RESUMO
This paper builds on a previous paper in which new ciprofloxacin extended-release tablets were developed based on a ciprofloxacin-based swellable drug polyelectrolyte matrix (SDPM-CIP). The matrix contains a molecular dispersion of ciprofloxacin ionically bonded to the acidic groups of carbomer, forming the polyelectrolyte-drug complex CB-CIP. This formulation showed that the release profile of the ciprofloxacin bilayer tablets currently commercialised can be achieved with a simpler strategy. Thus, since ciprofloxacin urine concentrations are associated with the clinical cure of urinary tract infections, the goal of this work was to compare the urinary excretion of SDPM-CIP tablets with those of the CIPRO XR® bilayer tablets. A batch of SDPM-CIP tablets was manufactured by the wet granulation method and the CB-CIP ionic complex was obtained in situ. Fasted healthy volunteers received a single oral dose of 500 mg ciprofloxacin of either formulation in a randomised crossover study. Urinary concentrations were assessed by HPLC at intervals up to 36 h. Pharmacokinetic parameters (rate of urinary excretion, maximum urine excretion rate, tmax, area under the curve, amount and percentage of the ciprofloxacin dose excreted in urine) showed no statistical differences between both formulations at any of the time intervals of collection. The processing conditions to obtain SDPM-CIP tablets are easy to scale up since they involve technology currently employed in the pharmaceutical industry and the process is less challenging to implement. In addition, SDPM-CIP tablets met pharmacopoeial quality specifications.
Assuntos
Antibacterianos , Ciprofloxacina , Polieletrólitos , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacocinética , Antibacterianos/urina , Ciprofloxacina/administração & dosagem , Ciprofloxacina/química , Ciprofloxacina/farmacocinética , Ciprofloxacina/urina , Estudos Cross-Over , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Método Duplo-Cego , Liberação Controlada de Fármacos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Polieletrólitos/administração & dosagem , Polieletrólitos/química , Polieletrólitos/farmacocinética , Comprimidos , Adulto JovemRESUMO
The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect. Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.5% w/v of timolol maleate (TM) were obtained and presented a counterionic condensation higher than 75%. For comparison a similar complex obtained with hyaluronic acid (HyH) was also prepared. Although the viscosity of HyNa-TM was significantly higher than that of HyH-TM, in vitro release of TM from both complexes showed a similar extended drug release profile (20-31% over 5h) controlled by diffusion and ionic exchange. Ocular pharmacokinetic study performed in normotensive rabbits showed that HyNa-TM complex exhibited attractive bioavailability properties in the aqueous humor (AUC and Cmax significantly higher and later Tmax) compared to commercial TM eye-drops. Moreover, a more prolonged period of lowered intra-ocular pressure (10h) and a more intense hypotensive activity was observed after instillation of a drop of HyNa-TM as compared to the eye-drops. Such behavior was related to the longer pre-corneal residence times (400%) observed with HyNa-TM complex. No significant changes in rabbit transcorneal permeation were detected upon complexation. These results demonstrate that the ability of HyNa to modulate TM release, together with its mucoadhesiveness related to the viscosity, affected both the pharmacokinetic and pharmacodynamic parameters. The HyNa-TM complex is a potentially useful carrier for ocular drug delivery, which could improve the TM efficacy and reduce the frequency of administration to improve patient compliance.
Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Ácido Hialurônico/administração & dosagem , Timolol/administração & dosagem , Antagonistas Adrenérgicos beta/química , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Córnea/efeitos dos fármacos , Córnea/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Ácido Hialurônico/química , Ácido Hialurônico/farmacocinética , Ácido Hialurônico/farmacologia , Pressão Intraocular/efeitos dos fármacos , Soluções Oftálmicas , Permeabilidade , Coelhos , Timolol/química , Timolol/farmacocinética , Timolol/farmacologiaRESUMO
Novel complexes consisting of Eudragit E100-risedronate are presented. The oral bioavailability of risedronate in rats was determined through its percentage excreted in urine after administration of complexed or free risedronate in fed and fasted conditions. The evaluation of the risedronate gastro-duodenal irritation potential was carried out by macroscopic and histological analyses in an experimental rat model. The degree of counterionic condensation between Eudragit E100 and risedronate was assessed by dialysis with, mechanistic information about the interaction with calcium and the release of risedronate from the complexes being obtained using physiological solution and simulated gastric fluid without pepsin. Non-significant differences were observed in the urinary excretion of risedronate when the complex or free risedronate was administered to fasted rats. However, the urinary excretion of risedronate in the complex group was 4-times higher than in the free risedronate group when animals were concomitantly administered with food. This behavior was related to the high degree of counterionic condensation in the complex (86.5%), which led to a reduction in the calcium induced rate and magnitude of risedronate precipitation and resulted in a decrease in the gastroduodenal damage from the complex, as evidenced by a lower frequency of gastric mucosae hemorrhage. A sustained release of risedronate from the complex was observed toward water, simulated gastric fluid or physiological solution, through an ionic-exchange mechanism. In conclusion, complexation with Eudragit E100 could be a useful strategy to overcome the unfavorable properties of risedronate.
Assuntos
Acrilatos/química , Bloqueadores dos Canais de Cálcio/farmacologia , Química Farmacêutica , Interações Alimento-Droga , Polímeros/química , Ácido Risedrônico/farmacologia , Estômago/efeitos dos fármacos , Administração Oral , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Ingestão de Alimentos , Jejum , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Ácido Risedrônico/química , Ácido Risedrônico/farmacocinéticaRESUMO
We report Doxorubicin ionic complexes with hyaluronic acid (HiH-Dx) or its sodium salt (HiNa-Dx) as tumor-targeting delivery system. The complexes were prepared in situ by mixing aqueous solutions of Dx.HCl with HiH or HiNa. Clear colloidal dispersions with a high degree of counterionic condensation (cc) were obtained. Affinity constants (logKcc) of HiNa-Dx and HiH-Dx were 7.96 and 8.08, respectively. Delivery rates of Dx from the complexes were measured in a Franz-type bicompartimental device. In line with the high affinity constants, loaded Dx was slowly released from the complexes. To test the targeting potential of the complexes, carcinogenic A549 cells overexpressing the CD44 receptors were used. HTR8/SVneo cells without overexpression of CD44 were used as control. In A549 cells, cytotoxicity of both HiH-Dx and HiNa-Dx complexes was 3-fold higher than that of the reference solution. However, no differences were observed between the complexes and free Dx solution in HTR8/SVneo cells. Flow cytometry data suggested successful uptake of Dx in cells, with a greater internalization of Dx in A549 cells than in HTR8/SVneo cells when the complexes were used. Similarly, microscopy imagines revealed a higher concentration of Dx in A549 cells with the complexes. This work provides more detailed information in order to contribute to more solid bases to evaluate the potentiality of Hi as an antineoplastic drug carrier convenient for being used in specific therapeutic indications with minimal side effects.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/químicaRESUMO
Therapeutic agents containing phosphate groups in their molecules have increasing therapeutic impact. The object of this study was to characterize the cationic polyelectrolyte Eudragit E100 (EuE100) as a carrier for drugs containing phosphate groups, using dexamethasone phosphate (DP) as a model. A series of EuE100-DP complexes was obtained by acid-base reaction in which DP neutralized 12.5-75% of the basic groups of EuE100. The solids obtained after solvent evaporation revealed by spectroscopic characterization the complete reaction between the components through the ionic interaction between the amine groups of EuE100 and the phosphate groups of DP. The reversibility of the counterion condensation, evaluated through the proton-withdrawing effect produced by the ionic exchange generated by titration with NaCl, showed a remarkable high affinity between EuE100 and DP. In line, drug delivery in bicompartimental Franz cells toward water as receptor medium was very slow (2% in 6 h). However, it was increased as water was replaced by NaCl solution, which upon diffusion generates ionic exchange. A sustained release of DP with noticeable zero order kinetics accounted for a remarkable high affinity, mainly due to the electrostatic attraction. The release rate remains constant regardless of the saline concentration of the media. Besides, the delivery control is maintained even in gastric simulated fluid, a property not informed previously for EuE100 complexes.
Assuntos
Acrilatos/química , Dexametasona/química , Dimetilaminas/química , Portadores de Fármacos/química , Ésteres/química , Organofosfatos/química , Polímeros/química , Aminas/química , Cátions/química , Cinética , Concentração Osmolar , Cloreto de Sódio/química , Solubilidade , Soluções/química , Solventes/química , Água/químicaRESUMO
Two polymorphic forms of a novel pharmaceutical compound, ciprofloxacin-saccharinate (CIP-SAC), are analyzed using one dimensional (1D) and two dimensional (2D) (1)H nuclear magnetic resonance (NMR) at fast magic angle spinning (MAS). Additionally (15)N spectroscopy and (1)H-(13)C correlation experiments were performed to complement our conclusions. The 1D (1)H NMR spectra of CIP and complexes reveal valuable information about the ionic bonding between ciprofloxacin and saccharine. Additionally, these spectra allow us to perform a clear characterization of each solid form, giving the number of molecules per unit cell in one of the polymorphs. From 2D (1)H-(1)H spectra obtained through double quantum correlations we can arrive at important conclusions about the hydrogen bonding, conformation, and intra and inter-molecular interactions present in these compounds. Comparing and contrasting the (1)H-(1)H correlation data obtained for both polymorphic forms and taking into account the single crystal structure data existing for the solid form CIP-SAC (II) was possible to extract some conclusions on the polymorph CIP-SAC (I) where no single crystal information is available. (1)H MAS NMR is shown to be an important tool in the field of polymorphism and for the characterization of multicomponent pharmaceutical compounds.
Assuntos
Ciprofloxacina/química , Espectroscopia de Ressonância Magnética/métodos , Sacarina/análogos & derivados , Sacarina/química , Cristalografia por Raios X , Teoria QuânticaRESUMO
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing ciprofloxacin hydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ciprofloxacin hydrochloride's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and BA data indicate that ciprofloxacin hydrochloride is a BCS Class IV drug. Therefore, a biowaiver based approval of ciprofloxacin hydrochloride containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Disponibilidade Biológica , Ciprofloxacina/química , Ciprofloxacina/uso terapêutico , Formas de Dosagem , Aprovação de Drogas , Excipientes , Humanos , Absorção Intestinal , Permeabilidade , Solubilidade , Equivalência TerapêuticaRESUMO
Carbomer hydrogels 971pNf, 934pNf and 940Nf loaded with ofloxacin were characterized and their antimicrobial properties evaluated. bactericidal profiles show improved efficacy and prolonged activity exhibited by ofloxacin-containing hydrogels against Pseudomonas aeruginosa. Analysis of bactericidal index (BI) values after a short time of drug exposure confirms the higher potency of hydrogels compared with that of ofloxacin. Increased BI values observed after 24 h indicate prolonged action against the microorganisms evaluated. The bacterial uptake of ofloxacin from hydrogels was higher than that obtained with a solution of free ofloxacin in both fluoroquinolone-sensitive and -resistant P. aeruginosa. The improved uptake in fluoroquinolone-resistant isolates was correlated with the viscosity of hydrogels. The performance of hydrogels seems to be related to their bioadhesive properties that allow prolonged contact time and the release of an effective amount of drug close to bacterial cells. Hence, hydrogels could be used in the development of more effective formulations for topical administration of antibiotics. Improved performance of an old antibiotic can preserve the use of new generation fluoroquinolones.
Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacologia , Ofloxacino/metabolismo , Ofloxacino/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Resinas Acrílicas , Adesividade , Ciprofloxacina/metabolismo , Ciprofloxacina/farmacologia , Fluoroquinolonas/metabolismo , Fluoroquinolonas/farmacologia , Humanos , Hidrogéis , Testes de Sensibilidade Microbiana , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/metabolismo , Reologia , ViscosidadeRESUMO
A new polymorphic form of ciprofloxacin saccharinate (CIP-SAC II) is presented, and compared with CIP-SAC I, a different polymorph which we had previously reported. The characterization techniques used were single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetry analysis and infrared and (13)C solid-state nuclear magnetic resonance spectroscopy. The results obtained from these techniques are consistent. Differential scanning calorimetry and thermogravimetric analysis showed that the reaction between the precursors is completed and the crystalline forms of both salts obtained (I and II) are highly pure. Infrared spectroscopy gave clear evidence of a salt formation. Solid-state nuclear magnetic resonance spectroscopy would indicate some degree of qualitative similarity in the intermolecular interaction scheme in both polymorphs, while thermal analysis data might indicate a difference in quantitative terms. A thorough single crystal structure determination of the new form CIP-SAC II allowed disclosing the most important inter- and intramolecular interactions.
Assuntos
Ciprofloxacina/química , Cristalização/métodos , Sacarina/química , Ciprofloxacina/síntese química , Cristalografia/métodos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Termogravimetria/métodosRESUMO
Mucoadhesive tablets containing nystatin (10 mg) were evaluated in vivo. The assays were carried out with 12 healthy volunteers and the concentration of nystatin in saliva was determined at different times. Tablets remained attached to the buccal mucosa during 270 min +/- 30 min. No evidence of ulceration or bleeding was observed. Typical appearance of intact human buccal mucosa was seen before and after contact with the tablet. The tablets were well accepted by the volunteers, although most of the volunteers reported a light bitter taste, probably due to nystatin. Concentration of nystatin in saliva was several times higher than MIC over a period of approximately 4.5 h, which was in agreement with the behavior observed in vitro. These results allow us to infer that the administration of these mucoadhesive tablets could be advantageous compared to conventional formulations and mucoadhesive extended-release tablets might produce better therapeutic performance than conventional formulations in the treatment of oral candidosis.