Extent Of Drug Release Research Articles

Overview on Natural Polymers: A Promising Pharmaceutical excipient in Mucoadhesive Drug Delivery System

This review aims to compile the current literature with a perspective on the role of natural polymers or polysaccharides in mucoadhesive drug delivery systems. Natural polymers are basically polysaccharides, biocompatible, non-toxic, stable, and economical. Polymers play an important role as excipients in designing the dosage form and influence drug release without any side effects. Natural polymers are of growing interest in the utilization of mucosal drug delivery as a novel technique due to their ability to interact with the mucosal layer of the body, improve the effectiveness of the drug, and prolong the residence time of the dosage form at the site of absorption. The bioadhesive polymers can exert control over the rate and extent of drug release and are selected in the formulation of mucoadhesive drug delivery systems. This review article discusses several aspects of mucoadhesive drug delivery, including the mechanism of mucoadhesion, mucus layer, and mucoadhesive polymers, with special reference to natural-based polysaccharides, as well as their applications and roles in different formulations developed by using polysaccharides in various dosage forms.

Functionalized calcium carbonate (FCC) as a novel carrier to solidify supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS)

Functionalized calcium carbonate (FCC), a novel pharmaceutical excipient, has shown promising properties in the field of oral drug delivery. The current study aimed at evaluating the feasibility of FCC as a carrier for the solidification of self-nanoemulsifying drug delivery systems (SNEDDS) containing the poorly water-soluble model drug carvedilol (CRV). Conventional, subsaturated SNEDDS (80 %-SNEDDSliquid) and supersaturated SNEDDS (200 %-SNEDDSliquid) were loaded onto FCC via physical adsorption at three ratios; 2.5:1, 3.0:1 and 3.5:1 (w/w) of FCC:SNEDDSliquid, respectively, generating free-flowing powders (SNEDDSFCC) with drug loading ranging from 0.8 % to 2.6 % (w/w) CRV. The emulsification of SNEDDSFCC in a USP II dissolution setup (in purified water) was characterized using dynamic light scattering, resulting in similar droplet sizes and PDIs as observed for their liquid counterparts. The morphology and physical state of the obtained SNEDDSFCC were characterized using scanning electron microscopy and differential scanning calorimetry. The physical stability and drug release upon dispersion were assessed as a function of storage time. The 200 %-SNEDDSliquid were physically stable for 6 days, however, solidification using FCC stabilized the supersaturated concentrations of CRV for a test period of up to 10 weeks (solidification ratios 3.0:1 and 3.5:1 (FCC:SNEDDSliquid)). SNEDDSFCC achieved an improved rate and extent of drug release upon dispersion compared to the crystalline CRV in tap water (pH 7.5), however, to a lesser extent than their liquid counterparts. After 8 weeks of storage (25 °C at dry conditions), FCC was still able to rapidly release the SNEDDSliquid and demonstrated the same rate and extent of drug release as freshly prepared samples. The solidification of 200 %-SNEDDSliquid in presence of FCC greatly improved the drug loading and showed an enhanced drug release profile compared to the conventional systems. In conclusion, FCC showed potential as a carrier for solidification of SNEDDS and for the development of novel supersaturated solid SNEDDS for the oral delivery of poorly water-soluble drugs.

Measurement uncertainty arising from sampling and analytical steps of dissolution test of glyburide tablets

The dissolution test is an essential technique used in pharmaceutical research to assess the rate and extent of drug release from a dosage form into a dissolution medium. Accurate and reliable dissolution test results are crucial to ensure the quality and efficacy of the drug product. The aim of this study was to evaluate the measurement uncertainty arising from the sampling and analytical steps of the dissolution test for glyburide tablets. Dissolution test was performed using 900 mL of phosphate buffer pH 7.3 as dissolution medium and a dissolution apparatus equipped with paddles rotating at 75 rpm for 60 min. Quantification was performed by HPLC-UV. The uncertainty arising from sampling was estimated through classical Analysis of Variance (ANOVA), using 8-sampling targets, two samples for each sampling target and two replicas for each sample, totalizing 32 analyses. Uncertainty arising from analytical steps considered the uncertainty from dissolution step (estimated using Monte Carlo method and regression equation obtained using DoE) and uncertainty from quantification step. The overall uncertainty value was found to be 6.33 %. The sources of uncertainty contributing to the overall measurement uncertainty of the dissolution test were estimated to be 76.09 % from sampling, 22.15 % from the dissolution step, and 1.76 % from the quantification step. The study emphasizes the importance of evaluating measurement uncertainty in dissolution testing to ensure reliable and accurate drug product quality control. The results demonstrate that the dissolution test of glyburide tablets presented high sampling uncertainty and did not pass the dissolution test within the specified limits, probably due to glyburide’s low solubility. Univariate and multivariate rejection limits were calculated in order to ensure reduced particular and total producer’s risk, respectively. This study provides useful insights for pharmaceutical industries to optimize their quality control processes and ensure the efficacy and safety of their products.

A Comprehensive Review on Role of Polymers in Transdermal Drug Delivery System

Transdermal drug delivery system has been emerged as one of the most effective controlled drug release system in topical formulation as it doesn’t undergo first pass metabolism in liver and can be directly absorbed into the systemic circulation. Polymers are used in TDDS as to increase its effectiveness in the control release of drug from the transdermal patch. Use of polymers in the TDDS has decreased the control release rate of drug from the patch. Use of polymers in combination has given more effectiveness of the drug release. This article gives a quality of information about the use of polymers in the Transdermal drug delivery system. Polymers also help in the adhesive nature of the drug to the skin and promote more extent of drug release from the dosage form. An advance in the use and amount of polymers used in the TDDS has been increased recently. This article provides the information about the use of Natural, semisynthetic and synthetic polymers in the TDDS. Use of natural polymers has been showed more impact in the TDDS and their use has showed fewer side effects like irritation, allergy, and this has been increased patient compliance and more effectiveness in drug release. Semisynthetic and synthetic polymers has been developed and used excessively in the TDDS for effective control release of the drug from the patches. A transdermal patch is defined as medicated adhesive patch which is placed above the skin to deliver a pre-determined dose of medication via skin with a predetermined rate of release to reach into the bloodstream. Article Details

Measurement uncertainty arising from sampling and analytical steps of dissolution test of prednisone tablets

Dissolution is used to determine the rate and extent of drug release from the dosage form into a dissolution medium, which allow to assess the batch-to-batch variability. Considering that the dissolution test is used to predict the vivo performance of the drug as well, it is important to guarantee the quality and reliability of dissolution test results. The aim of this work was to evaluate the measurement uncertainty arising from sampling and analytical steps of dissolution test of prednisone tablets. Dissolution test was performed using 900 mL of purified water as dissolution medium and a dissolution apparatus equipped with paddles rotating at 50 rpm for 30 min. Quantification was performed by UV spectrophotometer. Uncertainty arising from sampling was estimated using the duplicate method (empirical approach), using 17-sampling target, two samples for each sampling target, and three replicas for each sample, totalizing 102 analyses. Uncertainty arising from analytical steps considered the uncertainty from dissolution step (estimated using Monte Carlo method and regression equation obtained using DoE) and uncertainty from quantification step. Overall uncertainty value was found to be 2.2%, which is below the target uncertainty value (ut =2.5%). The contributions of uncertainty sources in this study were as follows: 24% from sampling uncertainty, 29% from the dissolution step uncertainty, and 47% from the quantification step uncertainty. The results of dissolution test should be compared to the specification limits (Q). According to the pharmacopeia requirements, the batch of the medicine should be declared compliant if the dissolved amount of prednisone for six tablets are above the specification limits + 5% (Q+5%=85%). Since the measured values for all six tablets (96.5%, 94.0%, 96,4%, 95.3%, 96.0%, and 96.9%) were above the multivariate acceptance limit (90.2%, calculate as the standard uncertainty multiplied by multivariate coverage factor), the batch of the prednisone tablets was declared complaint, with a reduced total risk of false decision (total risk value below 5%).

Gastroretentive drug delivery system of levofloxacin hemihydrate

The aim of the studies to formulate and develop mucoadhesive microcapsules of levofloxacin hemihydrates by using the mucoadhesive polymers for the treatment of H. pylori infection. Methods: Microspheres were prepared by Ionotropic gelation technique. To achieve the mucoadhesive and extended release property in this study, sodium alginate, chitosan and calcium chloride for formulating levofloxacin hemihydrate microcapsules. In vitro drug release and in-vitro mucoadhesiveness. Results: To achieve the mucoadhesive and extended release property in this study, mucoadhesive polymer, such as chitosan was used. Sodium dioctyl sulphosuccinate (DOSS) used as surfactant. The percentage yield for levofloxacin hemihydrate loaded microspheres was found to be in the range of 32.11±1.25% to 87.28±1.67%. Drug content of the levofloxacin hemihydrate loaded microspheres varied from 20.21±1.01% to 30.77±1.88%. The encapsulation efficiency of the prepared microspheres varied from 51.77±1.33% to 78.54±1.55%. The mean diameter of levofloxacin hemihydrate loaded microspheres were found to be in the range of 135.5±3.64 μm to 448.59±5.44μm Mucoadhesive property of the prepared microspheres varied from 45.81±1.32% to 82.97±0.82%. A significant decrease in the rate and extent of drug release was observed with the increase in sodium alginate concentration in beads.

Mitochondria-Targeted Photoactivatable Real-Time Monitoring of a Controlled Drug Delivery Platform.

The current anticancer therapies are limited by their lack of controlled spatiotemporal release at the target site of action. We report a novel drug delivery platform that provides on-demand, real-time, organelle-specific drug release and monitoring upon photoactivation. The system is comprised of a model anticancer drug doxorubicin, an alkyltriphenylphosphonium moiety to target mitochondria in cancer cells, and a hydroxycinnamate photoactivatable linker that is covalently attached to the drug and mitochondria-targeting moieties such that it can be phototriggered by either UV (one-photon) or NIR (two-photon) light to form a fluorescent coumarin product and facilitate the release of drug payload. The extent of drug release is quantified by the fluorescence intensity of the coumarin formed. Further, the photoactivatable prodrug accumulates in the mitochondria and shows light-triggered temporally controlled cell death. In the future, our platform can be tuned for any biological application of interest, offering immense value in biomedicine.

Magnetic Particle Imaging: An Emerging Modality with Prospects in Diagnosis, Targeting and Therapy of Cancer.

Simple SummaryMagnetic Particle Imaging (MPI) is an emerging imaging technique that provides quantitative direct imaging of superparamagnetic iron oxide nanoparticles. In the last decade, MPI has shown great prospects as one of the magnetic methods other than Magnetic Resonance Imaging with applications covering cancer diagnosis, targeting enhancement, actuating cancer therapy, and post-therapy monitoring. Working on different physical principles from Magnetic Resonance Imaging, MPI benefits from ideal image contrast with zero background tissue signal, enabling hotspot-type images similar to Nuclear Medicine scans but using magnetic agents rather than radiotracers. In this review, we discussed the relevance of MPI to cancer diagnostics and image-guided therapy as well as recent progress to clinical translation.Background: Magnetic Particle Imaging (MPI) is an emerging imaging modality for quantitative direct imaging of superparamagnetic iron oxide nanoparticles (SPION or SPIO). With different physics from MRI, MPI benefits from ideal image contrast with zero background tissue signal. This enables clear visualization of cancer with image characteristics similar to PET or SPECT, but using radiation-free magnetic nanoparticles instead, with infinite-duration reporter persistence in vivo. MPI for cancer imaging: demonstrated months of quantitative imaging of the cancer-related immune response with in situ SPION-labelling of immune cells (e.g., neutrophils, CAR T-cells). Because MPI suffers absolutely no susceptibility artifacts in the lung, immuno-MPI could soon provide completely noninvasive early-stage diagnosis and treatment monitoring of lung cancers. MPI for magnetic steering: MPI gradients are ~150 × stronger than MRI, enabling remote magnetic steering of magneto-aerosol, nanoparticles, and catheter tips, enhancing therapeutic delivery by magnetic means. MPI for precision therapy: gradients enable focusing of magnetic hyperthermia and magnetic-actuated drug release with up to 2 mm precision. The extent of drug release from the magnetic nanocarrier can be quantitatively monitored by MPI of SPION’s MPS spectral changes within the nanocarrier. Conclusion: MPI is a promising new magnetic modality spanning cancer imaging to guided-therapy.

Adaptive perfusion: An in vitro release test (IVRT) for complex drug products

In this work, adaptive perfusion, a pressure-driven separation method based on the principle of tangential flow filtration (TFF) was developed for investigating the rate and extent of drug release from drug products containing particulates, such as emulsions, suspensions, liposomes, drug-protein complexes. The TFF filters were pre-conditioned with unique conditioning solutions and processes to improve the fiber reproducibility and robustness. The adaptive perfusion method achieved size-based separation of the particulates with simultaneous analysis of the released drug as well as remaining drug. By contrast to conventional dialysis methods, the adaptive perfusion method can be used to measure the rate and extent of the drug release from drug solution, drug loaded micelles and nanoemulsions via adjustment of the filter molecular weight cutoff, feed flow rate or back-pressure. Notably, the adaptive perfusion method provided discriminatory drug release profiles for drug in solution, in micelles, and in small, medium, and large globule size nanoemulsions. The drug release profile obtained using adaptive perfusion method was found significantly faster (e.g., minutes rather than hours) and higher (e.g., >60%) than the release obtained using dialysis method. The IVRT method presented here is free from the constraints of rate-limiting factors, such as diffusion through dialysis membrane, and has potential to be extended further to examine the impact of manufacturing process on drug distribution and release characteristics of other challenging complex drug products.

Layered terbium hydroxides for simultaneous drug delivery and imaging.

Layered rare-earth hydroxides have begun to gather increasing attention as potential theranostic platforms owing to their extensive intercalation chemistry combined with magnetic and fluorescent properties. In this work, the potential of layered terbium hydroxide (LTbH) as a platform for simultaneous drug delivery and fluorescence imaging was evaluated. LTbH-Cl ([Tb2(OH)5]Cl·yH2O) was loaded with three nonsteroidal anti-inflammatory drugs (diclofenac, ibuprofen, and naproxen) via ion-exchange. Drug release studies in phosphate buffered saline (pH = 7.4) revealed all three formulations release their drug cargo rapidly over the course of approximately 5 hours. In addition, solid state fluorescence studies indicated that fluorescence intensity is strongly dependent on the identity of the guest anion. It was postulated that this feature may be used to track the extent of drug release from the formulation, which was subsequently successfully demonstrated for the ibuprofen loaded LTbH. Overall, LTbH exhibits good biocompatibility, high drug loading, and a strong, guest-dependent fluorescence signal, all of which are desirable qualities for theranostic applications.

Nanoparticles Incorporating a Fluorescence Turn-on Reporter for Real-Time Drug Release Monitoring, a Chemoenhancer and a Stealth Agent: Poseidon's Trident against Cancer?

The rate and extent of drug release under physiological conditions is a key factor influencing the therapeutic activity of a formulation. Real-time detection of drug release by conventional pharmacokinetics approaches is confounded by low sensitivity, particularly in the case of tissue-targeted novel drug delivery systems, where low concentrations of the drug reach systemic circulation. We present a novel fluorescence turn-on platform for real-time monitoring of drug release from nanoparticles based on reversible fluorescence quenching in fluorescein esters. Fluorescein-conjugated carbon nanotubes (CNTs) were esterified with methotrexate in solution and solid phase, followed by supramolecular functionalization with a chemoenhancer (suramin) or/and a stealth agent (dextran sulfate). Suramin was found to increase the cytotoxicity of methotrexate in A549 cells. On the other hand, dextran sulfate exhibited no effect on cytotoxicity or cellular uptake of CNTs by A549 cells, while a decrease in cellular uptake of CNTs and cytotoxicity of methotrexate was observed in macrophages (RAW 264.7 cells). Similar results were also obtained when CNTs were replaced with graphene. Docking studies revealed that the conjugates are not internalized by folate receptors/transporters. Further, docking and molecular dynamics studies revealed the conjugates do not exhibit affinity toward the methotrexate target, dihydrofolate reductase. Molecular dynamics studies also revealed that distinct features of dextran-CNT and suramin-CNT interactions, characterized by π-π interactions between CNTs and dextran/suramin. Our study provides a simple, cost-effective, and scalable method for the synthesis of nanoparticles conferred with the ability to monitor drug release in real-time. This method could also be extended to other drugs and other types of nanoparticles.

RETRACTED ARTICLE: Understanding mechanical characteristics of pH-responsive PEG 4000-based polymeric network for colorectal carcinoma: its acute oral toxicity study

The major objective of this study is to fabricate a very promising system by loading anticancer agent in it which could be given to the cancer patients by oral administration and additionally that will liberate drugs in large intestine (affected/cancerous area). Minimum or no exposure of chemotherapeutic agents to gastric/small intestine will significantly eliminate the problem of adverse drug reactions. Cancer patients are facing severe problem of side/adverse effects due to intravenous colorectal carcinoma chemotherapy. So, an oral drug delivery system is designed to substitute the intravenous drug therapy. This study reports the synthesis of hybrid polymeric polyethylene glycol hydrogels (PEGA 4000) based on acrylic acid (AA), ammonium peroxodisulfate and ethylene glycol dimethacrylate (EGDMA) by solution polymerization method. PEGA 4000 hydrogels were used for colon targeting of hydrophilic anti-carcinoma drug (oxaliplatin). Development of new structure was confirmed by Fourier transform infrared spectroscopy. Surface morphology of developed hydrogel slabs was examined by scanning electron microscopy. Thermal gravimetric analysis of hydrogels revealed that there was an increase in thermal stability of PEGA 4000 hydrogels. Swelling study was performed in acidic and basic pH medium provided important information on drug release characteristics of hydrogels. The release of oxaliplatin (OXP) was significantly retarded at pH 1.2, while rapid release was observed at pH 7.4. The release rate of OXP increased with increasing concentration of PEG 4000 and AA. However, extent of drug release was significantly reduced on increasing concentration of EGDMA. Mechanism of release has been evaluated by applying various mathematical kinetic models. The tensile mechanical strength and elongation at break were also observed on different formulations based on various ratios of reaction contents. The consequents of our study suggest that fabricated PEGA 4000 hydrogels could serve as suitable target release delivery system and toxicity study endorsed biocompatibility of hydrogels to biological system.

Design and Development of Transdermal Patches of Antipsychotic Drug: In vitro and Ex vivo Characterization

The purpose of the present research work was to design, assess, and estimate the developed transdermal matrix-type formulation comprising levosulpiride hydrochloride with the objective of enhancing the bioavailability and compliance of the patient. Transdermal films of levosulpiride were developed using a solvent casting method by hydroxypropyl methylcellulose (HPMC) E 15, Eudragit RL 100, and Eudragit RS100. In current research work, propylene glycol and oleic acid was used as plasticizer and permeation enhancers in different fractions. Among the batches, drug content uniformity with all formulations was perceived between 91.6 to 98%. Folding endurance of patches was good and indicates satisfactory flexibility. Developed transdermal films had the necessary physicochemical properties, for example, uniformity of drug content, weight, thickness, folding endurance, and dampness content. Franz diffusion cell was used for in vitro diffusion studies utilizing dialysis membrane as a pervasion boundary. Formulation F5 (Eudragit RL 100-1%, HPMC E15-9%) was found to be best among all batches of its consistent release rate for 12 hours and the extent of drug release 97.76%. F5 was the most palatable formulation as it firmly meets the standards and continuously permeated drugs for 12 hours that can keep up desired therapeutic concentration in plasma. The patches were exposed to transient stability studies and were observed to be constant and stable.

Implantable, Degradable, Therapeutic Terahertz Metamaterial Devices.

Metamaterial (MM) sensors and devices, usually consisting of artificially structured composite materials with engineered responses that are mainly determined by the unit structure rather than the bulk properties or composition, offer new functionalities not readily available in nature. A set of implantable and resorbable therapeutic MM devices at terahertz (THz) frequencies are designed and fabricated by patterning magnesium split ring resonators on drug-loaded silk protein substrates with controllable device degradation and drug release rates. To demonstrate proof-of-concept, a set of silk-based, antibiotics-loaded MM devices, which can serve as degradable antibacterial skin patches with capabilities to monitor drug-release in real time are fabricated. The extent of drug release, which correlates with the degradation of the MM skin patch, can be monitored by analyzing the resonant responses in reflection during degradation using a portable THz camera. Animal experiments are performed to demonstrate the in vivo degradation process and the efficacy of the devices for antibacterial treatment. Thus, the implantable and resorbable therapeutic MM devices do not need to be retrieved once implanted, providing an appealing alternative for in-vivo sensing and in situ treatment applications.

Formulating Amorphous Solid Dispersions: Impact of Inorganic Salts on Drug Release from Tablets Containing Itraconazole-HPMC Extrudate.

Amorphous solid dispersions (ASD) are increasingly used to improve the oral bioavailability of poorly water-soluble compounds. However, hydrophilic polymers in ASD have high water-binding properties and, upon water contact, they often form a gel on the surface of the tablet, impacting the rate and extent of drug release. Most inorganic salts decrease water solubility of organic solutes, changing the gel properties of hydrophilic polymers. In this study, the effect of inorganic salts on drug release from a tablet formulation containing an itraconazole (ITZ)-hydroxypropyl methyl cellulose (HPMC) extrudate was investigated. The cloud point of a 1% HPMC solution with and without inorganic salts (KCl, KH2PO4, KHCO3, and potassium iodate (KI)) was determined to classify the salts according to their salting-out or salting-in effect. A kosmotropic effect on HPMC was observed for KCl, KH2PO4, and KHCO3, whereas KI exhibited a chaotropic effect. To prove the effect of these salts on drug release, tablets containing 66% of ITZ-HPMC extrudate (20:80 w/w %), 4% croscarmellose sodium, 30% microcrystalline cellulose, and different types and amounts of KHCO3, KH2PO4, KCl, and KI were compressed (same solid fraction of 0.83-0.85). Tablets without salts showed a slow release and low peak concentrations during dissolution in simulated gastric fluids. By adding the kosmotropic salts to the tablets, the rate and extent of drug release were increased, whereas the chaotropic anion iodide had no effect. The effect was pronounced even with the addition of as little as 2% of inorganic salts and tended to increase with the increasing amount of salt in the formulation. Tablets without salt stored under either dry or humid conditions exhibited a large difference in dissolution profiles, whereas little variation was observed for tablets with kosmotropic salts. In conclusion, the effect of inorganic salts was mechanistically clarified on ASD containing commonly used HPMC. This approach can be beneficial to successfully develop robust formulations containing ASD.

Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films.

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt %. The release drops at 30 wt % and when DL ≥ 35 wt % there is virtually no drug release, behaving like a pure amorphous drug. In this Communication, the phase miscibility of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in the extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt %), it takes more than 12 h for AAPS to happen while in sharp contrast, it only needs less than 10 min for DL ≥ 32.5 wt %. During AAPS, amorphous drug accumulates on the surface of the film, which prevents further dissolution from the interior of the ASD. The current study provides a mechanistic understanding of the confounding drug release profile of ASDs as a function of DL and opens the door for studying drug-excipient (e.g., polymer, surfactant) interactions via XRF imaging in the future.

FORMULATION AND EVALUATION OF TRANSDERMAL PATCHES OF METOPROLOL TARTRATE USING PERMEATION ENHANCERS OF NATURAL AND SYNTHETIC ORIGIN

Objective: Oral metoprolol tartrate has a short elimination half-life (2-3h) and low bioavailability undergoes extensive first-pass metabolism and frequent dosing. The aim of the present investigation was to formulate, develop and evaluate metoprolol tartrate transdermal patches using various synthetic and natural penetration enhancers.
 Methods: Enhancers used were eugenol, limonene, basil oil, urea and SLS (sodium lauryl sulphate). Polymer used was chitosan and PEG 400 used as a plasticizer. Transdermal Films were prepared by using solvent casting method. FTIR and DSC were studied to assess any interaction between the drug and polymers. Films were evaluated for Physico-chemical Characteristics like thickness, weight variation, folding endurance, moisture loss, moisture absorption and drug content. In vitro skin permeation studies were performed using Keshary chien cell For 24 h across rat skin.
 Results: Chitosan was found to be a suitable polymer for matrix formation. 3.5% w/w was used to optimize to formulate transdermal patches. 1.5% of total solution v/v lactic acid was used for dissolution of chitosan. 2.5%v/v of total solution PEG 400 was used to provide plasticity and smoothness to the patches. From the evaluation of patches formulation, F10 containing Basil oil as penetration enhancer in the concentration of 1.5% v/v was found to be best among all batches because of its consistent release rate For 24 h and extent of drug release was 85.20%. It can be concluded that naturally occurring volatile oils i.e., terpenes appear acceptable permeation enhancer and shows the best permeation across skin as indicated by high percutaneous enhancement ability.
 Conclusion: The developed transdermal patches are stable, non-irritating, and had increased efficacy of metoprolol and therefore had a good potential for hypertension treatment.

Quality-by-Design based development and characterization of pioglitazone loaded liquisolid compact tablets with improved biopharmaceutical attributes

The present research work describes the formulation development of liquisolid compact tablets of pioglitazone for improving its dissolution performance and antidiabetic activity. Using Quality by Design (QbD) approach, a total of nine formulations were prepared as per the central composite design (CCD) by selecting colloidal silicon dioxide and microcrystalline cellulose as independent, while polyethylene glycol 400 was used as non-volatile solvent. The formulations were evaluated for Carr's index and disintegration time as the dependant variables. Kawakita and Heckel analysis carried out on the liquisolid compacts indicated dense nature of the particles along with good compaction characteristics. Aerosil 200 and microcrystalline cellulose showed plastic deformation suggesting improved compressibility. Moreover, the liquisolid compact tablets exhibited faster rate and extent of drug release than the directly compressed tablet. In vivo pharmacodynamic study performed on normal and diabetic male Swiss albino mice confirmed that optimized liquisolid compact tablet formulation showed better reduction of blood glucose level as compared to directly compressible tablet and pure drug. In a nutshell, the present work successfully construed that liquisolid compact technique can be a novel approach for improving dissolution performance of pioglitazone in potentiating its antidiabetic activity.

Congruent release of drug and polymer: A “sweet spot” in the dissolution of amorphous solid dispersions

Liquid-liquid phase separation (LLPS) occurs following amorphous solid dispersion (ASD) dissolution when the drug concentration exceeds the “amorphous solubility”, and is emerging as an important characteristic of formulations that may enhance the oral bioavailability of poorly soluble drugs. The purpose of this research was to identify criteria that impact the rate and extent of drug release and hence the occurrence or not of LLPS upon ASD dissolution. Specifically, the effect of drug log P, phase behavior of the hydrated but undissolved ASD matrix and the relative dissolution rates of drug and polymer were studied as a function of drug loading, using nilvadipine (Nil) (ClogP = 3.04) and cilnidipine (Cil) (ClogP = 5.54) as model drugs. The model polymer was poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA). Nil-PVPVA and Cil-PVPVA ASDs with different drug loadings were prepared. Surface area normalized dissolution rates of both the drug and the polymer from ASD tablets were studied. At a similar and relatively low drug loading (<20% w/w drug), dissolution of both Nil-PVPVA and Cil-PVPVA ASDs was found to switch from rapid, congruent (i.e., simultaneous) release of drug and polymer to incongruent release with slow release of drug. Only ASDs showing congruent release underwent LLPS, with the formation of amorphous drug-rich aggregates (~300nm). Scanning electron microscopy (SEM) and micro-computed tomography (micro-CT) showed the presence of characteristic “pits” on the surface of partially dissolved, incongruently releasing ASD tablets. These most likely arise due to faster polymer release in comparison to drug, whereby the drug-rich composition around these pits was confirmed by energy-dispersive X-ray (EDX) analysis and the surface drug enrichment on the compacts was confirmed by X-ray photoelectron spectroscopy (XPS). This study demonstrates two important findings, firstly, a link between congruent release of drug and polymer and the occurrence of LLPS and secondly, the switch between congruent and incongruent release of drug and polymer is a result of competitive kinetics between phase separation and the release rate of ASD components with minimal influence from drug hydrophobicity for two structural analogues.

Effect of Mild Hyperthermia on Transdermal Absorption of Nicotine from Patches.

Application of heat (hyperthermic conditions) on skin is known to enhance drug transfer and facilitate skin penetration of molecules. The aim of this work was to study the effect of hyperthermia on the drug release and skin permeation from nicotine transdermal patches. The drug release and skin permeation were characterized by in vitro release test and in vitro permeation test. The temperature was maintained at 32°C as control (simulating normal physiological skin temperature) and 42°C as hyperthermia condition. The in vitro release test was carried out using USP apparatus 5-Paddle over disk method for a transdermal patch. Skin permeation study was carried out across porcine skin using the flow through cells (PermeGear, Inc.) with an active diffusion area of 0.94cm2. Mechanistic studies (parameters such as partition coefficient, TEWL and electrical resistivity) were also performed to understand the mechanisms involved in determining the influence of hyperthermia on drug delivery from transdermal patches of nicotine. The rate and extent of drug release from nicotine patch was not significantly different at two temperatures (Cumulative release after 12h was 43.99 ± 3.29% at 32°C and 53.70 ± 5.14% at 42°C). Whereas, in case of in vitro permeation studies, the nicotine transdermal permeation flux for patch was threefold higher at 42°C (100.1 ± 14.83μg/cm2/h) than at 32°C (33.3 ± 14.83μg/cm2/h). The mechanistic studies revealed that the predominant mechanism of enhancement of drug permeation by hyperthermia condition is by the way of increasing the skin permeability. There is a potential concern of dumping of higher dose of nicotine via transdermal route.