Aim: Alendronate (AL) is a nitrogen-containing bisphosphonate drug that exhibits limited oral bioavailability due to predominantly hydrophilic molecular properties. To enhance oral absorption of this important osteoporosis drug, a novel ion-pairing strategy using the cationic polymer polyethylenimine (PEI) was explored as an initial step of an alternate oral drug delivery strategy that attempts to prepare polymer-encapsulated ion pair nanoparticles. Methodology: Electrostatically stabilized AL/PEI association complexes were fabricated by combining AL and PEI solutions prepared in 0.05 M acetate buffer, pH 5.0, at different AL/PEI charge ratios under stirring. The free fraction of AL after complexation with PEI was quantified spectrophotometrically at λ=300 nm using ferric chloride. Particle size distribution and zeta potential of ion pairs formed at different molar AL/PEI ratios were measured by dynamic laser light scattering. Results: The complexation efficiency of PEI was low until an AL/PEI charge ratio of1:1.7. Increasing PEI concentrations effectively decreased the free fraction of AL implying formation of stable ion pairs between the negatively charged AL and the positively charged polymer. The lowest fraction of free AL was 18.7% measured at an AL/PEI charge ratio of 1:33. The mean hydrodynamic diameter of nanoassemblies decreased with increasing AL/PEI charge ratio reaching a limiting value of 71±1.4 nm at AL/PEI=1:33. Corresponding zeta potential measured for these association complexes was +37±2.8 mV. Conclusion: AL/PEI charge ratio greater than 1:1.7 facilitates effective formation of electrostatically stabilized ion pairs that carry a significant positive surface charge indicative of substantial colloidal stability in aqueous solution. The small size of AL/PEI complexes fabricated at 1:33 favors these ion pairs for subsequent encapsulation into biocompatible polymers suitable for oral drug delivery.

Aim: Alendronate (AL) is a nitrogen-containing bisphosphonate drug that exhibits limited oral bioavailability due to predominantly hydrophilic molecular properties. To enhance oral absorption of this important osteoporosis drug, a novel ion-pairing strategy using the cationic polymer polyethylenimine (PEI) was explored as an initial step of an alternate oral drug delivery strategy that attempts to prepare polymer-encapsulated ion pair nanoparticles. Methodology: Electrostatically stabilized AL/PEI association complexes were fabricated by combining AL and PEI solutions prepared in 0.05 M acetate buffer, pH 5.0, at different AL/PEI charge ratios under stirring. The free fraction of AL after complexation with PEI was quantified spectrophotometrically at λ=300 nm using ferric chloride. Particle size distribution and zeta potential of ion pairs formed at different molar AL/PEI ratios were measured by dynamic laser light scattering. Results: The complexation efficiency of PEI was low until an AL/PEI charge ratio of1:1.7. Increasing PEI concentrations effectively decreased the free fraction of AL implying formation of stable ion pairs between the negatively charged AL and the positively charged polymer. The lowest fraction of free AL was 18.7% measured at an AL/PEI charge ratio of 1:33. The mean hydrodynamic diameter of nanoassemblies decreased with increasing AL/PEI charge ratio reaching a limiting value of 71±1.4 nm at AL/PEI=1:33. Corresponding zeta potential measured for these association complexes was +37±2.8 mV. Conclusion: AL/PEI charge ratio greater than 1:1.7 facilitates effective formation of electrostatically stabilized ion pairs that carry a significant positive surface charge indicative of substantial colloidal stability in aqueous solution. The small size of AL/PEI complexes fabricated at 1:33 favors these ion pairs for subsequent encapsulation into biocompatible polymers suitable for oral drug delivery.

Aim: Alendronate (AL) is a nitrogen-containing bisphosphonate drug that exhibits limited oral bioavailability due to predominantly hydrophilic molecular properties. To enhance oral absorption of this important osteoporosis drug, a novel ion-pairing strategy using the cationic polymer polyethylenimine (PEI) was explored as an initial step of an alternate oral drug delivery strategy that attempts to prepare polymer-encapsulated ion pair nanoparticles. Methodology: Electrostatically stabilized AL/PEI association complexes were fabricated by combining AL and PEI solutions prepared in 0.05 M acetate buffer, pH 5.0, at different AL/PEI charge ratios under stirring. The free fraction of AL after complexation with PEI was quantified spectrophotometrically at λ=300 nm using ferric chloride. Particle size distribution and zeta potential of ion pairs formed at different molar AL/PEI ratios were measured by dynamic laser light scattering. Results: The complexation efficiency of PEI was low until an AL/PEI charge ratio of1:1.7. Increasing PEI concentrations effectively decreased the free fraction of AL implying formation of stable ion pairs between the negatively charged AL and the positively charged polymer. The lowest fraction of free AL was 18.7% measured at an AL/PEI charge ratio of 1:33. The mean hydrodynamic diameter of nanoassemblies decreased with increasing AL/PEI charge ratio reaching a limiting value of 71±1.4 nm at AL/PEI=1:33. Corresponding zeta potential measured for these association complexes was +37±2.8 mV. Conclusion: AL/PEI charge ratio greater than 1:1.7 facilitates effective formation of electrostatically stabilized ion pairs that carry a significant positive surface charge indicative of substantial colloidal stability in aqueous solution. The small size of AL/PEI complexes fabricated at 1:33 favors these ion pairs for subsequent encapsulation into biocompatible polymers suitable for oral drug delivery.

Oral bioavailability of the anti-osteoporotic drug alendronate (AL) is limited to ≤ 1% due to unfavorable physicochemical properties. To augment absorption across the gastrointestinal mucosa, an ion pair complex between AL and polyethyleneimine (PEI) was formed and incorporated into nanostructured lipid carriers (NLCs) using a modified solvent injection method. When compared to free AL, ion pairing with PEI increased drug encapsulation efficiency in NLCs from 10% to 87%. Drug release from NLCs measured in vitro using fasted state simulated intestinal fluid, pH 6.5 (FaSSIF-V2) was significantly delayed after PEI complexation. Stability of AL/PEI was pH-dependent resulting in 10-fold faster dissociation of AL in FaSSIF-V2 than measured at pH 7.4. Intestinal permeation properties estimated in vitro across Caco-2 cell monolayers revealed a 3-fold greater flux of AL encapsulated as hydrophobic ion complex in NLCs when compared to AL solution (Papp = 8.43 ± 0.14 × 10−6 cm/s and vs. 2.76 ± 0.42 × 10−6 cm/s). Cellular safety of AL/PEI-containing NLCs was demonstrated up to an equivalent AL concentration of 2.5 mM. These results suggest that encapsulation of AL/PEI in NLCs appears a viable drug delivery strategy for augmenting oral bioavailability of this clinically relevant bisphosphonate drug and, simultaneously, increase gastrointestinal safety.

Oral bioavailability of the anti-osteoporotic drug alendronate (AL) is limited to ≤ 1% due to unfavorable physicochemical properties. To augment absorption across the gastrointestinal mucosa, an ion pair complex between AL and polyethyleneimine (PEI) was formed and incorporated into nanostructured lipid carriers (NLCs) using a modified solvent injection method. When compared to free AL, ion pairing with PEI increased drug encapsulation efficiency in NLCs from 10% to 87%. Drug release from NLCs measured in vitro using fasted state simulated intestinal fluid, pH 6.5 (FaSSIF-V2) was significantly delayed after PEI complexation. Stability of AL/PEI was pH-dependent resulting in 10-fold faster dissociation of AL in FaSSIF-V2 than measured at pH 7.4. Intestinal permeation properties estimated in vitro across Caco-2 cell monolayers revealed a 3-fold greater flux of AL encapsulated as hydrophobic ion complex in NLCs when compared to AL solution (Papp = 8.43 ± 0.14 × 10−6 cm/s and vs. 2.76 ± 0.42 × 10−6 cm/s). Cellular safety of AL/PEI-containing NLCs was demonstrated up to an equivalent AL concentration of 2.5 mM. These results suggest that encapsulation of AL/PEI in NLCs appears a viable drug delivery strategy for augmenting oral bioavailability of this clinically relevant bisphosphonate drug and, simultaneously, increase gastrointestinal safety.

Oral bioavailability of the anti-osteoporotic drug alendronate (AL) is limited to ≤ 1% due to unfavorable physicochemical properties. To augment absorption across the gastrointestinal mucosa, an ion pair complex between AL and polyethyleneimine (PEI) was formed and incorporated into nanostructured lipid carriers (NLCs) using a modified solvent injection method. When compared to free AL, ion pairing with PEI increased drug encapsulation efficiency in NLCs from 10% to 87%. Drug release from NLCs measured in vitro using fasted state simulated intestinal fluid, pH 6.5 (FaSSIF-V2) was significantly delayed after PEI complexation. Stability of AL/PEI was pH-dependent resulting in 10-fold faster dissociation of AL in FaSSIF-V2 than measured at pH 7.4. Intestinal permeation properties estimated in vitro across Caco-2 cell monolayers revealed a 3-fold greater flux of AL encapsulated as hydrophobic ion complex in NLCs when compared to AL solution (Papp = 8.43 ± 0.14 × 10−6 cm/s and vs. 2.76 ± 0.42 × 10−6 cm/s). Cellular safety of AL/PEI-containing NLCs was demonstrated up to an equivalent AL concentration of 2.5 mM. These results suggest that encapsulation of AL/PEI in NLCs appears a viable drug delivery strategy for augmenting oral bioavailability of this clinically relevant bisphosphonate drug and, simultaneously, increase gastrointestinal safety.

OBJECTIVE: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism. METHODS: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively. RESULTS: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ∼2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection. CONCLUSION: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.

OBJECTIVE: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism. METHODS: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively. RESULTS: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ∼2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection. CONCLUSION: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.

OBJECTIVE: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism. METHODS: The tablets were prepared using mixtures of P4/Pluronic® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively. RESULTS: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (∼25%) during the first 2 h but sustained the drug release for ∼48 h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ∼2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection. CONCLUSION: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.

Objective: Anthralin is one of the most effective drugs in psoriasis management. However, its side effects and unfavourable physicochemical properties limit its clinical use. Therefore, the objective of this study was to prepare and evaluate poly (ethylene glycol)-block-poly (ε-caprolactone) (PEG-b-PCL) nanoparticles as a potential delivery system for anthralin. Methods: PEG-b-PCL nanoparticles were prepared by the co-solvent evaporation method and evaluated using a variety of techniques. The effect of drug/polymer weight feed ratio on the nanoparticle size, drug loading capacity and encapsulation efficiency were studied. Drug release kinetics were studied using the dialysis bag method. Nanoparticle size was measured using dynamic light scattering and confirmed by transmission electron microscopy measurements. Results: PEG-b-PCL formed spherical nanoparticles having a diameter of 40 to 80 nm based on the polymer and level of drug loading. The size observed by TEM measurements was slightly smaller than that obtained by DLS due nanoparticle dryness during measurement. Drug loading capacity increased with increasing the drug/polymer ratio and a maximum loading of ~25% was obtained. Anthralin encapsulation in the nano particles resulted in ~120-fold increase in its aqueous solubility. Anthralin was released from the nanoparticles over a prolonged period of time where ~ 45% was released in 48 h. Conclusion: These results confirm the utility of PEG-b-PCL nanoparticles in enhancing the aqueous solubility and sustaining the release of athralin. Therefore, they might be used as a potential delivery system for the treatment of psoriasis.