- Drug release (immersing fiber in liquid medium) - Antibacterial activity agar diffusion method - Cytotoxicity human gingival fibroblasts	-	- Prolonged drug release after day 3 - Antibacterial activity against F. nucleatum, A. actinomycetemcomitans and P. gingivalis - No cytotoxic effect	[187]
Metronidazole	Periodontal pocket	Gel	Chitosan, lactic acid	-	Patients with moderate to severe chronic periodontitis - Gingival recession, plaque index, gingival index, and gingival bleeding time	- Significant decrease in clinical parameters and similar to that of a commercial gel	[86]
Metronidazole and levofloxacin	Periodontal pocket	Film	Chitosan	- Drug release Placing films in vial containing McIlvaine buffer, pH 6.6) - Antibacterial activity disc diffusion method	Patients with chronic periodontitis - Gingival index, plaque index and pocket depth	- Prolonged drug release - Significant decrease in clinical parameters - Antibacterial activity against S. aureus and E. coli	[188]
Minocycline	Periodontal pocket	In-situ forming cubic liquid crystal	Phytantriol /propylene glycol	- Drug release Dialysis membrane diffusion method	Ligation induced periodontitis in SPF rats	- Sustained release for four days - Reduction in gingival index, probing depth and alveolar bone loss	[91]
Minocycline	Periodontal pocket	Liposome	Hydrogenated soy phosphatidylcholine and cholesterol	- Cell proliferation rate MTT assay murine macrophages (ANA-1)	-	- Inhibition of the proliferation of macrophages - Stronger anti-inflammatory effects by suppression of TNF-α mRNA expression	[68]
Minocycline	Periodontal pocket	Strip	Polycaprolactone	-	Patients with chronic periodontitis - Subgingival plaque bacterial counts on day 3 (strips inserted in periodontal pocket)	Significant reduction in the proportions of C. gracillis, P. melaninogenica, and F. necrogenes by day 6	[189]
Moxifloxacin	Periodontal pocket	Nanoparticle loaded in situ gel	Nanoparticles: PLGA, PVA Gel: Poloxamer 407	- Drug release Dialysis diffusion method	- Ligation induced periodontitis in Sprague-Dawley rats - γ-scintigraphy analysis in rabbits	- Extended drug release and enhanced retention of the system - Higher efficacy with once-a-week application compared to that of twice-a-day application of a commercial gel - Almost complete recovery in 3 weeks	[156]
Moxifloxacin	Periodontal pocket	In situ gel	Poloxamer 407, Gellan gum, Carbopol 934P	- Drug release Franz diffusion cell - The antibacterial activity using agar cup method	-	- Prolonged drug release (9h) - Antimicrobial activity against S. aureus and E. coli in gel	[190]
Moxifloxacin	Oral cavity	Gel	Chitosan, Carbopol 940, HPMC	-Drug release Franz diffusion cells - Mucoadhesion Texture analyzer -Antimicrobial activity disk diffusion method	-	- Prolonged drug release - Enhanced antimicrobial activity against S. aureus and S. mutans in presence of chitosan	[96]
Tetracycline	Periodontal pocket	Nanofiber	PLGA and gum tragacanth	- Drug release (immersing membrane in PBS, pH 7.4) - Biocompatibility using Human dermal fibroblast cells - The antibacterial activity using agar plate method	-	- Sustained release for 75 days - Biocompatible - Antibacterial activity against S. aureus and P. aeruginosa	[191]
Tetracycline	Oral mucosa	Nanofiber	Chitosan and PVA	- Drug release Vial method - The antibacterial activity (using samples collected from human periodontal subgingival pocket of patients with chronic periodontitis) - Cytotoxicity analysis MTT assay (neonatal human dermal fibroblast cells)	-	- Sustained release (14 h) days - Antibacterial activity against F. nucleatum, P. micra, P. nigrescens, P. intermedia, E. nodatum, C. gracilis, C. rectus and C. showae, T. denticola, T. forsythia and P. gingivalis - No cytotoxic effect	[174]
Tetracycline	Implant surface	Nanofiber	PLA, PCL, and gelatin	- Antimicrobial activity agar diffusion assay - Murine derived osteoprecursor cell (MC3T3-E1) response	-	- Antimicrobial activity against A. actinomycetemcomitans, F. nucleatum, P. gingivalis, and P. intermedia - Significant increase in alkaline phosphatase levels indicating an osteogenic differentiation	[192]
Antiinflammatory agents
Aspirin and erythropoietin	Submucoperiosteous tissue	Hydrogel	Chitosan, β-sodium glycerophosphate, gelatin	- Drug release (adding PBS to hydrogel containing plates) - Cytotoxicity MTT assay (rat bone marrow stromal cells)	Ligature-induced periodontitis in nude mice and Wistar rats	- Sustained release for 21 days - Anti-inflammatory activity and significant periodontium regeneration - No cytotoxicity	[193]
Tenoxicam	Buccal mucosa	Film	Chitosan	- Drug release study (immersing films in artificial saliva)	Healthy volunteers - Mucoadhesion	- Controlled release for 6 h - Mucoadhesion time: 1.25 ± 0.17 h	[194]
Atorvastatin	Periodontal pocket	Gel	Base and water soluble chitosan	-	Ligature induced periodontitis in Wistar rats - Antiinflammatory and osteoclastic activity	- Enhanced anti-inflammatory effect in presence of chitosan - Bone and tissue healing after week 3 - No difference between water soluble and base chitosan	[85]
Atorvastatin and atorvastatin solid dispersions	Periodontal pocket	Gel	Base and water soluble chitosan	-Drug release Franz diffusion cells - Mucoadhesion and syringability Texture analyzer - Anti-inflammatory activity human gingival fibroblast induced cells	-	- Prolonged drug release - Suitable mucoadhesion and syringability - Decreased release of pro-inflammatory cytokines (IL-1β, IL-6, IL-8) and anti-inflammatory cytokines (IL-10, TGF-β1, TGF-β2 and TGF-β3), enhanced in presence of chitosan - No difference between atorvastatin and soluble atorvastatin solid dispersions	[195]
Natural products
Ziziphus jujuba extract	Buccal mucosa	Nanofibrous membrane	- Carbopol, polyacrylonitrile	- Drug release (immersing membrane in artificial saliva, pH 6.9) - Mucoadhesion using Universal Testing Machine -Antimicrobial activity against using the disk diffusion susceptibility test - Anti-inflammatory activity permm Permeability assay (Human umbilical vein endothelial cells-HUVEC)	-	- 80% drug release in 1h - Suitable mucoadhesion - Improved antimicrobial activity against P. gingivalis and F. nucleatum - Improved anti-inflammatory function on HUVEC	[196]
Scutellaria baicalensis and chlorhexidine	Buccal mucosa	Nanoparticle	Water-ethanol	-Antibacterial activity broth microdilution assay	-	- Inhibition of biofilms of S. mutans, S. sobrinus, F. nucleatum, and A. actinomycetemcomitans	[132]
Eucalyptol, menthol, thymol Sodium fluoride, eucalyptol, menthol, thymol	Oropharynx	Mouthwash	Alcohol, benzoic acid, methyl salicylate, poloxamer 407	- Antimicrobial activity agar plate test	- Male patients with pharyngeal gonorrhoea	- Significant reduction of total N. gonorrhoeae counts in vitro after 1-min exposure - Significantly reduced count of N. gonorrhoeae on the pharyngeal surface	[197]
Propolis	Periodontal pocket	Magnetic nanoparticle in liquid crystalline	Nanoparticle: Iron oxide Liquid crystal: Isopropyl myristate, polyoxyethylene oleyl ether	- Drug release Periodontal pocket simulator apparatus with a flow system - Antifungal activity broth macrodilution test - Cytotoxicity fibroblasts cell line (ATCC CCL-1.3)	-	- Prolonged drug release - Fungicide activity against Candida spp. - Very low cytotoxicity	[198]
Green tea Catechin	Periodontal pocket	Strip	Hydroxypropylcellulose	-	- Patients with advanced periodontitis - Antimicrobial study Gingival crevicular fluid (GCF) - The pocket depths (PD) measured using a standard periodontal probe	- Reduced pocket depth - Decrease in proportion of Prevotella spp. and P. gingivalis	[199]
Curcumin	Periodontal pocket	Sponge	Collagen	-	Patients with chronic periodontitis - Plaque index, gingival index, probing pocket depth and clinical attachment levels - microbiology N-benzoyl-DL-arginine-β-naphthylamide (BANA) test and microbial colony count	-Significant reduction in clinical and microbiological parameters, yet, lower efficacy when compared to chlorhexidine chip	[200]
Resveratrol	Periodontal pocket	Nanofiber	Polycaprolactone	- Drug release using USP Apparatus II - Morphology	-	- Rapid release in the first 4 h, followed by a prolonged release up to 12h	[201]
Royal Jelly(bee product)	Oral mucosa	Film	Chitosan and sodium alginate	- Drug release modified JP XIV dissolution apparatus	5-fluorouracil and mild abrasion induced oral mucositis in seven-week-old Golden Syrian hamsters -Myeloperoxidase activity (MPO) - Microscobic and macroscopic evaluations -Antiinflammatory activity Pro-inflammatory cytokines (TNF-α, interleukin-1β)	- Drug release for 4 h - Decrease in MPO activity - Improved recovery, on day 8 -Induction of pro-inflammatory cytokines	[202]
Miscellaneous
Metformin	Periodontal pocket	Film	Chitosan	- Drug release Vial method - Antibacterial activity disc diffusion method	Ligature induced + LPS injected periodontitis in Wistar rats	- Sustained drug release (11 days) - Antibacterial activity against P. gingivalis and T. forsythia - Effectively reduced alveolar bone destruction	[203]
Lactobacillus fermentum	Oral cavity	Film	Carboxymethylcellulose	- Probiotic bacteria release study (in simulated salivary fluid)	-	- Complete bacterial release in 4 min - Maintenance of probiotic viability and antioxidant activity	[204]
Bismuth subsalicylate	Oral mucosa	Nanoparticle		- Antibacterial activity agar diffusion - Cytotoxicity using human gingival fibroblast (HGF-1) cell line	-	- High antibacterial activity against A. actinomycetemcomitans, C. gingivalis, and P. Gingivalis - Low cytotoxicity	[136]
PolymP-n Active nanoparticles with silver and doxycycline	Coating hydroxyapatite discs	Nanoparticles	-	- Anti-biofilm activity - Antibacterial activity agar diffusion	-	- Destruction of biofilm formation - Antibacterial activity against S. oralis, A. naeslundii, V. parvula, F. nucleatum, P. gingivalis and A. actinomycetemcomitans	[205]
Fe3O4	Dentinal tubule	Liposome	PEG	- Ex-vivo evaluation in extracted human teeth	-	- Diffusion into dentinal tubules	[206]
Indocyanine green	Oral cavity	Nanosphere	PLGA, chitosan	- Antibacterial activity activity Blood agar plates	-	- Antimicrobial effect on P. gingivalis with indocyanine green ‐Nano/c with low‐level diode laser (0.5 W; 805 nm) irradiation	[150]
Pac-525(antimicrobial peptide)	Oral mucosa	Nanofiber	Composite membrane: Gelatin/Chitosan Hydroxyapatite nanoparticles Microspheres: PLGA	- Drug release study (immersing membrane in PBS, pH 7.4) - Osteogenic activity using rat bone marrow mesenchymal stem cells (rBMSCs) - The antibacterial activity using agar diffusion method	-	- A rapid release in the first 24 h, then a second burst release at around 4 days followed by a long-term sustained release - Promoted osteogenic differentiation - A good antibacterial activity against S. aureus and E. coli up to one month	[207]

PVA polyvinyl alcohol, PLGA poly(lactic-co-glycolic acid), PLA polylactic acid, PCL polycaprolactone, PVP polyvinylpyrrolidone, PEG polyethylene glycol, HPMC hydroxypropyl methylcellulose, TPP tripolyphosphate pentasodium, TNF tumor necrosis factor, IL interleukin, MTT dimethylthiazol-diphenyltetrazolium bromide