Production of extended release mini-tablets using directly compressible grades of HPMC

Context: Hypromellose (HPMC) has been previously used to control drug release from mini-tablets. However, owing to poor flow, production of mini-tablets containing high HPMC levels is challenging. Directly compressible (DC) HPMC grades have been developed by Dow Chemical Company.

Objective: To compare the properties of HPMC DC (METHOCEL? K4M and K100M) with regular (REG) HPMC grades.

Method: Particle size distribution and flowability of HPMC REG and DC were evaluated. 3?mm mini-tablets, containing hydrocortisone or theophylline as model drugs and 40% w/w HPMC DC or REG were produced. Mini-tablets containing HPMC DC grades were manufactured using a rotary press simulator at forces between 2–4?kN and speeds of 5, 10, 15 or 20?rpm. Mini-tablets containing HPMC REG were produced manually.

Results and discussion: The improved flowability of HPMC DC grades, which have a narrower particle size distribution and larger particle sizes, meant that simulated large scale production of mini-tablets with good weight uniformity (CV 1.79–4.65%) was feasible. It was not possible to automatically manufacture mini-tablets containing HPMC REG due to the poor flowability of the formulations. Drug release from mini-tablets comprising HPMC DC and REG were comparable. Mini-tablets containing HPMC DC illustrated a higher tensile strength compared to mini-tablets made with HPMC REG. Mini-tablets produced with HPMC DC at different compression speeds had similar drug release profiles.

Conclusions: Production of extended release mini-tablets was successfully achieved when HPMC DC was used. Drug release rate was not influenced by the different HPMC DC grades (K4M or K100M) or production speed.     

The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets

The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5–4?mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45–125?μm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125–355?µm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125–355?µm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.     

Film-coated matrix mini-tablets for the extended release of a water-soluble drug

Extended release (ER) of water-soluble drugs from hydroxypropylmethylcellulose (HPMC) matrix mini-tablets (mini-matrices) is difficult to achieve due to the large surface area to volume ratio of the mini matrices. Therefore, the aims of this study were to control the release of a water-soluble drug (theophylline) from mini-matrices by applying ER ethylcellulose film coating (Surelease®), and to assess the effects of Surelease®:pore former (Opadry®) ratio and coating load on release rates. Mini-matrices containing 40%w/w HPMC K100M CR were coated with 100:0, 85:15, 80:20, 75:25 or 70:30 Surelease®:Opadry® to different coating weight gains (6–20%). Non-matrix mini-tablets were also produced and coated with 80:20 Surelease®:Opadry® to different coating weight gains. At low coating weight gains, nonmatrix mini-tablets released the entire drug within 0.5?h, while at high coating weight gains only a very small amount (<5%) of drug was released after 12?h. The gel formation of HPMC prevented disintegration of mini-matrices at low coating weight gains but contributed to rupture of the film even at high coating weight gains. As a result, drug release from mini-matrices was slower than that from nonmatrix mini-tablets at low coating weight gains, yet faster at high coating weight gains. An increase in the lag time of drug release from mini-matrices was observed as the concentration of Opadry® reduced or the coating weight gain increased. This study has demonstrated the possibility of extending the release of a water-soluble drug from HPMC mini-matrices by applying ER film coating with appropriate levels of pore former and coating weight gains to tailor the release rate.     

Design and optimization of gastric floating sustained-release mini-tablets of alfuzosin hydrochloride based on a factorial design: in vitro/in vivo evaluation

Abstract

The purpose of this research was to develop multiple-unit gastric floating mini-tablets and to evaluate the possibility of using these mini-tablets as a delivery system to improve the drug absorption for drugs with a narrow absorption window. Mini-tablets were prepared using hydroxypropyl methylcellulose (HPMC K100M) and carbopol 971P as release retarding agents and sodium bicarbonate (NaHCO₃) as gas-forming agent. The properties of the prepared mini-tablets in terms of floating characteristic parameters and in vitro release were evaluated. Furthermore, in vivo gastric retention study in rats and in vivo pharmacokinetic study in rabbits of the optimized formulation were performed. The optimized mini-tablets containing 45% HPMC K100M, 15% stearyl alcohol, 13% carbopol 971P, and 12% NaHCO₃ were found to float immediately within 1?min and duration more than 9?h. The in vivo gastric retention study results indicated that the mini-tablets could retain in the stomach for more than 6.67?h. Furthermore, the AUC_0?t of the floating mini-tablets (6849.83?±?753.80?h ng·mL^?1) was significantly higher than that of marketed sustained-release tablets XATRAL®XL (4970.16?±?924.60?h ng·mL^?1). All these results illustrated that the gastric floating mini-tablets might be a promising drug delivery system for drugs with a narrow absorption window.     

A formulation approach for development of HPMC-based sustained release tablets for tolterodine tartrate with a low release variation

Objective: The purpose of this study was to develop hydroxypropylmethylcellulose (HPMC)-based sustained release (SR) tablets for tolterodine tartrate with a low drug release variation.

Methods: The SR tablets were prepared by formulating a combination of different grades of HPMC as the gelling agents. The comparative dissolution study for the HPMC-based SR tablet as a test and Detrusitol^® SR capsule as a reference was carried out, and the bioequivalence study of the two products was also conducted in human volunteers.

Results: The amount of HPMC, the grade of HPMC and the combination ratio of different grades of HPMC had remarkable effects on drug release from the SR tablets. Both the test and reference products had no significant difference in terms of comparative dissolution patterns in four different media (f₂ > 50). Furthermore, the dissolution method and rotation speed showed no effects on the drug release from the two products. The 90% confidence intervals of the AUC_0–36 and C_max ratios for the test and reference products were within the acceptable bioequivalence intervals of log0.8–log1.25.

Conclusions: A HPMC-based SR tablet for tolterodine tartrate with a low release variation was successfully developed, which was bioequivalent to Detrusitol^® SR capsule.     

Fabrication and in vitro evaluation of bidirectional release and stability studies of mucoadhesive donut-shaped captopril tablets

Objective: To obtain controlled release of captopril in the stomach, coated, mucoadhesive donut-shaped tablets were designed.

Materials and methods: Donut-shaped tablet were made of different ratios of diluents to polymer or combination of polymers by direct compression method. Top and bottom portions of the tablet were coated with water-insoluble polymer followed by mucoadhesive coating. Time of water penetration, measurement of tensile strength, mucoadhesion studies (static ex vivo and ex vivo wash-off) were taken into account for characterization of respective films. In vitro study has been performed at different dissolution mediums. Optimized batches were also prepared by wet granulation. Stability studies of optimized batches have been performed.

Results: The results of time of water penetration and tensile strength indicated positive response against water impermeation. Mucoadhesive studies showed that film thickness of 0.12?mm was good for retention of tablet at stomach. At pH 1.2, optimized batch of tablet made with hydroxypropyl methyl cellulose (HPMC) E15 as binder showed 80% w/w drug release within 4–5?h with maximum average release of 97.49% w/w. Similarly, maximum average releases of 96.36% w/w and 95.47% w/w were obtained with nearly same dissolution patterns using combination of HPMC E5 and HPMC E50 and sodium salt of carboxy methyl cellulose (NaCMC) 500–600 cPs instead of HPMC E15. The release profiles in the distilled water and pH 4.5 followed the above pattern except deviation at pH 6.8. Stability studies were not positive for all combinations.

Conclusion: Coated, mucoadhesive donut-shaped tablet is good for controlled release of drug in the stomach.     

Evaluation of hydrophilic,hydrophobic and waxy matrix excipients for sustained release tablets of Venlafaxine hydrochloride

Objective: Venlafaxine is freely soluble In water and administered orally as hydrochloride salt In two to three divided doses. In the present investigation different release retarding matrices have been evaluated for sustained release of venlafaxine hydrochloride (VH) from the formulated tablets.

Materials and methods: Sustained release matrix tablets were formulated using different hydrophilic, hydrophobic and waxy materials as matrix formers. Tableting was done by pre-compression, direct compression and hot melt granulation depending on the type of matrix material used and evaluated for different tests. The formulated tablets were compared with commercial venlafaxine products. In vitro drug dissolution profiles were fitted In different mathematical models to elucidate the release mechanism.

Results: Dissolution data showed that commercial formulations Venlor XR^® and Venfax PR^® released the entire drug withIn 8?h where as the formulated tablets with hydroxypropylmethylcellulose (HPMC) and cetyl alcohol as matrix formers provided sustained release of drug for 14–15?h. The release was found to follow Hixson Crowel and Higuchi kinetics for HPMC and cetyl alcohol tablets, respectively.

Conclusion: The developed matrix tablet formulations with HPMC and cetyl alcohol provided sustained release profiles for prolonged periods than commercial formulations.     

Release of Theophylline from Ethyl Cellulose Mecrocapsues Alone and in Conjuction with Fat Embedded (Precirol®) Granules and Hydroxypropyl Methycellulose

Abstract

Microcapsules of theophylline with ethyl cellulose were prepared by coacervation technique using cabosil® (silicon dioxide) as separant. Tablets were prepared from microcapsules, microcapsules + theophylline fat embedded granules, and microcapsules and hydroxypropyl methylcellulose 4000 (HPMC). Release was studied in vitro by the rotating basket method. Prolonged release of theophylline was observed from microcapsules with no drug dumping. The release from microcapsules was of first-order whereas that from all the tablet formulation was diffusion controlled according to the Higuchi model. Good correlation was found between release rate and core:wall ratio for all the systems. Decrease in hardness of tablets made from microcapsules alone decreased the release rate, indicating damage of microcapsules during compression. The tablets compressed from fat embedded granules, microcapsules with fat embedded granules, and microcapsules with HPMC gave a desired release for a 74 hour sustained release preparation.     

Effect of core size and excipients on the lag time and drug release from a pulsatile drug delivery system

Background: Pulsatile drug delivery system, based on a core-in-cup dry-coated tablet was examined and evaluated. The system consisted of three different parts: a core tablet (with increasing diameter), containing the active ingredient acting as reservoir; an impermeable outer shell; and a top cover layer barrier. The core tablet contained either caffeine or theophylline as model drugs. Objective: To investigate and evaluate how the geometrical characteristics of the core tablets, drugs, and excipients influence the behavior of the system presented, namely, lag time and drug release. Results and Discussion: Drug release exhibited a lag time period dependent on the core tablet size, drug solubility, and characteristics of polymer and polymer mixtures. The lag time was increased by increasing the core tablet diameter and the quantity of soluble lactose in the top cover layer. Conclusions: The quantity and characteristics of materials, the core tablet size, and the erosion of the top cover layer were found to be important factors in controlling the lag time and release. Increase in core tablet diameter resulted in lower lag times and greater release and release rates. Similarly, by increasing sufficiently the quantity of the soluble excipient lactose, in the top layer we observed a decrease of the lag times and an increase of release.     

Performance of Multilayered Particles: Influence of a Thin Cushioning Layer

ABSTRACT

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.     

Influence of Tablet Formulation and Size on the in Vztro Sustained-Release Behavior of Metoprolol Tartrate from Hydrophilic Matrices

Abstract

Metoprolol tartrate sustained-release tablets were manufactured in 2.8, 7.0 and 10.0 mm diameters. In order to achieve the sustained release of active ingredients, the hydrophilic cellulose polymers methylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose were used either alone or in combination. It was investigated, in particular, whether the mini-tablets encased in hard gelatine capsules as multiple units allow for the sustained release of the basic active ingredient, which is highly soluble in the acidic pH.

While a sustained release is possible from the 7.0 and 10.0 mm diameter tablets formulated on the basis of HPC and NaCMC mixtures, tablets with 2.8 mm diameter do not allow for an adequate control of metoprolol tartrate release during the gastrointestinal passage. Active ingredient release in the range of up to 80 % release and the tablet surface area above a minimum of approximately 300 mm² are correlated in a linear manner.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson’s disease: physical characterization and ex vivo drug permeation through buccal mucosa

Objective: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson’s disease.

Methods: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa.

Results: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6?h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets.

Conclusion: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson’s disease.     

Interpolymer complexation between copovidone and carbopol and its effect on drug release from matrix tablets

The interaction between copovidone and Carbopol 907 is pH dependent. When the pH of an aqueous solution fell below pH 4.5, a water-insoluble complex began to form and precipitate. This complex resulted from a hydrogen-bond-induced interaction between the carboxylic groups in Carbopol 907 and the carbonyl groups of N-vinylpyrrolidone repeat units in copovidone. Consisting of these two polymers at an approximate 1:1 weight ratio, the complex was an amorphous material with a glass transition temperature of 157?°C. The interpolymer complexation in situ was applied to modify drug release properties of Carbopol 907-based theophylline matrix tablets. The effect of copovidone on drug release was dependent on the pH of the dissolution medium. In a 0.1 N hydrochloride acid solution at pH 1.2 and 50?mM acetate buffer at pH 4.0, an insoluble tablet matrix was formed as a result of the in situ interpolymer complexation, and theophylline was released therefore via Fickian diffusion. In a 50?mM phosphate buffer at pH 6.8, drug release from the matrix tablets was still impacted by the in situ interpolymer complexation because of the low-pH microenvironment induced by Carbopol 907. As a result, drug release rate of the matrix tablet containing both polymers at pH 6.8 was slower than that of the matrix tablets containing individual polymers. We observed similar drug release rates at both pH 1.2 and pH 6.8 between tablets containing the physical blend of these two polymers and tablets containing preformed interpolymer complexes.     

A novel automated alternating current biosusceptometry method to characterization of controlled-release magnetic floating tablets of metronidazole

Context: Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets.

Objective: The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery.

Materials and methods: Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release.

Results: The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4?min, maintaining the flotation during more than 24?h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24?h was about 40%.

Conclusions: The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC).     

A Comparison of the Dissolution Characteristics of Theophylline from Film Coated Granules and Mini-Tablets

Granules and mini-tablets containing theophylline were film coated by fluidised bed technology with various amounts of ethylcellulose and Eudragit RL. Scanning electron micrographs of both whole and fractured film coated granules and mini-tablets were taken. In vitro dissolution studies were carried out on encapsulated samples of film coated material equivalent to about 150mg of theophylline. Dissolution studies were also carried out on individual granules and mini-tablets and the time for 10% release (t10% values) of drug were determined. A comparison of the dissolution profiles showed that granules required about 2.5 to 3 times more coating material than mini-tablets to achieve the same release rate. It is also shown from the t10% values that drug release from mini-tablets is more consistent than from granules. Since the mini-tablets contain uniform weights of theophylline, their use allows precise adjustment of the number of encapsulated mini-tablets for individual dosage titration.     

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept

Objective: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP).

Significance: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients.

Methods: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products.

Results: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6–7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4?ng/mL), longer time to reach maximum plasma concentration (4?h) and longer t_1/2 (7.236?h) compared to other groups.

Conclusions: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.     

Directly Compressed Mini Matrix Tablets Containing Ibuprofen: Preparation and Evaluation of Sustained Release

ABSTRACT

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium

Aim: The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions.

Materials and methods: Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any.

Results: Average particle diameter of the emulsions formed from the tablet was found to be below 100?nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation.

Conclusion: The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.     

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.