Influence of Hydroxypropyl Methylcellulose Mixture,Apparent Viscosity,and Tablet Hardness on Drug Release Using a 23 Full Factorial Design

ABSTRACT

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3–6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000–19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

The effect of pH,buffer capacity and ionic strength on quetiapine fumarate release from matrix tablets prepared using two different polymeric blends

The objective of this study was to investigate the effect of the different physiological parameters of the gastrointestinal (GI) fluid (pH, buffer capacity, and ionic strength) on the in vitro release of the weakly basic BCS class II drug quetiapine fumarate (QF) from two once-a-day matrix tablet formulations (F1 and F2) developed as potential generic equivalents to Seroquel^® XR. F1 tablets were prepared using blends of high and low viscosity grades of hydroxypropyl methylcellulose (HPMC K4M and K100LV, respectively), while F2 tablets were prepared from HPMC K4M and PEGylated glyceryl behenate (Compritol^® HD5 ATO). The two formulations attained release profiles of QF over 24?h similar to that of Seroquel^® XR using the dissolution medium published by the Food and Drug Administration (FDA). A series of solubility and in vitro dissolution studies was then carried out using media that simulate the gastric and intestinal fluids and cover the physiological pH, buffer capacity and ionic strength range of the GIT. Solubility studies revealed that QF exhibits a typical weak base pH-dependent solubility profile and that the solubility of QF increases with increasing the buffer capacity and ionic strength of the media. The release profiles of QF from F1, F2 and Seroquel^® XR tablets were found to be influenced by the pH, buffer capacity and ionic strength of the dissolution media to varying degrees. Results highlight the importance of studying the physiological variables along the GIT in designing controlled release formulations for more predictive in vitro–in vivo correlations.     

Development of a HPMC-based controlled release formulation with hot melt extrusion (HME)

The objective of this study was to develop hydroxypropyl methylcellulose (HPMC) based controlled release (CR) formulations via hot melt extrusion (HME) with a highly soluble crystalline active pharmaceutical ingredient (API) embedded In the polymer phase. HPMC is considered a challenging CR polymer for extrusion due to its high glass transition temperature (T_g), low degradation temperature, and high viscosity. These problems were partially overcome by plasticizing the HPMC with up to 40% propylene glycol (PG). Theophylline was selected as the model API. By using differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), dynamic mechanical analysis (DMA), and X-ray powder diffraction (XRPD), the physical properties of the formulations were systematically characterized. Five grades of HPMC (Methocel^®) – E6, K100LV, K4M, K15M, and K100M – were tested. The extrusion trials were conducted on a 16?mm twIn screw extruder with HPMC/PG placebo and formulations containing theophylline/HPMC/PG (30:42:28, w/w/w). The dissolution results showed sustained release profiles without burst release for the HPMC K4M, K15M, and K100M formulations. The extrudates have good dissolution stability after being stressed for 2 weeks under 40°C/75% RH open dish conditions and the crystalline API form did not change upon storage. Overall, the processing windows were established for the HPMC based HME-CR formulations.     

Development and optimization of press coated tablets of release engineered valsartan for pulsatile delivery

The present work is aimed to develop and optimize pulsatile delivery during dissolution of an improved formulation of valsartan to coordinate the drug release with circadian rhythm. Preliminary studies suggested that β cyclodextrin could improve the solubility of valsartan and showed A_L type solubility curve. A 1:1 stoichiometric ratio of valsartan to β cyclodextrin was revealed from phase solubility studies and Job’s plot. The prepared complex showed significantly better dissolution efficiency (p?<?0.05) compared to pure drug, which could be due to the formation of inclusion complex as revealed from FTIR and DSC studies. Continuous dissolution-absorption studies revealed that absorption of drug from valsartan β cyclodextrin complex was significantly higher (p?2 full factorial design was used to measure the response of HPMC K4M and EC on lag time and time taken for 90% drug release (T90). The optimized batch prepared according to the levels obtained from the desirability function had a lag time of 6?h and consisted of HPMC K4M:ethylcellulose in a 1:1.5 ratio with 180?mg of coating and revealed a close agreement between observed and predicted value (R^2?=?0.9694).     

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Influence of hydroxypropyl methylcellulose mixture,apparent viscosity,and tablet hardness on drug release using a 2(3) full factorial design

This study investigates the effects of three factors: (1) use of a mixture of two different grades of hydroxypropyl methylcellulose (HPMC), (2) apparent viscosity, and (3) tablet hardness on drug release profiles of extended-release matrix tablets. The lot-to-lot apparent viscosity difference of HPMC K15M on in vitro dissolution was also investigated. Four test formulations were made, each containing 10% of a very water-soluble active pharmaceutical ingredient (API), 32% HPMC K15M, or a mixture of HPMC K100LV and HPMC K100M, 56% diluents, and 2% lubricants. Each formulation was made at two hardness levels. A 2³ full factorial design was used to study various combinations of the three factors using eight experiments conducted in a randomized order. Dissolution studies were performed in USP apparatus I. The values of t_50% (time in which 50% drug is released) and t_lag (lag time, the time taken by the matrix tablet edges to get hydrated and achieve a state of quasi-equilibrium before erosion and the advance of solvent front through the matrix occur) were calculated from each dissolution profile. The similarity factor (f₂) was also calculated for each dissolution profile against the target dissolution profile. A simple Higuchi-type equation was used to analyze the drug release profiles. Statistical analysis using analysis of variance (ANOVA) and similarity factor (f₂) values calculated from the data indicated no significant difference among the t_50% values and dissolution profiles respectively for all formulations. Within the 3.3-6 kp hardness range investigated, dissolution rates were found to be independent of tablet hardness for all the formulations. Although significantly shorter lag times were observed for the tablets formulated with low- and high-viscosity HPMC mixtures in comparison to those containing a single grade of HPMC, this change had no significant impact on the overall dissolution profiles indicated by the similarity factor f₂ values. From this study it can be concluded that lot-to-lot variability in apparent viscosity of HPMC should not be a concern in achieving similar dissolution profiles. Also, results indicated that within the viscosity range studied (12,000-19,500 cps) an HPMC mixture of two viscosity grades can be substituted for another HPMC grade if the apparent viscosity is comparable. Also, the drug release is diffusion-controlled and depends mostly on the viscosity of the gel layer formed.     

Role of cellulose ether polymers on ibuprofen release from matrix tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE_{20 h}), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.     

Sustained Release Tablet Formulation for a New Iron Chelator

Abstract

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

Sustained Release Tablet Formulation for a New Iron Chelator

Sustained release tablet formulations for a new orally active iron chelator (1, 2, dimethyl-3-hydroxy-pyrid-4-one, DMHP or L1) have been developed. Coprecipitates containing DMHP and polymer were prepared and compressed into matrix-type tablets. The dissolution profiles as a function of (1) the type of polymer, and (2) polymer content, were determined. Both Eudragit types (RLPM and RSPM) and all hydroxypropylmethylcellulose (HPMC) grades (E4M, E10M, and K4M) exhibited significant sustained release activity. Above a certain ratio, increase in the polymer concentration did not provide any further decrease in the release rates. All grades of HPMC and both Eudragit RSPM and RLPM showed non-Fickian release kinetics. The role of HPMC and Eudragits in the formulation of a sustained release tablet of a water soluble drug is demonstrated.     

In vitro release of ketoprofen from hydrophilic matrix tablets containing cellulose polymer mixtures

The effect of cellulose ether polymer mixtures, containing both hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC K15M or K100M), on ketoprofen (KTP) release from matrix tablets was investigated. In order to evaluate the compatibility between the matrix components, Raman spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) experiments were performed. The results evidence the absence of significant intermolecular interactions that could eventually lead to an incompatibility between the drug and the different excipients. Formulations containing mixtures of polymers with both low and high viscosity grades were prepared by a direct compression method, by varying the polymer/polymer (w/w) ratio while keeping the drug amount incorporated in the solid dispersion constant (200?mg). The hardness values of different matrices were found within the range 113.8 to 154.9 N. HPLC analysis showed a drug content recovery between 99.3 and 102.1%, indicating that no KTP degradation occurred during the preparation process. All formulations attained a high hydration degree after the first hour, which is essential to allow the gel layer formation prior to tablet dissolution. Independent-model dissolution parameters such as t_10% and t_50% dissolution times, dissolution efficiency (DE), mean dissolution time (MDT), and area under curve (AUC) were calculated for all formulations. Zero-order, first-order, Higuchi, and Korsmeyer–Peppas kinetic models were employed to interpret the dissolution profiles: a predominantly Fickian diffusion release mechanism was obtained – with Korsmeyer–Peppas exponent values ranging from 0.216 to 0.555. The incorporation of HPC was thus found to play an essential role as a release modifier from HPMC containing tablets.     

Preparation of the traditional Chinese medicine compound recipe heart-protecting musk pH-dependent gradient-release pellets

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100-Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100-Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

Preparation of the Traditional Chinese Medicine Compound Recipe Heart-Protecting Musk pH-Dependent Gradient-Release Pellets

ABSTRACT

In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100–Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100–Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100–Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.     

Symbolic regression via genetic programming in the optimization of a controlled release pharmaceutical formulation

Symbolic regression via genetic programming (GP) was used in the optimization of a pharmaceutical zero-order release matrix tablet, and its predictive performance was compared to that of artificial neural network (ANN) models. Two types of GP algorithms were employed: 1) standard GP, where a single population is used with a restricted or an extended function set, and 2) multi-population (island model) GP, where a finite number of populations is adopted. The amounts of four polymers, namely PEG4000, PVP K30, HPMC K100 and HPMC E50LV were selected as independent variables, while the percentage of nimodipine released in 2 and 8 h (Y_2h, and Y_8h), respectively, and the time at which 90% of the drug was dissolved (t_90%), were selected as responses. Optimal models were selected by minimization of the Euclidian distance between predicted and optimum release parameters. It was found that the prediction ability of GP on an external validation set was higher compared to that of the ANNs, with the multi population and standard GP combined with an extended function set, showing slightly better predictive performance. Similarity factor (f₂) values confirmed GP's increased prediction performance for multi-population GP (f₂ = 85.52) and standard GP using an extended function set (f₂ = 84.47).     

Citric acid as a pH-modifying additive in an extended release pellet formulation containing a weakly basic drug

Background: An extended release pellet formulation (ACES®) of the weakly basic drug propiverine was developed with spheronized citric acid crystals as starter cores. Method: Coated pellets, consisting of several layers of functional coatings, were manufactured by fluid bed coating. Different coating levels were examined with regard to their effect on drug release. Release profiles from the formulations with or without pH modifier and the free base as well as the hydrochloride salt of the active ingredient were compared. Results: The coated citric acid starter cores led to a controlled release of the drug and the pH modifier, resulting from modulation of the microenvironmental pH throughout the dissolution period of 17 hours. If microcrystalline cellulose pellets are used as starter cores drug release is strongly pH-dependent. Significant differences in the drug release profiles were observed between the formulations containing the free drug base and those with the hydrochloride salt as a result of an altered microenvironmental pH. Conclusion: The presented extended release pellet formulation is able to maintain a low pH within the pellet core and thus a sufficiently high drug solubility. By maintaining a low pH inside the pellets, a controlled drug release can be achieved.     

Oxazepam Dissolution Rate from Hydroxypropylmethylcellulose Matrices

The effect of some formulation variables on the release rate of oxazepam from hydroxypropylmethylcellulose (HPMC) has been investigated. The principal factors affecting this parameter were the content and molecular weight of HPMC, and the drug particle size. pH modified the oxazepam solubility; however, the liberation mechanism was not affected. The oxazepam release mechanism from these matrices has been examined. Values of the diffusional exponent n were in the range 0.61-0.74, indicating that the release of drug was controlled by both diffusion and erosion. When the tablets contained 30% HPMC K100 and the oxazepam particle size was 0.210-0.250 mm, near-zero-order kinetics was obtained (n = 0.85), indicating that erosion plays an important role in the oxazepam liberation.     

Novel cyclodextrin-based film formulation intended for buccal delivery of atenolol

Background: Unknown influence of cyclodextrin on the properties of the film formulation aimed for buccal application. Aim: Development and characterization of a novel bioadhesive film formulation for buccal atenolol delivery containing drug/cyclodextrin inclusion. Method: Interaction between atenolol and randomly methylated β-cyclodextrin (RAMEB) in solution was studied by phase solubility studies. The complex in solid state was prepared by the freeze-drying method and characterized by differential scanning calorimetry and Fourier-transformed infrared spectroscopy (FTIR). The drug, free or in complex form, was incorporated into polymeric films prepared by the casting method using ethylcellulose (EC), polyvinyl alcohol (PVA), and hydroxypropyl methylcellulose (HPMC). The prepared film formulations were characterized in terms of swelling, bioadhesion, and in vitro drug release. Results: The formation of a stabile inclusion complex (K_s = 783.4?±?21.6 M^?1) in 1:1 molar stoichiometry was confirmed in solution and in solid state. The swelling properties of films were predominated by the type of polymer used in the formulation. In vitro bioadhesive properties of the films were well correlated with the swelling properties of the polymers used in the formulation. Although incorporation of the drug, free or in complex form, decreased the bioadhesion of the films, PVA- and HPMC-based formulations retained suitable bioadhesive properties. Higher atenolol solubility upon complexation with RAMEB increased the drug dissolution rate under conditions designed to be similar to those on the buccal mucosa, but it has decreased the drug release rate from the PVA and HPMC film formulation, leading to a sustained drug release pattern. In the case of EC-based films, RAMEB promoted drug release. Other parameters that influenced the drug release rate were associated with the structure of the polymer used in the formulation, swelling characteristics of the films, and the interaction between atenolol and hydrophilic polymers that was demonstrated by FTIR analysis. Conclusion: Incorporation of atenolol in the form of an inclusion complex into hydrophilic films may be an appropriate strategy to prepare a suitable formulation for buccal drug delivery.     

New sustained release of Zidovudine Matrix tablets − cytotoxicity toward Caco-2 cells

Objective: The aim of this study was to adjust the zidovudine (AZT) release from solid tablets to an ideal profile, by developing matrices comprising swellable polymers with nonswellable ones.

Methods: Directly compressed matrices comprised different ratios of hydroxypropylmethylcellulose K15M and K100M, ethylcellulose, and methacrylic acid (Eudragit^® RS PO and Eudragit^® RL PO) were prepared. Technological characterization and evaluation of the in vitro release behavior were carried out. Cell density and viability following drug exposure were evaluated by the SRB method, for the Caco-2 line, while cell morphology was assessed upon Trypan blue staining.

Results: A specific formulation containing 5% of each excipient ? HPMC K15M, HPMC K100M, Eudragit^® RS PO, and Eudragit^® RL PO ? was found to yield the best release profile. Application of the Korsmeyer–Peppas model to the dissolution profile evidenced that a non-Fickian (anomalous) transport is involved in the drug release. Regarding the influence of the tablets’ composition on the drug’s cytotoxic effect toward the Caco-2 cell line, a reduction of cell biomass (0–15%) was verified for the distinct AZT formulations tested, F19 having displayed the highest cytotoxicity, after 24 and 48?h of incubation. Additionally, a high reversibility of the AZT effect was observed.

Conclusions: The results showed that the simultaneous application of both hydrophilic and hydrophobic polymers can modulate the drug release process, leading to an improved efficacy and patient compliance. All AZT formulations studied were found to be cytotoxic against Caco-2 cells, F19 being the most effective one.     

Basic drug--enterosoluble polymer coevaporates: development of oral controlled release systems

Precipitation of basic drugs within oral prolonged release systems, at the higher pH values of the intestine, would affect drug release. Coevaporates of a model basic drug verapamil HCl, in single or mixed polymer systems, containing Eudragit L100 (L100) and ethyl cellulose or Eudragit RS100, were prepared from ethanolic solution. XRD and DSC indicated loss of crystallinity of the drug in the coevaporates. The presence of the enterosoluble polymer in the system was found to aid in faster dissolution of the drug at higher pH values. This was affected by the presence and type of retarding polymer present in the system. Compression of the coevaporates resulted in either very slow release of the drug or undesirable changes in the release profile. Pelletization of a coevaporate containing drug and L100 yielded systems, which released the drug uniformly when studied by the buffer change method in simulated gastric (SGF) and intestinal (SIF) fluids. The presence of L100 in intimate contact with the drug was found to be essential for the desirable drug release properties of the system. The drug release occurred predominantly by diffusion in SGF and by a combination of diffusion and polymer dissolution/erosion in SIF. Appropriate choice of release modifiers and formulation variables and development of suitable formulations can yield systems which compensate for the reduced solubility of the drug in the higher pH environments of the intestine.     

Preliminary evaluation of the in vitro release and in vivo absorption in rabbits of the modified-release dosage forms

Objective: The suitability of the rabbit as an animal model for the primary screening and selection of the pilot scale batches during the early stages of the formulation development was studied.

Materials and methods: Three modified-release formulations of aminophylline consisted of Carbopol® 971P/HPMC K4M (F-I), and HPMC K100M (F-II) or HPMC K4M (F-III) were used. Commercial products were Aminofilin retard 350?mg tablets, Srbolek, Serbia (R-I) and Phyllocontin^® 350, tablets Purdue Frederic, Canada (R-II).

Results: Calculated release rate constants and the ?2 values between R-I/F-I (84.1) and R-II/F-III (83.4) indicated similar in vitro release while the coefficient n showed presence of different mechanisms of release from Anomalous transport, Fickian diffusion to Case-II transport. Higher T_max, was found in the rabbits, dosed with F-II (12.00?h), F-III (10.50?h), and R-II (15.00?h) formulation. The highest C_max (9.22?mg/L) was obtained with F-II, similar lower values was seen for F-I and F-III, while commercial products showed the lowest values R-I (5.58?mg/L) and R-II (4.18?mg/L). Higher AUC values were detected for all three formulations (from 115.90 to 204.06 mgh/L) in relation to commercial products (105.33 and 113.25 mgh/L).

Discussion and conclusion: The results demonstrated a good correlation of Level A (r² = 0.97) for the two formulations (F-I, F-III) and commercial product (R-I) indicates that there is a reasonable assumption that the rabbit might be use as a model for the preliminary comparison of scale up formulations in the early stages of the product development.     

Peroral Sustained-Release Film-Coated Pellets as a Means to Overcome Physicochemical and Biological Drug-Related Problems. I. In Vitro Development and Evaluation

Abstract

In vitro preformulation testing has shown that the solubility and dissolution rate of the model drug compound ucb 11056 are highly pH dependent. Considering this, different sustained-release (SR) oral dosage forms of ucb 11056 were developed aiming to obtain the most constant and complete release of the drug during transit in the gastrointestinal (GI) tract. Classical approaches based on the use of SR formulations such as hydrophilic matrix tablets or pellets coated with one film-forming polymer (Eudragit NE30D or L30D-55) did not fulfill all expectations on the basis of their in vitro evaluation, i.e., the drug release and pattern remained highly dependent on the pH of the dissolution medium. Therefore, taking advantage of the flexibility of release adjustment obtainable from coating of pellets with different kinds of pH-sensitive film layers, a quite satisfactory pH independence of the release characteristics was obtained using formulation blends of neutral and anionic acrylic polymers. For the selected SR pellets batch 15 coated with NE30D/L30D-55 (7:3), the tridimensional topographic representation of the drug release versus time and pH showed that, notwithstanding the pH-dependent aqueous solubility of the drug, the release profiles were relatively homogeneous for any pH value ranging between 1 and 7.