Model drug release from matrix tablets composed of HPMC with different substituent heterogeneity

The release of a model drug substance, methylparaben, was studied in matrix tablets composed of hydroxypropyl methylcellulose (HPMC) batches of the USP 2208 grade that had different chemical compositions. It was found that chemically heterogeneous HPMC batches with longer sections of low substituted regions and lower hydroxypropoxy content facilitated the formation of reversible gel structures at a temperature as low as 37°C. Most importantly, these structures were shown to affect the release of the drug from matrix tablets, where the drug release decreased with increased heterogeneity and a difference in T80 values of 7h was observed between the compositions. This could be explained by the much lower erosion rate of the heterogeneous HPMC batches, which decreased the drug release rate and also released the drug with a more diffusion based release mechanism compared to the less heterogeneous batches. It can therefore be concluded that the drug release from matrix tablets is very sensitive to variations in the chemical heterogeneity of HPMC.     

Release of theophylline and carbamazepine from matrix tablets - Consequences of HPMC chemical heterogeneity

The release of theophylline and carbamazepine from matrix tablets composed of microcrystalline cellulose, lactose and hydroxypropyl methylcellulose (HPMC) was studied. The aim was to investigate the effect of different substituent heterogeneities of HPMC on the drug release from matrix tablets composed of either 35% or 45% HPMC. The release of the poorly soluble carbamazepine was considerably affected by the HPMC heterogeneity, and the time difference at 80% drug release was more than 12 h between the formulations of different HPMC batches. This was explained by slower polymer erosion of the heterogeneous HPMC and the fact that carbamazepine was mainly released by erosion. In addition, results from magnetic resonance imaging showed that the rate of water transport into the tablets was similar. This explained the comparable results of the release of the sparingly soluble theophylline from the two formulations even though the polymer erosion and the swelling of the tablets were considerably different. Thus, it can be concluded that the drug release was highly affected by the substituent heterogeneity, especially in the case of carbamazepine, which was released mainly by erosion.     

The effect of chemical heterogeneity of HPMC on polymer release from matrix tablets

Polymer release from hydrophilic matrix tablets, composed of hydroxypropyl methylcellulose, was studied for seven different polymer batches. A time difference of more than 80 h between fully dissolved tablets was noticed although the batches were of the same pharmaceutical substituent (USP 2208) and viscosity (100 cps) grade. To find the functionality related parameters for polymer release from hydrophilic matrix tablets the polymer samples were characterised according to size and chemical composition. The size of the polymers was characterised by size-exclusion chromatography with multi-angle light scattering and refractive index detection. The average amount of substituents was measured with nuclear magnetic resonance and the distribution of the substituents along the cellulose chain was determined with high-performance anion-exchange chromatography with pulsed amperometric detection after acid and enzymatic hydrolysis. The results indicated that other types of interactions apart from entanglements were present between the polymer chains, which seemed to affect the polymer release. Most importantly, this study has shown a correlation between the polymer release and the substituent pattern, where the samples with slow release also were more heterogeneously substituted along the polymer chain. From this we can conclude that polymer release is very sensitive to alterations in chemical composition.     

The influence of HPMC viscosity as FRC parameter on the release of low soluble drug from hydrophylic matrix tablets

The importance of functionality-related characteristics (FRC) of hydroxypropyl methylcellulose (HPMC) described in the pharmacopeia monograph can be evaluated only for selected formulation or technological process. The aim of our work was to investigate the influence of apparent viscosity as one of the FRC for two batches of the same HPMC grade on the release properties of diclofenac sodium from HPMC matrix tablets. Our results show that two batches of HPMC differ in viscosity significantly and as a consequence, the significant differences were observed in the release profiles as well. HPMC-B sample has higher viscosity and therefore higher average molecular weight, thus the erosion and drug release were slower compared to HPMC-A sample with lower apparent viscosity. It can be concluded that batch-to-batch viscosity variation of the same HPMC grade can lead to the different release profiles; therefore the specification limits of some FRC should be postulated during the development of each individual formulation. However, the viscosity interval as FRC can not be generalized, because it is different for different tablet compositions.     

In vitro controlled release of alfuzosin hydrochloride using HPMC-based matrix tablets and its comparison with marketed product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r2 value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

In Vitro Controlled Release of Alfuzosin Hydrochloride Using HPMC-Based Matrix Tablets and Its Comparison with Marketed Product

The present study is an attempt to formulate a controlled-release matrix tablet formulation for alfuzosin hydrochloride by using low viscous hydroxy propyl methyl cellulose (HPMC K-100 and HPMC 15cps) and its comparison with marketed product. Different batches of tablets containing 10 mg of alfuzosin were prepared by direct compression technique and evaluated for their physical properties, drug content, and in vitro drug release. All the formulations had a good physical integrity, and the drug content between the batches did not vary by more than 1%. Drug release from the matrix tablets was carried out for 12 hr and showed that the release rate was not highly significant with different ratios of HPMC K-100 and HPMC15cps. Similar dissolution profiles were observed between formulation F3 and the marketed product throughout the study period. The calculated regression coefficients showed a higher r² value with zero-order kinetics and Higuchi model in all the cases. Although both the models could be applicable, zero-order kinetics seems to be better. Hence, it can be concluded that the use of low viscous hydrophilic polymer of different grades (HPMC K-100 and HPMC 15cps) can control the alfuzosin release for a period of 12 hr and was comparable to the marketed product.     

Formulation and Optimization of a Sustained-Release Tablet of Ketorolac Tromethamine

The objective of our study was to formulate a sustained-release tablet of Ketorolac tromethamine, which is a nonsteroidal anti-inflammatory agent. A 2 3 full factorial design (8 runs) was selected. The variables studied were the amount of drug (30 and 40 mg), ratio of hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC) (240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-controlled matrix tablets were manufactured by direct compression of formulation ingredients using a Stokes single punch tablet press. Dissolution tests were performed using USP apparatus 3 (Bio-Dis II), at various pHs to mimic the conditions that exist in the gastrointestinal tract. Responses studied included time for 50% of the drug to dissolve (T 50), diffusional exponent (n) that characterizes the release mechanism, and percent friability of the tablets. Analysis of variance indicated that the release rate (T 50) was affected by the HPMC/NaCMC ratio, amount of drug, and two-way and three-way interactions; whereas the amount of drug, HPMC/NaCMC ratio, ethylcellulose, and the interaction between drug and HPMC/NaCMC and HPMC/NaCMC and ethylcellulose and also three-way interactions were significantly affecting the diffusional exponent (n) . The release mechanism was found to be super-case II transport. The friability of the tablets was significantly affected by all three factors: amount of drug, HPMC/NaCMC ratio, and amount of ethylcellulose. The formulation giving the best release characteristics was identified.     

Formulation and optimization of a sustained-release tablet of ketorolac tromethamine

The objective of our study was to formulate a sustained-release tablet of Ketorolac tromethamine, which is a nonsteroidal anti-inflammatory agent. A 2 3 full factorial design (8 runs) was selected. The variables studied were the amount of drug (30 and 40 mg), ratio of hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC) (240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-controlled matrix tablets were manufactured by direct compression of formulation ingredients using a Stokes single punch tablet press. Dissolution tests were performed using USP apparatus 3 (Bio-Dis II), at various pHs to mimic the conditions that exist in the gastrointestinal tract. Responses studied included time for 50% of the drug to dissolve ( T 50 ), diffusional exponent ( n ) that characterizes the release mechanism, and percent friability of the tablets. Analysis of variance indicated that the release rate ( T 50 ) was affected by the HPMC/NaCMC ratio, amount of drug, and two-way and three-way interactions; whereas the amount of drug, HPMC/NaCMC ratio, ethylcellulose, and the interaction between drug and HPMC/NaCMC and HPMC/NaCMC and ethylcellulose and also three-way interactions were significantly affecting the diffusional exponent ( n ). The release mechanism was found to be super-case II transport. The friability of the tablets was significantly affected by all three factors: amount of drug, HPMC/NaCMC ratio, and amount of ethylcellulose. The formulation giving the best release characteristics was identified.     

Parameters affecting the drug release from in situ gelling nasal inserts.

The purpose of the study was to investigate the influence of physicochemical drug properties, drug loading, and composition of the release medium on the drug release from in situ gelling nasal inserts. Sponge-like nasal inserts of carrageenan and HPMC K15M with the model drugs oxymetazoline HCl, diprophyllin, and acetaminophen (APAP) were prepared by lyophilization. Drug release studies at different drug loadings were performed in various release media. Raman analysis, DSC, and SEM were conducted to analyze the physical state of the drugs in the inserts. All drugs were dissolved in the solid HPMC inserts and were released at similar rates at all investigated loadings except for the least soluble APAP. APAP concentrations in the hydrating HPMC K15M inserts in excess of its solubility limit resulted in reduced relative release rates at higher drug loadings. Drug-polymer interactions (formation of less soluble drug-polymer salts) resulted in a slower release of oxymetazoline HCl from carrageenan inserts than from HPMC K15M inserts. Changes in the composition of the release medium affected the water uptake of carrageenan but not of HPMC K15M inserts. Oxymetazoline release from carrageenan inserts increased with higher Na+-content of the medium because of ion exchange and at low (pH 2) as well as at high pH (pH 10). The osmolality of the release medium had no effect. The solubility of the drug, its physical state in the polymer matrix, and drug-polymer interactions governed the drug release from nasal inserts. The release from inserts prepared with oppositely charged polymers and drugs was influenced by electrostatic drug-polymer interactions and by the composition of the release medium.     

Formulation study and drug release mechanism of a new theophylline sustained-release preparation

Two matrix theophylline tablets with different release mechanisms were compared. Tablet A was a swelling/disintegration-type wax matrix made of hydrophobic wax granules, consisting of stearic acid, hydrogenated oil and glycerol esters of fatty acids, and hydrophilic polymer granules composed primarily of hydroxypropyl methylcellulose (HPMC). We named Tablet A the cluster tablet. Tablet B was a gel matrix made of hydrophobic ethylcellulose granules, consisting of ethylcellulose and hydrogenated oil, and hydrophilic polymer granules consisting of HPMC and hydroxylpropylmethylcellulose acetate succinate (HPMCAS). The formulations were screened in vitro according to their dissolution characteristics. The drug release from each preparation was analyzed using release kinetics theories. In Tablet A, the value of the exponent(n) representing the apparent diffusion mechanism determined from the Korsmeyer-Peppas model equation was about 0.6 and was unlikely to be affected by the rotation speed. In Tablet B, the value of the exponent(n) by the Korsmeyer-Peppas model equation changed with the paddle rotation speed. These results suggested that the drug release mechanism of Tablet B is greatly affected by the extent of physical force in the gastrointestinal tract.     

Binding and release of drugs into and from thermosensitive poly(N-vinyl caprolactam) nanoparticles.

Three model drug substances, the beta-blocking agents nadolol and propranolol and a choline-esterase inhibitor tacrine, were used in order to determine how different drug molecules affect the behavior of thermally responsive polymer nanoparticles composed of poly(N-vinylcaprolactam) (PVCL). Pure PVCL particles in water exist in a swollen state at room temperature, but the size of the particles decreases discontinuously when the temperature is raised above the volume phase transition temperature. At temperatures above this transition temperature, water is expelled out from the nanoscopic hydrogel particles. Light scattering studies revealed that the more hydrophobic drug substances, propranolol and tacrine, considerably swell the PVCL-microgel. The more hydrophilic drug, nadolol, decreased the transition temperature of PVCL particles, whereas the transition temperature values of pure PVCL particles and that of the added propranolol and tacrine were quite similar. Attenuated drug release results showed that the beta-blocking agents were tightly bound to the microgel, and this was more evident at higher temperatures. On the contrary, the release of tacrine across the cellulose membrane was increased when PVCL particles were present. Thus, both physical and chemical properties of the drugs clearly affected their binding to PVCL particles and the release of drugs was affected by the temperature.     

Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component.

The effects of component nature, proportion and processing on the release rate and mechanism were investigated for tablets comprising drug, cellulosic polymer and hydrophobic components. Four drugs differing in solubility (diclofenac sodium, ibuprofen, naproxen and indomethacin), two cellulosic polymers (HPC and HPMC) and hydrophobic Emvelop were used in two levels of mass fraction and weight ratio of drug:carrier and of cellulosic-hydrophobic component. Compression was applied after granulation or physical mixing. Drug release was evaluated in pH 6.5 phosphate buffer BP and elucidation of the release mechanism was attempted by fitting kinetic models. Statistical significance of the effects of formulation variables on the release rate and mechanism expressed by the coefficient, k, and exponent, n, of the power law kinetic model, respectively, was evaluated by ANOVA. It was found that for the release mechanism most significant is the effect of drug solubility followed by cellulosic polymer type, mixing procedure and drug mass fraction. Significant interaction between drug solubility and type of cellulosic polymer indicated that alteration in the swelling of HPMC and HPC is caused by the drug solubility. Weight ratio of cellulosic-hydrophobic component does not affect the release mechanism, but only the release rate. Similarly, for the release rate most significant was found the effect of drug solubility, followed by cellulosic polymer type, weight ratio of cellulosic-hydrophobic component, mixing method and drug mass fraction. Also significant were the interactions of drug solubility with the type and proportion of the cellulosic polymer and the processing applied. Depending on the drug solubility and type of polymer present, wet granulation can increase or decrease the release rate.     

Physicochemical interactions between drugs and superdisintegrants

We have evaluated the interactions between superdisintegrants and drugs with different physicochemical characteristics, which may affect the in‐vivo absorption e.g. after mucosal administration. The binding of sodium salicylate, naproxen, methyl hydroxybenzoate (methylparaben), ethyl hydroxybenzoate (ethylparaben), propyl hydroxybenzoate (propylparaben), atenolol, alprenolol, diphenhydramine, verapamil, amitriptyline and cetylpyridinium chloride monohydrate (CPC) to different superdisintegrants (sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone) and one unsubstituted comparator (starch) was studied spectrophotometrically. An indication of the in‐vivo effect was obtained by measuring the interactions at physiological salt concentrations. SSG was investigated more thoroughly to obtain release profiles and correlation between binding and ionic strength. The results showed that the main interactions with the anionic hydrogels formed by SSG and CCS were caused by ion exchange, whereas the neutral crospovidone exhibited lipophilic interactions with the non‐ionic substances. The effect of increased ionic strength was most pronounced at low salt concentrations and the ion exchange interactions were almost completely eradicated at physiological conditions. The release profile of diphenhydramine was significantly affected by the addition of salt. It was thus concluded that the choice of buffer was of great importance for in‐vitro experiments with ionic drugs. At physiological salt concentrations the interactions did not appear to be strong enough to influence the in‐vivo bioavailability of any of the drug molecules.     

盐酸丁螺环酮缓释片的制备及体外释放研究

目的 :为了减少给药次数和减小药物的毒副作用 ,制备盐酸丁螺环酮缓释片。方法 :采用亲水凝胶骨架材料 (HPMC)制备该缓释片 ,并考察药物与HPMC不同比例组成、HPMC不同粘度等对该水溶性药物释放的影响。结果 :药物 /HPMC之比为影响释放过程的主要因素 ,HPMC(高粘度 )的粘度与药物释放无关 ,且该骨架片的释药与释放介质的 pH无关。 结论 :该缓释片制备工艺简单 ,缓释速率可控。     

Drug release behavior of polymeric matrix filled in capsule

A single unit sustainable drug release system was developed using hydroxypropyl methylcellulose (HPMC)-based matrices filled in capsule as the drug delivery device. Release behavior of propranolol HCl from these capsules was investigated and least square fitting was performed for the dissolution data with the different mathematical expressions. Effect of diluent, polymer, pH and hydrodynamic force on the drug release from the developed systems was investigated. The utilization of HPMC as a matrix former extended the drug release longer than 8 h. HPMC viscosity grades affected the drug release, that is, increasing the amount of fillers such as lactose and dibasic calcium phosphate enhanced the drug release rate of HPMC matrices. The hydrodynamic force, type and amount of incorporated polymer apparently influenced the drug release. The physiochemical properties of polymers and interaction between HPMC and other polymers were important factors for prolongation of the drug release. The release mechanism from HPMC-based matrices in capsules was the non-Fickian transport in which the sustainable drug release of HPMC capsules could be achieved by the addition of polymeric matrix.     

Macromolecular composition and drug-loading effect on the delivery of paclitaxel and folic acid from acrylic matrices

Drug delivery systems based on synthetic polymers are widely employed in the treatment of several pathologies. In particular, the use of implantable devices able to release one or more active principles in a topic site with a controlled delivery kinetic represents an important improvement in this field. However, the release kinetic, that could be affected by different parameters, like polymer composition or chemical nature and initial drug loading, represents one of the problems related to the implantation of delivery systems. In this study, acrylic membranes with different macromolecular composition were prepared and studied analyzing delivery kinetic properties. Drug delivery systems were prepared using as matrix the copolymer poly(methylmethacrylate-co-butylmethacrylate) in three different compositions and folic acid (less hydrophobic) or Paclitaxel (more hydrophobic) as drugs, to evaluate the effect of macromolecular composition and hydrophilicity degree on the release properties. In addition, the effect of the initial drug loading was considered, loading drug delivery systems with four different initial drug percentages. Results showed a direct dependence of kinetics from macromolecular composition, hydrophilicity degree of solutes, and initial drug loading, allowing one to conclude that it is possible to design and to develop drug delivery systems starting from poly(methylmethacrylate-co-butylmethacrylate) matrices with specific properties by varying these three parameters.     

In vitro Evaluation of the Effect of Combination of Hydrophilic and Hydrophobic Polymers on Controlled Release Zidovudine Matrix Tablets

The aim of the present study was to prepare and characterize controlled-release matrix tablets of zidovudine using hydrophilic HPMC K4 M or Carbopol 934 alone or in combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using USP XXIV dissolution apparatus No.2 (paddle) type. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. The in vitro results of controlled – release zidovudine tablets were compared with conventional marketed tablet Zidovir. The in vitro drug release study revealed that HPMC K4 M or Carbopol 934 preparation was able to sustain the drug release near to 6 hours. Combining HPMC K4 M or Carbopol 934 with ethyl cellulose sustained the drug release for nearly 12 h. The in vitro evaluation showed that the drug release may be by diffusion along with erosion. Results suggest that the developed controlled-release tablets of zidovudine could perform therapeutically better than marketed dosage forms, leading to improve efficacy, controlling the release and better patient compliance.     

Preparation of a novel floating ring capsule-type dosage form for stomach specific delivery

Study objectives were to develop a unique floating ring capsule dosage form which combines gastric soluble and insoluble portions, and to evaluate its suitability for stomach specific drug delivery. New floating ring capsules were developed using different polymers and were compared for various parameters. The formulation with HPMC and sodium CMC has better floating properties. The effects of polymers concentration on drug release were studies by in vitro release studies. The interaction studies of combined drug with polymers were determined using FT-IR spectroscopy. The entrapped air within the gel barrier and lower densities of HPMC and sodium CMC resulted in better floating behavior. Steady slow gel formations showed prolonged drug release. The in vitro release rates were generally found to be faster with low concentration of carbopol showing release within 2 h, while formulations containing high amount of HPMC showed release in 8 h. In particular, the higher concentration of HPMC formulation shows the best drug release performance. A very low change in peak shift was observed only with sodium alginate formulations. Further, FT-IR measurements confirmed the absence of any chemical interactions. Results indicate that new floating ring capsule is a promise dosage form for stomach specific delivery.     

阿奇霉素缓释阴道栓的处方优化

目的:优化阿奇霉素缓释阴道栓的处方。方法:采用硬脂酸聚烃氧酯(S-40)为基质,以羟丙基甲基纤维素(HPMC)为缓释材料、甘油为保湿剂等制备阿奇霉素缓释阴道栓。以累积释药百分率和栓剂硬度为考察指标、8%HPMC和甘油在处方中的用量为考察因素,采用正交设计法进行处方优化,并进行验证试验及体外释药模型拟合。结果:优化后处方组成为阿奇霉素6g,8%HPMC23.52g,甘油29.40g,无水乙醇3g,尼泊金乙酯0.59g,S-40294g。由优化后处方制备的3批栓剂平均含量99.5%,硬度符合要求,体外释放重复性和均一性良好,180min时累积释药百分率均大于98%,体外释药动力学符合Higuchi方程。结论:优化后的阿奇霉素缓释阴道栓处方可行,制备工艺稳定,重复性好,符合缓释制剂要求。