Polymer-amino-functionalized silica composites for the sustained-release multiparticulate system.

This study presents an interesting and promising strategy for producing an oral multiparticulate formulation of the sustained-release of diclofenac sodium (DS) consisting of subunits closed inside hard gelatin capsules (each capsule contains ~50mg of diclofenac sodium). The subunits in the form of beads were produced through the encapsulation of diclofenac sodium dispersed within a nondisintegrating polymer carrier by a silica gel functionalized with the 3-aminopropyl groups. The hybrid silica gel, which plays the role of enteric coating, was fabricated by the gelation of the liquid silica precursors mixture (i.e. tetraethoxysilane (TEOS) and (3-aminopropyl)triethoxysilane (APTES)) in the vapor phase of ammonia. The conducted studies reveal that the introduction of the hybrid silica gel into the solid DS dispersion facilitates prolonged release in the neutral environment of the intestine. Since the ability of the multiparticulate formulation to control the release of the drug depends on the properties of its subunits, studies involving the low temperature N2 sorption, DSC analysis together with spectroscopic techniques (XRD, SEM, 29Si MAS NMR) were conducted.

THE PROCESS OF MASS TRANSFER ON THE SOLID-LIQUID BOUNDARY LAYER DURING THE RELEASE OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE FROM TABLETS IN A PADDLE APPARATUS.

The release study of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) from two formulations of the tablets in the paddle apparatus using different rotation speeds to characterize the process of mass transfer on the solid-liquid boundary layer was carried out. The dissolution process of active substances was described by values of mass transfer coefficients, the diffusion boundary layer thickness and dimensionless numbers (Sh and Re). The values of calculated parameters showed that the release of DIC and PAP from tablets comprising potato starch proceeded faster than from tablets containing HPMC and microcrystalline cellulose. They were obtained by direct dependencies between Sh and Re in the range from 75 rpm to 125 rpm for both substances from all tablets. The description of the dissolution process with the dimensionless numbers make it possible to plan the drug with the required release profile under given in vitro conditions.

Encapsulation of diclofenac sodium within polymer beads by silica species via vapour-phase synthesis.

The present study concerns the preparation of ternary composites via the in situ encapsulation of solid dispersion of diclofenac sodium within the acrylic polymer beads. The encapsulating species were produced through the hydrolysis and condensation of the silica precursors (tetraethoxysilane or ethyltriethoxysilane) introduced into the solid dispersion. The transformation of precursors occurred in the vapor phase of ammonia. A great advantage of the presented vapor-phase method is preventing the desorption of the highly soluble drug during gelation of silica precursors, which stands in contrast to the conventional sol-gel processes occurring in the solution. The conducted studies, involving the low temperature N2 sorption together with spectroscopic techniques, provide insight into the structural differences of drug loaded particles. They reveal that the formation of silica gel accompanies the conversion of the drug into its amorphous form. Finally, the desorption profiles of diclofenac sodium demonstrate that the deposition of silica gel successfully diminishes the degree of the initial drug desorption while significantly modifying its release rate.

PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS.

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-µm column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose.

DISSOLUTION PROPERTIES AND KINETIC STUDY OF SULFADIMIDINE AND TRIMETHOPRIM TABLETS CONTAINING FOUR DIFFERENT SUPERDISINTEGRANTS.

The objective of this study was to evaluate and compare the effect of four superdisintegrants such as croscarmellose sodium (Ac-Di-Sol), crospovidone (Kollidon CL and with smaller particle sizes Kollidon CL-F), sodium starch glycolate (Explotab) in combination with ß-lactose and microcrystalline cellulose (Avicel PH-102) as base excipients exhibiting properties of directly compressed tablets and increasing the disintegration and the dissolution rate of sulfadimidine sodium (SDD-Na) and trimethoprim (TMP). All tablets were prepared by direct compression method and superdisintegrants were used at 2% for all formulations. The tablets were evaluated with regard to uniformity of weight, hardness, friability, drug content, disintegration time and dissolution properties. Dissolution properties such as t50% and t80% (time to release 50 and 80% of drug), DP3045 (percent of drug dissolved in 30 and 45 min) and the dissolution rate constant value (K) were considered in comparing the dissolution results. The results showed that crospovidone (Kollidon CL) provides the shortest disintegration time and the fastest rate of dissolution for both TMP and SDD-Na. The kinetic study of the dissolution data reveals that in vitro release profiles of TMP and SDD-Na can be best explained by first order model or by Higuchi model. The obtained data were plotted into Korsmeyer-Peppas equation to find out the confirmed diffusion mechanism. For TMP release, the values of the release exponent are beyond the limits of Korsmeyer model, so-called, power law. For SDD-Na release, exponent values are characteristic for anomalous transport (non-Fickian) or the value of the release exponent is beyond the limits of Korsmeyer model.

Dissolution Studies of Papaverine Hydrochloride from Tablets in Three Pharmacopoeia Apparatuses.

BACKGROUND: In tablet production, the most important aspects are the physical properties of the tablets and their dissolution studies, which can be performed in four pharmacopoeial apparatuses. There are differences between them in construction and action, so differences in the results obtained are possible. OBJECTIVES: The aim of the study was to compare the release of a model drug substance (papaverine hydrochloride) from tablets in three pharmacopoeial dissolution apparatus: a basket, a paddle (closed system) and flow-through cell (open system). MATERIAL AND METHODS: The one series of tablets were produced by direct compression in a tablet press. The physical properties of the tablets (weight and size uniformity test, friability and hardness tests, disintegration time test), drug content and the release study of papaverine hydrochloride from tablets were studied in three dissolution apparatuses. The content of the active substance was studied spectrophotometrically. RESULTS: All tablets met the pharmacopoeic requirements. Over 80% of the model substance released from the tablets after 14 min in flow through the cell apparatus, while in the basket and paddle apparatuses after about 7 min 30 sec. After 20 min, the amount of the substance released in all apparatuses was over 90%. CONCLUSIONS: The release profiles of the drug substance in paddle and basket apparatuses were similar, while in the flow-through cell apparatus it was slightly slower. When the study conditions and composition of the tablets are the same, the release profile of the drug can be affected by the type of dissolution apparatus.

Influence of Polymer Type on the Physical Properties and Release Profile of Papaverine Hydrochloride From Hard Gelatin Capsules.

BACKGROUND: The capsule is one of the most important solid dosage forms in the pharmaceutical industry. It is easier and faster to produce than a tablet, because it requires fewer excipients. Generally, capsules are easy to swallow and mask any unpleasant taste of the substances used while their release profiles can be easily modified. Papaverine hydrochloride was used as a model substance to show different release profiles using different excipients. OBJECTIVES: The main aim of the study was to analyze the impact of using different polymers on the release profile of papaverine hydrochloride from hard gelatin capsules. MATERIAL AND METHODS: Six series of hard gelatin capsules containing papaverine hydrochloride as a model drug and different excipients were made. Then, the angle of repose, flow rate, mass flow rate and volume flow rate of the powders used for capsule production were analyzed. The uniform weight and disintegration time of the capsules were studied. The dissolution study was performed in a basket apparatus, while the amount of papaverine hydrochloride released was determined spectrophotometrically at 251 nm. RESULTS: Only one formula of powder had satisfactory flow properties, while all formulas had good Hausner ratios. The best properties were from powder containing polyvinylpyrrolidone 10k. The disintegration time of capsules varied from 1:30 min to 2:00 min. As required by Polish Pharmacopoeia X, 80% of the active substance in all cases was released within 15 minutes. The capsules with polyvinylpyrrolidone 10k were characterized by the longest release. On the other hand, capsules containing microcrystalline cellulose had the fastest release profile. CONCLUSIONS: Using 10% of different polymers, without changing the other excipients, had a significant impact on the physical properties of the powders and papaverine hydrochloride release profile. The two most preferred capsule formulations contained either polyvinylpyrrolidone 10k or microcrystalline cellulose.

The effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice.

BACKGROUND: According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2-4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. METHODS: The antidepressant-like effect was assessed by the forced swim test in mice. RESULTS: Ifenprodil potentiated the antidepressant-like effect of imipramine (15mg/kg) and fluoxetine (5mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5mg/kg) or tianeptine (15mg/kg). CONCLUSION: The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.

The effect of excipients on the release kinetics of diclofenac sodium and papaverine hydrochloride from composed tablets.

For increased analgesic effect, new composed tablets containing diclofenac sodium (DIC) with an addition of papaverine hydrochloride (PAP) were prepared to investigate the mechanism of release of the active substances from tablets with different excipients in eight different formulations. To detect the possible interactions between active substances and excipients differential scanning calorimetry (DSC) was used. A shift of the melting point and enthalpy values of the physical mixtures of tablets components suggested a kind of interaction between components in certain formulations, however, the tabletting process was not disturbed in any of them. Kinetics of drug release from formulations was estimated by zero order, first order and Higuchi and Korsmeyer-Peppas models using results of dissolution of DIC and PAP from tablets. The study revealed that the mechanism of release of active substances was dependent on the excipients contained in tablets and the best fitted kinetics models were obtained for formulations with potentially prolonged release of DIC and PAP.

[Influence of polymer type on the physical properties and the release study of papaverine hydrochloride from tablets]. / Wplyw rodzaju polimeru na wlasciwosci fizyczne i proces uwalniania chlorowodorku papaweryny z tabletek.

BACKGROUND: Polymers are widely used in drug manufacturing. Researchers studied their impact on the bioavailability of active substances or on physical properties of tablets for many years. OBJECTIVES: To study the influence of polymer excipients, such as microcrystalline cellulose (Avicel PH 101, Avicel PH 102), croscarmellose sodium, crospovidone or polyvinylpyrrolidone, on the release profile of papaverine hydrochloride from tablets and on the physical properties of tablets. MATERIAL AND METHODS: Six series of uncoated tablets were prepared by indirect method, with previous wet granulation. Tablets contained papaverine hydrochloride and various excipients. The physical properties of the prepared granules, tablets and the release profile of papaverine hydrochloride from tablets were examined. The content of papaverine hydrochloride from the release study were determined spectrophotometrically. RESULTS: All tablets met the pharmacopoeia requirements during following tests: the disintegration time of tablets, uncoated tablets resistance to abrasion, the weight uniformity and dose formulations, their dimensions, the resistance to crushing of tablets and the drug substance content in the tablet. In four cases more than 80% of papaverine was released up to 2 min, in one formula it was up to 5 min, and in last one up to 10 min. CONCLUSIONS: Tablets containing crospovidone disintegrated faster than tablets with croscarmellose sodium. Adding gelatinized starch to the tablet composition increased the disintegration time, hardness and delayed the release of papaverine. During the wet granulation process, granules containing polyvinylpyrrolidone were characterized by a suitable flow properties and slightly prolonged disintegration time. Tablets containing Avicel PH 102 compared to tablets with Avicel PH 101 had less weight loss during the test of mechanical resistance, improved hardness and faster release profile of papaverine from tablets.

[Modern polymers in matrix tablets technology]. / Nowoczesne polimery w technologii tabletek matrycowych.

Matrix tablets are the most popular method of oral drug administration, and polymeric materials have been used broadly in matrix formulations to modify and modulate drug release rate. The main goal of the system is to extend drug release profiles to maintain a constant in vivo plasma drug concentration and a consistent pharmacological effect. Polymeric matrix tablets offer a great potential as oral controlled drug delivery systems. Cellulose derivatives, like hydroxypropyl methylcellulose (HPMC) are often used as matrix formers. However, also other types of polymers can be used for this purpose including: Kollidon SR, acrylic acid polymers such as Eudragits and Carbopols. Nevertheless, polymers of natural origin like: carragens, chitosan and alginates widely used in the food and cosmetics industry are now coming to the fore of pharmaceutical research and are used in matrix tablets technology. Modern polymers allow to obtain matrix tablets by 3D printing, which enables to develop new formulation types. In this paper, the polymers used in matrix tablets technology and examples of their applications were described.

[Application of ß-cyclodextrin in the formulation of ODT tablets containing ibuprofen]. / Zastosowanie ß-cyklodekstryn w formulacji tabletek ODT zawierajacych ibuprofen.

BACKGROUND: Oral disintegrating tablet (ODT) dissolves or disintegrates in saliva and then it is swallowed. Diluent in direct compression formulation has a dual role: it increases bulk of the dosage form and it promotes binding of the constituent particles of the formulation. Hence, selection of diluent is important in tablets produced by direct compression method. OBJECTIVES: The aim of this work was to exame feasibility of preparing and optimizing oral disintegrating tablet formulation using ß-cyclodextrin as a diluent. MATERIAL AND METHODS: 400 mg round tablets were prepared by direct compression method on single punch tablet press using flat plain-face. 60% ß-CD and MCC (microcrystalline cellulose - MCC-Vivapur 102) were used at different proportions for all the formulations. 5% of Kollidon CL was added as superdisintegrant. The eight formulations prepared were assessed for weight variation, thickness, disintegration time, hardness and dissolution rate according to FP IX. A dissolution test was performed at 37ºC using the paddle method at 50 rpm with 900 mL phosphate buffer (pH 6.8) as a dissolution medium. RESULTS: The content of ibuprofen sodium was found inside the ± 5% of the theoretical value. Hardness values of presented tablets were in the range 0.11-0.15 kG/mm2. Friability of the tablets lower than 1% indicates that the developed formulations can be processed and handled without excessive care. Disintegration time was in the range of 86 to 161 s. CONCLUSIONS: The results confirm the good mechanical properties of tablets containing ß-CD. A composition with 20% ß-CD and 40% MCC fulfilled a maximum requisite of an optimum formulation. These properties were similar to Ludiflash, the formulation used for comparison purposes. In the present study, higher concentration of ß cyclodextrin was found to improve the hardness of tablets without increasing the disintegration time.

[Production and assessing release of imipramine and magnesium from tablets]. / Technologia otrzymywania i ocena uwalniania imipraminy i magnezu z tabletek.

BACKGROUND: In the pharmaceutical technology there is a trend to produce tablets composed of several medicinal substances to increase therapeutic effect and reduce the frequency of drug administration. In the literature there are reports concerning pharmacological studies in which a potentiation of the effects has been observed after a co-administration of antidepressant imipramine and magnesium. Currently, there is no formulation on the market comprising imipramine and magnesium, therefore, it was decided to produce uncoated tablets. In order to prepare the tablets by direct compression, it was necessary to select suitable excipients. OBJECTIVES: The aim of the study was to elaborate the composition and to prepare the tablets with imipramine and magnesium, as well as to assess the quality of the tablets by physical characteristics and by the release study of the active substances. MATERIAL AND METHODS: In order to prepare the tablets, compositions of different polymers and other excipients were added. The tablets were produced by direct compression method in a tablet press. Physical properties of the obtained tablets and the release of the active substances into an acidic medium in a paddle apparatus were tested. The contents of imipramine and magnesium were determined by different methods: spectrophotometrically and atomic absorption spectrometry, respectively. RESULTS: The composition of excipients necessary to produce tablets comprising imipramine and magnesium was established. All of prepared tablets were in compliance with the pharmacopoeial requirements. The release tests showed that above 80% of imipramine was released within 20-35 min and 80-76% of magnesium up to 45 min from the composed tablets and one-ingredient tablets, respectively. CONCLUSIONS: The compositions of excipients for tablets consisting of imipramine and magnesium were presented. The active substances were released within 45 min in the acidic medium, and the administration of these substances in the composed tablets did not affect pharmaceutical availability.

Release kinetics of papaverine hydrochloride from tablets with different excipients.

The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release.

Simultaneous release of diclofenac sodium and papaverine hydrochloride from tablets and pellets using the flow-through cell apparatus described by dimensionless equations.

The release of diclofenac sodium and papaverine hydrochloride from tablets and pellets using the flow-through cell apparatus was studied. The influence of excipients and of a size of the solid dosage forms on the amount of the released substances at the intervals of time using the different rates of flow of the dissolution medium was investigated. Physical parameters corresponding to the dissolution process as the mass transfer coefficient, the thickness of the boundary diffusion layer and the concentration of the saturated solution at this layer were calculated. The results of release were described by dimensionless equations.

A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice.

Both clinical and preclinical studies demonstrate the antidepressant activity of the functional NMDA receptor antagonists. In this study, we assessed the effects of two glycine/NMDA receptor ligands, namely L-701,324 (antagonist) and D: -cycloserine (a partial agonist) on the action of antidepressant drugs with different pharmacological profiles in the forced swim test in mice. Swim sessions were conducted by placing mice individually in glass cylinders filled with warmed water for 6 min. The duration of behavioral immobility during the last 4 min of the test was evaluated. The locomotor activity of mice was measured with photoresistor actimeters. L-701,324 and D: -cycloserine given with reboxetine (administered in subeffective doses) did not change the behavior of animals in the forced swim test. A potentiating effect was seen when both tested glycine site ligands were given concomitantly with imipramine or fluoxetine in this test. The lesion of noradrenaline nerve terminals produced by DSP-4 neither altered the baseline activity nor influenced the antidepressant-like action of L-701,324 or D: -cycloserine. The depletion of serotonin by p-CPA did not alter baseline activity in the forced swim test. However, it completely antagonized the antidepressant-like action produced by L-701,324 and D: -cycloserine. Moreover, the antidepressant-like effects of imipramine, fluoxetine and reboxetine were abolished by D: -serine, a full agonist of glycine/NMDA receptors. The present study demonstrates that glycine/NMDA receptor functional antagonists enhance the antidepressant-like action of serotonin, but not noradrenaline-based antidepressants and such their activity seems to depend on serotonin rather than noradrenaline pathway.

Involvement of NMDA receptor complex in the anxiolytic-like effects of chlordiazepoxide in mice.

In the present study, we demonstrated that low, ineffective doses of N-methyl-D-aspartic acid (NMDA) receptor antagonists [competitive NMDA antagonist, CGP 37849, at 0.312 mg/kg intraperitoneally (i.p.), antagonist of the glycine(B) sites, L-701,324, at 2 mg/kg i.p., partial agonist of glycine(B) sites, D-cycloserine, at 2.5 mg/kg i.p.] administered jointly with an ineffective dose of the benzodiazepine, chlordiazepoxide (CDP, 2.5 mg/kg i.p.), significantly increased the percentage of time spent in the open arms of the elevated plus-maze (index of anxiolytic effect). Furthermore, CDP-induced anxiolytic-like activity (5 mg/kg i.p.) was antagonized by NMDA (75 mg/kg i.p.) and by an agonist of glycine(B) sites of the NMDA receptor complex, D-serine [100 nmol/mouse intracerebroventricularly (i.c.v.)]. The present study showed a positive interaction between γ-aminobutyric acid (GABA) and glutamate neurotransmission in the anxiolytic-like activity in the elevated plus-maze test in mice and this activity seems to particularly involve the NMDA receptors.

NMDA and AMPA receptors are involved in the antidepressant-like activity of tianeptine in the forced swim test in mice.

It is known that tianeptine exhibits antidepressant-like activity. Its influence on the glutamatergic system is also known, but the mechanisms involved in this activity remain to be established. The aim of this study was to investigate the involvement of the glutamate pathway in the antidepressant-like action of tianeptine. We investigated the effects of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor ligands on tianeptine-induced activity in the forced swim test (FST) in mice. The antidepressant-like activity of tianeptine (30 m/kg, ip) was significantly antagonized by D-serine (100 nmol/mouse icv) and NBQX (10 mg/kg, ip). Moreover, low, ineffective doses of the glycine/NMDA site antagonist L-701,324 (1 mg/kg, ip) administered together with low, ineffective doses of tianeptine (20 mg/kg, ip) exhibited a significant reduction of immobility time in the FST. These doses of the examined agents, which did have an effect in the FST, did not alter locomotor activity. The present study indicates that the antidepressant-like activity of tianeptine in the FST involves both NMDA and AMPA receptors and suggests that the interaction between serotonergic and glutamatergic transmission may play an important role in the action of tianeptine.

Determination of diclofenac sodium and papaverine hydrochloride in tablets by HPLC method.

A HPLC method for simultaneous determination of diclofenac sodium and papaverine hydrochloride in tablets was developed and validated. The determination was performed with a Zorbax SB-C18 column, mobile phase: methanol-water (60:40, v/v), flow rate: 1 mL min(-1) and UV detection at 278 nm.