Bootstrap Statistics and Its Application in Disintegration and Dissolution Data Analysis.

Disintegration time (DT) and rate of drug dissolution in different media are among the most widely studied crucial parameters for various types of drug products. In the ever-evolving landscape of generic formulation development, dissolution comparison of reference and test products is the major reliable in vitro method of establishing product similarity. This is one of the most widely accepted methods of proving pharma equivalency between two drug products. A well-studied match between the disintegration and dissolution profile of the test and reference formulations can ensure in vitro product similarity. Various statistical approaches have been employed to establish product performance similarity; among them, the similarity factor (f2) calculation based approach is the most widely accepted and explored method to date. However, the f2 statistics fail to predict the similarity of batches with unit-to-unit variability. Bootstrap statistical analysis of dissolution data between the test and reference products was introduced to overcome the problems associated with batches with unit variability. Bootstrap can also be applied to extract statistically significant results by treating a series of data from different batches, which can further help to understand the trend. The current review depicts different case study based approaches to show the applications of bootstrap statistics in disintegration and dissolution similarity evaluation for both conventional and additively manufactured solid dosage forms. It is concluded that bootstrap statistics can be a very promising and reliable data analytical tool for establishing in vitro product similarity for both conventional and additively manufactured formulations with a high level of intraunit variability.

Decellularized extracellular matrix-based bioengineered 3D breast cancer scaffolds for personalized therapy and drug screening.

Breast cancer (BC) is the second deadliest cancer after lung cancer. Similar to all cancers, it is also driven by a 3D microenvironment. The extracellular matrix (ECM) is an essential component of the 3D tumor micro-environment, wherein it functions as a scaffold for cells and provides metabolic support. BC is characterized by alterations in the ECM. Various studies have attempted to mimic BC-specific ECMs using artificial materials, such as Matrigel. Nevertheless, research has proven that naturally derived decellularized extracellular matrices (dECMs) are superior in providing the essential in vivo-like cues needed to mimic a cancer-like environment. Developing in vitro 3-D BC models is not straightforward and requires extensive analysis of the data established by researchers. For the benefit of researchers, in this review, we have tried to highlight all developmental studies that have been conducted by various scientists so far. The analysis of the conclusions drawn from these studies is also discussed. The advantages and drawbacks of the decellularization methods employed for generating BC scaffolds will be covered, and the review will shed light on how dECM scaffolds help develop a BC environment. The later stages of the article will also focus on immunogenicity issues arising from decellularization and the origin of the tissue. Finally, this review will also discuss the biofabrication of matrices, which is the core part of the bioengineering process.

A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development.

Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.

Premix technologies for drug delivery: manufacturing, applications, and opportunities in regulatory filing.

Active pharmaceutical ingredients (APIs) and excipients can be carefully combined in premix-based materials before being added to dosage forms, providing a flexible platform for the improvement of drug bioavailability, stability, and patient compliance. This is a promising and transformative approach in novel and generic product development, offering both the potential to overcome challenges in the delivery of complex APIs and viable solutions for bypassing patent hurdles in generic product filing. We discuss the different types of premixes; manufacturing technologies such as spray drying, hot melt extrusion, wet granulation, co-crystal, co-milling, co-precipitation; regulatory filing opportunities; and major bottlenecks in the use of premix materials in different aspects of pharmaceutical product development.

Rebamipide nanocrystal with improved physicomechanical properties and its assessment through bio-mimicking 3D intestinal permeability model.

This study investigated the formulation and characterization of rebamipide nanocrystals (REB-NCs) to enhance the solubility and permeability of rebamipide, an anti-ulcer medication known for its low aqueous solubility and permeability, classified as BCS class IV. Employing high-pressure homogenization and wet milling techniques, we successfully achieved nanonization of rebamipide, resulting in stable nanosuspensions that were subsequently freeze-dried to produce REB-NCs with an average particle size of 223 nm. Comprehensive characterization techniques, including Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC) confirmed the crystalline nature of the nanocrystals and their compatibility with the selected excipients. The saturation solubility study revealed a remarkable three-fold enhancement in PBS pH 7.4 compared to rebamipide API, indicating the effectiveness of the nanocrystal formulation in improving drug solubility. Furthermore, 3D in-vitro permeability assessments conducted on Caco-2 cell monolayers demonstrated an noticeable increase in the permeability of REB-NCs relative to the pure active pharmaceutical ingredient (API), highlighting the promise of this formulation to enhance drug absorption. The dissolution profile of the nanocrystal tablets exhibited immediate release characteristics, significantly outperforming conventional formulations in terms of the dissolution rate. This research underscores the potential of nanomilling as a scalable, environment-friendly, and less toxic approach to significantly enhance the bioavailability of rebamipide. By addressing the challenges associated with the solubility and permeability of poorly water-soluble drugs, our outcome offers insightful information into developing efficient nanomedicine strategies for enhancing therapeutic outcomes.

Manifesting the Dasatinib-gallic acid co-amorphous system to augment anticancer potential: Physicochemical characterization, in silico molecular simulation, ex vivo permeability, and in vitro efficacy.

Dasatinib (DAB) has been explored for repurposing in the treatment of breast cancer (BC) due to its known effectiveness in treating leukemia, in addition to its role as a tyrosine kinase inhibitor. Gallic acid (GA) was chosen as a co-former due to its anticancer potential in BC, as demonstrated in several previous studies. DAB is a low-solubility drug, which is a significant hurdle for its oral bioavailability. To address this limitation, a DAB and GA co-amorphous (DAB-GA-CA) system was developed using liquid-assisted grinding and ball mill technology to enhance solubility, bioavailability, and anti-tumor efficacy. Physical characterization investigation revealed that the emergence of the halo diffractogram in PXRD, single glass transition temperature (Tg) value at 111.7 °C in DSC thermogram, and irregularly shaped blocks with loose, porous surfaces in SEM analysis indicated the formation of the DAB-GA-CA system at 1:1 M ratio. Furthermore, FTIR, Raman spectroscopy, in-silico molecular docking, and molecular dynamic studies confirmed the intermolecular hydrogen connections between DAB and GA. Moreover, the outcomes of the ligands (DAB and GA) and receptors (BCL-2, mTOR, estrogen receptor, and HER-2) docking studies demonstrated that both DAB and GA could interact with those receptors, leading to preventive action on BC cells. Additionally, the solubility and dissolution rate significantly improved at pH 6.8, and the permeability study indicated that DAB-GA-CA showed 1.9 times higher apparent permeability compared to crystalline DAB. Furthermore, in vitro cytotoxicity assessments of the DAB-GA-CA system revealed 3.42 times lower IC50 than free DAB. The mitochondrial membrane depolarization, apoptotic index, and reactive oxygen species formation in MCF-7 cells were also notably higher in the DAB-GA-CA system than in free DAB. Hence, this research suggests that the DAB-GA-CA system could substantially enhance oral delivery, solubility, and therapeutic efficacy.

Selenium nanoparticle-functionalized injectable chitosan/collagen hydrogels as a novel therapeutic strategy to enhance stem cell osteoblastic differentiation for bone regeneration.

Stem cells are an essential consideration in the fields of tissue engineering and regenerative medicine. Understanding how nanoengineered biomaterials and mesenchymal stem cells (MSCs) interact is crucial for their role in bone regeneration. Taking advantage of the structural stability of selenium nanoparticles (Se-NPs) and biological properties of natural polymers, Se-NPs-functionalized, injectable, thermoresponsive hydrogels with an interconnected molecular structure were prepared to identify their role in the osteogenic differentiation of different types of mesenchymal stem cells. Further, comprehensive characterization of their structural and biological properties was performed. The results showed that the hydrogels undergo a sol to gel transition with the help of ß-glycerophosphate, while functionalization with Se-NPs significantly enhances their biological response through stabilizing their polymeric structure by forming Se-O covalent bonds. Further results suggest that Se-NPs enhance the differentiation of MSCs toward osteogenic lineage in both the 2D as well as 3D. We demonstrated that the Se-NPs-functionalized hydrogels could enhance the differentiation of osteoporotic bone-derived MSCs. We also focused on specific cell surface marker expression (CD105, CD90, CD73, CD45, CD34) based on the exposure of healthy rats' bone marrow-derived stem cells (BMSCs) to the Se-NP-functionalized hydrogels. This study provides essential evidence for pre-clinical/clinical applications, highlighting the potential of the nanoengineered biocompatible elastic hydrogels for bone regeneration in diseased bone.

Correction: Selenium nanoparticle-functionalized injectable chitosan/collagen hydrogels as a novel therapeutic strategy to enhance stem cell osteoblastic differentiation for bone regeneration.

Correction for 'Selenium nanoparticle-functionalized injectable chitosan/collagen hydrogels as a novel therapeutic strategy to enhance stem cell osteoblastic differentiation for bone regeneration' by Khaled Alajmi et al., J. Mater. Chem. B, 2024, 12, 9268-9282, https://doi.org/10.1039/D4TB00984C.

Surface engineered nanodiamonds: mechanistic intervention in biomedical applications for diagnosis and treatment of cancer.

In terms of biomedical tools, nanodiamonds (ND) are a more recent innovation. Their size typically ranges between 4 to 100 nm. ND are produced via a variety of methods and are known for their physical toughness, durability, and chemical stability. Studies have revealed that surface modifications and functionalization have a significant influence on the optical and electrical properties of the nanomaterial. Consequently, surface functional groups of NDs have applications in a variety of domains, including drug administration, gene delivery, immunotherapy for cancer treatment, and bio-imaging to diagnose cancer. Additionally, their biocompatibility is a critical requisite for theirin vivoandin vitrointerventions. This review delves into these aspects and focuses on the recent advances in surface modification strategies of NDs for various biomedical applications surrounding cancer diagnosis and treatment. Furthermore, the prognosis of its clinical translation has also been discussed.

Fabrication and optimization of extended-release beads of diclofenac sodium based on Ca++ cross-linked Taro (Colocasia esculenta) stolon polysaccharide and pectin by quality-by-design approach.

The present investigation was aimed to fabricate and optimize extended-release beads of diclofenac sodium based on an ion-cross-linked matrix of pectin (PTN) and taro (Colocasia esculenta) stolon polysaccharide (TSP) with 23 full factorial design. Total polysaccharide concentration (TPC), polysaccharide ratio (PR), and cross-linker concentration ([CaCl2]) were taken as independent factors with two levels of each. Initially, TSP was extracted, purified, and characterized. Fourier-transform infrared spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC) showed drug-polymer compatibility. The study also revealed the significant positive effect of TSP on drug entrapment efficiency (DEE) and sustaining drug release. The response variables (DEE, cumulative % drug-release at 1, 2, 4, 6, and 10 h, release-constant, time for 50 % and 90 % drug release (T50%, T90%), release-similarity factor (f2), and difference factor (f1) were analyzed, and subsequently, independent fabrication variables were numerically optimized by Design-Expert software (Version-13; Stat-Ease Inc., Minneapolis). The optimized batch exhibited appreciable DEE of 88.5 % (± 2.2) and an extended-release profile with significantly higher T50%, T90%, and release-similarity factor (f2) of 4.7 h, 11.4 h, and 71.6, respectively. Therefore, the study exhibited successful incorporation of the novel TSP as a potential alternative adjunct polysaccharide in the pectin-based ion-cross-linked inter-penetrating polymeric network for extended drug release.

Exploring novel and fast stability or sameness evaluation tool for different categories of injectable formulations.

The establishment of drug product stability and sameness is the heart of generic formulation development. For regulatory filing, various instrumental methods are used on a case basis to establish the generic and innovator product sameness in multiple aspects. Here in the present study, we explored the applicability of the Time-correlated single photon counting (TCS-PC) technique as a fast, reliable, and nondestructive method for establishing the sameness of three different categories of injectable formulations, namely, Amphotericin B liposome for injection, enoxaparin injection, and iron sucrose injection. All three category formulations were evaluated in their native and artificially induced post degradation state to identify the discrimination power of the used instrumental techniques. The degradation of materials were confirmed by high performance liquid chromatography (HPLC). Based on the product category, pre and post-degradation samples were evaluated by selective instrumental methods like differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), fluorescence spectroscopy, particle size analysis by dynamic light scattering (DLS), small angle X-ray scattering (SAXS), Raman spectroscopy, inductively coupled plasma optical-emission spectrometry (ICP-OES) and circular dichroism study. All pre and post-degradation samples were further analyzed by TCS-PC. We observed that, TCS-PC can identify the differences between the initial and post degradation samples in very less time with promising discrimination power across the different injectable formulation types. Thus TCS-PC can be used as a fast and promising stability or sameness evaluation tool for different injectable drug products.

Exploring the interaction between extracellular matrix components in a 3D organoid disease model to replicate the pathophysiology of breast cancer.

In vitro models are necessary to study the pathophysiology of the disease and the development of effective, tailored treatment methods owing to the complexity and heterogeneity of breast cancer and the large population affected by it. The cellular connections and tumor microenvironments observed in vivo are often not recapitulated in conventional two-dimensional (2D) cell cultures. Therefore, developing 3D in vitro models that mimic the complex architecture and physiological circumstances of breast tumors is crucial for advancing our understanding of the illness. A 3D scaffold-free in vitro disease model mimics breast cancer pathophysiology by allowing cells to self-assemble/pattern into 3D structures, in contrast with other 3D models that rely on artificial scaffolds. It is possible that this model, whether applied to breast tumors using patient-derived primary cells (fibroblasts, endothelial cells, and cancer cells), can accurately replicate the observed heterogeneity. The complicated interactions between different cell types are modelled by integrating critical components of the tumor microenvironment, such as the extracellular matrix, vascular endothelial cells, and tumor growth factors. Tissue interactions, immune cell infiltration, and the effects of the milieu on drug resistance can be studied using this scaffold-free 3D model. The scaffold-free 3D in vitro disease model for mimicking tumor pathophysiology in breast cancer is a useful tool for studying the molecular basis of the disease, identifying new therapeutic targets, and evaluating treatment modalities. It provides a more physiologically appropriate high-throughput platform for screening large compound library in a 96-384 well format. We critically discussed the rapid development of personalized treatment strategies and accelerated drug screening platforms to close the gap between traditional 2D cell culture and in vivo investigations.

Investigation on processing variables for the preparation of fluconazole-loaded ethyl cellulose microspheres by modified multiple emulsion technique.

Fluconazole-loaded ethyl cellulose microspheres were prepared by alginate facilitated (water-in-oil)-in-water emulsion technology and the effects of various processing variables on the properties of microspheres were investigated. Scanning electron microscopy revealed spherical nature and smooth surface morphology of the microspheres except those prepared at higher concentration of emulsifiers and higher stirring speeds. The size of microspheres varied between 228 and 592 mum, and as high as 80% drug entrapment efficiency was obtained depending upon the processing variables. When compared up to 2 h, the drug release in pH 1.2 HCl solution was slower than in pH 7.4 phosphate buffer saline solution. However, this trend was reversed at high shear conditions. The microspheres provided extended drug release in alkaline dissolution medium and the drug release was found to be controlled by Fickian-diffusion mechanism. However, the mechanism shifted to anomalous diffusion at high shear rates and emulsifier concentrations. The aging of microspheres did not influence the drug release kinetics. However, the physical interaction between drug and excipients affected the drug dissolution behaviors. X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC) analysis revealed amorphous nature of drug in the microspheres. Fourier transform infrared (FTIR) spectroscopy indicated stable character of fluconazole in the microspheres. The stability testing data also supported the stable nature of fluconazole in the microspheres. The fluconazole extracted from 80% drug-loaded formulation showed good in vitro antifungal activity against Candida albicans. Thus, proper control of the processing variables involved in this modified multiple emulsion technology could allow effective incorporation of slightly water soluble drugs into ethyl cellulose microspheres without affecting drug stability.

Comparative bio-safety and in vivo evaluation of native or modified locust bean gum-PVA IPN microspheres.

Strategically developed natural polymer-based controlled release multiparticulate drug delivery systems have gained special interest for "spatial placement" and "temporal delivery" of drug molecules. In our earlier study, locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (LBG-PVA IPN), carboxymethylated locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (CMLBG-PVA IPN) and acrylamide grafted locust bean gum-poly(vinyl alcohol) interpenetrating polymer network (Am-g-LBG-PVA IPN) were prepared and characterized. The present study deals with accelerating stability testing, comparative bio-safety and single dose in vivo pharmacokinetic study of all three IPN microspheres for controlled oral delivery of buflomedil hydrochloride (BH). From the stability study, it was observed that the particles were stable throughout the study period. From toxicity and biodegradability study it was proved that the microspheres were safe for internal use and complied with bio-safety criterion. From the in vivo pharmacokinetic study in rabbits, it was observed that the CMLBG-PVA IPN microspheres possessed almost similar Tmax value with BH oral suspension. However, in comparison between the LBG-PVA and Am-g-LBG-PVA IPN microspheres, the later showed well controlled release property than the first in biological condition. Thus, this type of delivery system might be useful to achieve the lofty goals of the controlled release drug delivery.

Synthesis, characterization and evaluation of methacrylamide grafted gellan as sustained release tablet matrix.

In the present study, the microwave induced synthesis of polymethacrylamide-grafted-gellan gum (PMaa-g-GG) was carried out by free radical initiation using cerric (IV) ammonium nitrate (CAN) as redox initiator. Concentrations of methacrylamide (Maa), CAN and microwave irradiation time were taken as variable synthetic parameters. The modified polysaccharide obtained from different synthetic conditions was then characterized by FTIR, CHN analysis, DSC and powder X-ray diffraction. The yield and extent of grafting were assessed by determining percentage grafting, percentage grafting efficiency, percentage conversion and these were correlated with elemental analysis. The acute oral toxicity study of modified polysaccharide was performed as per OECD guideline. Histological comparison of different organs between control and test animal showed no significant difference. Sustained release tablets of diclofenac sodium (DS) were prepared with modified gellan. In vitro dissolution study showed the tablets were capable of releasing the drug over a period of 8 h.

Current pharmaceutical design on adhesive based transdermal drug delivery systems.

Drug-in-adhesive transdermal drug delivery matrix exploits intimate contact of the carrier with stratum corneum, the principal skin barrier to drug transport, to deliver the actives across the skin and into the systemic circulation. The main application challenges of drug-in-adhesive matrix lie in the physicochemical properties of skin varying with age, gender, ethnicity, health and environmental condition of patients. This in turn poses difficulty to design a universal formulation to meet the intended adhesiveness, drug release and drug permeation performances. This review focuses on pressure-sensitive adhesives, and their adhesiveness and drug release/permeation modulation mechanisms as a function of adhesive molecular structure and formulation attributes. It discusses approaches to modulate adhesive tackiness, strength, elasticity, hydrophilicity, molecular suspension capability and swelling capacity, which contribute to the net effect of adhesive on skin bonding, drug release and drug permeation.

Interpenetrating polymer network of locust bean gum-poly (vinyl alcohol) for controlled release drug delivery.

A novel interpenetrating polymer network (IPN) microspheres of locust bean gum (LBG) and poly (vinyl alcohol) (PVA) was developed for oral controlled release of buflomedil hydrochloride (BH) by emulsion crosslinking method using glutaraldehyde as crosslinker. The effects of gum-polymer ratio, concentration of crosslinker and internal phase viscosity were evaluated thoroughly. Drug entrapment efficiency, particle size distribution, swelling property and in vitro release characteristics with kinetic modelling of microspheres were evaluated. The microspheres were characterised by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), solid state C(13) NMR, X-ray diffraction study (XRD) and differential scanning colorimetry (DSC). The microspheres showed control release property without showing any incompatibility in IPN device. Hence, IPN microspheres of LBG and PVA can be used as a potential carrier for controlled oral delivery of highly water soluble drugs like BH.

Microwave-induced solid dispersion technology to improve bioavailability of glipizide.

OBJECTIVES: The effect of microwave (MW) irradiation and conventional heating (CH) on solid dispersion (SD) of poorly water-soluble glipizide (GPZ) and polyethylene glycol 4000 (PEG 4000) were studied in detail. METHODS: The chemical stability of GPZ on exposure to MW irradiation and CH was confirmed by high-performance liquid chromatography, Fourier transform infra red spectroscopy, proton nuclear magnetic resonance and mass spectroscopy studies. Comparative bioavailability studies were performed in rabbits using glipizide sustained-release tablets prepared using MW irradiation (MW-SD) or CH (CH-SD), with Glytop 2.5 mg SR as a reference. KEY FINDINGS: The MW-assisted melt mixing showed higher efficiency than CH in obtaining a homogeneous mixture having glass transparency. The polymorphic transformation of GPZ in each case was further confirmed by powder X-ray diffraction study. The solubility of GPZ in phosphate buffer pH 6.8 was greater for MW-SD (72.250 ± 0.154 µg/ml) than CH-SD (46 ± 0.201 µg/ml). The MW-SD matrix tablet (2.5 mg) displayed retarded drug release (releasing 99.320 ± 4.992% drug in 12 h). In-vivo pharmacokinetic study in rabbits revealed that the relative bioavailability of GPZ from MW-SD tablets improved greatly (153.73 ± 9.713%). CONCLUSIONS: MW-induced SD technology could be a better alternative to CH-SD for the enhanced solubility and bioavailability of GPZ.

Microwave assisted synthesis of acrylamide grafted locust bean gum and its application in drug delivery.

Acrylamide grafted copolymer of locust bean gum was prepared by microwave irradiation using ceric ammonium nitrate as redox initiator. The grafting process was optimized in terms of irradiation time, amount of initiator and acrylamide by using constant amount of native locust bean gum. The grafted gum was characterized by Fourier transform infrared spectroscopy (FT-IR), (13)C nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), X-ray diffraction study (XRD), differential scanning calorimetry (DSC), elemental analysis, contact angle, viscosity, molecular weight, swelling and biodegradability studies. The grafted gum was found to be biodegradable and non-toxic. It was further used to prepare controlled-release matrix tablet of buflomedil hydrochloride. The in vitro release profile of the tablet showed the rate controlling property of acrylamide grafted locust bean gum was similar to that of hydroxypropyl methylcellulose (HPMC-K15M).

Microwave assisted synthesis and characterization of acrylamide grafted gellan, application in drug delivery.

The synthesis of acrylamide-grafted-gellan gum was carried out by microwave-assisted free radical polymerization using cerric ammonium nitrate (CAN) as redox initiator. A series of graft copolymers, varying in amount of acrylamide, CAN and microwave irradiation time was prepared. The modified gum was extracted with 20% (v/v) methanol to remove the homopolymer formed during polymerization reaction. These graft copolymers were characterized by FTIR, (13)C NMR, CHN, SEM, rheological studies and DSC studies. Comparison of grafting parameters such as grafting efficiency, percentage grafting and percentage conversion were carried out among various series of graft copolymers and then correlating it with elemental analysis, DSC, viscosity results. The acute oral toxicity study of grated gum was evaluated as per OECD guideline. Tablets were prepared by incorporating antidiabetic drug metformin hydrochloride (MTF) in grafted gum along with excipients. In vitro studies were performed on prepared tablet formulations showing release up to 8 h.