Sustained Release Minitablets Research Articles

Development and optimization of guaifenesin sustained release mini-tablets for adult and geriatric patients.

Aim: The main aim of this study was to formulate and optimize sustained release mini-tablets of guaifenesin.Materials & methods: Guaifenesin granules were successfully prepared using different blend ratios of carnauba wax to drug by melt granulation method. The properties of granules were further modified by combining them with ethyl cellulose. The obtained granules were then mixed and compressed into mini-tablets using a tablet press machine. The resulting mini-tablets were characterized in terms of weight, thickness, hardness, drug content and in vitro drug release.Results: Mini-tablets with 1:6 carnauba wax to drug ratio showed superior physicochemical characteristics, releasing about 100.03% of guaifenesin over 8h. Ethyl cellulose offers a great potential to accurately control drug release from mini-tablets.Conclusion: The prepared mini-tablets seem to be a very promising alternative to guaifenesin conventional formulations and can be used in adults and elderly people.

Formulation and evaluation of pH activated dosage form as minitablets in capsule for delivery of fesoterodine

ObjectivesIn the present study, an attempt is made to develop novel multifunctional sustained-release minitablets in a capsule system by film coating Fesoterodine for the treatment of urinary incontinence (increased urinating frequency). MethodologyThe direct compression technique was used to formulate the minitablets, and coating was applied using hydroxypropyl methylcellulose (HPMC) phthalate. The pre-formulation study was performed using tools like differential scanning calorimetry (DSC), infrared spectroscopy (IR) and post-formulation parameters such as hardness, thickness, weight variation, uniformity, and drug release. Drug release kinetics were studied for the formulations F1–F11. ResultsAll the pre- and post-formulation parameters were found to be within the limits. F1 and F2 result in burst release of the drug within 30 minutes. For the F3, F4, and F5 formulations, HPMC phthalate-coated minitablets show almost 100% drug release in 3, 4, and 5 hours, respectively. F6, F7, and F8 (2.5%, 5%, and 10% formaldehyde-coated minitablets, respectively) show drug releases in the small intestine, and the release was prolonged for 24 hours, whereas F9, F10, and F11 (2.5%, 5%, and 10% glutaraldehyde-coated minitablets, respectively) release in the small intestine, but drug release takes more than 20 hours. ConclusionFilm-coated minitablets were satisfactorily developed in terms of various post-compression parameters like hardness, thickness, friability, weight variation, and content uniformity. IR and DSC studies revealed no significant drug excipient interactions. HPMC phthalate-coated minitablets released in the buffer, and it was supposed that the drug releases in the intestine, which leads to better absorption and follows Korsmeyer-Peppas release kinetics.

Study on effect of SuperTab 40LL on compression characteristics of musk sustained-release mini-tablets based on mathematical models

In this paper, co-processed lactose SuperTab 40 LL was selected as fillers to study the preparation of musk sustained-release mini-tablets in the Xihuang multiple-unit drug release system. Musk sustained-release tablets containing different proportions of SuperTab 40 LL and MCC were prepared under various pressures, and then the compressibility and compactibility of these prescriptions were evaluated by Walker, Heckel and Ryshkewitch-Duckworth equations. In addition, the fluidity of the prescriptions was evaluated by parameters of Kawakita equation. There was a comprehensive analysis of the effect of SuperTab 40 LL on musk sustained-release mini-tablets combined with the appearance of SuperTab 40 LL and their tensile strength. The results shown that SuperTab 40 LL had better compression process through the Heckel equation, and the direct compression process of drug powders with excipients can be analyzed by the Kawakita and Ryshkewitch-Duckworth equations. As a new type of co-processed lactose, SuperTab 40 LL had a good fluidity and compactibility. SuperTab 40 LL may undergo particle crushing and plastic deformation during the compression process, which increased the contact area and bonding sites between the particles, and aggregated and shaped the mixed powder easy. Moreover, MCC showed a synergistic effect, and the combined application with SuperTab 40 ll could effectively improve the fluidity and compressibility of the musk sustained-release powder. When the ratio of SuperTab 40 LL and MCC was 2∶1, musk sustained-release mini-tablets had a high drug loading capacity and good compactibility in line with the design objectives.

In-vitro Functionality of Clozapine Biphasic Release Minitablet Using Advanced Statistical Tools

Background: The better control of the drug release with immediate effect is the major concern to achieve better therapeutic action and patient compliance. The failure of the solid dispersion complex during storage as well as in-vivo is another concern for the oral solid dosage form. Objective: The prime objective of the present study was to optimize the biphasic minitablet incorporating quality by design approach using the combination of waxy erodible and water-impermeable excipients. Exploration of Soluplus as a precipitation inhibitor and Dexolve as a solubility enhancer in oral solid dosage form was the secondary objective. Methods: The drug-Excipient compatibility study was assessed by FTIR. Clozapine was chosen as a model drug that has poor aqueous solubility. The complex was formulated using B-cyclodextrin or HP B-CD or Dexolve by kneading method. The screening of solubility enhancers and their amount were performed based on phase solubility study. The precipitation inhibitor was screened as per the parachute effect study. Immediate release minitablets were formulated using a direct compression method using different disintegrating agents. The IR minitablets were evaluated for different evaluation parameters. The sustained release minitablets were formulated by hot-melt granulation technique incorporating the Precirol ATO 5 as a waxy excipient and ethyl cellulose as water impermeable excipient. The SR minitablet was optimized using a central composite design. The amount of Precirol ATO 5 and ethyl cellulose were chosen as independent variables and % drug release at 1, 6, and 10 h was selected as responses. The designed batches were evaluated for different pre and post-compressional parameters. The IR and SR minitablets were filled in a capsule as per dose requirement and evaluated for in-vitro drug release. The in-vivo plasma concentration was predicted using the Back calculation of the Wagner - Nelson approach. Results: Drug - Excipient study revealed that no significant interaction was observed. Dexolve was screened as a solubility enhancer for the improvement of the solubility of clozapine. The Soluplus was chosen as a precipitation inhibitor from the parachute effect study. The immediate-release tablet was formulated using Prosolv EASYtab SP which yielded less disintegration time with better flowability. The sustained release mini-tablet was formulated using Precirol ATO 5 and ethyl cellulose. Two-dimensional and three-dimensional plots revealed significant effect of the amount of Precirol ATO 5 and ethyl cellulose. The overlay plot locates the optimized region. The in-vitro drug release study revealed the desired drug release of the final combined formulation. The in-vivo plasma concentration-time confirms the drug release up to 12h. Conclusion: The biphasic mini-tablets were formulated successfully for better control of drug release leads to high patient compliance. The use of soluplus as a precipitation inhibitor is explored in the oral solid dosage form for a poorly aqueous drug. Prosolv EASYtab SP was incorporated in the formulation as super disintegrant. The amount of Precirol ATO 5 and ethyl cellulose significantly affected drug release in sustained-release minitablet. The approach can be useful in the industry.

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

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 AUC0−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.

Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs

Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (<0.1%). The melt-granulated captopril in matrix systems containing 50% EC (45P, 100P or 100FP) and the melt-granulated metformin hydrochloride in reservoir systems coated with Kollicoat® SR 30D and Opadry® II (80:20 with 10% weight gain or 70:30 with 20% weight gain) exhibited release profiles adequate to sustained release formulations, for over 450min. Therefore, carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs.

Design and characterization of cefuroxime axetil biphasic floating minitablets

Biphasic floating minitablets of cefuroxime axetil were prepared by melt granulation technique using two different grades of gelucire namely 50/13 and 43/01 to maintain constant plasma drug concentration. Loading dose of cefuroxime axetil was formulated as immediate release (IR) minitablets by using hydrophilic grade of gelucire 50/13. Maintenance dose was formulated as floating sustained release (SR) minitablets by using hydrophobic grade of gelucire 43/01. The prepared IR and SR granules were subjected to micromeritic studies and scanning electron microscopy. Fourier transform infrared spectroscopy (FT-IR) study revealed that drug and selected carriers were compatible. In vitro dissolution study of optimized IR minitablets showed more than 85% of loading dose dissolved within 30 min. Optimized SR minitablets showed zero lag time with floating duration more than 12 h. The drug release from SR minitablets was linear with square root of time with non-Fickian diffusion-controlled release. The optimized batch of minitablets was filled into 0 size hard gelatin capsule. In vitro dissolution study for capsule showed an immediate burst release followed by SR up to 12 h. There is no significant change in dissolution data after storage at 40 °C and 75% RH for three months. Microbiological assay of dissolution samples of optimized minitablets filled in capsules showed proportionate increase in inhibition of growth against Escherichia coli up to 12 h samples. In vivo bioavailability study in albino rabbits showed three times improvement in oral bioavailability.

Development of enteric coated sustained release minitablets containing mesalamine

The aim of this study was to develop and evaluate a multiparticulate modified release system, composed of minitablets with a sustained release matrix system coated with a pH-dependent release polymer, using mesalamine as a model drug. Polyox® WSR 1105 was the polymer used in the matrix system and Eudragit® L30D55 was used as a pH-dependent polymer. The minitablets (with 20%, 30% or 40% Polyox® concentration) were prepared by dry granulation, which led to good quality minitablets. The developed minitablets were coated in a fluidized bed at 8% of the coating level. Dissolution studies were performed in media that simulated the gastrointestinal tract (pH 1.4, 6.0 and 7.2) and showed that formulations with higher Polyox® concentrations were capable of retaining the drug release in pH 1.4. All formulations prolonged the drug release and presented zero-order kinetic behaviour. The Korsmeyer-Peppas model demonstrated that formulations with 20% or 30% of polymer exhibited anomalous transport behaviour, whilst the 40% sample exhibited super case II model transportation. Dissolution efficiency showed that only the formulations containing 20% and 40% polymer could be considered statistically different.

Development and evaluation of sustained-release Compritol® 888 ATO matrix mini-tablets

Context: Sustained-release mini-tablets are a potentially suitable for paediatric drug delivery or as multi-particulate dosage forms.Objective: To evaluate the potential for developing lipophilic matrix mini-tablets and to assess the effects of Compritol® 888 ATO concentration on drug release from differently sized mini-tablets prepared by direct compression.Methods: A formulation comprising theophylline as a model soluble drug, 15% w/w Compritol® 888 ATO as the inert matrix-forming agent, with dibasic dicalcium phosphate anhydrous and lactose as diluents was evaluated by producing 12 mm tablets at a range of compression speeds and forces. The same formulation and further formulations with 25, 35 or 45% w/w Compritol® 888 ATO were evaluated by producing 2, 3 and 4 mm mini-tablets.Results and Discussion: Drug release from matrix tablets was sustained over a period of 12 hours and release rate varied according to the compression force and speed employed. The rate of drug release from matrix mini-tablets was more rapid and increasing Compritol® 888 ATO concentration resulted in slower release rates. The rate of drug release from matrix mini-tablets was inversely proportional to mini-tablet size (2 mm > 3 mm > 4 mm). Drug release from the matrix tablets and mini-tablets followed square-root of time kinetics.Conclusion: Tailored drug release from matrix mini-tablets may achieved by altering the size of mini-tablet or level of Compritol® 888 ATO in the formulation and this may have potential in the development of paediatric formulations or multi-particulate dosage forms.

A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules

We developed and optimized a novel pseudoephedrine hydrochloride (PSE) sustained-release dosage form. The system comprises immediate-release mini-tablets (IRMT) and sustained-release mini-tablets (SRMT) contained in a hydroxypropyl methylcellulose (HPMC) capsule. The IRMT contained PSE, excipients and low-substituted hydroxypropyl cellulose (a disintegrant), and the tablets were coated with HPMC, a water-soluble polymer. IRMT prepared with varying amounts of low-substituted hydroxypropyl cellulose all dissolved completely within the first 60 min, so low-substituted hydroxypropyl cellulose content does not greatly influence PSE release. The SRMT contained only PSE and excipients, and were coated with a mixture of HPMC and the water-insoluble polymer ethylcellulose. The PSE release profile for the SRMT could be controlled by varying the thickness of the coat, and the lag time could be controlled by varying the amount of ethylcellulose present in the polymer coat. PSE was released immediately from our encapsulated mini-tablet system and release was sustained over an extended period of time: the PSE in the IRMT dissolved within 60 min, whereas the PSE in the SRMT was released over 8–10 h. This system can be modified to yield various extended drug-release profiles, thereby harnessing the benefits of both SRMT and IRMT.

Development and evaluation of new multiple-unit levodopa sustained-release floating dosage forms

This work relates to the development and the in vitro evaluation of sustained-release minitablets (MT), prepared by melt granulation and subsequent compression, which are designed to float over an extended period of time. Levodopa was used as a model drug. The importance of the composition and manufacturing parameters of the MT on their floating and dissolution properties was then examined. The investigation showed that MT composition and MT diameter had the greatest influence on drug release, which was sustained for more than 8 h. By using the same formulation, the best floating properties were obtained with 3 mm MT prepared at low compression forces ranging between 50 and 100 N. Their resultant-weight (RW) values were always higher than those obtained with a marketed HBS dosage form within 13 h. When they were filled into gelatin capsules, no sticking was observed. By evaluating the dissolution profiles of levodopa at different pH values, it was found that dissolution profiles depend more on the prolonged-release ability of Methocel ® K15M than on the pH-dependent solubility of levodopa. Finally, the robustness of the floating MT was assessed by testing the drug release variability in function of the stirring conditions during dissolution tests.

Characterization and in vivo evaluation of ocular minitablets prepared with different bioadhesive Carbopol–starch components

The purpose of this study was to evaluate different bioadhesive ocular formulations based on drum dried waxy maize ® starch (DDWM), Amioca ® starch and Carbopol ® 974P. The concentrations of Carbopol ® 974P in the mixtures varied between 5 and 25% (w/w). The rheological properties of the non-sterilized and gamma-irradiated physical blends of Carbopol ® 974P with either DDWM or Amioca ® were compared to those of the corresponding co-spray dried Amioca ® starch/Carbopol ® powders. Higher viscosity or consistency values were measured for sterilized co-spray dried powder mixtures containing an amount of Carbopol ® 974P equal or above 15% (w/w) compared to the physical blends. Sustained release minitablets (Ø 2 mm, 6 mg), consisting of sodium fluorescein as model drug and the bioadhesive powders, were manufactured at a compression force of 1.25 kN. Afterwards, the tablets were sterilized with gamma-irradiation. The amount of Carbopol ® in the co-spray dried powder mixtures on the one hand and gamma-irradiation on the other hand had no significant influence on the crushing strength and friability of the minitablets evaluated. However, these two factors affected the in vitro release properties of the minitablets. The slowest release was obtained with tablets containing 25% Carbopol ® 974P, which unfortunately possess mucosal irritating properties. By using co-spray dried Amioca ® with 15% (w/w) Carbopol ® 974P, a slower release can be achieved compared to the physical mixtures of DDWM or Amioca ® starch with Carbopol ® 974P. Moreover, this ocular formulation is very promising and is preferred, as it did not cause any mucosal irritation and released the model drug for at least 12 h, after application in the fornix.

Valproat Retard in der Epilepsietherapie

In an observational study under routine clinical setting data after administration of once daily evening dosing of valproate sustained release minitablets were recorded in 359 patients with epilepsy aged between 12 and 86 years. Patients were either newly treated with valproate sustained release minitablets (N = 58) or switched from conventional valproate (N = 124) or from sustained release valproate (N = 138) to the once daily evening dosing. In 39 patients other antiepileptic drugs were replaced. At the end of the 7-week observational period most patients (65.4 %) received a daily dose of 10 to less than 18 mg/kg body weight followed by 17.4 % receiving doses in the therapeutically recommended range of 18 - 24 mg/kg. 8.6 % and 7.4 % of patients received more than 24 mg/kg or less than 10 mg/kg body weight, respectively. As expected, in both groups with valproate pre-treatment the mean morning valproate plasma levels increased by approximately 10 microg/ml after switch to once evening dosing with sustained release minitablets. The mean seizure frequency decreased from 2.1 to 0.5 in the 318 patients with data before the beginning and at the end of the investigation. At the final examination 137 patients (62.3 %) were seizure free, and further 60 patients (27.3 %) experienced a seizure reduction of more than 50 % (responder) of those 220 patients who experienced seizures in the last 7 weeks before the study. The efficacy and tolerability was rated in more than 95 % of the cases by the patient and the investigator as good or very good. The compliance/acceptance of the valproate sustained release minitablets was rated as good or very good in almost all patients. These results confirm the excellent benefit-risk ratio of the valproate sustained release minitablets and underline the importance of a simple compliance-improving dose regimen for effective seizure control.

Modulation of combined-release behaviors from a novel “tablets-in-capsule system”

A multifunctional and multiple unit system, which contains versatile mini-tablets in a hard gelation capsule, is developed by preparing Rapid-release Mini-Tablets (RMTs), Sustained-release Mini-Tablets (SMTs), Pulsatile Mini-Tablets (PMTs), and Delayed-onset Sustained-release Mini-Tablets (DSMTs), each with various lag times of release. Based on the combinations of mini-tablets, multiplied pulsatile drug delivery system (DDS), site-specific DDS, slow/quick DDS, quick/slow DDS, and zero-order DDS could be obtained. Velocity–time curve, instead of the cumulative percentage drug release profile, is plotted. The nonlinear least square model fit program is applied to process the velocity data of dissolution. The test curves coincided with the theoretical curves from simple summation of v– t equations of individual mini-tablets. Therefore, the programmed DDS can be predicted by adding the v– t equations of various mini-tablets to calculate the theoretical equations and be implemented.

The use of artificial neural networks for the selection of the most appropriate formulation and processing variables in order to predict the in vitro dissolution of sustained release minitablets.

The objective of this work was to apply artificial neural networks (ANNs) to examine the relative importance of various factors, both formulation and process, governing the in-vitro dissolution from enteric-coated sustained release (SR) minitablets. Input feature selection (IFS) algorithms were used in order to give an estimate of the relative importance of the various formulation and processing variables in determining minitablet dissolution rate. Both forward and backward stepwise algorithms were used as well as genetic algorithms. Networks were subsequently trained using the back propagation algorithm in order to check whether or not the IFS process had correctly located any unimportant inputs. IFS gave consistent rankings for the importance of the various formulation and processing variables in determining the release of drug from minitablets. Consistent ranking was achieved for both indices of the release process; ie, the time taken for release to commence through the enteric coat (T(lag)) and that for the drug to diffuse through the SR matrix of the minitablet into the dissolution medium (T9(0-10)). In the case of the T(lag) phase, the main coating parameters, along with the original batch blend size and the blend time with lubricant, were found to have most influence. By contrast, with the T(90-10 phase), the amounts of matrix forming polymer and direct compression filler were most important. In the subsequent training of the ANNs, removal of inputs regarded as less important led to improved network performance. ANNs were capable of ranking the relative importance of the various formulations and processing variables that influenced the release rate of the drug from minitablets. This could be done for all main stages of the release process. Subsequent training of the ANN verified that removal of less relevant inputs from the training process led to an improved performance from the ANN.