Studies on Controlled-Release Formulations of Diclofenac Sodium

The effects of various polymers on the release of diclofenac sodium from their matrices have been evaluated. In vitro release profiles of diclofenac sodium from ethylcellulose and hydroxypropylmethylcellulose (HPMC) K4M matrices showed that decreasing the concentration of ethylcellulose and increasing the concentration of HPMC K4M resulted in an increase in the release rate of diclofenac sodium. An increase in the amount of lactose in matrix resulted in an increase in the release rate of diclofenac sodium. It is suggested that the use of ethylcellulose or Precirol containing relatively large percentage concentrations of lactose in matrices will not provide zero-order release of diclofenac sodium from matrices. The best-fit release kinetics with the highest correlation coefficients was achieved with the Higuchi's plot followed by the zero-order. A straight line relationship was established bemeen the T_50% and the ratio of HPMC K4M to diclofenac sodium.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, II. Combination Resin Formulations

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,II. Combination Resin Formulations

Abstract

Theophylline tablet formulations containing a combination of cationic and anionic acrylic resins were prepared and evaluated. Equal amounts of Eudragit RSPM (cationic resin) and Eudragit L100 (anionic resin) were included at the 15% level (total polymer content) into the tablet formulations. Pressure-hardness profiles with theophylline-resin compacts (4:1) demonstrated that compacts containing the RSPM resin were the most compressible. The dissolution profiles for theophylline in acidic media showed slower release rates from tablets containing the combined resins than from those containing each of the single resins. It was proposed that this decrease in drug release rate was a result of a solid state interaction between the oppositely charged polymers. As the amount of retardant in the matrix increased, the release rates in acidic media decreased. In pH 7.4 phosphate buffer, much faster release was seen due to the higher solubility of the Eudragit L-100 resin at this pH level. Tablet hardness between the range of 6.8 kg to 15 kg showed minimal influences on the dissolution rate. Recompression and relubrication of the tablet formulation containing both polymers, produced a decrease in release rates of theophylline from the tablet matrix.     

In Vivo Evaluation of Two Novel Controlled-Release Nitrendipine Formulations

The objective of this work is to assess two novel controlled-release nitrendipine formulations, i.e., sustained-release nitrendipine microspheres having solid dispersion structure and a novel pH-dependent gradient-release delivery system for nitrendipine in healthy male volunteers, which were prepared by current authors. Domestic commercial nitrendipine tablets and Baypress? nitrendipine tablets were employed as reference formulations. In a randomized, single-dose, fasting-state, crossover study design with a 1-week washout period, each subject received a 40-mg nitrendipine formulation. Plasma samples were collected over a 25-hour period after oral administration and were analyzed by a validated method using high performance liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined using a noncompartmental analysis. The results provided evidence that the time to maximum plasma concentration of two novel controlled-release nitrendipine formulations were statistically significant prolonged in comparison with that of Baypress? nitrendipine tablets. The relative bioavailabilities of test formulations were intensively improved compared with the domestic nitrendipine tablets, while the ratio is in a range of 80–120% in comparison with Baypress? nitrendipine tablets. It is concluded that the two types of controlled-release systems are feasible for improving the dissolution rate of nitrendipine and obtaining a long-acting in vivo as well.     

Relating In Vitro/In Vivo Data of Two Controlled-Release Metformin Formulations

This study was conducted to compare the bioavailability of two controlled-release metformin preparations (Diabetmin Retard and Glucophage Retard) and also to correlate the in vitro and in vivo data obtained with the two preparations. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using area under the plasma concentration–time curve AUC_0?∞, time to reach peak plasma concentration T_max, and peak plasma concentration C_max, while correlation was determined between in vitro release and in vivo absorption. Diabetmin Retard demonstrated a slower rate of in vitro release, but a faster rate of in vivo absorption than Glucophage Retard. However, the in vivo absorption of both products was found to be slower than that of drug released in vitro. A satisfactory relationship could be established between the in vitro and in vivo results, but there was no rank order correlation. No statistically significant difference was observed between the two preparations in the parameters AUC_0?∞ and C_max. However, a slight but statistically significant difference was observed between the T_max values, but it may not be therapeutically significant. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC_0?∞ values, as well as the logarithmic transformed C_max values, of Diabetmin Retard over those of Glucophage Retard was within the acceptance criteria of 0.80–1.25.     

Controlled-Release Frusemide Microcapsules: Preformulation Studies

Microencapsulation of plain frusemide or its solid-dispersion with PEG 6000 was achieved by phase-separation coacervation. Formulations showed reasonable in-vitro dissolution behaviour were assessed for their absorption rates by LD₅₀ testing in mice. Toxicity studies showed close agreement between the increase in lethal dose and the decrease in dissolution rate and revealed that the formulation containing frusemide as fused mixture with PEG 6000 and microencapsulated with polystyrene, in frusemide-PEG 6000-polystyrene weight ratio of 2:2:1, was the formula of choice for prolonging the absorption, hence, the action of frusemide.     

Diclofenac Sodium Microcapsules: In Vitro Testing Considerations

Despite the great proliferation of microcapsules in the pharmaceutical field, there are no official guidelines for “in vitro” testing. This lack of official information means that many devices and processes have to be used to determine accurately the dissolution characteristics of microcapsules. Our objective is to review the “in vitro” dissolution tests performed by researchers and to establish the best conditions to test diclofenac sodium microcapsules obtained by using a polymeric solvent extraction method, with three different in vitro systems. Some mathematical adjustments have been made with the results, in order to establish the most appropriate in vitro dissolution system.     

Controlled-Release Frusemide Microcapsules: Preformulation Studies

Abstract

Microencapsulation of plain frusemide or its solid-dispersion with PEG 6000 was achieved by phase-separation coacervation. Formulations showed reasonable in-vitro dissolution behaviour were assessed for their absorption rates by LD₅₀ testing in mice. Toxicity studies showed close agreement between the increase in lethal dose and the decrease in dissolution rate and revealed that the formulation containing frusemide as fused mixture with PEG 6000 and microencapsulated with polystyrene, in frusemide-PEG 6000-polystyrene weight ratio of 2:2:1, was the formula of choice for prolonging the absorption, hence, the action of frusemide.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro–in vivo correlation was observed for these products.     

Formulation and Evaluation of Diclofenac Sodium Using Hydrophilic Matrices

Controlled-release tablets (having near zero-order release) of diclofenac sodium, a water-soluble drug, were prepared using hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC), and Carbopol 934. Tablets were also prepared with mixtures of polymers of NaCMC, HPMC, and Carbopol 934. The optimum ratio of drug : HPMC : NaCMC was found to be 1 : 2 : 1. A combination of nonionic polymer HPMC and anionic NaCMC polymer matrix resulted in near zero-order release of diclofenac sodium. The results obtained were in agreement with the earlier reports. It is observed that increasing polymer content produces more sustained effect. A combination of nonionic polymer HPMC and anionic polymer NaCMC as the polymer matrix resulted in near zero-order release of diclofenac sodium. Drug release from the matrix did not follow Fick's law of diffusion and exhibited near zero-order release. Results of the bioavailability studies indicated that formulation 4 with drug : HPMC : NaCMC equal to 1 : 2 : 1 was similar to the marketed product Dicloran SR and showed better bioavailability than Voveran SR. A statistically significant difference was seen between Voveran SR and the other two products. A good in vitro-in vivo correlation was observed for these products.     

The Influence of Formulation on the Dissolution Profile of Diclofenac Sodium Tablets

ABSTRACT

In attempts to design delayed-release tablets of diclofenac sodium, seven experimental batches were produced. The influence of super-disintegrant croscarmellose sodium (CCS), the granulation process, and the thickness of Eudragit® L 100 coating film were evaluated. The values of dissolution efficiency and the similarity factor were used to compare the dissolution profiles of each experimental batch and the reference Voltaren®. Both methods appear to be applicable and useful in comparing dissolution profiles. Based on such values four batches were considered similar when contrasted with the reference. The results suggest an optimal relationship between the amount of CCS and the thickness of the coating film, which provides appropriate dissolution rate of diclofenac sodium from the dosage forms.     

Formulation Design and Optimization of Modified-Release Microspheres of Diclofenac Sodium

The present study deals with the preparation of microspheres of diclofenac sodium using cross-linked poly(vinyl alcohol) (PVA). A central composite design consisting of a two-level full factorial design superimposed on a star design was employed for developing the microspheres. The PVA to the drug ratio X₁ and amount of glutaraldehyde cross-linking agent X₂ were chosen as the independent variables. The time required for 50% drug dissolution t₅₀ in phosphate buffer (pH 7.2) was selected as the dependent variable. An optimum polynomial equation was generated for the prediction of the response variable t₅₀. Based on the results of multiple linear regression analysis and F statistics, it may be concluded that sustained action can be obtained when X₁ and X₂ are kept at high levels. The X₁X₂ interaction was found to be statistically significant. A response surface plot is presented to show the effects of X₁ and X₂on t₅₀. The drug release pattern fit the Higuchi model well. A model was validated for accurate prediction of the drug dissolution profile with constraints on the percentage drug release in the first, fifth, and seventh hours. The data of a selected batch were subjected to an optimization study, and an optimal formulation was fabricated. Good agreement was observed between the predicted and the observed dissolution profiles of the optimal formulation.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins, III. Influence of Filler Excipient.

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Controlled-Release Theophylline Tablet Formulations Containing Acrylic Resins,III. Influence of Filler Excipient.

Abstract

The selection of a filler excipient was demonstrated to have a dramatic effect on the release properties of theophylline from matrix tablets containg an acrylic resin polymer as the retardant substance. Theophylline tablets were formulated to contain 60 percent drug, 28 percent filler excipient, 10 percent Eudragit S100, 1.5 percent fumed silica and 0.5 percent magnesium stearate. Release rates were most rapid when microcrystalline cellulose was the filler excipient and the slowest when calcium sulfate was used as the diluent. Dissolution rates decreased in acidic medium as the level of Eudragit S100 increased from zero to fifteen percent. In pH 7.4 phosphate buffer, USP, the converse held true because of the high solubility of the resin at this pH value. There was no difference between dissolution rates at pH 1.1 and pH 4.0. Tablet porosity was influenced significantly by the filler excipient. Higher porosity usually resulted in greater theophylline dissolution rates. When sucrose was employed as the filler excipient, tablet porosity was inversely related to tablet hardness.     

Influence of Alcohol on the Release of Tramadol from 24-h Controlled-Release Formulations During In Vitro Dissolution Experiments

Recent warnings by regulatory bodies and a product recall by the FDA have generated much interest in the area of dose dumping from controlled-release opioid analgesic formulations when coingested with alcohol. It was the aim of this study to address this issue and in doing so, gain understanding on how alcohol-induced effects may be avoided. In this study, tramadol release from Ultram® ER tablets and T-long® capsules was significantly increased in the presence of ethanol. Conversely, a decrease in the rate of tramadol release was seen from Tridural? extended-release tablets in the presence of alcohol.     

Formulation and Pharmacokinetic Studies of Acyclovir Controlled-Release Capsules

Acyclovir controlled-release capsules (CRCs) were prepared by a three-step process: [1] melt granulation of acyclovir; [2] coating of granules with ethylcellulose; [3] incorporation of coated granules into hard gelatin capsules. In vitro release experiments showed that the main factors affecting the release rate were the mean particle size of the acyclovir raw material and the amount of coating material applied. Release of acyclovir from the capsules was in accordance with the Higuchi equation. Pharmacokinetic studies in dogs after oral administration of acyclovir controlled-release capsules showed that the formulation was successful in providing slow release of acyclovir and was superior to a commercially available controlled-release formulation.     

Sustained Release Microspheres of Diclofenac Sodium Using PEGylated Rosin Derivatives

The PEGylated derivatives of rosin-PD-1 and PD-2 synthesized and characterized earlier () were investigated as potential materials for sustained release microsphere prepared by emulsion solvent evaporation method using diclofenac sodium (DCS) as model drug. All the microspheres exhibited smooth surfaces intercepted by pores; their sizes (d₉₀) ranged between 11–24 μm. The entrapment efficiency (< 80%) of the microspheres increased proportionally with derivative concentration. Presence of solvent like isopropyl alcohol or dichloromethane rendered the microspheres with large sizes but with reduced drug entrapment. Microspheres with small size were obtained at an optimum viscosity of liquid paraffin; any change lead to increase in the particle size. Magnesium stearate was found to be most suitable detackifier in the present system. The drug release was directly related to the particle size—small sized microspheres released drug at a faster rate. The dissolution data complied with Higuchi equation while the mechanism of drug release was Fickian diffusion (n ～ 0.5). Controlled inhibition of edema, as tested by hind paw edema method, was observed for 10 h when the microspheres were administered intraperitoneally. The present study found the derivatives as promising materials for preparing microspheres for sustained delivery of DCS.     

Use of a Novel Modified TSI for the Evaluation of Controlled-Release Aerosol Formulations. I

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.