Interaction between a cationic polymethacrylate (Eudragit E100) and anionic drugs.

The interaction between a cationic polymethacrylate (Eudragit E, EU) and a set of 7 drugs having acid groups (AH) was studied. Two series of complexes were prepared (EU-AH50 and EU-AH50Cl50), in both 50% of the basic groups of EU were neutralized with AH but in the second, the remaining groups were further neutralized with HCl. These products were stable solid ionic complexes that were characterized through infrared spectroscopy and X-ray power diffraction. All EU-AH50Cl50 at 5-10mg/ml produced clear optically isotropic aqueous dispersions. This result was in line with the increase of the apparent solubility of the low solubility AH assayed. The species distribution, as determined on the complex of diclofenac, showed a degree of counterion condensation as high as 97.9%. The reversibility of the counterion condensation, as well as the affinity between EU and AH, was evaluated through the proton withdrawing effect produced by the ionic exchange generated by titration with NaCl. Besides, drug delivery in bicompartimental Franz cells towards water as receptor medium was very slow. However, it was increased as water was replaced by NaCl solution that upon diffusion generates ionic exchange. Therefore, the EU-AH system behaves as a reservoir of drug able to deliver it in simulated biological fluid.

A ciprofloxacin extended release tablet based on swellable drug polyelectrolyte matrices.

The aim of this work was the development of extended release tablets of 500 mg of ciprofloxacin based on swellable drug polyelectrolyte matrices (SDPM). A set of complexes of carbomer, ciprofloxacin and sodium, (CB-Cip)(50)Na( x ), having a molar ratio Cip/CB acid groups of 0.5 and variable proportions of Na(+) was used to prepare SDPM. Characterization of complexes by FT-IR, powder X-ray diffraction and thermal analysis revealed that Cip, in its protonated form, is ionically bonded to the functional groups of CB. Rates of fluid uptake of (CB-Cip)(50)Na( x ) matrices as well as Cip release in simulated gastric fluid were modulated by changes in the proportion of Na(+) incorporated in the complexes. A direct correlation between fluid uptake and delivery rate was observed along the series of matrices. Release rates were modulated from 1.4 mg/min to 25 mg/min in going from (CB-Cip)(50)Na(10) to (CB-Cip)(50)Na(14). The analysis of kinetic data suggest that rates of swelling, ionic pair dissociation and drug diffusion play a role in the kinetic control of delivery. Complexes were satisfactorily prepared and processed together with small amounts of antiadherent and lubricant excipients to obtain a series of extended release SDPM tablets through the current tableting technology processes. Cip release from matrices was widely modulated by the composition of the complexes yielding a flexible system that allows selecting a composition that releases in 120 min 90% of the dose in simulated gastric fluid.

Application of 1-Dimensional and 2-Dimensional Solid-State Nuclear Magnetic Resonance Spectroscopy to the Characterization of Morphine, Morphine Hydrochloride, and Their Hydrates.

The detailed knowledge of the solid forms of a drug is a key element in pharmaceutical development. Morphine (MOR) is an opiate alkaloid widely used to treat severe acute and chronic pain. Much of the available information on its solid state dates from several decades ago. In order to obtain updated and reliable information, 1-dimensional (1D) and 2-dimensional solid-state nuclear magnetic resonance spectroscopy were used and complemented with powder X-ray diffraction, FTIR, and Raman spectroscopy and thermal analysis. 13C cross-polarization with magic angle spinning 1D spectra accomplish a complete identification of the related forms of MOR. Remarkably, 1H-13C heteronuclear correlation spectra together with FTIR results gave clear evidence that neither MOR nor its hydrate crystallizes as a zwitterion. Our results indicate that the hydrogen bonds in the anhydrate forms have a different nature or strength than in their respective hydrates. The unique information obtained would be useful for the characterization of MOR as a bulk drug, dosage forms, and future developments.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization.

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

Analgesia enhancement and prevention of tolerance to morphine: beneficial effects of combined therapy with omega-3 fatty acids.

OBJECTIVES: Recent evidence associates omega-3 fatty acids (O3) with pain reduction. The aim of this work was to evaluate the antinociceptive effect of O3, either alone or in combination with morphine after acute and chronic administration in rats. As well, a new pharmaceutical mixture that allows the concomitant administration of O3 and morphine as an oral solution was developed. METHODS: Animals were fed on a control or an experimental diet supplemented with O3. They were subjected to the hot-plate test to assess analgesic effect and tolerance to the analgesic effect of morphine. The open-field test was carried out to determine if the differences in the response latency can be related to non-specific sedative effects. KEY FINDINGS: O3 dietary supplementation increased the response latency compared with the control group. Acute treatment with morphine in these groups resulted in an additive antinociceptive effect not related to locomotor activity. Chronic coadministration of morphine with O3 attenuated the development of tolerance. Oral administration of the new pharmaceutical mixture showed analgesic activity with a subtherapeutic dose of morphine. CONCLUSION: This finding suggests a role for O3 as adjuncts to opioids in pain therapy and might contribute to the reduction of the occurrence of morphine side-effects.

In vitro pharmacodynamic properties of a fluoroquinolone pharmaceutical derivative: hydrochloride of ciprofloxacin-aluminium complex.

Some in vitro pharmacodynamic properties of a new aqueous soluble ciprofloxacin (CIPX) derivative, the hydrochloride of its aluminum complex: (HCl.CIPX)(3)Al, are reported. Although (HCl.CIPX)(3)Al had the same MIC as CIPX, the minimum bactericidal activity against Escherichia coli was 2-fold higher than that of CIPX and the rate of killing was slightly delayed compared with time-kill curves obtained with CIPX. (HCl.CIPX)(3)Al showed a longer post-antibiotic effect (PAE). As pharmacodynamic properties of CIPX are not drastically affected by being complexed with aluminium, the increased aqueous compatibility of the complex remains as the main formulation factor for liquid dosage forms.

Ototopical ciprofloxacin in a glycerin vehicle for the treatment of acute external otitis.

We conducted a prospective, randomized, controlled, double-blind study of 33 patients to compare the efficacy and tolerability of a new glycerin formulation of ototopical 0.3% ciprofloxacin with that of a conventional aqueous formulation of ciprofloxacin for the treatment of acute external otitis. Outcomes measures were resolution of discharge, swelling, pain, and redness and the incidence of adverse side effects. Patients were examined on three occasions: on the day of enrollment (visit 1), 48 to 72 hours later (visit 2), and 7 days after enrollment (visit 3). At visit 2, the patients in the glycerin group showed a significantly greater resolution of discharge. We observed the same pattern with respect to swelling, pain, and redness, which resolved more quickly in the glycerin group, although not significantly so. All patients were cured by visit 3, and the two treatments were equally well tolerated. On the basis of our findings, we conclude that the glycerin formulation of ototopical 0.3% ciprofloxacin appears to be at least as effective as the aqueous form in the treatment of acute external otitis--and in the case of otorrhea, more so.

Enhanced intestinal permeability and oral bioavailability of enalapril maleate upon complexation with the cationic polymethacrylate Eudragit E100.

The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug.

[Modification of solid dosage forms: survey in a hospital of the Province of Cordoba]. / Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la Provincia de Córdoba.

BACKGROUND: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16 and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. OBJECTIVES: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. METHODS: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. RESULTS: We analyzed 700 prescriptions for 113 patients, of which 61 (54%) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. CONCLUSION: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.

[Importance of the information systems in public health programs: diabetic patients databases]. / Importancia de los sistemas de información en programas de salud publica: bases de datos de pacientes diabéticos.

AIMS: To describe the characteristics of diabetic patients' population attended in the public health sector of Alta Gracia city. To analyze the use of amount of monthly dispensations as indicator of adherence to treatment, by comparing the results between settings. To assess the coordination of public facilities for patients attention. DESIGN: observational descriptive-analytical study. SETTINGS: Hospital Arturo Umberto Illia (HAUI) and Dirección de Salud Pública (DSP). Alta Gracia (province of Córdoba, Argentina). SUBJECTS: diabetic patients belonging to health programs at public facilities. MAIN MEASURES: demographic and epidemiological variables, amount of monthly dispensations, percentage of global adherence and coordination of settings. RESULTS: From diabetic patients' total (n=540): 52% were attended at HAUI, 39% at DSP, and 9% at both settings; 55% were female, and the average age was about 56 years old; 81% were type 2 Diabetes Mellitus (DM), 1% type 2 insulin-requiring DM, and 17% type 1 DM; the general mean of amount of monthly dispensations by patient was 4,9 in 12 months. Lack of trained personnel for information managing in both facilities was observed. CONCLUSIONS: The databases allowed knowing some demographic characteristics of diabetic population attended in the public sector of Alta Gracia. The dispensing frequency during 12 months was able to be used as an adherence to treatment indicator. The scarce coordination between care levels and jurisdictions (provincial and municipal) were confirmed. For decision making it is necessary to generate and maintain information systems.

Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives.

The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

Characterization of the solubility and solid-state properties of saccharin salts of fluoroquinolones.

Saccharinates salts of the fluoroquinolone antibiotics norfloxacin, ciprofloxacin, ofloxacin, and enrofloxacin were obtained as pure crystalline anhydrous solids with sweet taste. The products were characterized by one- ((13)C) and two-dimensional ((1)H-(13)C) dimensions solid state Nuclear Magnetic Resonance and infrared spectroscopy showing ionic interactions between the saccharine amide and the fluoroquinolone piperazine. Several intermolecular bindings were also identified. Thermal behavior and powder X-ray diffraction provided complementary evidences of salt formation. The series of products showed improved properties with respect to water solubility. A solubility model was developed. These salts would be a good way forward to developing more suitable formulations of these APIs.

NMR and IR characterization of the aluminium complexes of norfloxacin and ciprofloxacin fluoroquinolones.

A set of new aluminium complexes of norfloxacin (NOR) and ciprofloxacin (CIP) that show an improvement in their pharmaceutical properties were studied using solution and solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy. The complexes synthesized with two different methods were compared. One of these methods will allow formulation of the compounds at production scale. High-resolution (13)C spectra were obtained with the cross-polarization and magic angle spinning (CP-MAS) experiment. These spectra were assigned by comparing them with the solution data of the pure drug and by using a quaternary carbon edition technique. The carbon relaxation times in the rotating frame, T(1rhoC), were measured for all the complexes. A two-exponential decay evidences that the complexes are nonhomogeneous. The short T(1rhoC) values are in the range 320-1100 micros and the long values in the range 1.8-7 ms. (27)Al MAS NMR spectra revealed an octahedral coordination between the aluminium ion and oxygens of the pure drug, supporting a 3:1 ligand:metal stoichiometry in both CIP and NOR complexes. The stretching and deformation modes of carboxylic acid and carboxylate and keto groups were analyzed by IR. This technique shows that the same modes are present in the aluminium complexes obtained by the two methods and that the coordination of the fluoroquinolone to aluminium occurs through the 4-keto and 3-carboxylic groups.

Modificación de formas farmacéuticas sólidas: relevamiento en un hospital de la Provincia de Córdoba / [Modification of solid dosage forms: survey in a hospital of the Province of Cordoba].

BACKGROUND: In the hospital setting is frequent to manipulate solid dosage forms (SDF, tablets 16 and capsules), which can affect their physicochemical and biopharmaceutical properties, the pharmacoloeffect and sometimes to cause the appearance of undesirable side effects. OBJECTIVES: To identify the medicines whose SDF is altered in a Hospital of Cordoba (Argentina), to determine how these modifications are made and to establish whether they were properly performed or not. METHODS: We retrospectively analyzed the prescriptions made between the 5th and the 11th of March of 2012 and identified impaired requesting SDF modifications. Open interviews were held with nurses and service visits to each hospital to determine how they manipulated the SDF. RESULTS: We analyzed 700 prescriptions for 113 patients, of which 61 (54

) had manipulations of the received SDF (49 for medical prescription, 7 because they had nasogastric tubes, 3 due to patient choice and 2 by nursing decision). Twenty three medicines were manipulated, but only 12 were correctly manipulated. The major changes were partition of tablets and grinding of tablets or microgranules and dispersible in water. CONCLUSION: The SDF of several medicines is altered in the analyzed hospital, many times without medical indication and scientific justification. It would be appropriate to conduct training courses and establish closer collaborations between pharmacy and nursing units in the investigated hospital.