Controlled Release Hydrophilic Matrix Tablet Formulations of Isoniazid: Design and In Vitro Studies

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer–Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f ₂ metric values. The release profiles found to follow Higuchi’s square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.     

参芍片联合酒石酸美托洛尔片对冠心病心绞痛患者氧化应激、血管内皮功能和心肌损伤标志物的影响

摘要 目的：探讨参芍片联合酒石酸美托洛尔片对冠心病心绞痛患者氧化应激、血管内皮功能和心肌损伤标志物的影响。方法：病例选取自我院2018年9月~2021年7月期间收治的110例冠心病心绞痛患者,按照入院的奇偶顺序将患者分为对照组（55例）和观察组（55例）,对照组患者接受酒石酸美托洛尔片治疗,观察组患者接受参芍片联合酒石酸美托洛尔片治疗,观察两组临床总有效率、心电图总有效率,对比两组临床症状、氧化应激[超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH-PX）]、血管内皮功能[内皮素（ET）、血管内皮生长因子（VEGF）、一氧化氮（NO）]和心肌损伤标志物[心肌肌钙蛋白（cTn）、肌酸激酶同工酶（CK-MB）、脑钠肽（BNP）]水平变化,记录两组用药的不良反应发生率。结果：与对照组相比,观察组的临床总有效率、心电图总有效率进一步升高（P<0.05）。观察组治疗12周后心绞痛发作次数较对照组少,心绞痛持续时间较对照组短,6 min步行试验距离长于对照组（P<0.05）。治疗12周后,观察组VEGF、ET水平低于对照组,NO水平高于对照组（P<0.05）。治疗12周后,观察组CK-MB、cTn、BNP水平低于对照组（P<0.05）。治疗12周后,观察组MDA水平低于对照组,SOD、GSH-PX水平高于对照组（P<0.05）。两组不良反应发生率组间对比无差异（P>0.05）。结论：参芍片联合酒石酸美托洛尔片治疗冠心病心绞痛患者,可促进症状改善,减轻机体氧化应激和血管内皮损伤,发挥较好的心肌保护作用。     

琥珀酸美托洛尔与美托洛尔对慢性充血性心衰患者心功能的影响

目的：探讨琥珀酸美托洛尔缓释片与美托洛尔片对慢性心力衰竭患者的心功能的影响。方法：选取慢性充血性心衰患者182例临床患者资料,排除67例不符合入选标准病例后,按照服用美托洛尔剂型（缓释片、平片）分为两组,两组均为常规利尿剂ACEI等治疗。美托洛尔组患者服用每日服用25mg-50mg的美托洛尔治疗,均分2次服用。琥珀酸美托洛尔组每日服用23．75-95mg琥珀酸美托洛尔缓释片进行治疗。评价治疗前和治疗12个月后的相关指标,包括：一日5次的平均心率（晨起前,8时,12时,16时,夜间休息前共5次平均心率）、LVDd、EF、BUN、Crea。结果：治疗12个月后,两组患者心率均下降．琥珀酸美托洛尔组与美托洛尔组相比下降更明显（64．0±5．4VS69．5±7．6,P〈0．05）、LVDd、EF、BUN、Crea等指标在两组之间没有差别。结论：慢性充血性心衰患者应用琥珀酸美托洛尔较美托洛尔平片相比可明显降低平均心率。但对于心功能肾功能的影响。琥珀酸关托洛尔较美托洛尔平片相比无明显差异。     

Influence of Formulation Factors on Tablet Formulations with Liquid Permeation Enhancer Using Factorial Design

For a drug with low bioavailability, a matrix tablet with liquid permeation enhancer (Labrasol®) was formulated. Factorial design was used to evaluate the effect of three formulation factors: drug percentage, polymer type (Methocel® K100M or Eudragit® L 100-55), and tablet binder percentage (Plasdone® S-630) on tablet characteristics. Tablets were prepared by direct compression and characterized. Compressibility index values ranged between 15.90% and 29.87% and tablet hardness values from 7.8 to 29.78 Kp. Eudragit®-containing formulations had better compressibility index values with higher tablet hardness. Time for 75% of drug release (T ₇₅) was calculated, and formulations containing Eudragit® L 100-55 had faster release rates than tablet formulations with Methocel® K100M. Formulations with Methocel® K100M fit well in the Higuchi model as indicated by their R ² values (>0.98). Among all the formulation factors studied, polymer type displayed the highest and statistically significant effect on compressibility index, tablet hardness, and dissolution rate. Statistical design helped in better understanding the effect of formulation factors on tablet characteristics important for designing formulations with desired characteristics.     

Evaluation of Poly(2-Ethyl-2-Oxazoline) Containing Copolymer Networks of Varied Composition as Sustained Metoprolol Tartrate Delivery Systems

Segmented copolymer networks (SCN) based on poly(2-ethyl-2-oxazoline) and containing 2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, and/or methyl methacrylate segments have been evaluated as potential sustained release systems of the water soluble cardioselective β-blocker metoprolol tartrate. The structure and properties of the drug carriers were investigated by differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy. Swelling kinetics of SCNs in various media was followed, and the conditions for effective MT loading were specified. MT-loaded SCNs with drug content up to 80 wt.% were produced. The release kinetics of metoprolol tartrate from the systems was studied and it was shown that the conetworks of different structure and composition are able to sustain the metoprolol tartrate release without additional excipients.     

Preparation and Evaluation of Sustained-Release Matrix Tablets Based on Metoprolol and an Acrylic Carrier Using Injection Moulding

Sustained-release matrix tablets based on Eudragit RL and RS were manufactured by injection moulding. The influence of process temperature; matrix composition; drug load, plasticizer level; and salt form of metoprolol: tartrate (MPT), fumarate (MPF) and succinate (MPS) on ease of processing and drug release were evaluated. Formulations composed of 70/30% Eudragit RL/MPT showed the fastest drug release, substituting part of Eudragit RL by RS resulted in slower drug release, all following first-order release kinetics. Drug load only affected drug release of matrices composed of Eudragit RS: a higher MPT concentration yielded faster release rates. Adding triethyl citrate enhanced the processability, but was detrimental to long-term stability. The process temperature and plasticizer level had no effect on drug release, whereas metoprolol salt form significantly influenced release properties. The moulded tablets had a low porosity and a smooth surface morphology. A plasticizing effect of MPT, MPS and MPF on Eudragit RS and Eudragit RL was observed via DSC and DMA. Solubility parameter assessment, thermal analysis and X-ray diffraction demonstrated the formation of a solid solution immediately after production, in which H-bonds were formed between metoprolol and Eudragit as evidenced by near-infrared spectroscopy. However, high drug loadings of MPS and MPF showed a tendency to recrystallise during storage. The in vivo performance of injection-moulded tablets was strongly dependent upon drug loading.     

Fabrication of Modified Release Tablet Formulation of Metoprolol Succinate using Hydroxypropyl Methylcellulose and Xanthan Gum

The present investigation was undertaken to fabricate modified release tablet of metoprolol succinate using hydroxypropyl methylcellulose (HPMC) and xanthan gum as a matrixing agent. A 3² full factorial design was employed for the optimization of formulation. The percentage drug released at a given time (Y ₆₀, Y ₂₄₀ and Y ₇₂₀) and the time required for a given percentage of drug to be released (t _50%) were selected as dependent variables. The in vitro drug dissolution study was carried out in pH 6.8 phosphate buffer employing paddle rotated at 50 rpm. The similarity factor (f ₂) was calculated for selection of best batch considering mean in vitro dissolution data of Seloken® XL as a reference profile. It is concluded that the desired drug release pattern can be obtained by using a proper combination of HPMC (high gelling ability) and xanthan gum (quick gelling tendency). The economy of xanthan gum and faster hydration rate favors its use in modified release tablets. The matrix integrity during dissolution testing was maintained by using hydroxypropyl methylcellulose.     

Formulation Study and Evaluation of Matrix and Three-layer Tablet Sustained Drug Delivery Systems Based on Carbopols with Isosorbite Mononitrate

The purpose of this research was to develop and evaluate different preparations of sustained delivery systems, using Carbopols as carriers, in the form of matrices and three-layer tablets with isosorbite mononitrate. Matrix tablets were prepared by direct compression whereas three-layer tablets were prepared by compressing polymer barrier layers on both sides of the core containing the drug. The findings of the study indicated that all systems demonstrated sustained release. The properties of the polymer used and the structure of each formulation appear to considerably affect drug release and its release rate. The three-layer formulations exhibit lower drug release compared to the matrices. This was due to the fact that the barrier-layers hindered the penetration of liquid into the core and modified drug dissolution and release. The geometrical characteristics/structure of the tablets as well as the weight/thickness of the barriers-layers considerably influence the rate of drug release and the release mechanisms. Kinetic analysis of the data indicated that drug release from matrices was mainly attributed to Fickian diffusion while three-layer tablets exhibited either anomalous diffusion or erosion/relaxation mechanisms. The advantage of Carbopol formulations is that a range of release profiles can easily be obtained through variations in tablet structure and thus Carbopols are appropriate carriers of oral sustained drug delivery systems for soluble drugs such as the isosorbite mononitrate.     

两种剂型美托洛尔对不稳定心绞痛患者心率变异性及QT离散度的影响及疗效观察

目的:探讨两种剂型美托洛尔对冠心病不稳定心绞痛患者心率变异性(HRV)及QT离散度的影响及观察两种剂型美托洛尔对不稳定心绞痛患者的临床疗效.方法:100例不稳定心绞痛患者被随机分为平片组及缓释片组,在常规冠心病治疗基础上,分别服用美托洛尔平片(25mg)和缓释片(23.75)开始,逐步增加剂量,观察治疗前后HRV及QT离散度的情况及观察两种剂型美托洛尔对不稳定心绞痛患者的临床疗效情况.结果:与治疗前比较,两组治疗14d后平片组与缓释片组HRV、QT离散度指标均改善,缓释片组优于平片组(P＜0.05),美托洛尔平片治疗组总有效率为80％,美托洛尔缓释片治疗组总有效率为84％.结论:应用美托洛尔缓释片治疗不稳定性心绞痛比美托洛尔平片在控制心率变异性及QT离散度方面更好,在本研究中,美托洛尔与琥珀酸美托洛尔均能改善不稳定心绞痛患者预后,但两者比较对疗效无明显差异.     

Stability Enhancement of Drug Layered Pellets in a Fixed Dose Combination Tablet

The purpose of this research was to develop a stable fixed dose combination tablet for a model DPP-IV inhibitor and metformin hydrochloride. The dipeptidyl peptidase IV (DPP-IV) inhibitor was particularly challenging to formulate due to its significant chemical instability and moisture sensitivity. Various formulation strategies were investigated and placed on accelerated stability to determine the lead approach and critical quality attributes. The lead formulation investigated was a drug layered pellet containing the DPP-IV inhibitor, which was further coated with various seal coats and moisture barriers, then compressed into a tablet with compression aids and granulated metformin hydrochloride. The investigations revealed that the drug layered pellets compressed into a fixed dose combination tablet yielded a unique stability enhancement. The stability was highly dependent on the final tablet water content and could be further improved by the addition of moisture barrier coatings. A fundamental understanding of the key critical quality attributes for the fixed dose combination product containing a DPP-IV inhibitor and metformin hydrochloride as an oral solid dosage form were established. This research identified a formulation approach to enable a successful commercial product to be developed.     

Oral Delivery of Peptide Formulations and Their Cellular Evaluation

International Journal of Peptide Research and Therapeutics - The development of peptide-based formulations presents numerous challenges to the formulator due to their complexity, delicate structure...     

Impact of Vibration and Agitation Speed on Dissolution of USP Prednisone Tablets RS and Various IR Tablet Formulations

Dissolution testing is an in vitro procedure which is widely used in quality control (QC) of solid oral dosage forms and, given that real biorelevant test conditions are applied, can also be used as a predictive tool for the in vivo performance of such formulations. However, if a dissolution method is intended to be used for such purposes, it has to deliver results that are only determined by the quality of the test product, but not by other variables. In the recent past, more and more questions were arising on how to address the effects of vibration on dissolution test results. The present study was performed to screen for the correlation of prednisone dissolution of USP Prednisone Tablets RS with vibration caused by a commercially available vibration source as well as to investigate how drug release from a range of immediate release formulations containing class 1–4 drugs of the biopharmaceutical classification scheme is affected by vibration when performing dissolution experiments at different agitation rates. Results of the present study show that the dissolution process of oral drug formulations can be affected by vibration. However, it also becomes clear that the degree of which a certain level of vibration impacts dissolution is strongly dependent on several factors such as drug properties, formulation parameters, and the design of the dissolution method. To ensure the establishment of robust and predictive dissolution test methods, the impact of variation should thus be considered in method design and validation.KEY WORDS: dissolution, USP prednisone calibrator tablets, variability, vibration meter, vibration source     

A Menthol-Based Solid Dispersion Technique for Enhanced Solubility and Dissolution of Sulfamethoxazole from an Oral Tablet Matrix

A menthol-based solid dispersion was designed to improve the intrinsic solubility of the poorly soluble sulfamethoxazole- a class II drug molecule of Biopharmaceutics Classification System (BCS) displaying widespread antibacterial activity. Solid dispersions of menthol and sulfamethoxazole were compressed with hydroxypropyl methylcellulose (HPMC) into suitable sulfamethoxazole-loaded matrix tablets for oral drug delivery. The sulfamethoxazole-loaded solid dispersions and compressed tablets were characterized for their physicochemical and physicomechanical properties such as changes in crystallinity, melting point, molecular transitions, and textural analysis for critical analysis of their effects on the solubility and dissolution of sulfamethoxazole. The formulations were further evaluated for swelling, degradation, solubility, and in vitro drug release behavior. In vitro drug release from the sulfamethoxazole-loaded matrix tablets displayed a minimum and maximum fractional release of 0.714 and 0.970, respectively. The tablets further displayed different release rate profiles over the study periods of 12, 16, 48, and 56 h which were attributed to the varying concentrations of menthol within each formulation. Menthol was determined as a suitable hydrophilic carrier for sulfamethoxazole since it functioned as a solubilizing and release-retarding agent for improving the solubility and dissolution of sulfamethoxazole as well as controlling the rate at which it was released.KEY WORDS: crystallinity, menthol, oral solubility and dissolution, solid dispersion, sulfamethoxazole     

Modulation of Tramadol Release from a Hydrophobic Matrix: Implications of Formulations and Processing Variables

In the present investigation, hydrogenated cottonseed oil (HCSO) was evaluated as a sustained release matrix for a freely soluble drug, tramadol. Hydrophobic matrix tablets of tramadol, was evaluated by compression of physical mixture of drug and wax, dispersion of drug in HCSO by hot fusion or solubilisation techniques. The method of preparation of tablet had a significant effect on drug release with higher release observed from direct compression matrices and slower release from matrix prepared by dispersion (hot-fused matrices). Influence of addition of hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and surfactants like sodium lauryl sulphate and polysorbate 20 to HCSO matrix on drug release was investigated. The added excipients exhibited a propensity to enhance drug release from the HCSO matrix. NaCMC was effective at a lower ratio (<10% w/w) and when incorporated at higher level made HCSO matrix to erode and disintegrate in a short period.     

Evaluation of Citrus Fibers as a Tablet Excipient

The consumption of fibers is associated with many health benefits, such as a reduction of cardiovascular and gastrointestinal diseases, control of body weight, and prevention of diabetes. Despite the widespread use of fiber supplements such as capsules or tablets, there is an almost complete lack of information concerning the technological properties of functional fibers used in nutraceutical formulations. The aim of this work was to characterize the technological properties of citrus fibers necessary for their use as a processing aid in tableting. The results obtained showed that citrus fibers share many properties of other polysaccharides used as tableting excipients, such as thermal behavior and compaction mechanism, together with an appreciable tabletability. However, the most interesting properties resulted from their disintegration power. Citrus fibers behaved in a similar manner to the well-known super disintegrant croscarmellose sodium and resulted to be little susceptible to their concentration, to lubricant type, and lubricant concentration. Thus, this work supports the idea of a potential use of citrus fibers as “active” substances and processing aid in the tableting of nutraceutical products and also as functional excipient in pharmaceutical tablets formulation.     

Formulation and Evaluation of Bi-layer Tablet of Metoclopramide Hydrochloride and Ibuprofen

The aim of this study was to prepare bi-layer tablet of Metoclopramide Hydrochloride (MTH) and Ibuprofen (IB) for the effective treatment of migraine. MTH and IB were formulated as immediate and sustained release layer respectively. MTH was formulated as immediate release layer by using various disintegrants like Ac-Di-Sol, Polyplasdone XL, Explotab, Agar and Gellan Gum. Treated form of gellan gum and agar was prepared and compared for their disintegrant efficiency with other disintegrants. IB was formulated as sustained release layer using hydrophilic matrix (hydroxypropylmethylcellulose [HPMC K₄M]). The effect of concentration of hydrophilic matrix (HPMC K₄M), binder (polyvinylpyrollidone [PVP K₃₀]) and buffer (sodium bicarbonate) on IB release was studied. The dissolution study of sustained release layer showed that an increasing amount of HPMC or PVP K₃₀ results in reduced IB release. The inclusion of buffer (sodium bicarbonate) enhanced the release of IB from sustained release layer. The rational for formulation of bi-layer tablet of these two drugs in combination was (1) MTH increases the absorption of acidic non-steroidal anti-inflammatory drug (NSAID) by increasing gastric motility. So sequential release of MTH (as immediate release) and IB (as sustained release) was suitable for treatment of migraine. (2) MTH was degraded when prolonged contact with acidic NSAID. Bi-layer tablet was suitable for preventing direct contact of these two drugs and thus to maximize the efficacy of combination of two drugs for migraine.     

Comparison of TSH Levels with Liquid Formulation Versus Tablet Formulations of Levothyroxine in the Treatment of Adult Hypothyroidism

ObjectiveA great number of factors can interfere with levothyroxine (LT4) tablet absorption, leading to increased serum thyroid-stimulating hormone (TSH) levels and, accordingly, to increased LT4 requirements. LT4 oral solution (LT4-OS) is a novel formulation with a pharmacokinetics profile different from those of tablets. The aim of this study was to retrospectively evaluate whether serum TSH levels were decreased after switching adult hypothyroid patients from the tablet to LT-OS.MethodsWe retrospectively evaluated 53 outpatients on LT4 replacement therapy (consumed within 1 hour before breakfast) who switched from LT4 tablets to LT4-OS without changing the daily dose. We compared preswitch TSH (TSH1) with TSH level 60 to 90 days after the switch (TSH2) and examined the clinical differences between the patients whose TSH did and did not drop after the switch.ResultsAfter the switch, TSH levels decreased from a median value of 3.04 (interquartile range [IQR] 1.75-6.80) to 2.30 (IQR 1.21-3.81) μIU/mL, and the difference was significant (P = .0034). We observed a TSH reduction (TSH2/TSH1 ratio < 1) in 36/53 (67.9%) of patients; the median TSH2/TSH1 ratio was 0.71 (IQR 0.37-1.14). In the group of patients whose TSH dropped, we observed an increased frequency of factors interfering with LT4 absorption (P = .014). The median TSH2/TSH1 ratios were 0.50 (IQR 0.31-0.72) and 0.85 (IQR 0.65-1.36) for patients with and without interfering factors, respectively.ConclusionOur study confirms that LT4-OS could have an increased absorption rate in comparison to LT4 tablets, especially in the presence of other factors interfering with LT4 absorption. (Endocr Pract. 2014;20:657-662)     

Design and Formulation of Mebeverine HCl Semisolid Formulations for Intraorally Administration

Gel formulations of mebeverine hydrochloride (MbHCl) containing hydroxypropylmethylcellulose (HPMC), metolose (MTL), and poloxamer 407 (PLX) were prepared to be used in the treatment of different oral painful conditions. HPMC was used as a mucoadhesive gel base while MTL and PLX were used to prepare sol–gel thermosensitive gels. MTL and PLX formulations showed proper sol–gel transition temperature for intraoral application. Formulations were evaluated in terms of their viscosity, mechanical properties, mucoadhesivity, stability, and in vitro drug release. The formulation prepared with 2% of HPMC K100M provided the highest viscosity at room temperature. However, the viscosity of HPMC–PLX mixture showed a significant increase at body temperature. The greatest mucoadhesion was also noted in HPMC–PLX combinations. Texture profile analysis exhibited the differences of the adhesion, hardness, elasticity, cohesiveness, and compressibility of the formulations. The release profiles of MbHCl were obtained, and non-Fickian release was observed from all the formulations. The formulations were stored at different temperature and relative humidity. No significant changes were observed at the end of the 3 months. HPMC–PLX formulation of MbHCl was chosen for in vivo studies, and it remained longer than dye solution on the rabbit’s intraoral mucosal tissue. It was found worthy of further clinical evaluation.     

Formulation Variables Influencing Drug Release from Layered Matrix System Comprising Chitosan and Xanthan Gum

The purpose of this study was to investigate the formulation variables influencing the drug release from the layered tablets containing chitosan and xanthan gum as matrix component. Increasing the amount of lactose could diminish pH sensitive release behavior of these matrix tablets. Effect of formulation variables on drug release from the prepared three-layered matrix tablets was investigated. The amount of drug loading did not affect the drug release which was influenced by the hydrodynamic force and the matrix composition. An increase in stirring rate correspondingly increased the release rate. Moreover, incorporation of soluble diluents in core or barrier could enhance the drug release. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi’s and zero order) was carried out to study the drug release mechanism. Most dissolution profiles of the prepared three-layered tablets provided a better fit to zero order kinetic than to first order kinetic and Higuchi’s equation.