How Biodegradable Polymers Can be Effective Drug Delivery Systems for Cannabinoids? Prospectives and Challenges

Figures & data

Figure 1 Scheme of endocannabinoid system (ESC) specific to the skin.

Figure 2 Scheme of a polymer-drug conjugate structure (the Ringsdorf’s model).¹⁷²

Figure 3 Schematic structure of polymeric micelles (PMs).¹⁷⁷

Figure 4 Schematic structure of (A) polymeric nanosphere and (B) polymeric nanocapsule.¹⁸¹

Figure 5 Schematic structure of liposome.¹⁹³

Table 1 The Innovative Biodegradable Polymers-Based DDSs for Cannabinoids Delivery

Type of DDS	Drug	Polymer used in the Formulation	Size, Zeta potential (ζ) and Entrapment Efficiency (EE)	In vitro Studies			In vivo Studies				Additional Studies	Reference
				Release Kinetics	Cell Line Tested	Cell Viability	Animal Model	Cell Line	Pharmacokinetics Study	Pharmacodynamics Study
Nanoparticles (NPs)	CBD	PLGA	192.90 ± 2.41 nm EE = 70.31 ± 0.69% ζ = −6.270 ± 0.927 mV	In PBS pH 6.5: about 45% of the drug was released within 24h. In PBS pH 5.0: about 65% of the drug was released within 24h.	T24 and SV-HUC-1	In T24 cells: at a concentration of 50 µM, after 48h, cell viability was approximately 20%. In SV-HUC-1 cells: at a concentration of 50 µM, after 48 h, cell viability was approximately 90%.	-	-	-	-	About 80% of mucin binding efficiency; about 25% of cellular uptake within 2h.	[235]
Nanoparticles (NPs)	CBD	PLGA CS coated	287.20 ± 0.90 nm EE = 78.52 ± 0.82% ζ = 3.370 ± 0.158 mV	In PBS pH 6.5: about 7% of the drug was released within 24h. In PBS pH 5.0: about 7% of the drug was released within 24h.	T24 and SV-HUC-1	In T24 cells: at a concentration of 50 µM, after 48h, cell viability was approximately 40%. In SV-HUC-1 cells: at a concentration of 50 µM, after 48 h, cell viability was approximately 80%.	-	-	-	-	About 95% of mucin binding efficiency; about 75% of cellular uptake within 2h.	[235]
Nanoparticles (NPs)	CBD	PLGA	240.1 ± 10.1 nm EE = 82% ζ = −21.5 ± 0.60 mV	-	THP-1, HMC3	In THP-1 cells: at a concentration 0.1 mg/mL NPs exhibited cytotoxic effects. Lower concentrations were not cytotoxic. In HMC3 cells: at a concentration of 0.1 mg/mL significant reduction in dsDNA concentration, while no differences in metabolic activity.	-	-	-	-	NPs reduced the inflammatory response in PCC cells. NPs restored mitochondrial functions in Mito Stress assay.	[236]
Nanoparticles (NPs)	CBD	PLGA RG^® 502	236 ± 12 nm ζ = −16,6 ± 1.2 mV EE = 95.23 ± 3.30%	In PBS pH 7.4: around 100% of the drug was released within 96h.	SKOV-3	IC50 = 29.64 ± 2.94 µM (after 24h) IC50 = 20.88 ± 1.25 µM (after 48h)	CAM (fertilized chicken eggs)	SKOV-3	-	About 80% tumor growth inhibition.	CBD NPs were stable during 3 months of storage. In Western Blot CBD NPs have shown higher PARP cleavage compared to the CBD solution.	[237]
Nanoparticles (NPs)	CBD	PEG1014-(LA)100	121.8 ± 1.1 nm ζ= −39.9 mV EE = 46.04%	-	-	-	Sprague-Dawley male adult rats	-	Pharmacokinetic parameters in the brain: Cmax = 94 ng/g Tmax = 30 min AUC0 - 4h = 7341 ng/g Biodistribution assay has shown the following mass of CBD in each tissue: Spinal cord 7761 ng Brain 21 ng No detectable CBD in spleen and liver.	-	CBD NPs were stable during 31 days of storage, with no significant change in particle size. The electromyography has shown the alleviation of pain within 10 minutes after intrathecal injection of CBD NPs.	[238]
Nanoparticles (NPs)	CBD	PEG-b-PCL	At 25^°C: 79 ± 1 nm 51 ± 1 nm ζ = −15.0 ± 0.2 mV At 37^°C: 63 ± 1 nm 40 ± 1 nm ζ = −24.0 ± 0.3 mV EE = 102 ± 2%	In HCl pH 1.2: about 10% of the drug was released within 2h. In PBS pH 6.8: about 80% of the drug was released within 1h.	-	-	Sprague Dawley male rats	-	Pharmacokinetics data after oral administration: Tmax = 0.3 ± 0.1 h Cmax = 21.0 ± 4.1 ng/mL AUC0.25–24h = 51.9 ± 14.0 ng/mL x h	-	-	[239]
Nanoparticles incorporated into 3D-printed alginate film	CBD	PF127	166 nm EE = 99.35 ± 2.35% Films’ thickness - 0.8 ± 0.002 mm Films’ weight - 0.73 ± 0.15 g Films’ porosity - 11.00 ± 0.002	In PBS pH 7.4: films 4, 8 and 12 mg/mL released about 90%, 85% and 80% of the drug within 7 h respectively.	HaCaT	NPs at a concentration of 0.1 mg/mL did not exhibit cytotoxicity within 24 h. At concentration of 0.1 mg/mL around 40% cell viability after 48h. NPs cytotoxicity is strongly connected to their concentration.	-	-	-	-	pH value of the obtained films was 6–7. In vitro wound healing assay showed short-term effects on the healing process. In vitro, the study of antibacterial activity showed the following growth inhibition zones: S. aureus - 12.7 ± 1.2 mm Bacillus spp.- 11.7 ± 0.6 mm	[240]
Nanoparticles incorporated into 3D printed alginate film	CBG	PF127	188 nm EE = 98.39 ± 1.87% Films’ thickness - 0.8 ± 0.002 mm Films’ weight - 0.73 ± 0.15 g Films’ porosity - 11.00 ± 0.002	In PBS pH 7.4: films 4, 8 and 12 mg/mL released 35%, 33% and 21% of the drug within 7 h respectively.	HaCaT	NPs at a concentration of 0.1 mg/mL did not exhibit cytotoxicity within 48 h. NPs cytotoxicity strongly connected to their concentration.	-	-	-	-	pH value of the obtained films was 6–7. In vitro wound healing assay showed short-term effect on the healing process. In vitro study of antibacterial activity showed following growth inhibition zones: S. aureus - 13.3±1.5 mm Bacillus spp.- 10.3 ± 0.6 mm E. coli - 7.0 ± 0.1 mm	[240]
Microspheres	CBD	PCL	For formulation 15/150 (drug/polymer ratio): 54.81 ± 22.21 µm EE = 99.09 ± 5.14% For formulation 30/150 (drug/polymer ratio): 51.10 ± 21.60 µm EE = 104.41 ± 5.20%	In PBS pH 7.4: about 20% of the drug was released from both formulation within 24h.	MDA-MB-231	For formulation 15/150 (drug/polymer ratio): About 50% after 9 days. For formulation 30/150 (drug/polymer ratio): About 60% after 9 days	-	-	-	-	-	[241]
Microsphere incorporated gelatin/nano-hydroxyapatite scaffolds	CBD	PLGA RG^® 503H	11.6 ± 1.3 µm EE = 70.12 ± 4.46%	In PBS pH 7.4: 71.25 ± 3.28% of the drug was released from the microspheres within 25 days. 44.37 ± 4.15% of the drug was released from the scaffold within 25 days.	Mesenchymal stem cells	MTT assay have not shown any changes in cell viability.	Adult male Wistar rats	-	-	Histological study of newly formed tissues showed higher degree of tissue formation in the group treated with microsphere incorporated scaffold. Histomorphometry study showed the highest density of osseous and cartilaginous tissues in the group treated with microsphere incorporated scaffold.	In qRT-PCR study the microsphere incorporated scaffold showed higher expression of OCN compared to free scaffold and control.	[242,243]
Microparticles	CBD	PCL	50 µm EE = 99.09 ± 5.14%	In PBS pH 7.4: about 90% of the drug was released within 10 days.	-	-	Athymic nude mice	U87MG	-	CBD-loaded microparticles caused tumor growth inhibition and reduction in tumor volume and weight.	Immunofluorescence study showed reduced cancer cell proliferation, enhanced apoptosis and decreased tumor vascularization.	[244]
Microparticles	CBD	PLGA RG^® 502	24.17 ± 2.32 µm EE = 94.62 ± 4.62%	In PBS pH 7.4: about 95% of the drug was released within 42 days.	MCF-7 and MDA-MB-231	In MCF-7 cells: Around 40% cell viability after 2 days. In MDA-MB-231 cells: About 30% cell viability after 2 days.	CAM (fertilized chicken eggs)	MDA-MB-231	-	About 70% tumor growth inhibition. Around 1.8-fold reduction in tumor growth.	-	[245]
Microparticles	CBD	PLGA RG^® 504	24.12 ± 1.25 µm EE = 57.63 ± 6.34%	In PBS pH 7.4: about 80% of the drug was released within 42 days.	-	-	-	-	-	-	-	[245]
Microparticles embedded in CS/PVA hydrogel	CBD	PLGA	81 ± 8 µm EE = 52.0 ± 0.3%	-	hDPCs	No cytotoxicity against hDPCs cells.	-	-	-	-	Antibacterial assay against S. aureus showed no bacterial inhibition for 2.5% PLGA-CBD microparticles formulation. Higher concentration of PLGA-CBD microparticles in hydrogels exhibited increased antimicrobial activity.	[246]
Micelles	CBD	Cinnamyl modified polyglycolide/PCL PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50	51.0 ± 1.8 nm ζ = −6.61 ± 3.10 mV EE = 95.0%	In PBS pH 7.4: about 35% of the drug was released within 24h.	HL-60 and HUT-78	Against HL-60: IC50 = 3.00 µg/mL Against HUT-78: IC50 = 8.30 µg/mL	-	-	-	-	CBD was loaded during micelle formation.	[247]
Micelles	CBD	Cinnamyl modified polyglycolidol/PCL PG50-b-PPO4-b-[P(CyCL)4-co-(CL)40]-b-PPO4-b-PG50	57.0 ± 1.4 nm ζ = 4.19 ± 2.50 mV EE = 92.0%	In PBS pH 7.4: about 40% of the drug was released within 24h.	HL-60 and HUT-78	Against HL-60: IC50 = 3.20 µg/mL Against HUT-78: IC50 = 8.00 µg/mL	-	-	-	-	CBD was loaded into preformed micelles.	[247]
Micelles	CBD	Polyglycolidol/PCL PG45-b-PCL35-b-PG45	56.0 ± 2.7 nm ζ = −2.61 ± 2.10 mV EE = 91.0%	In PBS pH 7.4: about 50% of the drug was released within 24h.	HL-60 and HUT-78	Against HL-60: IC50 = 2.33 µg/mL Against HUT-78: IC50 = 5.26 µg/mL	-	-	-	-	CBD was loaded during micelle formation.	[247]
Micelles	CBD	Polyglycolidol/PCL PG45-b-PCL35-b-PG45	50.0 ± 3.8 nm ζ = 2.90 ± 2.40 mV EE = 82.0%	In PBS pH 7.4: about 60% of the drug was released within 24h.	HL-60 and HUT-78	Against HL-60: IC50 = 2.29 µg/mL Against HUT-78: IC50 = 5.17 µg/mL	-	-	-	-	CBD was loaded into preformed micelles.	[247]
Nanoemulsion (NE)-filled hydrogel	CBD	CS	Droplet size 1 mg CBD/g of NE: 126 ± 3 nm 5 mg CBD/g of NE: 102 ± 3 nm	-	WS1	MTT assay has not shown any changes in cell viability and cytotoxicity at a concentration of 0.5 to 1.5 mg/mL.	-	-	-	-	Ex vivo skin penetration parameters: For NE: Steady-state flux - 403.37 ± 130.09 µg/cm^Citation2 h^−1 Q30h = 572.56 ± 211.11 µg/cm^2 Permeation coefficient - 80.67 ± 211.11 mg/cm^2h For NE-filled hydrogel: Steady-state flux - 475.68 ± 162.57 µg/cm^2h^−1 Q30h = 709.22 ± 220.62 µg/cm^2 Permeation coefficient - 95.14 ± 32.51 mg/cm^2h. Tape stripping experiments: For NE: Total amount of CBD recovered in the stratum corneum - 3853.20 ± 543.06 ng/cm^Citation2 Achieved penetration depth - 10.493 ± 3.958 µm For NE-filled hydrogel: Total amount of CBD recovered in the stratum corneum - 2745.41 ± 1022.44 ng/cm^2 Achieved penetration depth - 14.644 ± 8.338 µm	[248]
Nanoparticles (NPs)	CB13	PLGA	Particle size within range 253–344 nm EE ~ 70% Strongly negative ζ	In PBS pH 7.4: about 60% of the drug was released within 15 days.	Caco-2	Negligible growth inhibition. Around 100% cell viability after 24h.	Cd/57 male mice	-	Biodistribution assay showed following percentage of nanoparticles in each tissue (after 24 h): Heart ~ 15% Liver ~ 30% Spleen ~30% Lungs ~ 5% Kidney ~ 5% Brain ~ 20%	-	Mucoadhesion tests performed on duodenum, jejunum and ileum sections showed respectively 55%, 30% and 12% of mucoadhesion.	[249]
Nanoparticles (NPs)	CB13	PLGA CS modified	EE ~ 71% Strongly positive ζ	In PBS pH 7.4: about 50% of the drug was released within 15 days.	Caco-2	Negligible growth inhibition. Around 100% cell viability after 24h.	Cd/57 male mice	-	Biodistribution assay showed following percentage of nanoparticles in each tissue (after 24 h): Heart ~ 15% Liver ~ 30% Spleen ~30% Lungs ~ 5% Kidney ~ 5% Brain ~ 20%	-	Mucoadhesion tests performed on duodenum, jejunum and ileum sections showed respectively 85%, 60% and 15% of mucoadhesion.	[249]
Nanoparticles (NPs)	CB13	PLGA Eudragit^® RS modified	EE ~ 83% Strongly positive ζ	In PBS pH 7.4: about 35% of the drug was released within 15 days.	Caco-2	Negligible growth inhibition. Around 100% cell viability after 24h.	Cd/57 male mice	-	Biodistribution assay showed following percentage of nanoparticles in each tissue (after 24 h): Heart ~ 5% Liver ~ 25% Spleen ~50% Lungs ~ 5% Kidney ~ 5% Brain ~ 15%	-	Mucoadhesion tests performed on duodenum, jejunum and ileum sections showed respectively 75%, 35% and 10% of mucoadhesion.	[249]
Nanoparticles (NPs)	CB13	PLGA Lecithin modified	EE ~ 81% Slightly negative ζ	In PBS pH 7.4: About 90% of the drug was released within 15 days.	Caco-2	Negligible growth inhibition. Around 100% cell viability after 24h.	-	-	-	-	-	[249]
Nanoparticles (NPs)	CB13	PLGA Vitamin E modified	EE ~ 76% Slightly negative ζ	In PBS pH 7.4: about 80% of the drug was released within 15 days.	Caco-2	Negligible growth inhibition. Around 100% cell viability after 24h.	-	-	-	-	-	[249]
Nanoparticles (NPs)	CB13	PLGA	EE = 73.4 ± 8.0%	In PBS pH 7.4: about 50% of the drug was released within 150 minutes.	Caco-2 and THP1	Around 100% cell viability of Caco-2 cells.	-	-	-	-	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels. Around 25 particles per cell in cellular uptake study in Caco-2 cells. Cellular uptake study in THP1 cells showed the best results for PLGA NPs, compared to CS coated PLGA NPs and PEG-ylated PLGA NPs.	[250]
Nanoparticles (NPs)	CB13	PLGA CS coated	EE = 75.3 ± 7.2%	In PBS pH 7.4: About 45% of the drug was released within 150 minutes.	Caco-2 and THP1	Around 100% cell viability of Caco-2 cells.	-	-	-	-	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels. Around 100 particles per cell in cellular uptake study in Caco-2 cells. Cellular uptake study in THP1 cells showed the best results for PLGA NPs, compared to CS coated PLGA NPs and PEG-ylated PLGA NPs.	[250]
Nanoparticles (NPs)	CB13	PEG-ylated PLGA	EE = 79.4 ± 9.0%	In PBS pH 7.4: about 45% of the drug was released within 150 minutes.	Caco-2 and THP1	Around 100% cell viability of Caco-2 cells.	-	-	-	-	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels. Around 5 particles per cell in cellular uptake study in Caco-2 cells. Cellular uptake study in THP1 cells showed the best results for PLGA NPs, compared to CS-coated PLGA NPs and PEG-ylated PLGA NPs.	[250]
Nanoparticles (NPs)	CB13	PLGA	196.0 ± 12.6 nm ζ = −31.4 ± 5.89 mV EE = 73.4 ± 8.0%	In HCl medium pH 2.0: about 2% of the drug was released within 30 minutes. In PBS pH 7.4: about 58% of the drug was released within 15 days.	-	-	Adult male Harlan Sprague-Dawley rats	-	-	Studies in an animal neuropathic pain model showed a significant, dose-dependent analgesic effect that was kept for up to 3 days.	-	[251]
Nanoparticles (NPs)	CB13	PLGA-PEG	207.6 ± 24.5 nm ζ = −24.97 ± 4.11 mV EE = 80.1 ± 8.2%	In HCl medium pH 2.0: about 6% of the drug was released within 30 minutes. In PBS pH 7.4: about 90% of the drug was released within 15 days.	-	-	Adult male Harlan Sprague-Dawley rats	-	-	Studies in an animal neuropathic pain model showed the dose-dependent analgesic effect that was kept up to 11 days (at 6.8 mg/kg).	-	[251]
Nanoparticles (NPs)	CB13	PLGA PEG-coated	654.4 ± 185.5 nm ζ = 0.45 ± 3.18 mV EE = 79.4 ± 9.0%	In HCl medium pH 2.0: about 6% of the drug was released within 30 minutes. In PBS pH 7.4: about 82% of the drug was released within 15 days.	-	-	Adult male Harlan Sprague-Dawley rats	-	-	Studies in an animal neuropathic pain model showed a significant analgesic effect that was kept up to 5 days (at 6.8 mg/kg), a significant antinociceptive effect compared to free CB13 after 9h and mechanical antihypertensive effect maintained for up to 5 days.	-	[251]
Nanoparticles (NPs)	THC	PLGA	290.10 ± 60.30 nm ζ = −34.78 ± 5.98 mV EE = 95.5 ± 0.2%	In PBS pH 7.4: about 60% of the drug was released within 10 days.	A-549 and MRC-5	In the MRC-5 cell line around 100% cell viability at all THC concentrations. In A-549 cell line around 90% cell viability at a 50 µM concentration of THC.	-	-	-	-	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels.	[252]
Nanoparticles (NPs)	THC	PLGA CS coated	746.89 ± 100.76 nm ζ = 78.21 ± 7.65 mV EE = 96.3 ± 0.6%	In PBS pH 7.4: about 60% of the drug was released within 10 days.	-	-	-	-	-	-	-	[252]
Nanoparticles (NPs)	THC	PEG-ylated PLGA	587.90 ± 98.01 nm ζ = 0.46 ± 0.06 mV EE = 97.4 ± 0.3%	In PBS pH 7.4: about 85% of the drug was released within 10 days.	A-549, MRC-5 and LL2	In A-549 cells: IC50 = 42.3±29.3 µM Around 40% cell viability at 50 µM concentration of THC. In MRC-5 cells: IC50 = 76.2 ± 20.6 µM Around 70% cell viability at 50 µM concentration of THC. In LL2 cells: greater reduction in cell viability in comparison to free THC.	Immunocompetent female C57BL/6 mice	LL2	-	No statistically significant differences in tumor volume reduction and cumulative survival were found.	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels.	[252]
Nanoparticles (NPs)	THC	PEG-ylated PLGA CS coated	789.67 ± 95.32 nm ζ = 5.34 ± 0.98 mV EE = 94.9 ± 0.8%	In PBS pH 7.4: about 65% of the drug was released within 10 days.	A-549 and MRC-5	In MRC-5 cell line around 100% cell viability at all THC concentrations. In A-549 cell line around 70% cell viability at 50 µM concentration of THC.	-	-	-	-	Blood compatibility studies showed haemocompatibility, no significant effect on haemolysis, complement system activation, plasma clotting time and sP-selectin release levels.	[252]
Microparticles	THC	PCL	50 µm EE = 84.55 ± 13.6%	In PBS pH 7.4: about 80% of the drug was released within 10 days.	-	-	Athymic nude mice	U87MG	-	THC-loaded microparticles caused tumor growth inhibition and reduction in tumor volume and weight.	Immunofluorescence study showed reduced cancer cell proliferation, enhanced apoptosis and decreased tumor vascularization.	[244]
Gel	THC	CS	-	In PBS pH 6.0: 50% of the drug was released within 1h. The release exhibited first-order kinetics.	-	-	Male New Zealand albino rabbits	-	Cmax = 31 ± 4 ng/mL Tmax = 45 min AUC0 min - ∞ = 3759 ± 776 ng/mL/min Vd = 9037 ± 4287 mL/kg Clearance = 41.5 ± 8.7 mL/min/kg	-	Chitosan gel slightly increased bioavailability of THC after nasal administration, compared to solution of THC.	[253]
Nanoparticles (NPs)	CBD-rich Cannabis extract	PEG-b-PCL	63.8 nm EE = 99.9%	In PBS pH 7.4: around 50% of the drug was released within 24h.	-	-	Female Swiss albino mice	-	-	Sustained, stronger analgesic effect, reduction of thermal hyperalgesia and mechanical allodynia compared to non-encapsulated extract.	Acute toxicity test showed no signs of toxic effects after oral administration.	[254]
Micelles	Cannabis sativa extract (73.16% w/v of THC)	PEG-b-PCL	63.7 ± 3.7 nm EE = 49.6 ± 0.5%	In PBS pH 7.4: about 80% of the drug was released within 120h.	-	-	Female Swiss albino mice	-	-	Lack of adverse effects. In the electronic von Frey test micelles enhanced the analgesic effect of THC and provided sustained effect up to 24h. Micelles provided 50% pain protection in phenylquinone-induced writhing test.	In vitro gastrointestinal stability assay has shown no significant changes in the particle size.	[255]
Micelles	Cannabis sativa extract (73.16% w/v of THC)	m-PEG-b-P(CL-co-MPC) bearing oleyl derivatives	46.8 ± 5.6 nm EE = 59.4 ± 2.7%	In PBS pH 7.4: about 90% of the drug was released within 120h.	-	-	Female Swiss albino mice	-	-	Lack of adverse effects. In the electronic von Frey test micelles provided sustained analgesic effect up to 48h. Micelles provided 67% pain protection in phenylquinone-induced writhing test.	In vitro gastrointestinal stability assay has shown no significant changes in the particle size.	[255]
Micelles	Cannabis sativa extract (73.16% w/v of THC)	m-PEG-b-P(CL-co-MPC) bearing lauryl derivatives	47.9 ± 6.5 nm EE = 47.0 ± 2.8%	In PBS pH 7.4: about 70% of the drug was released within 120h.	-	-	Female Swiss albino mice	-	-	Lack of adverse effects. In the electronic von Frey test the highest analgesic effect was observed 1h and 2h post administration. Micelles provided 74% pain protection in phenylquinone-induced writhing test.	In vitro gastrointestinal stability assay has shown no significant changes in the particle size.	[255]
Microcapsules	Full-spectrum Cannabis extract: THC, THCA, CBN, CBNA, CBD, CBDA, CBG, CBGA, CBC, CBCA	Alginate CS coated	460 ± 250 µm ζ = 15 ± 6 mV EE between 86% and 104%	Release study was performed in simulated gastric fluid. In gastric phase about 13–21% of the cannabinoids was released. In the intestinal phase a burst release was observed, followed by a sustained release (between 73% and 93%).	-	-	-	-	-	-	Stability study exhibited t1/2 between 2 and 5 weeks, except CBD (60 days), THCA (90 days) and CBN (170 days).	[256]
Microdepot	Full-spectrum Cannabis extract: CBD, CBDA, THC, CBG, CBC, CBDV, CBDVA, THCV, CBGA	PCL	257.80 ± 2.49 µm EE between 90% and 103.5%	In PBS pH 7.4: 70% of CBD, 52–64% of CBDV, CBG, THC and CBC was released within 21 days.	-	-	Adult male mice	-	Sustained drug delivery with close to zero-order kinetics during 1^st week and slower release rate within 2^nd week. About 90% of CBDV and CBG, 80% of CBC and CBD, 60% of THC was released within 14 days.	-	In anticonvulsant activity study in mice microdepots showed higher survival rates, increased latency to first tonic-clonic seizure and reduction in the incidence of tonic-clonic seizures compared to the group administered with Cannabis extract.	[257]

Abbreviations: A-549, human lung adenocarcinoma cell line; AUC, area under the curve; Caco-2, human colon adenocarcinoma cell line; CBC, cannabichromene; CBCA, cannabichromenic acid; CBDA, cannabidiolic acid; CBDV, cannabidivarin; CBDVA, cannabidivarinic acid; CBGA, cannabigerolic acid; CBN, cannabinol; CBNA, cannabinolic acid; C_max, maximum concentration of the drug; hDPCs, primary human dental pulp cells; HMC3, human microglial cell line; HL-60, acute myeloid leukemia cell line; HUT-78, Sezary Syndrome cell line; IC₅₀, drug concentration required to inhibit 50% of cell growth; LL2, murine lung cancer cell line; MCF-7, oestrogen receptor positive breast cancer cell line; MDA-MB-231, oestrogen, progesterone and HER-2 receptors negative breast cancer cell line; MRC-5, human embryo lung fibroblast cell line; OCN, anti-osteocalcin antibody; PCC, primary cortical cells; PBS, phosphate-buffered saline; Q_30h, cumulative amount of CBD permeated through the skin at the end of the 30 h of the experiment; THCA, ∆⁹-tetrahydrocannabinolic acid; THCV, (-)-trans-∆⁹-tetrahydrocannabivarin; THP1, human monocytic cell line; T_max, time to reach maximum concentration of the drug; U87MG, human glioma cells; V_d, volume of distribution; WS1, human normal skin fibroblast cell line.

Zoltowska K, Sobczak M, Oledzka E. Polyurethanes in pharmacy — current state and perspectives of the development. Polimery. 2014;59(10):689–698. doi:10.14314/polimery.2014.689

 Web of Science ®Google Scholar

Perumal S, Atchudan R, Lee W. A Review of Polymeric Micelles and Their Applications. Polymers. 2022;14(12):2510. doi:10.3390/polym14122510

 PubMed Web of Science ®Google Scholar

Budnicka M, Gadomska-Gajadhur A, Ruskowski P, Synoradzki L. Biodegradable polymers for the treatment of tuberculosis Part I. Epidemiology, therapy and treatment methods. Polimery. 2017;62(10):711–719. doi:10.14314/polimery.2017.711

 Web of Science ®Google Scholar

Nsairat H, Khater D, Sayed U, Odeh F, Al Bawab A, Alshaer W. Liposomes: structure, composition, types, and clinical applications. Heliyon. 2022;8(5):e09394. doi:10.1016/j.heliyon.2022.e09394

 PubMed Web of Science ®Google Scholar

Chen S, Deng C, Zheng W, et al. Cannabidiol Effectively Promoted Cell Death in Bladder Cancer and the Improved Intravesical Adhesion Drugs Delivery Strategy Could Be Better Used for Treatment. Pharmaceutics. 2021;13(9):1415. doi:10.3390/pharmaceutics13091415

 PubMed Web of Science ®Google Scholar

Chevalier MT, Al-Waeel M, Alsharabasy AM, Rebelo AL, Martin-Saldaña S, Pandit A. Therapeutic Polymer-Based Cannabidiol Formulation: tackling Neuroinflammation Associated with Ischemic Events in the Brain. Mol Pharm. 2024;acs.molpharmaceut.3c00244. doi:10.1021/acs.molpharmaceut.3c00244

 PubMedGoogle Scholar

Fraguas-Sánchez AI, Torres-Suárez AI, Cohen M, et al. PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: in Vitro and In Ovo Assessment. Pharmaceutics. 2020;12(5):439. doi:10.3390/pharmaceutics12050439

 PubMed Web of Science ®Google Scholar

Muresan P, Woodhams S, Smith F, et al. Evaluation of cannabidiol nanoparticles and nanoemulsion biodistribution in the central nervous system after intrathecal administration for the treatment of pain. Nanomed Nanotechnol Biol Med. 2023;49:102664. doi:10.1016/j.nano.2023.102664

 PubMed Web of Science ®Google Scholar

Shreiber-Livne I, Sulimani L, Shapira A, Procaccia S, Meiri D, Sosnik A. Poly(ethylene glycol)-b-poly(epsilon-caprolactone) nanoparticles as a platform for the improved oral delivery of cannabidiol. Drug Deliv Transl Res. 2023;13:3192–3203. doi:10.1007/s13346-023-01380-1

 PubMed Web of Science ®Google Scholar

Monou PK, Mamaligka AM, Tzimtzimis EK, et al. Fabrication and Preliminary In Vitro Evaluation of 3D-Printed Alginate Films with Cannabidiol (CBD) and Cannabigerol (CBG) Nanoparticles for Potential Wound-Healing Applications. Pharmaceutics. 2022;14(8):1637. doi:10.3390/pharmaceutics14081637

 PubMed Web of Science ®Google Scholar

Hernán Pérez de la Ossa D, Ligresti A, Gil-Alegre ME, et al. Poly-ε-caprolactone microspheres as a drug delivery system for cannabinoid administration: development, characterization and in vitro evaluation of their antitumoral efficacy. J Control Release. 2012;161(3):927–932. doi:10.1016/j.jconrel.2012.05.003

 PubMed Web of Science ®Google Scholar

Kamali A, Oryan A, Hosseini S, et al. Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects. Mater Sci Eng C. 2019;101:64–75. doi:10.1016/j.msec.2019.03.070

 PubMed Web of Science ®Google Scholar

Kamali A, Oryan A, Hosseini S, et al. Corrigendum to Cannabidiol-loaded microspheres incorporated into osteoconductive scaffold enhance mesenchymal stem cell recruitment and regeneration of critical-sized bone defects. Mater Sci Eng C. 2021;126:112179. doi:10.1016/j.msec.2021.112179

 PubMed Web of Science ®Google Scholar

Hernán Pérez De La Ossa D, Lorente M, Gil-Alegre ME, et al. Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme. PLoS One. 2013;8(1):e54795. doi:10.1371/journal.pone.0054795

 PubMed Web of Science ®Google Scholar

Fraguas-Sánchez AI, Fernández-Carballido A, Simancas-Herbada R, Martin-Sabroso C, Torres-Suárez AI. CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer. Int J Pharm. 2020;574:118916. doi:10.1016/j.ijpharm.2019.118916

 PubMedGoogle Scholar

David C, De Souza JF, Silva AF, et al. Cannabidiol-loaded microparticles embedded in a porous hydrogel matrix for biomedical applications. J Mater Sci Mater Med. 2024;35(1):14. doi:10.1007/s10856-023-06773-9

 PubMed Web of Science ®Google Scholar

Toncheva-Moncheva N, Dimitrov E, Grancharov G, Momekova D, Petrov P, Rangelov S. Cinnamyl-Modified Polyglycidol/Poly(ε-Caprolactone) Block Copolymer Nanocarriers for Enhanced Encapsulation and Prolonged Release of Cannabidiol. Pharmaceutics. 2023;15(8):2128. doi:10.3390/pharmaceutics15082128

 PubMed Web of Science ®Google Scholar

Huestis MA. Human Cannabinoid Pharmacokinetics. C&b. 2007;4(8):1770–1804. doi:10.1002/cbdv.200790152

 Google Scholar

Demisli S, Galani E, Goulielmaki M, et al. Encapsulation of cannabidiol in oil-in-water nanoemulsions and nanoemulsion-filled hydrogels: a structure and biological assessment study. J Colloid Interface Sci. 2023;634:300–313. doi:10.1016/j.jcis.2022.12.036

 PubMed Web of Science ®Google Scholar

Durán-Lobato M, Muñoz-Rubio I, Holgado MÁ, Álvarez-Fuentes J, Fernández-Arévalo M, Martín-Banderas L. Enhanced Cellular Uptake and Biodistribution of a Synthetic Cannabinoid Loaded in Surface-Modified Poly(lactic-co-glycolic acid) Nanoparticles. J Biomed Nanotechnol. 2014;10(6):1068–1079. doi:10.1166/jbn.2014.1806

 PubMed Web of Science ®Google Scholar

Durán-Lobato M, Martín-Banderas L, Gonçalves LMD, Fernández-Arévalo M, Almeida AJ. Comparative study of chitosan- and PEG-coated lipid and PLGA nanoparticles as oral delivery systems for cannabinoids. J Nanopart Res. 2015;17(2):61. doi:10.1007/s11051-015-2875-y

 Web of Science ®Google Scholar

Berrocoso E, Rey-Brea R, Fernández-Arévalo M, Micó JA, Martín-Banderas L. Single oral dose of cannabinoid derivate loaded PLGA nanocarriers relieves neuropathic pain for eleven days. Nanomed Nanotechnol Biol Med. 2017;13(8):2623–2632. doi:10.1016/j.nano.2017.07.010

 PubMed Web of Science ®Google Scholar

Martín-Banderas L, Muñoz-Rubio I, Prados J, et al. In vitro and in vivo evaluation of Δ9-tetrahidrocannabinol/PLGA nanoparticles for cancer chemotherapy. Int J Pharm. 2015;487(1–2):205–212. doi:10.1016/j.ijpharm.2015.04.054

 PubMedGoogle Scholar

Al-Ghananeem AM, Malkawi AH, Crooks PA. Bioavailability of Δ 9 -tetrahydrocannabinol following intranasal administration of a mucoadhesive gel spray delivery system in conscious rabbits. Drug Dev. Ind. Pharm. 2011;37(3):329–334. doi:10.3109/03639045.2010.513009

 PubMed Web of Science ®Google Scholar

Román-Vargas Y, Porras-Arguello JD, Blandón-Naranjo L, Pérez-Pérez LD, Benjumea DM. Evaluation of the Analgesic Effect of High-Cannabidiol-Content Cannabis Extracts in Different Pain Models by Using Polymeric Micelles as Vehicles. Molecules. 2023;28(11):4299. doi:10.3390/molecules28114299

 PubMed Web of Science ®Google Scholar

Porras JD, Román Y, Palacio J, Blandón-Naranjo L, Benjumea D, Pérez LD. Amphiphilic block copolymers bearing fatty acid derivatives as vehicles for THC in the development of analgesic oral formulations. React Funct Polym. 2024;195:105811. doi:10.1016/j.reactfunctpolym.2023.105811

 Web of Science ®Google Scholar

Villate A, San Nicolas M, Olivares M, Aizpurua-Olaizola O, Usobiaga A. Chitosan-Coated Alginate Microcapsules of a Full-Spectrum Cannabis Extract: characterization, Long-Term Stability and In Vitro Bioaccessibility. Pharmaceutics. 2023;15(3):859. doi:10.3390/pharmaceutics15030859

 PubMed Web of Science ®Google Scholar

Uziel A, Gelfand A, Amsalem K, et al. Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect. ACS Appl Mater Interfaces. 2020;12(21):23707–23716. doi:10.1021/acsami.0c04435

 PubMed Web of Science ®Google Scholar