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1.
Mol Pharm ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32841038

RESUMO

The aim of this study was to develop hydrophobic ionic drug polymer complexes in order to provide sustained drug release from self-emulsifying drug delivery systems (SEDDS). Captopril (CTL) was used as an anionic model drug to form ionic complexes with the cationic polymers Eudragit RS, RL, and E. Complexes of polymer to CTL charge ratio 1:1, 2:1, and 4:1 were incorporated in two SEDDS, namely FA which was 40% Kolliphor RH 40, 20% Kolliphor EL, and 40% castor oil and FB, which was 40% Kolliphor RH 40, 30% glycerol, 15% Kolliphor EL, and 15% castor oil. Blank and complex loaded SEDDS were characterized regarding their droplet size, polydispersity index (PDI), and zeta potential. Resazurin assay was performed on Caco-2 cells to evaluate the biocompatibility of SEDDS. Release of CTL from SEDDS was determined in release medium containing 0.2 mg/mL of 5,5'-dithiobis(2-nitrobenzoic acid) (DNTB) allowing quantification of free drug released into solution via a thiol/disulfide exchange reaction between CTL and DNTB forming a yellow dye. The droplet size of SEDDS FA and SEDDS FB were in the range of 100 ± 20 nm and 40 ± 10 nm, respectively, with a PDI < 0.5. The zeta potential of SEDDS FA and SEDDS FB increased after the incorporation of complexes. Cell viability remained above 80% after incubation with SEDDS FA and SEDDS FB in a concentration of 1% and 3% for 4 h. Without any polymer, CTL was entirely released from both SEDDS within seconds. In contrast, the higher the cationic lipophilic polymer to CTL ratio in SEDDS, the more sustained was the release of CTL. Among the polymers which were evaluated, Eudragit RL provided the most sustained release. SEDDS FA containing Eudragit RL and CTL in a ratio of 1:1 released 64.78 ± 8.28% of CTL, whereas SEDDS FB containing the same complex showed a release of 91.85 ± 1.17% within 1 h. Due to the formation of lipophilic ionic polymer complexes a sustained drug release from oily droplets formed by SEDDS can be achieved. Taking into account that drugs are otherwise instantly released from SEDDS, results of this study might open the door for numerous additional applications of SEDDS for which a sustained drug release is essential.

2.
Biomacromolecules ; 21(9): 3658-3667, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32803961

RESUMO

The aim of this study was to synthesize polymeric excipients that can form mucoadhesive hydrogels containing amphotericin B (AmB) for the treatment of mucosal leishmaniasis. 2-(2-Acryloylaminoethyldisulfanyl)-nicotinic acid (ACENA) was copolymerized with N-vinyl pyrrolidone to obtain thiolated polyvinylpyrrolidone (PVP) that was then complexed with AmB to improve its solubility. The resulting structure of thiolated PVP was evaluated by 1H nuclear magnetic resonance to confirm S-protected thiol groups, and the average molecular mass was determined by size exclusion chromatography. Moreover, variants of thiolated PVP-AmB were studied for the thiol content, amount of complexed AmB, cytotoxicity, mucoadhesive properties, and antileishmaniasis activity. The highest achieved degree of thiolation was 772 ± 24.64 µmol/g, and the amount of complexed AmB was 27.05 ± 0.31 µmol per g of polymer. Thiolated PVP and thiolated PVP-AmB variants (0.5% m/v) showed no cytotoxicity, whereas the equivalent concentration of free AmB reduced Caco-2 cell viability to 70% within 24 h. Thiol-functionalized PVP and PVP-AmB complexes displayed 7.66- and 7.20-fold higher adhesion to the mucosal surface in comparison to unmodified PVP and PVP-AmB, respectively. In addition, variants of thiolated PVP-AmB complexes displayed 100% antileishmaniasis activity in comparison to the 80% killing efficiency of Fungizone, which has been applied in the equivalent AmB concentration of 0.2 µg/mL. Thiol-functionalized PVP proved to be a promising novel excipient for the delivery of AmB providing enhanced solubility and improved mucoadhesive properties which are beneficial for the treatment of mucosal leishmaniasis.

3.
Int J Biol Macromol ; 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810533

RESUMO

The absorption of BCS III drugs can be improved by inhibiting the P-glycoprotein (P-gp) efflux and by increasing the mucoadhesion of natural polymers. In the present study, an esterification of sodium alginate (SA) with thioglycolic acid (TGA) was applied for the preparation of thiolated sodium alginate (TSA). The Ellman's test was applied to quantify the thiol group and a di-sulphide bond test was performed to confirm any SS linkages. The FTIR, DSC, XRD, 1H NMR and charring point determinations were confirmed the thiol group of TSA. The gel like rheological properties with porcine mucous was confirmed by viscoelasticity properties and the mucoadhesion with the rabbit intestine was carried out after compression of 30 mg tablets of TSA. The content of thiol group was in the range of 320-730 µmoL/g of the polymer. The FTIR spectrum showed a characteristic peak of sulfhydryl group at 2557 cm-1 in TSA and the reduction of the charring point from 220 °C to 178 °C was confirmed the thiolation of TSA. A direct relationship of mucoadhesion and swelling was observed with the concentration of TGA and SA, respectively. The prepared microspheres were 2-7 µm in size, excellent rheological properties and non-fickian drug release behavior was observed.

4.
Mol Pharm ; 17(8): 3129-3139, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32598849

RESUMO

This study hypothesized that long carbon chain cationic arginine (Arg) esters can be considered as toxicologically harmless preservatives. Arg-esters with C18 and C24 carbon chains, namely, arginine-oleate (Arg-OL) and arginine-decyltetradecanoate (Arg-DT), were synthesized. Structures were confirmed by FT-IR, 1H NMR, and mass spectroscopy. Both Arg-esters were tested regarding hydrophobicity in terms of log Poctanol/water, critical micelle concentration (CMC), biodegradability, cytotoxicity, hemolysis, and antimicrobial activity against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), Bacillus subtilis (B. subtilis), and Enterococcus faecalis (E. faecalis). Log Poctanol/water of arginine was raised from -1.9 to 0.3 and 0.6 due to the attachment of C18 and C24 carbon chains, respectively. The critical micelle concentration of Arg-OL and Arg-DT was 0.52 and 0.013 mM, respectively. Both Arg-esters were biodegradable by porcine pancreatic lipase. In comparison to the well-established antimicrobials, benzalkonium chloride (BAC) and cetrimide, Arg-esters showed significantly less cytotoxic and hemolytic activity. Both esters exhibited pronounced antimicrobial properties against Gram-positive and Gram-negative bacteria comparable to that of BAC and cetrimide. The minimum inhibitory concentration (MIC) of Arg-esters was <50 µg mL-1 against all tested microbes. Overall, results showed a high potential of Arg-esters with long carbon chains as toxicologically harmless novel preservatives.

5.
Carbohydr Polym ; 242: 116395, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32564864

RESUMO

The potential of Cys-Cys ligands for the development of a novel type of S-protected thiomers was evaluated. S-protected thiomers chitosan-N-acetylcysteine-mercaptonicotinamide (CS-NAC-MNA) and chitosan-N-acetylcysteine-N-acetylcysteine (CS-NAC-NAC) were synthesized and characterized. Viscosity of polymers in presence of various concentrations of S-amino acids was monitored. Mucoadhesive properties were evaluated. FT-IR characterization confirmed the covalent attachment of NAC-MNA and NAC-NAC. Attached sulfhydryl groups were found in the range of 550 µmol/g. In the presence of amino acids bearing a free thiol group viscosity of both polymers increased. This increase in viscosity depended on the amount of added free thiols. Maximum force required to detach CS-NAC-MNA and CS-NAC-NAC from porcine intestinal mucosa was 1.4- and 2.7-fold higher than that required for chitosan, respectively. CS-NAC-MNA adhered up to 3 h, whereas CS-NAC-NAC adhered even for 8 h on this mucosa. Accordingly, the Cys-Cys substructure could be identified as highly potent ligand for the design of mucoadhesive polymers.

6.
Carbohydr Polym ; 237: 116092, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32241444

RESUMO

The purpose of this study was to synthesize S-protected thiolated hyaluronic acid (HA) and to evaluate its potential for 3D cell culture scaffold. S-protected thiolated HA was synthesized by the covalent attachment of N-acetyl-S-((3-((2,5-dioxopyrrolidin-1-yl)oxy)-3-oxopropyl)thio)cysteine hydrazide ligand to the HA. Hydrogels were characterized for texture, swelling behavior and rheological properties. Furthermore, the potential of S-protected thiolated HA hydrogels as a scaffold for tissue engineering was evaluated by cell proliferation studies with Caco-2 and NIH 3T3 cells. It showed enhanced cohesion upon addition of N-acetyl cysteine (NAC). Dynamic viscosity of S-protected thiolated HA hydrogel was increased up to 19.5-fold by addition of NAC and 10.1-fold after mixing with mucus. Furthermore, Caco-2 and NIH 3T3 cells encapsulated into hydrogels proliferated in-vitro. As this novel S-protected thiolated HA is stable towards oxidation and forms highly cohesive gels when getting into contact with endogenous thiols due to disulfide-crosslinking, it is a promising tool for 3D cell culture scaffold.

7.
Int J Pharm ; 577: 119040, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31953091

RESUMO

The purpose of this study was to synthesize a highly mucoadhesive tetradeca-thiolated ß-cyclodextrin (ß-CD) by replacement of all primary OH groups at C-6 position and all secondary OH groups at C-2 position of ß-CD backbone viaSH groups and to evaluate its rheological and mucoadhesive properties in-vitro. Primary and secondary OH groups of ß-CD were substituted by SH groups using a microwave-assisted method. The structure of tetradeca-thiolated ß-CD was confirmed by FTIR and 1H NMR spectroscopy. The modified ß-CD was evaluated for SH content, thiol stability towards oxidation and cytotoxicity. Moreover, the viscoelastic behavior of the modified oligomer was investigated via rheological studies with porcine intestinal mucus and fibrous structural protein keratin, whereas mucoadhesive properties were evaluated using different porcine mucosae. Tetradeca-thiolated ß-CD oligomer displayed 8144 ± 317 µmol thiol groups per gram. These thiol groups displaying a pKa value of 8.2 were stable at pH 4 but prone to oxidation at higher pH values. The newly synthesized thiolated CD did not show any cytotoxicity to Caco-2 cells at a concentration of 0.5% (m/v) within 24 h. Due to the addition of 0.5 and 2% (m/v) tetradeca-thiolated ß-CD to mucus and keratin, the dynamic viscosity was increased up to 7.6- and 5.9- fold, respectively, within 4 h at 37 °C. Moreover, in-vitro mucoadhesion studies of tetradeca-thiolated CD showed 78.6-, 60.3-, 62.3- and 49.3- fold improved mucoadhesion on intestinal, buccal, bladder and vaginal mucosa as compared to unmodified ß-CD, respectively. According to these results, tetradeca-thiolated ß-CD might be a promising auxiliary agent to provide a prolonged residence time of drug delivery systems on different mucosal surfaces.

8.
ACS Appl Mater Interfaces ; 12(7): 7942-7950, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31985207

RESUMO

The purpose of the study was to develop a per-6-thiolated α-cyclodextrin (α-CD) by substituting all primary hydroxyl groups of α-CD with thiol groups and to assess its solubility-improving and permeation-enhancing properties for a BCS Class IV drug in vitro as well as in vivo. The primary hydroxyl groups of α-CD were replaced by iodine, followed by substitution with -SH groups. The structure of per-6-thiolated α-CD was approved by FT-IR and 1H NMR spectroscopy. The per-6-thiolated was characterized for thiol content, -SH stability, cytotoxicity, and solubility-improving properties by using the model BCS Class IV drug furosemide (FUR). The mucoadhesive properties of the thiolated oligomer were investigated via viscoelastic measurements with porcine mucus, whereas permeation-enhancing features were evaluated on the Caco-2 cell monolayer and rat gut mucosa. Furthermore, oral bioavailability studies were performed in rats. The per-6-thiolated α-CD oligomer displayed 4244 ± 402 µmol/g thiol groups. These -SH groups were stable at pH ≤ 4, exhibiting a pKa value of 8.1, but subject to oxidation at higher pH. Per-6-thiolated α-CD was not cytotoxic to Caco-2 cells in 0.5% (m/v) concentration within 24 h. It improved the solubility of FUR in the same manner as unmodified α-CD. The addition of per-6-thiolated α-CD (0.5% m/v) increased the mucus viscosity up to 5.8-fold at 37 °C within 4 h. Because of the incorporation in per-6-thiolated α-CD, the apparent permeability coefficient (Papp) of FUR was 6.87-fold improved on the Caco-2 cell monolayer and 6.55-fold on the intestinal mucosa. Moreover, in vivo studies showed a 4.9-fold improved oral bioavailability of FUR due to the incorporation in per-6-thiolated α-CD. These results indicate that per-6-thiolated α-CD would be a promising auxiliary agent for the mucosal delivery of, in particular, BCS Class IV drugs.

9.
Int J Pharm ; 573: 118863, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31765777

RESUMO

The aim of the present study was to develop hydrophobic H-bond pairs (HHPs) of leuprolide (LEU) with non-ionic surfactants to improve its membrane permeability. LEU was lipidized via hydrophobic H-bond pairing (HHP) with the sucrose esters (SEs) sucrose laurate HLB 15 (SLA-15), sucrose palmitate HLB 16 (SPA-16), sucrose stearate HLB 11 (SST-11) and sucrose stearate HLB 15 (SST-15). HHPs were evaluated regarding precipitation efficiency in water, zeta potential, log Pn-octanol/water and dissociation behavior at various pH over time. Cytotoxic potential of HHPs of LEU with SST-11 was investigated on Caco-2 cells. Subsequently, ex vivo permeation studies were carried out across freshly excised Sprague-Dawley rat intestinal mucosa. At a molar ratio of LEU to SEs of 1:≥1 a precipitation efficiency of above 50% was achieved. Zeta potential of complexes was neither influenced by the type nor the amount of added surfactants. Log Pn-octanol/water of LEU was up to 250-fold increased due to HHP utilizing SST-11. Dissociation studies showed that HHPs of LEU with SST-11 dissociate up to 20% in gastrointestinal (GI) pH conditions within 4 h. Moreover, HHPs of LEU with SST-11 exhibited no cytotoxicity. Ex vivo permeation studies revealed 2-fold improved membrane permeation of HHPs of LEU with SST-11 compared to free LEU. Findings of this study show that HHP can be considered as a promising strategy to improve membrane permeation.

10.
Colloids Surf B Biointerfaces ; 184: 110527, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31577976

RESUMO

It was aim of this study to synthesize micro-composites comprising halloysite nanotubes (HNTs) and the cationic polymer chitosan as mucoadhesive sustained release drug delivery system. Micro-composites were characterized for preparation yield, size, micromeritic properties and swelling behavior. Chemical composition of micro-composites was characterized by FTIR, XRD and TGA. Scanning electron microscopy (SEM) was used to study their surface morphology. Micro-composites were studied for adhesion on intestinal mucosa as well as for release behavior of metoclopramide hydrochloride used as model drug. Preparation yield was found to be in the range of 35.14 ± 1.5-53.97 ± 5.23%. Micro-composites exhibited a mean size range of 0.151 ± 0.49 µm. SEM showed a spherical shape with rough curved porous surface. Micro-composites exhibited excellent flowability and maximum swelling at acidic pH. XRD results showed crystalline nature of micro-composites. HNTs/micro-composites with highest concentration of chitosan displayed maximum adherence of 89 ± 1.79% on intestinal mucosa after 3 h. Drug release recorded was 66.8% at pH 1.2 and 46.7% at pH 5.5 within 25 h. Chitosan coated HNTs showed remarkable mucoadhesion and sustained release of metoclopramide proving their suitability as mucoadhesive drug delivery system.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Metoclopramida/química , Nanotubos/química , Adesividade , Liberação Controlada de Fármacos , Humanos , Mucosa Intestinal/química , Tamanho da Partícula , Porosidade , Propriedades de Superfície
11.
Mol Pharm ; 16(6): 2817-2825, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31070926

RESUMO

The aim of the present study was to develop zeta potential-changing polyphosphate nanoparticles (pp-NPs) in order to overcome the diffusion barrier of the mucus gel layer and to provide an enhanced cellular uptake. pp-NPs were obtained by in situ gelation between cationic polyethylene imine and anionic polyphosphate. The resulting pp-NPs were characterized with regard to size and zeta potential. Phosphate release studies were carried out by incubation of pp-NPs with isolated as well as cell-associated intestinal alkaline phosphatase (IAP) and quantified by malachite green assay. Correspondingly, change in the zeta potential was measured, and pp-NPs were analyzed by scanning electron microscopy studies. Mucus permeation studies were performed with porcine intestinal mucus via the transwell insert method and rotating tube method. Furthermore, cell viability and cellular uptake were investigated on Caco-2 cells. The resulting pp-NPs displayed a mean size of 269.16 ± 1.12 nm and a zeta potential between -9 and -10 mV in the characterization studies. Within 4 h, a remarkable amount of phosphate was released from pp-NPs incubated with isolated IAP as well as cell-associated IAP and zeta potential raised up from -9.14 ± 0.45 to -1.75 ± 0.46 mV. Compared with dephosphorylated polyphosphate nanoparticles (de-pp-NPs), a significantly enhanced mucus permeation of pp-NPs was observed. Moreover, pp-NPs did not exhibit cytotoxicity. Cellular uptake increased 2.6-fold by conversion of pp-NPs to de-pp-NPs following enzymatic cleavage. Taking the comparatively simple preparation method and the high mucus-permeating properties of pp-NPs and high cellular uptake properties of de-pp-NPs into account, these nanocarriers might be promising novel tools for mucosal drug delivery.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Polietilenoimina/química , Polifosfatos/química , Animais , Células CACO-2 , Sobrevivência Celular/fisiologia , Humanos , Intestinos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Suínos
12.
Int J Pharm ; 564: 180-187, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30981873

RESUMO

Intravesical mucoadhesive self-emulsifying drug delivery system (SEDDS) have been developed via synthesis and incorporation of S-protected chitosan CS-MNA into SEDDS. N-acetyl cysteine-6-mercaptonicotinamide (NAC-6-MNA) was synthetized via disulphide exchange reaction between N-acetyl cysteine and 6-mercaptonicotinamide dimer. NAC-6-MNA was attached to chitosan (CS) via carbodiimide mediated amide bond formation. The S-protected chitosan (CS-MNA) and chitosan (CS) were complexed with sodium dodecyl sulfate (CS-SDS and CS-MNA-SDS) and incorporated in SEDDS at a concentration of 1% (m/m). SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS were characterized regarding size and zeta potential. 6-MNA release from SEDDS-CS-MNA-SDS in presence of glutathione was evaluated. Mucoadhesive properties of these novel formulations were assessed via rheology measurements and residence time evaluation on porcine bladder. Cytotoxicity of formulations was determined on porcine bladder. S-protected chitosan displayed 465.42 ±â€¯75.64 µmol of NAC-6-MNA per gram of polymer. SEDDS and SEDDS-CS-SDS and SEDDS-CS-MNA-SDS displayed a size of 22.5 ±â€¯0.9, 37.4 ±â€¯0.1 and 98.5 ±â€¯5.7 nm at a concentration of 20% (m/v) in simulated urine pH 6.2, and a zeta potential of -5.1 ±â€¯0.2, -1.6 ±â€¯0.1 and -1.4 ±â€¯0.2 mV at a concentration of 1% (m/v) in water at pH 6, respectively. 80% of MNA was released from SEDDS-CS-MNA-SDS in presence of glutathione. Viscosity of SEDDS-CS-SDS/mucus and SEDDS-CS-MNA-SDS/mucus was 6- and 18-fold higher than SEDDS/mucus after 90 min incubation. 2.6%, 5.8% and 14% of SEDDS, SEDDS-CS-SDS and SEDDS-CS-MNA-SDS remained on bladder mucosa within 120 min, respectively. No pronounced bladder cytotoxicity was observed in presence of 0.5% (m/v) formulations. According to these results, SEDDS-CS-MNA-SDS might be a promising carrier for intravesical drug administration.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Niacinamida/química , Adesividade , Administração Intravesical , Animais , Sobrevivência Celular/efeitos dos fármacos , Quitosana/administração & dosagem , Emulsões , Membrana Mucosa/química , Muco , Niacinamida/administração & dosagem , Dodecilsulfato de Sódio/administração & dosagem , Dodecilsulfato de Sódio/química , Suínos , Bexiga Urinária/química , Bexiga Urinária/efeitos dos fármacos
13.
Future Microbiol ; 14: 411-424, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30854897

RESUMO

AIM: The purpose of this study was to develop S-protected thiolated α-cyclodextrin-iodine complexes providing prolonged mucosal residence time and sustained release of the antimicrobial agent. MATERIALS & METHODS: First, L-cysteine was conjugated with 2-mercaptonicotinic acid to generate cysteine-2-mercaptonicotinic acid (Cys-MNA). Subsequently, α-CD was oxidized with NaIO4 and Cys-MNA was bound to the resulting aldehyde groups via reductive amination. Finally, iodine was incorporated into complex. RESULT: S-protected thiolated α-CD displayed 3804 µmol/g MNA groups. The inclusion constant (KC) between iodine and S-protected thiolated α-CD was 5.37 × 104 M-1. In vitro release of iodine was around 15% per hour, whereas mucoadhesive properties showed 38-fold improvement in mucoadhesion. The complex did not show cytotoxicity at a concentration of 0.5% (m/v). In addition, complexes exhibited pronounced antimicrobial activity against Staphylococcus aureus and Escherichia coli. CONCLUSION: According to these results, S-protected thiolated α-CD-iodine complex might be a promising novel formulation for the mucosal use of iodine.


Assuntos
Antibacterianos/química , Mucosa Intestinal/química , Iodo/química , Ácidos Nicotínicos/química , Compostos de Sulfidrila/química , alfa-Ciclodextrinas/química , Adsorção , Animais , Antibacterianos/farmacologia , Células CACO-2 , Escherichia coli/efeitos dos fármacos , Humanos , Iodo/farmacologia , Cinética , Estrutura Molecular , Oxirredução , Staphylococcus aureus/efeitos dos fármacos , Suínos , alfa-Ciclodextrinas/farmacologia
14.
Int J Biol Macromol ; 130: 148-157, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30779984

RESUMO

The aim of this study was to synthesize novel polymeric excipients forming mucoadhesive films for treatment of vaginal microbial infections. 2-(2-Amino ethyldisulfanyl) nicotinic acid was conjugated with gellan gum via amide bond formation. The structure of the resulting S-protected gellan gum was confirmed by 1H NMR. S-protected gellan gum variants were characterized for thiol content, cytotoxicity, rheological behaviour and film forming capability. Depending on the added amount of AMENA degree of thiolation was 81 ±â€¯13 (S-GG 81) and 174 ±â€¯16 (S-GG 174) µmol/g, respectively. Vaginal films were casted from S-protected gellan gum variants and studied for adherence to vaginal mucosa, drug release and antimicrobial activity. S-protected gellan gum remained biocompatible showing >87% cell viability. S-GG 81 and S-GG 174 exhibited 1.84- and 4.3-fold increased dynamic viscosity in porcine mucus in comparison to unmodified gellan gum, respectively. Compared to gellan gum films, thiol functionalized gellan gum films showed 3-fold improved adhesion on mucosal surface over a period of 3 h along with significant antimicrobial activity. Moreover, S-protected gellan gum provided a sustained release of metronidazole. According to these results, S-protected gellan gum proved to be a promising novel excipient for casting vaginal films, exhibiting strongly improved mucoadhesive and antimicrobial properties.


Assuntos
Portadores de Fármacos/química , Metronidazol/química , Metronidazol/farmacologia , Membrana Mucosa/química , Polissacarídeos Bacterianos/química , Enxofre/química , Vagina/química , Adesividade , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Células CACO-2 , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Teste de Materiais , Reologia , Suínos
15.
Mol Pharm ; 15(8): 3527-3534, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30047266

RESUMO

The aim of this study was to synthesize iodine containing polymeric excipients for mucosal treatment of microbial infection exhibiting a prolonged mucosal residence time by forming an adhesive gel on the mucosal surface. In order to achieve this aim, 2-(2 acryloylamino-ethyldisulfanyl)-nicotinic acid (ACENA) was copolymerized with N-vinylpyrrolidone (NVP) to obtain thiolated polyvinylpyrrolidone (PVP) for complexation with iodine. The average molecular mass of different thiolated PVP variants was determined by size exclusion chromatography. The structure of thiolated PVP was confirmed by 1H NMR. Thiolated PVP variants were characterized for thiol content, cytotoxicity, iodine loading capacity, rheological behavior, and adhesion time on mucosa. The highest achieved degree of thiolation was 610 ± 43 µmol/g, and the maximum recorded iodine loading was 949 ± 31 µmol/g of polymer. Thiolated PVP variants (0.5% m/v) showed no toxicity after incubation on Caco-2 cells for the period of 3 and 24 h, respectively. Thiolated PVP and thiolated PVP-iodine complexes exhibited a 5.4- and 4.4-fold increased dynamic viscosity in porcine mucus in comparison to PVP and PVP-iodine complex, respectively. Compared to PVP and PVP-iodine complex thiol-functionalized PVP and PVP-iodine complexes demonstrated significantly prolonged attachment to mucosal surface over a period of 3 h. Thiol functionalized PVP proved to be a promising novel excipient for complexation with iodine and to exhibit strongly improved mucoadhesive properties.


Assuntos
Adesivos/farmacologia , Anti-Infecciosos Locais/farmacologia , Excipientes/farmacologia , Povidona-Iodo/farmacologia , Compostos de Sulfidrila/farmacologia , Adesivos/síntese química , Animais , Anti-Infecciosos Locais/síntese química , Células CACO-2 , Composição de Medicamentos/métodos , Excipientes/síntese química , Glicoproteínas/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Povidona-Iodo/síntese química , Compostos de Sulfidrila/síntese química , Suínos
16.
J Control Release ; 271: 55-59, 2018 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-29287908

RESUMO

Self-emulsifying drug delivery systems (SEDDS) are considered as a potential platform for mucosal drug delivery. The in vitro-in vivo correlation, however, is in particular for this type of delivery systems considerably poor resulting quite often in a simple trial and error approach in order to optimize formulations. One reason for this situation is certainly the lack of appropriate methods to determine the drug release from SEDDS in vitro, as the process is particularly troublesome. For quantification of the drug in the release medium the oily droplets need to be separated. In most studies this is achieved by utilizing a separating membrane such as dialysis membranes or filters having a huge impact on the obtained release profile. Moreover, sink conditions are very often not provided. As drug release from SEDDS is based on a simple diffusion process from a lipophilic liquid phase into an aqueous liquid phase, a likely more meaningful way to characterize the release behaviour might be just the determination of the distribution coefficient (log DSEDDS/RM) of the drug between the SEDDS pre-concentrate and the release medium (RM). As log D is simply the measure of the difference in solubility of a compound in two phases, it can be determined by measuring solubility of drug or drug complex in the SEDDS pre-concentrate and in the release medium in a separate manner. The impact of log DSEDDS/RM on the in vivo drug release behaviour is discussed including various case studies.


Assuntos
Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Emulsões
17.
Bioimpacts ; 7(3): 177-192, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29159145

RESUMO

Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol). Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (χ) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Results: The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non-Fickian diffusion or anomalous mechanism. Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH-sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery.

18.
Des Monomers Polym ; 20(1): 308-324, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29491802

RESUMO

In present investigation new formulations of Sodium Alginate/Acrylic acid hydrogels with high porous structure were synthesized by free radical polymerization technique for the controlled drug delivery of analgesic agent to colon. Many structural parameters like molecular weight between crosslinks (Mc ), crosslink density (Mr ), volume interaction parameter (v2,s ), Flory Huggins water interaction parameter and diffusion coefficient (Q) were calculated. Water uptake studies was conducted in different USP phosphate buffer solutions. All samples showed higher swelling ratio with increasing pH values because of ionization of carboxylic groups at higher pH values. Porosity and gel fraction of all the samples were calculated. New selected samples were loaded with the model drug (diclofenac potassium).The amount of drug loaded and released was determined and it was found that all the samples showed higher release of drug at higher pH values. Release of diclofenac potassium was found to be dependent on the ratio of sodium alginate/acrylic acid, EGDMA and pH of the medium. Experimental data was fitted to various model equations and corresponding parameters were calculated to study the release mechanism. The Structural, Morphological and Thermal Properties of interpenetrating hydrogels were studied by FTIR, XRD, DSC, and SEM.

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