Development Of Oral Formulations Research Articles

Ethanol-based solubility-enabling oral drug formulation development: Accounting for the solubility-permeability interplay

The aim of the current work was to investigate the key factors that govern the success/failure of an ethanol-based solubility-enabling oral drug formulation, including the effects of the ethanol on the solubility of the drug, the permeability across the intestinal membrane, the drug's dissolution in the aqueous milieu of the gastrointestinal tract (GIT), and the resulting solubility-permeability interplay. The concentration-dependent effects of ethanol-based vehicles on the solubility, the in-vitro Caco-2 permeability, the in-vivo rat permeability, and the biorelevant dissolution of the BCS class II antiepileptic drug carbamazepine were studied, and a predictive model describing the solubility-permeability relationship was developed. Significant concentration-dependent solubility increase of CBZ was obtained with increasing ethanol levels, that was accompanied by permeability decrease, both in Caco-2 and in rat perfusion studies, demonstrating a tradeoff between the increased solubility afforded by the ethanol and a concomitant permeability decrease. When ethanol absorption was accounted for, an excellent agreement was achieved between the predicted permeability and the experimental data. Biorelevant dissolution studies revealed that minimal ethanol levels of 30 % and 50 % were needed to fully dissolve 1 and 5 mg CBZ dose respectively, with no drug precipitation.In conclusion, key factors to be accounted for when developing ethanol-based formulation include the drug's solubility, permeability, the solubility-permeability interplay, and the drug dose intended to be delivered. Only the minimal amount of ethanol sufficient to solubilize the drug dose throughout the GIT should be used, and not more than that, to avoid unnecessarily permeability loss, and to maximize overall drug absorption.

Potential Effects of Essential Oil from Plinia cauliflora (Mart.) Kausel on Leishmania: In Vivo, In Vitro, and In Silico Approaches.

In the search for new chemotherapeutic alternatives for cutaneous leishmaniasis (CL), essential oils are promising due to their diverse biological potential. In this study, we aimed to investigate the chemical composition and leishmanicidal and anti-inflammatory potential of the essential oil isolated from the leaves of Plinia cauliflora (PCEO). The chemical composition of PCEO showed β-cis-Caryophyllene (24.4%), epi-γ-Eudesmol (8%), 2-Naphthalenemethanol[decahydro-alpha] (8%), and trans-Calamenene (6.6%) as its major constituents. Our results showed that the PCEO has moderate cytotoxicity (CC50) of 137.4 and 143.7 μg/mL on mice peritoneal exudate cells (mPEC) and Vero cells, respectively. The PCEO was able to significantly decrease mPEC infection by Leishmania amazonensis and Leishmania braziliensis. The value of the inhibitory concentration (IC50) on amastigote forms was about 7.3 µg/mL (L. amazonensis) and 7.2 µg/mL (L. braziliensis). We showed that PCEO induced drastic ultrastructural changes in both species of Leishmania and had a high selectivity index (SI) > 18. The in silico ADMET analysis pointed out that PCEO can be used for the development of oral and/or topical formulation in the treatment of CL. In addition, we also demonstrated the in vivo anti-inflammatory effect, with a 95% reduction in paw edema and a decrease by at least 21.4% in migration immune cells in animals treated with 50 mg/kg of PCEO. Taken together, our results demonstrate that PCEO is a promising topical therapeutic agent against CL.

Development of oral formulation of Lepidium seeds significantly decreases the high blood glucose levels in diabetic rats: in vitro formulation and in vivo antidiabetic performance

Background Lepidium sativum, Garden Cress (GC), seeds have a lot of natural molecules with a pronounced activity against different disorders. It was reported that GC seeds have the ability to lower the blood glucose level. Aim The aim of this work was to formulate GC seeds into oral tablets containing a fixed dose of the grounded seeds. Furthermore, the anti-diabetic performance of the prepared tablets was studied in the streptozotocin rats’ model in comparison with positive control metformin. Methods Micrometrics of GC grounded seeds with different excipients were investigated. Then, GC tablets were prepared via direct compression technique. GC tablets were characterized for their uniformity of dosage unit, friability, hardness, disintegration time, and in vitro release. The antidiabetic effect was studied in rats for a period of 28 days. Glycosylated hemoglobin, liver performance, and lipid levels include total cholesterol (TC), triglycerides (TGs), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were also estimated. In addition, histopathological study of liver and pancreas was also performed. Results Prosolv®EasyTab produced tablets with higher hardness, lower disintegration time, and fast release. GC tablets significantly lower the elevated blood glucose level. In addition, they have antihyperlipidemic activity, hepatocellular protective role and restore the histology of the liver and pancreas. Conclusion GC tablets could be a promising alternative formulation to control the high blood glucose level in diabetic rats rather than chemically derivatized drugs.

Amphiphilic block copolymers bearing fatty acid derivatives as vehicles for THC in the development of analgesic oral formulations

Cannabis-based therapeutics have gained increasing attention for their potential health benefits; however, the efficient administration of hydrophobic constituents such as Δ9-tetrahydrocannabinol (THC) remains a challenge. This study explores a novel approach employing amphiphilic block copolymers to encapsulate a THC-rich extract to enhance its analgesic effect. The synthesis of amphiphilic block copolymers involves sequential ring-opening polymerization of caprolactone and a cyclic carbonate with pedant alkyne moieties. This is followed by an alkyne/azide click reaction with fatty acid derivatives. These copolymers are used to encapsulate the THC-rich extract. These extract-loaded micelles exhibit nanometric sizes, uniform distribution, and high colloidal stability in simulated gastrointestinal fluids. The release kinetic assessment of THC from the micelles displays controlled and sustained profiles, which are influenced by the hydrophobic nature of the copolymer core. In vivo evaluations using a murine model revealed the safety of micellar formulations, with minimal impact on behavior and organ health. Remarkably, micellar systems demonstrated prolonged analgesic effects in both mechanical and chemical pain models, outperforming nonencapsulated THC. This study introduces a pioneering approach to cannabis-based analgesics with prolonged activity, harnessing the potential of the tailored design of amphiphilic block copolymers to enhance the delivery and efficacy of hydrophobic cannabinoids.

Molecular and qualitative characterization of compatibility between valacyclovir hydrochloride and excipients as raw materials for the development of solid oral dosage formulation

Objectives: The objective of this present study is to know the compatibility of valacyclovir hydrochloride (VCH) with common excipients that would be utilized to develop solid oral dosage forms. Several spectroscopy techniques were used to know the possible interactions of VCH with excipients. More, a molecular docking study was also carried out to see the interaction of VCH with excipients. In vitro study of a physical mixture of VCH with excipients was executed to know the release of a drug. Material and Methods: Several analytical techniques such as differential scanning calorimetry, nuclear magnetic resonance spectrometer, and Fourier-transform infrared (FTIR) spectroscopy have been utilized to know the drug-excipient compatibility. Further, possible interactions between valacyclovir and different excipients were assessed by thin-layer chromatography. In vitro dissolution studies in different sets of experiments were done to determine the influence of the hydrophobic and hydrophilic nature of excipients (on the dissolution profile of VCH using USP II-type dissolving apparatus). Moreover, in silico molecular docking studies were also done to know any possible molecular interactions among drugs and excipients using AutoDock VINA 1.2.0 software and GROMACS 5.0 software. Results: FTIR and 1H NMR spectra of VCH and physical mixtures of VCH and excipients were compared and it was observed that no significant deviation of characteristic peaks in infrared spectroscopy and 1H NMR signals was detected. The endothermic peak of VCH in the physical mixtures of drugs and excipients was found in approximately the same position. In vitro dissolution studies displayed the influence of the hydrophobic and hydrophilic nature of excipients on the dissolution profile of VCH. For the physical mixture of VCH with lactose (LAC) and dicalcium phosphate (DP), % drug release was found to be 31.96% and 33.16% at 10 min, whereas the amount of % drug released for the mixture of VCH and talc was 25.00%. For two other excipients such as LAC and DP, the % drug release was determined to be 42.96% and 41.64%, respectively, for 30 min. The docking study also provided insights into the lowest energy conformations. Docking study anticipated that the number of interactions were more between valacyclovir and LAC (four nos.) in comparison to valacyclovir and microcrystalline cellulose (MCC) (two nos.). This interaction showed that in vitro drug release for the physical mixture of VCH with MCC was higher than a mixture of valacyclovir with LAC. Conclusion: A compatibility study of VCH by analytical techniques established that VCH was compatible with utilized excipients. Drug dissolution of VCH and physical mixture of MCC exhibited the maximum amount of drug release whereas a mixture of VCH with magnesium stearate released the minimum amount of drug for both short (10 min.) and long (30 min.) period. Docking studies disclosed that the LAC complex showed less deviation with less root mean square deviation value in comparison to the microcrystalline complex. Thus, the LAC complex has more hydrogen bonds and it was more stable as compared with the MCC complex. Therefore, VCH and used excipients could be used for solid dose formulations.

Analysis of drug factors in 5-aminolevulinic acid photodynamic therapy for oral potentially malignant disorder.

This study aimed to analyze the influence of drug factors on the efficacy of 5-aminolevulinic acid (ALA) photodynamic therapy for oral potentially malignant disorder to improve clinical efficacy and promote clinical rational drug use. Literature on the treatment of oral potentially malignant disorder by using ALA photodynamic therapy was collected and analyzed from PubMed, ISI Web of Knowledge database, CNKI, VIP, and Wanfang database. A total of 690 cases were collected, with an average complete response rate of 65.94%. The groups treated with 16.8% methyl aminolevulinate cream, local topical, once a week, and pre-activation time of 2-4 hours were better than the other subgroups, with average complete response rates of 100%, 66.91%, 78.28%, and 77.54%, respectively. Drug factors have direct influence on the curative effect. The development of novel oral ALA formulations from the perspective of drug improvement is an important strategy to improve efficacy.

Development and validation of pharmaceutical oral formulation of bilayer tablet of sustained release and immediate release of gliclazide

Development and validation of pharmaceutical oral formulation of bilayer tablet of sustained release and immediate release of gliclazide

Preparation of capsaicin-loaded ultrafine fiber film and its application in the treatment of oral ulcers in rats

A drug-loaded diaphragm is an easy-to-use and effective drug delivery system that is often used to treat mouth ulcers. In this study, an ultrafine fiber film loaded with capsaicin was successfully prepared using the electrospinning technology. poly-l-lactic acid and gelatin were selected as the matrix materials to form the composite fiber, and trifluoroethanol was used as a co-solvent for poly-l-lactic acid, gelatin and capsaicin to prepare the spinning solution, which was simple to fabricate. The prepared fiber films were characterized based on their microscopic morphology and tested to derive their mechanical properties. Thereafter, the capsaicin release behavior of the film was investigated. In vitro experiments revealed certain anti-inflammatory and antibacterial abilities while animal experiments revealed that the capsaicin-loaded ultrafine fiber film could promote the healing of oral ulcers in rats. Healing of the tongue tissue in rats administered 10% capsaicin-loaded fiber film was found to be better than that in rats administered the commercial dexamethasone patch. Overall, this development strategy may prove to be promising for the development of oral ulcer patch formulations.

Development of Child-Friendly Oral Formulations Containing Celecoxib: Biopharmaceutical Considerations for Formulation Scientists

Purpose: Recently, different international regulatory agencies and task forces have encouraged the pharmaceutical industry to develop child-friendly oral dosage forms. The biopharmaceutical classification system (BCS) has emerged as a tool that facilitates the development of traditional, reformulated, and novel oral dosage forms. Little research was conducted to evaluate the applicability of the BCS in developing child-friendly oral dosage forms. This study was conducted to assess the effects of age-related developmental changes in the composition and volume of gastrointestinal fluids on the solubility and performance of oral formulations containing celecoxib.
 Methods: Solubility studies were conducted at 37 ºC in the pH range of 1.2 to 6.8 in 13 different age-appropriate biorelevant media that reflected the gastric and proximal small environments in fasted and fed states for adults and pediatric populations. Quantities of celecoxib were determined using a validated HPLC method. The permeability class of celecoxib was determined using in vivo pharmacokinetic parameters, and experimental and computational molecular descriptions.
 Results: The solubility of celecoxib in the adult fed-state simulated gastric fluid was lower than that in the pediatric fed-state gastric media representative of neonates (birth to 28 days) fed soy-based formula. Similarly, the solubility of celecoxib in adult fasted-state simulated intestinal media was lower than that in the pediatric fasted-state intestinal media formulated with bile salt concentrations 50% of the adult levels. However, solubility values of celecoxib were lower in the other pediatric media compared to adult media. The age-appropriate pediatric to adult solubility ratios were outside the 80 to 125% range in 3 and was borderline in 1 out of 9 pediatric to adult solubility ratios.
 Conclusions: The solubility ratios of celecoxib exhibited significant variability in about 44.4% of the media. This indicated that significant age-related variability could be predicted for oral formulations containing celecoxib intended for pediatric use. Formulation scientists should consider the significant biopharmaceutical considerations when developing child-friendly oral formulations.

Solubility Enhancement of Anticancer Drug Belinostat via the Co-crystallization Strategy: Synthesis, Characterization, and Antitumor Activity In Vitro Evaluation

Belinostat (PXD101), a biopharmaceutical classification system II (BCSII) drug approved for treating refractory T-cell lymphoma, is currently administered by intravenous injection. To improve patient compliance, the development of oral formulations of PXD101 has attracted attention. Because the solubility and dissolution rate of active pharmaceutical ingredients can affect the therapeutic effect of the oral formulations, this work explores solid-state form modification of PXD101 by co-crystallization with four coformers, namely, theophylline, isonicotinamide (INA), isoniazid (INH), and l-proline (l-Pro) to solve the problem of poor water solubility. The four cocrystals were obtained on the basis of N–H···O, O–H···O, and O–H···N synthons. All the four obtained multicomponent crystals were characterized by powder X-ray diffraction (PXRD) and thermal analysis, meanwhile, crystal structure determination was performed by single-crystal XRD. The results of CrystalCMP show the similar packing patterns of PXD101-INA and PXD101-INH cocrystals. The data analysis from powder dissolution experiments suggested that the apparent solubility of the obtained multicomponent crystals is 1.14–2.22 times more than that of PXD101, and PXD101-l-Pro shows a completely different dissolution behavior from that of the other three cocrystals. Finally, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay experiments demonstrated that the PXD101-INA cocrystal can significantly inhibit the proliferation of Michigan Cancer Foundation-7 (MCF-7) cells even at a low concentration (0.01 μM). Such results shed light on the potential value of multicomponent crystals in the further development of pharmaceutical products.

Liposomal Amphotericin B for Treatment of Leishmaniasis: From the Identification of Critical Physicochemical Attributes to the Design of Effective Topical and Oral Formulations.

The liposomal amphotericin B (AmB) formulation, AmBisome®, still represents the best therapeutic option for cutaneous and visceral leishmaniasis. However, its clinical efficacy depends on the patient's immunological status, the clinical manifestation and the endemic region. Moreover, the need for parenteral administration, its side effects and high cost significantly limit its use in developing countries. This review reports the progress achieved thus far toward the understanding of the mechanism responsible for the reduced toxicity of liposomal AmB formulations and the factors that influence their efficacy against leishmaniasis. It also presents the recent advances in the development of more effective liposomal AmB formulations, including topical and oral liposome formulations. The critical role of the AmB aggregation state and release rate in the reduction of drug toxicity and in the drug efficacy by non-invasive routes is emphasized. This paper is expected to guide future research and development of innovative liposomal formulations of AmB.

The Development and Clinical Applications of Oral Arsenic Trioxide for Acute Promyelocytic Leukaemia and Other Diseases.

Appreciation of the properties of arsenic trioxide (ATO) has redefined the treatment landscape for acute promyelocytic leukaemia (APL) and offers promise as a treatment for numerous other diseases. The benefits of ATO in patients with APL is related to its ability to counteract the effects of PML::RARA, an oncoprotein that is invariably detected in the blood or bone marrow of affected individuals. The PML::RARA oncoprotein is degraded specifically by binding to ATO. Thus ATO, in combination with all-trans retinoic acid, has become the curative treatment for ATO. The multiple mechanisms of action of ATO has also paved the way for application in various condition encompassing autoimmune or inflammatory disorders, solid organ tumours, lymphomas and other subtypes of AML. The development of oral formulation of ATO (oral ATO) has reduced costs of treatment and improved treatment convenience allowing widespread applicability. In this review, we discuss the mechanisms of action of ATO, the development of oral ATO, and the applications of oral ATO in APL and other diseases.

Investigation of the internalization and transport mechanism of Codonopsis Radix polysaccharide both in mice and Caco-2 cells

For Codonopsis Radix polysaccharides (CRPs), oral administration is generally considered the most convenient route for patients. However, the details of its absorption and transport mechanisms remain unclear. In this study, we aimed to evaluate the oral absorption of CPA (an inulin-type fructan extracted from CRPs) in mice and Caco-2 cells. It was labeled with fluorescein isothiocyanate, and the fluorescence derivative (FCPA) was used to trace the behavior of CPA. The results showed that FCPA could be absorbed after oral administration and has a wide tissue distribution, including in the stomach, intestine, kidneys, and liver. FCPA was poorly absorbed, and its internalization was time- and energy-dependent, as well as dependent on cholesterol- and dynamin-mediated endocytosis. Confocal laser scanning microscopy showed successful cellular internalization of FCPA from the cytoplasm to the nucleus. In addition, we found that FCPA was trafficked to endosomes and lysosomes, and that tubulin was required for its intracellular transport. These findings add new details to our knowledge of the internalization and transport mechanisms of CPA, which may prove useful to the development and application of oral formulations of CRPs.

Biomimetic and temporal-controlled nanocarriers with ileum transporter targeting for achieving oral administration of chemotherapeutic drugs

BackgroundOral chemotherapy is preferred for patients with cancer owing to its multiple advantages, including convenience, better patient compliance, and improved safety. Nevertheless, various physical barriers exist in this route that hamper the development of oral chemotherapeutic formulations, including destruction of drugs in the gastrointestinal tract (GIT), low permeability in enterocytes, and short residence time in the intestine. To overcome these limitations, it is necessary to design an efficient oral drug delivery system with high efficacy and improved safety.ResultsHerein, we designed novel glycocholic acid (GCA)-functionalized double layer nanoparticles (GCA-NPs), which can act via an endogenous pathway and in a temporally controlled manner in the intestine, to enhance the oral bioavailability of hydrophobic chemotherapeutic drugs such as paclitaxel (PTX). GCA-NPs were composed of quercetin (Qu)-modified liposomes (QL) coated with GCA-chitosan oligosaccharide conjugate (GCOS). The GCA-NPs thus prepared showed prolonged intestinal retention time and good GIT stability due to the presence of chitosan oligosaccharide (COS) and enhanced active transportation via intestinal apical sodium-dependent bile acid transporter (ASBT) due to the presence of GCA. GCA-NPs also efficiently inhibited intestinal P-gp induced by Qu. PTX-loaded GCA-NPs (PTX@GCA-NPs) had a particle size of 84 nm and an entrapment efficiency of 98% with good stability. As a result, the oral bioavailability of PTX was increased 19-fold compared to that of oral Taxol® at the same dose. Oral PTX@GCA-NPs displayed superior antitumor efficacy and better safety than Taxol® when administered intravenously.ConclusionsOur novel drug delivery system showed remarkable efficacy in overcoming multiple limitations and is a promising carrier for oral delivery of multiple drugs, which addresses several challenges in oral delivery in the clinical context.Graphical

Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics

AimsThe aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. MethodsIntravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. ResultsThe population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. ConclusionsThe current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.

Design and Evaluation of Two-Step Biorelevant Dissolution Methods for Docetaxel Oral Formulations.

Dissolution is a pivotal tool for oral formulations. Dissolution could be used to either reduce the risk of product failure through quality control or predict and understand in vivo performance of drug formulations. The latter is always challenging because multiple factors such as selection of media, gastrointestinal components, physiological factors, consideration of fasted and fed state are involved. Previously published dissolution methods such as one-step dissolution in individual simulated gastric fluid, simulated intestinal fluid, or phosphate buffer saline did not signify the realistic gastrointestinal transit effect. Docetaxel (DTX), a poorly water-soluble drug, is commercially available only as injectable dosage forms, and thus many publications studied the development of oral DTX formulations. In our previous report, we developed oral lipid-based DTX granules that showed higher oral absorption in rats compared to DTX powder. However, one-step dissolution in simulated gastric fluid showed no difference between DTX granules and DTX powder. Therefore, the present study aimed to develop new two-step biorelevant dissolution methods for DTX oral formulations. In the study, new two-step biorelevant dissolution methods in fasted or fed states with pancreatin were developed and compared with other previously reported dissolution methods. The new two-step biorelevant dissolution methods successfully discriminated the difference of dissolution between DTX granules and DTX powder, which reflected the in vivo difference of absorption of these two formulations. Moreover, food effects were confirmed for DTX. The new dissolution methods have the potential to be used to predict and understand in vivo performance of oral solid dosage forms.

Versatile Oral Insulin Delivery Nanosystems: From Materials to Nanostructures.

Diabetes is a chronic metabolic disease characterized by lack of insulin in the body leading to failure of blood glucose regulation. Diabetes patients usually need frequent insulin injections to maintain normal blood glucose levels, which is a painful administration manner. Long-term drug injection brings great physical and psychological burden to diabetic patients. In order to improve the adaptability of patients to use insulin and reduce the pain caused by injection, the development of oral insulin formulations is currently a hot and difficult topic in the field of medicine and pharmacy. Thus, oral insulin delivery is a promising and convenient administration method to relieve the patients. However, insulin as a peptide drug is prone to be degraded by digestive enzymes. In addition, insulin has strong hydrophilicity and large molecular weight and extremely low oral bioavailability. To solve these problems in clinical practice, the oral insulin delivery nanosystems were designed and constructed by rational combination of various nanomaterials and nanotechnology. Such oral nanosystems have the advantages of strong adaptability, small size, convenient processing, long-lasting pharmaceutical activity, and drug controlled-release, so it can effectively improve the oral bioavailability and efficacy of insulin. This review summarizes the basic principles and recent progress in oral delivery nanosystems for insulin, including physiological absorption barrier of oral insulin and the development of materials to nanostructures for oral insulin delivery nanosystems.

Practical and operational considerations related to paediatric oral drug formulation: An industry survey

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.

Effervescent based nano-gas carrier enhanced the bioavailability of poorly aqueous soluble drug: A comprehensive mechanistic understanding

The low aqueous solubility of drug molecules is a considerable hurdle to produce the desired pharmacological effect through any biological route of drug administration. Hence, most of the chemotherapeutic drugs exhibit low bioavailability as well as non-specific toxic effects on the human body. Luteolin (LUT), one of the richest flavonoids, is proven to be a cancer preventive agent for numerous human cancer cell lines. The hydrophobicity of LUT, on the other hand, is a major concern for it's low oral bioavailability. On this account, we have utilized a versatile strategy to engineer a novel effervescent based self-assemble nano-gas drug carrier (NG) for poorly water-soluble compounds, which is hypothesized to be a self-emulsifying agent for drug molecules in the intestinal aqueous environment to form nanoemulsion and eventually escalate the efficacy. The size of the optimized nanoformulation after characterization was found to be 450 ± 100 nm with a negative surface charge (zeta potential value of −27.8 mV). Additionally, SAXS analysis verified the conversion of the carrier into nano-micelles. In vitro studies show NG has a lot of potential for improving LUT's solubility and as a result, LUT can show a significant effect (approximately 2-fold) on pancreatic cancer cell lines at minimal concentration. The permeability enhancement effect of our excipients also showed an additional advantage for the utilization of this concept in the oral formulation development of drug compounds.

Nanocrystals with different stabilizers overcome the mucus and epithelial barriers for oral delivery of multicomponent Bufadienolides

Using nanocrystals (NCs) technology may be a promising drug delivery strategy for oral administration of multicomponent anticancer drugs. However, the intestinal epithelium and the mucus layer on the intestine extremely limited drug transport and absorption by orally. In this study, we selected multicomponent inartificial compound Bufadienolides (BU) with broad spectrum antitumor activity as the model drug to prepare BU NCs with different stabilizers by wet grinding, and explored the efficiency of penetrating through the mucus layer and transporting intestinal epithelial cells in vitro and ex vivo. Results revealed that BU NCs can dramatically improve dissolution behavior synergistically and the efficiency of mucus permeation. Besides, we found that BU NCs with different stabilizers enhanced cellular uptake, which was mainly attributed to increasing or changing the endocytosis pathway and plasma membrane/Endoplasmic reticulum (ER) pathway involved in the transmembrane transport of NCs. Furthermore, BU NCs could definitely improve intestinal absorption efficiency and change the absorption site of BU ex vivo. This multi-angle exploration will provide reference for the development of BU oral delivery formulations.