Fasted State Simulated Gastric Fluid Research Articles

Rolled-up gastroretentive oral dosages for controlled release of riboflavin and propranolol

We present a simple approach to make gelatin gastroretentive oral dosages for controlled release of riboflavin and propranolol. The approach is based on rolling-up of thin self-adhesive gelatin films, on which the reservoirs of the drugs are formed by casting. The radial position of the reservoir and, hence, the lag time and the rate of the drugs release are determined by the lateral position of the reservoir on the film before rolling. Gelatin is stabilized against dissolving in the gastric environment by enzymatic cross-linking mediated by transglutaminase (Tgase). The dosages, which have the form of tight scrolls, are stabilized against unrolling by the crosslinking of the consecutive layers. The scrolls swell in the release media, Fasted State Simulated Gastric Fluid (FaSSGF), to the dimensions which make difficult their passage by the human pyloric sphincter, but remain mechanically robust to resist the stomach peristaltic contractions during at least 24 h, sufficient for the drug release. Eventually the scrolls are degraded by the release media and can be evacuated from the stomach.

In Vitro and In Vivo Evaluation of Dark Chocolate as Age-appropriate Oral Matrix

Swallowing difficulties encountered by geriatric patients who undergo polypharmacy represent a significant challenge that hampers patient compliance and therapeutic management. As an appealing and sensory-pleasing, chocolate-based formulations have emerged as a potential alternative oral dosage form suitable for both the elderly and paediatric populations. However, the extent to which the incorporation of drugs into a chocolate matrix affects their oral availability remains unclear. Therefore, the objective of this investigation was to explore the in vitro and in vivo performance of an ibuprofen-based chocolate dosage form. A matrix based on dark chocolate and the model drug was prepared at two distinct temperatures: 50 and 80 °C. In vitro release studies revealed that ibuprofen formulated through co-melting at 80 °C exhibited a statistically significant slower drug release (p < 0.05) compared to formulations prepared at 50 °C in both FaSSGF (fasted-state simulated gastric fluid) and lipolysis media. The enzymatic degradation of chocolate in the presence of lipase accelerated in vitro ibuprofen release from chocolate matrices. To delve deeper into the bioavailability of ibuprofen within the chocolate formulations, we conducted an in vivo assessment, comparing the pharmacokinetic profiles of ibuprofen in its conventional suspension form with our chocolate-based dosage forms. A notable drop (p < 0.05) in the maximum serum concentration of ibuprofen when incorporated into co-melted or solid-suspension chocolate matrices. However, no significant differences in plasma exposure were observed between the two formulations. These findings shed a light on the potential of chocolate to extend of ibuprofen when integrated into various chocolate matrices, showcasing the potential held by these innovative formulations.

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.

High-Affinity Extended Bisphosphonate-Based Coordination Polymers as Promising Candidates for Bone-Targeted Drug Delivery.

Extended bisphosphonate-based coordination polymers (BPCPs) were produced when 1,1'-biphenyl-4,4'-bisphosphonic acid (BPBPA), the analogue of 1,1'-biphenyl-4,4'-dicarboxylic acid (BPDC), reacted with bioactive metals (Ca2+, Zn2+, and Mg2+). BPBPA-Ca (11 Å × 12 Å), BPBPA-Zn (10 Å × 13 Å), and BPBPA-Mg (8 Å × 11 Å) possess channels that allow the encapsulation of letrozole (LET), an antineoplastic drug that combined with BPs treats breast-cancer-induced osteolytic metastases (OM). Dissolution curves obtained in phosphate-buffered saline (PBS) and fasted-state simulated gastric fluid (FaSSGF) demonstrate the pH-dependent degradation of BPCPs. Specifically, the results show that the structure of BPBPA-Ca is preserved in PBS (∼10% release of BPBPA) and collapses in FaSSGF. Moreover, the phase inversion temperature nanoemulsion method yielded nano-Ca@BPBPA (∼160 d. nm), a material with measurably higher (>1.5x) binding to hydroxyapatite than commercial BPs. Furthermore, it was found that the amounts of LET encapsulated and released (∼20 wt %) from BPBPA-Ca and nano-Ca@BPBPA are comparable to those of BPDC-based CPs [i.e., UiO-67-(NH2)2, BPDC-Zr, and bio-MOF-1], where other antineoplastic drugs have been loaded and released under similar conditions. Cell viability assays show that, at 12.5 μM, the drug-loaded nano-Ca@BPBPA exhibits higher cytotoxicity against breast cancer cells MCF-7 and MDA-MB-231 [relative cell viability (%RCV) = 20 ± 1 and 45 ± 4%] compared with LET (%RCV = 70 ± 1 and 99 ± 1%). At this concentration, no significant cytotoxicity was found for the hFOB 1.19 cells treated with drug-loaded nano-Ca@BPBPA and LET (%RCV = 100 ± 1%). Collectively, these results demonstrate the potential of nano-Ca@BPCPs as promising drug-delivery systems to treat OM or other bone-related diseases because these present measurably higher affinity, allowing bone-targeted drug delivery under acidic environments and effecting cytotoxicity on estrogen receptor-positive and triple-negative breast cancer cell lines known to induce bone metastases, without significantly affecting normal osteoblasts at the metastatic site.

Design of Extended Bisphosphonate-Based Coordination Polymers as Bone-Targeted Drug Delivery Systems for Breast Cancer-Induced Osteolytic Metastasis and Other Bone Therapies.

The coordination between benzene 1,4-bis(bisphosphonic acid) (BBPA), the bisphosphonate (BP) analogue of benzene 1,4-dicarboxylic acid (BDC), and bioactive metals led to the formation of extended bisphosphonate-based coordination polymers (BPCPs). Four distinct crystalline phases were obtained, namely, BBPA-Ca forms I and II, BBPA-Zn, and BBPA-Mg. Among these, BBPA-Ca forms I (7 × 9 Å2) and II (8 × 12 Å2) possess channels large enough to encapsulate 5-fluorouracil (5-FU), a drug prescribed in combination with BPs to treat breast cancer-induced osteolytic metastases (OM). Dissolution curves show a 14% release of BBPA from BBPA-Ca form II in phosphate-buffered saline, while ∼90% was released in fasted-state simulated gastric fluid. These results suggest that this material is relatively stable in neutral environments yet collapses in acidic conditions. Moreover, the phase inversion temperature method decreased the particle size of BBPA-Ca form II, resulting in nano-Ca@BBPA (∼134 d.nm). Binding assays showed a higher affinity of nano-Ca@BBPA (∼97%) to hydroxyapatite than BBPA (∼70%) and significantly higher binding than commercial BPs, zolendronic (3.0×), and risedronic (2.4×) acids after 24 h. Furthermore, both BBPA-Ca form II and nano-Ca@BBPA presented comparable drug loading and release (∼30 wt % 5-FU) relative to BDC-based CCs (UiO-66, MIL-53, and BDC-Zr) where other pharmaceutical compounds (caffeine, ibuprofen, aspirin, and α-cyano-4-hydroxycinnamic acid) have been encapsulated. Cell viability assays established that drug-loaded nano-Ca@BBPA increases the cytotoxicity of a triple-negative human breast cancer cell line (MDA-MB-231) when compared to 5-FU (%RCV = 8 ± 5 vs 75 ± 1% at a 100 μM). At the same concentration, no significant decrease in cell viability was observed for normal human osteoblast-like hFOB 1.19 cells (%RCV = 85 ± 1%). Collectively, these results demonstrate the feasibility of nano-Ca@BBPA as a potential drug delivery system (DDS), with high affinity to bone tissue, to treat bone-related diseases such as OM.

Solid lipid nanoparticles cyclodextrin-decorated incorporated into gellan gum-based dry floating in situ delivery systems for controlled release of bioactive compounds of safflower (Carthamus tinctorius. L): A proof of concept study in biorelevant media

Safflower (Carthamus tinctorius L.) has been explored as a source of natural antioxidant. However, quercetin 7-O-beta-D-glucopyranoside and luteolin 7-O-beta-D-glucopyranoside, as its bioactive compounds, possessed poor aqueous solubility, limiting its efficacy. Here, we developed solid lipid nanoparticles (SLNs) decorated with hydroxypropyl beta-cyclodextrin (HPβCD) incorporated into dry floating gel in situ systems to control the release of both compounds. Using Geleol® as a lipid matrix, SLNs were <200 nm in size with >80 % of encapsulation efficiency. Importantly, following the decoration using HPβCD, the stability of SLNs in gastric environment was significantly improved. Furthermore, the solubility of both compounds was also enhanced. The incorporation of SLNs into gellan gum-based floating gel in situ provided desired flow and floating properties, with <30 s gelation time. The floating gel in situ system could control the release of bioactive compounds in FaSSGF (Fasted-State Simulated Gastric Fluid). Furthermore, to assess the effect of food intake on release behavior, we found that the formulation could show a sustained release pattern in FeSSGF (Fed-State Simulated Gastric Fluid) for 24 h after being released in FaSGGF for 2 h. This indicated that this combination approach could be a promising oral delivery for bioactive compounds in safflower.

Characterizing interspecies differences in gastric fluid properties to improve understanding of in vivo oral drug formulation performance

An in-depth understanding of the properties of gastric fluid(s) prior to an in vivo pharmacokinetic investigation can vastly improve predictions of in vivo performance. Previously, properties of animal and human gastric fluids have been characterized with varying methods. Unfortunately, characterization has often not been thorough, and some properties, such as density and viscosity, have not been reported. Here, human, porcine and canine gastric fluids were harvested and characterized for pH, viscosity, surface tension, density, and osmolarity. We found that the variability of pH and surface tension between dogs was significantly higher than the variability between pigs, and, furthermore, gastric fluids collected from the same canine species (beagles) housed in two different countries (Denmark and China) had surprisingly different pH values. Next, an in vitro dissolution study in diluted gastric fluids from each species was performed using minitablets containing ibuprofen. Human gastric fluids and porcine gastric fluids showed similar dissolution profiles and corroborated well with biorelevant human Fasted State Simulated Gastric Fluid (FaSSGF). In contrast, differences in canine gastric fluids caused highly variable dissolution results. We systematically compared our findings to those in the literature and based on this evaluation, propose obtaining aspirates from the animals used for in vivo studies to ensure knowledge on the fluid properties affecting the performance of the formulated drug in question.

Preparation and evaluation of a lipid-based drug delivery system to ımprove valsartan oral bioavailability: pharmacokinetic and pharmacodynamic analysis

Antihypertensive treatment reduces the risk of cardiovascular complications in patients with high mortality with hypertension. Valsartan is highly selective antihypertensive that is rapidly absorbed after oral administration, but its oral bioavailability is only 25%. It is absorbed from the upper part of the gastrointestinal tract but is less soluble in this acidic environment. We aimed to develop a lipid-based formulation to produce a self-emulsifying drug delivery system (SEDDS) for valsartan. Solubility studies were performed to identify the components of the SEDDS that provided the best dissolution of valsartan. Ternary phase diagrams were drawn using the titration method with oil, surfactants and co-surfactants in which valsartan was highly soluble, and microemulsion formulations with the highest area were determined. Characterization and in vitro release studies were performed to optimize the formulation. In vitro release profiles of commercial and SEDDS formulations showed the F2 formulation release rate increased at pH 1.2 fasted state simulated gastric fluid. After oral administration, plasma drug concentrations in rats indicate that the F2 formulation provided a 4.2-fold greater AUC for valsartan than the commercial formulaiton, resulting in an 8.5-fold greater Cmax. These findings suggest the F2 formulation increases valsartan solubility, resulting in an improved oral pharmacokinetic profile. According to the pharmacodynamic study, the F2 formulation is more effective than the commercial formulation in restoring systolic and diastolic blood pressure within a few hours.

Survival of human coronavirus 229E at different temperatures on various food-contact surfaces and food and under simulated digestive conditions

The COVID-19 pandemic caused by SARS-CoV-2 has had a major impact on human health and the global economy. Various transmission possibilities of SARS-CoV-2 have been proposed, such as the surface of food in the cold chain and food packaging, as well as the fecal-oral route, although person-to-person contact via droplets and aerosols has been confirmed as the main route of transmission. This study evaluated the survivability of HCoV-229E, a SARS-CoV-2 surrogate, in suspension, on food-contact surfaces and on food at various temperatures, and in simulated digestive fluids by TCID50 assay. In suspension, HCoV-229E survived after 5 days at 20 °C with a 3.69 log reduction, after 28 days at 4 °C with a 3.07 log reduction, and after 12 weeks at –20 °C with a 1.18 log reduction. On food-contact surfaces, HCoV-229E was not detected on day 3 on stainless steel (SS), plastic (LDPE), and silicone rubber (SR) at 20 °C with a 3.28, 3.24 and 3.28 log reduction, respectively, and survived after 28 days on SS and LDPE at 4 °C with a 3.13 and 2.88 log reduction, respectively, and survived after 12 weeks on SS, LDPE, and SR at –20 °C with a 1.92, 1.32 and 1.99 log reduction, respectively. On food, HCoV-229E was not detected on day 3 on lettuce and day 4 on chicken breast and salmon at 20 °C with a 3.61, 3.26 and 3.08 log reduction, respectively, and on day 14 on lettuce and day 21 on chicken breast and salmon at 4 °C with a 3.88, 3.44 and 3.56 log reduction, respectively. The virus remained viable for 12 weeks in all foods at –20 °C with 2–2.47 log reduction. In addition, in simulated digestive fluid experiments, HCoV-229E was relatively resistant in simulated salivary fluid (SSF; pH 7, 5), fed state simulated gastric fluid (FeSSGF; pH 3, 5, 7), and fasted state simulated intestinal fluid (FaSSIF; pH 7). However, the virus was less tolerant in fasted state simulated gastric fluid (FaSSGF; pH 1.6) and fed state simulated intestinal fluid (FeSSIF; pH 5). Therefore, this study suggested that HCoV-229E remained infectious on various food-contact surfaces and foods; in particular, it survived longer at lower temperatures and survived depending on the pH of the simulated digestive fluid.

Quantitative assessment of disintegration rate is important for predicting the oral absorption of solid dosage forms containing poorly soluble weak base drugs

This study aimed to develop a novel in silico modeling and simulation that considers the disintegration rate in the stomach to predict the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs. Oxatomide and manidipine hydrochloride were used as model drugs. First, the in vitro disintegration rate and dissolution rate were determined in biorelevant media that simulate the gastrointestinal fluids in fasted humans using a USP apparatus II paddle dissolution tester. Next, the oral absorption of the dosage forms was predicted using the novel simulation model coupled with not only the dissolution rate but also the estimated disintegration rate. As the in vitro disintegration time was 45 min or longer for both drugs in Fasted State Simulated Gastric Fluid, the disintegration rate of these dosage forms was considered slow as immediate release (IR) tablets. While the predicted and observed pharmacokinetic profiles of both drugs were comparable using the new model, the conventional model, which did not consider the disintegration step, underestimated the oral absorption of both drugs. Thus, our novel simulation model coupled with the disintegration rate estimated from in vitro tests is promising for predicting the in vivo performance of oral solid dosage forms with slow disintegration rates containing poorly soluble weak base drugs.

Direct visualizing of paracetamol immediate release tablet disintegration in vivo and in vitro

The purpose of the present study was to study tablet disintegration by direct visualization, in vivo and in vitro. Based on literature data, a standard conventional paracetamol (CP) tablet, Panodil®, and a rapidly absorbed paracetamol (RP) tablet, Panodil® Zapp, were chosen as model systems to study tablet disintegration in the human stomach. Based on the obtained in vivo results, an in vitro disintegration method was designed to reproduce the visualized disintegration process occurring in the human stomach.For the clinical study, CP and RP tablets fastened to digital endoscopic camera capsules were administered to fasted human volunteers (n = 4). The disintegration time and process were visualized by the real time video recordings, using the endoscopic camera capsule. The average disintegration time was found to be 26 ± 13 min and 10 ± 7 min, for CP (n = 4) and RP (n = 4) tablets, respectively.It was possible to reproduce the in vivo disintegration data in vitro using a USP 2 dissolution apparatus with 250 mL of viscous Fasted State Simulated Gastric Fluid (vFaSSGF*), simulating the rheological profile of human fasted state gastric fluid following administration of a glass of water. The viscosity of the simulated fasted state gastric fluid was found to have a large impact on the disintegration time of the tested immediate release tablets. Therefore, it is recommended to mimic gastric fluid viscosity during in vitro tablet disintegration studies.

HPLC-UV method validation for quantification of β-carotene in the development of sustained release supplement formulation containing solid dispersion-floating gel in situ

Despite the health benefits of β-carotene, its activity has been hampered by poor aqueous solubility and low oral bioavailability. Therefore, it is crucial to develop a new approach to overcome these problems. In this study, we developed a dry powder supplement comprising a combination approach of solid dispersion and floating gel in situ of β-carotene to enhance the solubility and achieve sustained release behavior. Here, we validated an HPLC method to quantify β-carotene as per the guidelines from ICH. The analytical method was validated in methanol and Fasted-State Simulated Gastric Fluid (FaSSGF) to determine β-carotene in recovery and in vitro release studies, respectively. A simple HPLC method using Xselect CSH™ C18 column (Waters, 3.0 × 150 mm) with the particle size of 3.5 µm was validated with 100% acetonitrile as the mobile phase. The calibration curves were found to be linear with LLOQ values < 3 ng/mL. Importantly, the method was accurate and precise without a carry over effect and successfully applied to determine the β-carotene concentration in the content analysis of the compound and in vitro drug release from floating gel in situ laden with solid dispersion formulations. The sensitivity of the method obtained here offers a wide potential use in various applications in drug delivery systems.

Physico-chemical characterization of aspirated and simulated human gastric fluids to study their influence on the intrinsic dissolution rate of cinnarizine

To elucidate the critical parameters affecting drug dissolution in the human stomach, the intrinsic dissolution rate (IDR) of cinnarizine was determined in aspirated and simulated human gastric fluids (HGF). Fasted aspirated HGF (aspHGF) was collected from 23 healthy volunteers during a gastroscopic examination. Hydrochloric acid (HCl) pH 1.2, fasted state simulated gastric fluid (FaSSGF), and simulated human gastric fluid (simHGF) developed to have rheological, and physico-chemical properties similar to aspHGF, were used as simulated HGFs. The IDR of cinnarizine was significantly higher in HCl pH 1.2 (952 ± 27 µg/(cm2·min)) than in FaSSGF pH 1.6 (444 ± 7 µg/(cm2·min)), and simHGF pH 2.5 (49 ± 5 µg/(cm2·min)) due to the pH dependent drug solubility and viscosity differences of the three simulated HGFs. The shear thinning behavior of aspHGF had a significant impact on the IDR of cinnarizine, indicating that the use of FaSSGF, with viscosity similar to water, to evaluate gastric drug dissolution, might overestimate the IDR by a factor of 100–10.000, compared to the non-Newtonian, more viscous, fluids in the human stomach. The developed simHGF simulated the viscosity of the gastric fluids, as well as the IDR of the model drug, making it a very promising medium to study gastric drug dissolution in vitro.

Synergistic antimicrobial interactions of nisin A with biopolymers and solubilising agents for oral drug delivery

In order to develop bacteriocins, like the lantibiotic nisin A, into effective alternatives to existing antibiotics, their biophysical and physicochemical properties must first be assessed, from solubility, to susceptibility and absorption. It has been well established that formulation strategies at early drug development stages can be crucial for successful outcomes during preclinical and clinical phases of development, particularly for molecules with challenging physicochemical properties. This work elucidates the physicochemical challenges of nisin A in terms of its susceptibility to digestive enzymes like pepsin, pancreatin and proteinase K and its poor solubility at physiological pHs. Low solution concentrations, below the minimum inhibitory concentration against Staphylococcus aureus, were obtained in phosphate buffered saline (PBS, pH 7.4) and in fasted state simulated intestinal fluid (FaSSIF, pH 6.5), while higher solubilities at more acidic pH’s such as in a KCl/HCl buffer (pH 2) and in fasted state simulated gastric fluid (FaSSGF, pH 1.6) are observed. Tween® 80 (0.01% v/v) significantly increased the solution concentration of nisin A in PBS (pH 7.4, 24 hr). Pancreatin doubled nisin A’s solution concentration at pH 7.4 (PBS) but reduced its’ inhibitory activity to ∼ 20%, and pepsin almost completely degraded nisin (after 24 hr), but retained activity at biologically relevant exposure times (∼15 min). Harnessing synergism between nisin A and either glycol chitosan or ε-poly lysine, combined with the solubilizing effect of Tween®, increased the antimicrobial activity of nisin A six fold in an in vitro oral administration model.

A novel in vitro approach to investigate the effect of food intake on release profile of valsartan in solid dispersion-floating gel in-situ delivery system

Valsartan (VAL) is a BCS class II drug with low solubility and high permeability and, thus, its formulations often encounter low bioavailability problems. Its low bioavailability can be improved through enhanced formulation, such as incorporating it into a solid dispersion system (SD). The absorption can be further enhanced through gastroretentive systems. Herein, we developed a novel combination delivery approach consisting of floating in-situ gel and SD. VAL was incorporated with polymer carrier PVP and PEG 6000 and its solubility was then evaluated. The study found that VAL-SD containing PVP K-30 as the carrier with drug:PVP K-30 ratio of 1:3 shown highest solubility in different media. Moreover, DSC and XRD evaluations exhibited the change of VAL from crystal to amorphous following SD formulation. The SD was then formulated into floating in-situ gel preparations using sodium alginate as gel forming compound and HPMC as the controlled release matrix. The prepared VAL-SD floating in-situ gels were evaluated for their physical properties and drug release profile. The results showed that all physical evaluation of the floating in-situ gel formula possessed desirable physical properties and the use of HPMC in floating in-situ gel was able to sustain the in vitro release of VAL for 24 h in biorelevant media. Importantly, the effect of food intake on VAL release was also investigated, for the first time, showing that the VAL release could be controlled in FaSSGF (Fasted-State Simulated Gastric Fluid) in 2 h and FeSSGF (Fed-State Simulated Gastric Fluid) onwards. Thus, in can be hypothesized that the food intake did not affect the VAL release after 2 h in an empty gastric environment. Leading on from these results, in vivo studies in an animal model should be carried out to further assess the potency of this system.

Biorelevant dissolution models to assess precipitation of weak base drug

The impact of precipitation can affect the amount of drug absorbed, thereby affecting the amount of drug in the systemic body. The precipitation process is preceded by a supersaturation phase, caused by decreased drug solubility in the gastrointestinal tract. This precipitation occurs for weak base drugs with low solubility. When the drug entering the small intestine, the solubility of weak base drugs decrease, then occurs supersaturation, which leads to precipitation, so that drug precipitation is one of a challenge for the pharmaceutical industry in drug development. Precipitation testing of water-soluble weak base drugs can be carried out by the pH shift method to describe the gastrointestinal pH gradient from gastric to small intestine. This pH change can cause supersaturation and then trigger precipitation, especially for weak base drugs. The methods that can used to assess precipitation drug is modification of the USP dissolution which are two compartment and multi compartment model. The choice of dissolution medium play an important role in the test results. The use of bio relevant medium can produce closer in vitro and in vivo correlations than the use of buffers. Generally, the medium used to simulate the weakly condition in the small intestine is FaSSIF (Fasted State Simulated Intestinal Fluid) or FeSSIF (Fed State Stimulate Intestinal Fluid) medium. The medium used to simulate the acidic condition in the stomach is FaSSGF (Fasted state simulated gastric fluid) or FeSSGF (Fed state simulated gastric fluid) medium.

Evaluation of Bio-Mechanistic Behavior of Liquid Self-Microemulsifying Drug Delivery System in Biorelevant Media

The aim of the study is to mechanistically investigate the drug loci, structural integrity, chemical interactions, and absorption behavior of the liquid self-microemulsifying drug delivery system (SMEDDS). The loci of drug molecules in self-forming microemulsions in biorelevant media (fasted state simulated gastric fluid and fed state simulated intestinal fluid) were investigated by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Chemical interactions were observed through attenuated total reflectance spectroscopy (ATR). The structural integrity of self-forming microemulsions in biorelevant media was determined by small angle X-ray scattering (SAXS) and fluorescence resonance energy transfer (FRET). Morphological features of self-forming microemulsion were determined by confocal laser scanning microscopy. In vitro, lipid digestion behavior was evaluated for particle size, zeta potential, free fatty acids (FFA), and drug released through standard protocols. In-house characterizations were determined through standard methodologies. 1H and 13C NMR revealed that drug loci were found in a majority in the oily core region in the self-forming microemulsion. The ATR signifies that no inherent chemical was observed in the liquid SMEDDS and drug-loaded self-microemulsions in the biorelevant media. Structural integrity was well maintained during the dispersive and digestive phases in the gastrointestinal lumen during lipolysis in biorelevant conditions, as revealed by SAXS and FRET. An in vitro digestion study in biorelevant conditions depicts no fluctuations in size and zeta potential with a predominant release of FFA and drug, and was to be revealed physiologically acceptable for clinical applications.

Overdose and Alcohol Sensitive Immediate Release System (OASIS) for Deterring Accidental Overdose or Abuse of Drugs.

Death from an accidental or intentional overdose of sleeping tablets has increased exponentially in the USA. Furthermore, the simultaneous consumption of sleeping tablets with alcoholic beverages not only intensifies the effect of sleeping tablets but also leads to blackouts, sleepwalking, and death in many cases. In this article, we proposed a unique and innovative technology to prevent multi-tablet and alcohol-associated abuse of sleeping tablet. Agonist- and antagonist-loaded polymeric filaments of appropriate Eudragit® polymers were prepared using hot melt extrusion. Metoprolol tartrate and hydrochlorothiazide were used as model drugs in place of zolpidem tartrate (agonist-BCS class I) and flumazenil (antagonist-BCS class IV), respectively. Crushed filaments were converted into a tablet with a novel rapidly soluble co-processed alkalizing agent. Dissolution studies of single tablet and multiple tablets (5) in fasted state simulated gastric fluid (FaSSGF) confirmed that the release of the agonist was significantly (p < 0.0001) reduced in multi-tablet dissolution. Furthermore, the release of antagonist was significantly higher when tablet was exposed to FaSSGF+20% ethanol and various alcoholic beverages. Thus, appropriate use of Eudragit® polymer's chemistry could help design a tablet to prevent the release of agonist in case of overdose and simultaneous release of antagonist when consumed with alcohol.

Silk industry waste protein: isolation, purification and fabrication of electrospun silk protein nanofibers as a possible nanocarrier for floating drug delivery

Amongst assorted regio-selective and targeted oral drug delivery strategies accepted for the gastro-retentive drug delivery system (GRDDS), the floating drug delivery system (FDDS) holds a major share as clinically accepted formulations. The major objective of the present investigation was to explore the silk industry waste protein, silk fibroin (SF) as a possible electrospun nanocarrier for the FDDS. In a nutshell, electrospinning (ES) is one of the flexible and astonishing strategies for the fabrication of porous electrospun nanofibers (NFs), which offers the potential to amend the floating profile, dissolution rate, solubility, and release patterns of the drug, etc as per compendial requirements. Looking at the prospects of floating SF-NFs preparation, we have isolated and lyophilized the SF from industrial waste cocoons and prepared drug-loaded SF single polymer nanofibers (SPN). Lafutidine (LF) being a good candidate for GRDDS selected as a model drug, which is an excellent proton pump inhibitor, mainly used in the treatment of gastric ulcers. Finally, the obtained LF loaded SF-NFs (LF-SF-NFs) were successfully analyzed for physicochemical characteristics, porosity, swelling index, antioxidant activity, mucoadhesion strength, floating properties, enzymatic degradation, and accelerated stability study, etc. Further, these LF-SF-NFs were evaluated for percent drug content, weight variation, in-vitro dissolution in 0.1 N hydrochloric acid (HCl, pH:1.2) and fasted state simulated gastric fluid (FSSGF), and accelerated stability study. It has shown significant floating time >18 h, about 99% ± 0.58% floating buoyancy with sustained release up to 24 h. LF-SF-NFs showed good compatibility, entrapment efficiency, antioxidant activity, mucoadhesion strength, enzymatic degradation, and long term stability. Soon, the essential floating and drug release profiles can claim single polymer (SF) based electrospun protein NFs as a possible novel oral nanocarrier for FDDS.

In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.