Improved Drug Release Research Articles

Functionalized bacterial cellulose nanowhiskers as long‐lasting drug nanocarrier for antibiotics and anticancer drugs

A nano drug carrier based on sustainable and biocompatible nanocellulose was developed for use in prolonged drug releases. The grafting of β‐cyclodextrin (βCD) on bacterial cellulose nanowhiskers (BCNC) using citric acid (CA) as a green linker was performed. This led to the formation of functionalized BCNC‐grafted‐βCD (BCNC‐g‐βCD). Broad‐spectrum antibiotic Ciprofloxacin (CIP) and anticancer drugs Doxorubicin (DOX) and Paclitaxel (PTX) were used as model drugs. These model drugs were conjugated to BCNC‐g‐βCD to form the drug‐nanocarrier systems (BCNC‐g‐βCD‐drug). The change in the nanowhiskers’ surface chemistry, morphology, and crystallinity was characterized by FTIR, solid‐state 13C NMR, scanning electron microscopy (SEM), atomic force microscopy (AFM), and x‐ray diffraction (XRD). The functionalized nanowhiskers showed a significant increase in the drug payloads, which ranged from 495 ±4–810 ±7 μg/mg, along with a radical improvement in the drug release profiles. For all of the developed drug‐conjugated nanocarriers, the initial burst releases were reduced effectively. The observed drug releases showed a sustained and controlled manner, with cumulative releases of 75–90 % over 5–5.5 days. Nevertheless, an improved drug release performance was observed in the acidic pH of 6.4 that mimicked extracellular tumor cells. In vitro drug release data were fitted zero‐order kinetic model with drug release constants (K0) of 0.68, 0.74, and 0.79 μg drug/h (at pH 6.4 and 37 °C) for BCNC‐g‐βCD‐CIP, BCNC‐g‐βCD‐DOX, and BCNC‐g‐βCD‐PTX nanosystems, respectively. The observed higher payloads along with the slow releases of drugs from the developed nanocarrier suggests its promising potential for reducing the frequent daily dosing and minimizing systemic toxicity of loaded drugs.

Novel Solid Dispersions Increasing the Solubility of Prothionamide

Water solubility of prothionamide and its solid dispersions with polyethylene glycol-1500, polyvinylpyrrolidone-10000, and β-cyclodextrin was studied. The most promising results were obtained with the solid dispersion with polyvinylpyrrolidone, which provided a 2.6-fold general increase of drug’s solubility and about a 6-fold dissolution rate increase, the maximal values among the studied drug forms. The results of complex physicochemical studies suggested that the improved drug release was due to micronization and solubilizing action of the polymer. A principal factor was the destruction of the crystal lattice and formation of amorphous particles in the solid dispersion. The obtained data can be useful for the development of modified pharmaceutical forms of prothionamide with improved drug release profile.

Silver Nanoparticles Incorporated in pH-Sensitive Nanocomposite Hydrogels Based on Carboxymethyl Chitosan-Poly (Vinyl Alcohol) for Use in a Drug Delivery System

The CMCh-PVA/Ag nanocomposite hydrogels have been introduced a new technique to deliver drugs, which is dependent on pH. They were prepared successfully in situ by forming of Ag nanoparticles within swollen CMCh-PVA hydrogels. The resulting hydrogels were examined by running various experimental procedures such as FT-IR, XRD, EDX, SEM, and TGA. XRD and EDX patterns verified the formation of Ag nanoparticles in the hydrogel networks; moreover, the formation of Ag nanoparticles with size range from 21 to 81 nm within the hydrogel matrix was confirmed by SEM micrographs. It was shown that increased Ag+ concentration led to increased number of Ag nanoparticles. The prepared nanocomposite hydrogels were studied in terms of the swelling behavior at the pH of 2.1 (simulated gastric fluid) and pH 7.4 (simulated intestinal fluid); the results show that the prepared nanocomposite hydrogels outperformed the pure CMCh-PVA hydrogels in terms of swelling capacity. The antibacterial activity of the nanocomposite hydrogels was examined, and mechanisms involved in their synthesis were reported; the results showed an excellent antibacterial behavior of the nanocomposite hydrogel. To study the efficiency of this new category of nanocomposite hydrogels to be used as an in vitro drug release test to controlled drug delivery system. Also, for CMCh-PVA hydrogels-containing Ag nanoparticles sustained and controlled drug releases were observed that increased with increase in Ag nanoparticles content which can lead to prolong the release of the drug. The objective of this study is to prepare a new, improved drug release using pH-sensitive polymers of carboxymethyl chitosan-PVA with the weight ratios of 3:1, 1:1, and 1:3 containing AgNPs. In this study, to synthesize the new CMCh-PVA/Ag nanocomposite hydrogels efficiently, the Ag+ ions were reduced in the CMCh-PVA hydrogel medium in situ. The effect of the concentration of the Ag nanoparticles in gel content measurement, the swelling/deswelling ratio and drug release behavior and antibacterial activity for the Gram-negative E. coli and Gram-positive S. aureus bacteria was considered.

Optimising the release rate of naproxen liqui-pellet: a new technology for emerging novel oral dosage form

Liqui-pellet is a new dosage form stemming from pelletisation technology and concept from liquisolid technology. In spite of liqui-pellet overcoming a major hurdle in liquisolid technology through achieving excellent flow property with high liquid load factor, the formulation requires to be optimised in order to improve drug release rate. Liqui-pellets of naproxen containing Tween 80, Primojel, Avicel and Aerosil were extruded and spheronised. Flowability test confirmed that all liqui-pellet formulations have excellent-good flow property (Carr’s index between 3.9–11.17%), including liqui-pellets with a high liquid load factor of 1.52, where 38% of the total mass is co-solvent. This shows a relatively high liquid load factor can be achieved in liqui-pellet without compromising the flowability, which is one of the key novelty of this work. It was found that the improved drug release rate was due to the remarkably improved disintegration of the supposedly non-disintegrating microcrystalline-based pellet; the optimised liqui-pellet seems to explode into fragments in the dissolution medium. At pH 1.2, the optimised formulation had ~ 10% more drug release than non-optimised formulation after 2 h, and at pH 7.4, the drug release of the optimised pellet was nearing 100% at ~ 15 min, whereas the none-optimised pellet only achieved ~ 79% drug release after 2 h. DSC and XRPD indicated an increase in the dissolution rate could be due to molecularly dispersion of naproxen in the pellets. Overall results showed that liqui-pellet exhibited an enhanced drug release and the capacity for high liquid load factor whilst maintaining excellent flowability, rendering it a potentially commercially feasible drug delivery system.

FORMULATION AND IN VITRO CHARACTERISATION OF SOYBEAN OIL-HPMCK4M BASED BIGEL MATRIX FOR TOPICAL DRUG DELIVERY

Objective: Hydrogels with scope for utilization in numerous fields possess limited applications due to problems in incorporating wide range of drugs and crossing the lipophilic barrier of the skin. Attempts to overcome these problems by developing organogel hold drawbacks. Challenges posed by drug lipophilicity or skin permeation can be solved by developing bigel formed via combination of lipophilic and hydrophilic gel phases in a definite proportion. The objective of the present study is to formulate and characterize matrix type bigel of soybean oil and HPMCK4M for topical drug delivery.
 Methods: Four batches of bigels were developed with two organogel formulations of soybean oil containing 20 and 22% w/v Span 60. Both organogels and bigels were examined for compatibility by FTIR spectroscopy, hemocompatibility and characterized for physical appearance, pH, rheological behavior and in vitro drug release pattern.
 Results: FTIR study confirmed compatibility between paracetamol and components of organogel or bigel. The oily feel of organogels disappeared with bigels which possessed a creamy and smooth texture. Pseudoplastic behaviour was confirmed by Ostwald-de wale power-law model in both organogels and bigels. Improved drug release was observed in bigel (BG1) formulation containing 3%w/v HPMCK4M and soybean oil based organogel with 20% w/v Span 60 as compared to the corresponding organogel (OG1). Organogels were foundto follow either zero-order kinetics (OG1) or Korsmeyer-Peppasmodel (OG2) while the formation of matrix was exhibited in bigels with drug diffusion predominantly of non-Fickian type.
 Conclusion: Therefore, bigels of soybean oil based organogel with HPMCK4M hydrogel formed gel matrix demonstrating improved drug release for topical application compared to organogel.

Expedited Tablet Formulation Development of a Highly Soluble Carbamazepine Cocrystal Enabled by Precipitation Inhibition in Diffusion Layer.

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer. Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine-nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation. The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.

PEGylated polylactide (PLA) and poly (lactic-co-glycolic acid) (PLGA) copolymers for the design of drug delivery systems

PEGylated polylactide (PLA) and poly (lactic-co-glycolic acid) (PLGA) copolymers are biodegradable polyesters, widely employed in the last decades for the design of drug delivery systems such as polymeric hydrogels and nanocarriers (e.g. micelles and nanoparticles). The coupling with polyethylene glycol (PEG) offers some advantages with the respect to PLA and PLGA, including a higher hydrophilicity and a prolonged retention time for nanoparticulate systems, as well as the possibility of preparing thermoresponsive hydrogels. A large variety of pharmacologically active-compounds (small molecules, natural compounds or biomolecules such as proteins, peptides, oligonucleotides) has been formulated and delivered through PEGylated PLA or PLGA copolymers. Due to the high number of papers recently published about the use of these biodegradable copolymers in drug delivery, PEGylated PLA or PLGA copolymers are being still attractive. Their potential applications have been also broadened by the developing of ligand-functionalized copolymers, enabling an “active drug targeting” for nanoparticulate systems. The present review summarizes the recent advances in drug delivery systems based on PEGylated PLA or PLGA copolymers, focusing on self-assembled micelles and thermoresponsive hydrogels as well as nanoparticles. A particular consideration has been given to functionalized PEGylated PLA/PLGA nanoparticles for active drug delivery. Further advances in the design of PEGylated PLA/PLGA delivery systems will be beneficial for an improved drug release and targeting in the light of novel personalised therapeutic strategies.

Enzyme-/Redox-Responsive Mesoporous Silica Nanoparticles Based on Functionalized Dopamine as Nanocarriers for Cancer Therapy

Mesoporous silica nanoparticles (MSNs) have been proved potential nanocarriers for efficient stimuli-triggered drug delivery systems (DDSs) in cancer therapy. We have developed a novel pepsin enzyme-responsive MSN based on mussel mimetic coating of dopamine for controlled release of drug delivery via a facile one-pot strategy. Herein, to improve drug release efficiency for cancer therapy, a novel dual-sensitive (enzyme- and redox-) MSN based on functionalized dopamine containing both peptide and disulfide bonds was designed and prepared. In detail, cystine-dopamine (Cy-DA) was newly synthesized and used as a monomer to self-polymerize into a coating on MSNs via simple a one-pot reaction to give rise to a chemotherapy drug [e.g., doxorubicin (DOX)] delivery system poly-Cy-DA-MSN. The in vitro cellular cytotoxicity tests of normal Marc-145 cells and HeLa cells showed that poly-Cy-DA-MSN was nontoxic, highly biocompatible, and suitable as drug carriers in controlled release DDS (CDDS). Because of the peptide...

Polydopamine-based Implantable Multifunctional Nanocarpet for Highly Efficient Photothermal-chemo Therapy

We report a design and fabricate multifunctional localized platform for cancer therapy. Multiple stimuli-responsive polydopamine (PDA) was used for surface modification of electrospun doxorubicin hydrochloride (DOX) loaded polycaprolactone (PCL) fibers to make a designated platform. Photothermal properties such as photothermal performance and stability of the resulting composite mats were studied under the irradiation of the near-infrared (NIR) laser of 808 nm. With the incorporation of PDA into the fiber, a remarkable increase of local temperature was recorded under NIR illumination in a concentration-dependent manner with excellent stability. Drug released assay results revealed PDA coated PCL-DOX mats showed pH and NIR dual responsive behavior thereby exhibiting improved drug release in an acidic medium compared to physiological pH condition (pH 7.4) which is further increased by NIR exposure. The cancer activity in vitro of the mats was evaluated using cell counting (CCK) and live and dead cell assays. The combined effect of NIR mediated hyperthermia and chemo release resulting improved cells death has been reported. In summary, this study presents a major step forward towards a therapeutic model to cancer treatment utilizing pH and NIR dual responsive property from PDA alone in a fibrous mat.

Experimental investigations, cytotoxicity and cellular uptake outcomes of physically modified duloxetine HCl inclusion complexes

Duloxetine HCl, an antidepressive drug, has poor water solubility and poor oral absorption leading to low bioavailability of the drug. The drug is also found to be acid labile, resulting in degradation in gastric environment. To overcome such drawbacks, inclusion complexation process was explored to improve the solubility and dissolution rate of duloxetine HCl by formulating its complexes with beta-cyclodextrin using different complexation techniques. Equimolar complexes of the drug with β-CD (1:1 molar) were prepared based on phase solubility analysis. Behaviour of complexes was characterized both in solution state and in solid state using DSC, FTIR, SEM, 1H NMR and PXRD techniques. Molecular docking studies were also carried out to investigate mode of inclusion and stability. Also, the cell culture studies, viz. MTT assay and cellular uptake, were investigated. Apparent stability or association constant (Ks) was predicted to be 165.64 M−1. Results of characterization techniques indicate the drug to be completely included in the hydrophobic cavity of β-CD, and hence, the physicochemical properties of the drug differ from parent molecule. Cytotoxicity studies indicated low IC50 value for complexes in comparison with native drug moiety, and cellular uptake of the complex was also found to be improved in case of complexed drug at different time points. Enhanced solubility and improved drug release was observed for physically characterized less crystalline complexes. Cellular uptake is also reported to be appreciably enhanced in complexed form. Thus, the process has logistic approach in reducing the dose of drug and related side effects.

Formulation and Characterization of Eplerenone Nanoemulsion Liquisolids, An Oral Delivery System with Higher Release Rate and Improved Bioavailability.

Because Eplerenone (EPL) is a Biopharmaceutical Classification System (BCS) class-II drug and is prone to extensive liver degradation, it suffers from poor bioavailability after oral administration. This work aimed to prepare liquisolids loaded with EPL-nanoemulsions (EPL-NEs) that have a higher drug release rate and improved bioavailability by the oral route. Based on solubility studies, mixtures of Triacetin (oil) and Kolliphor EL/PEG 400 surfactant/co-surfactant (Smix) in different ratios were used to prepare EPL-NE systems, which were characterized and optimized for droplet size, zeta potential, polydispersity index (PDI), and drug content. Systems were then loaded onto liquisolid formulations and fully evaluated. A liquisolid formulation with better drug release and tableting properties was selected and compared to EPL-NEs and conventional EPL oral tablets in solid-state characterization studies and bioavailability studies in rabbits. Only five NEs prepared at 1:3, 1:2, and 3:1 Smix met the specified optimization criteria. The drug release rate from liquisolids was significantly increased (90% within 45 minutes). EPL-NE also showed significantly improved drug release but with a sustained pattern for four hours. Liquisolid bioavailability reached 2.1 and 1.2 relative to conventional tablets and EPL-NE. This suggests that the EPL-NE liquisolid is a promising oral delivery system with a higher drug release rate, enhanced absorption, decreased liver degradation, and improved bioavailability.

Process optimization of ecological probe sonication technique for production of rifampicin loaded niosomes

The aim of the present study was to develop an optimized niosome formulation for the encapsulation of a poorly water-soluble drug by the ecological probe sonication method. Pluronic L121 and Span 60 were used as surface active agents and the optimization of the composition was made with the aid of Design of Experiment (DoE) concept. Rifampicin was used as a model drug. Concentration levels of charge inducing agent, dicetylphosphate (DCP), and Pluronic L121 were studied as variables. Prepared niosomes with varying concentrations of DCP and Pluronic L121 resulted in small sized niosomes with sizes ranging from 190 nm to 893 nm. During the four weeks stability testing, the particle sizes were reduced slightly. The formulation containing 2 mg of DCP resulted in most stable niosomes with 75.37% entrapment efficiency. All the niosomal formulations showed higher in vitro drug release rates as compared to bulk drug formulation. As a conclusion, rifampicin loaded niosomes prepared with Pluronic L121 and Span 60 resulted in stable, small sized niosomes with improved drug release profile.

An Evaluation of Curcumin-Encapsulated Chitosan Nanoparticles for Transdermal Delivery.

Curcumin-loaded chitosan nanoparticles were synthesised and evaluated in vitro for enhanced transdermal delivery. Zetasizer® characterisation of three different formulations of curcumin nanoparticles (Cu-NPs) showed the size ranged from 167.3 ± 3.8nm to 251.5 ± 5.8nm, the polydispersity index (PDI) values were between 0.26 and 0.46 and the zeta potential values were positive (+ 18.1 to + 20.2mV). Scanning electron microscopy (SEM) images supported this size data and confirmed the spherical shape of the nanoparticles. All the formulations showed excellent entrapment efficiency above 80%. FTIR results demonstrate the interaction between chitosan and sodium tripolyphosphate (TPP) and confirm the presence of curcumin in the nanoparticle. Differential scanning calorimetry (DSC) studies of Cu-NPs indicate the presence of curcumin in a disordered crystalline or amorphous state, suggesting the interaction between the drug and the polymer. Drug release studies showed an improved drug release at pH 5.0 than in pH 7.4 and followed a zero order kinetics. The in vitro permeation studies through Strat-M® membrane demonstrated an enhanced permeation of Cu-NPs compared to aqueous curcumin solution (p ˂0.05) having a flux of 0.54 ± 0.03μgcm-2h-1 and 0.44 ± 0.03μgcm-2h-1 corresponding to formulations 5:1 and 3:1, respectively. The cytotoxicity assay on human keratinocyte (HaCat) cells showed enhanced percentage cell viability of Cu-NPs compared to curcumin solution. Cu-NPs developed in this study exhibit superior drug release and enhanced transdermal permeation of curcumin and superior percentage cell viability. Further ex vivo and in vivo evaluations will be conducted to support these findings.

Study on Formulation development and shelf life indicating stability of Artesunate loaded Self-nanoemulsifying Drug Delivery System

Solubility plays an important role in the formulation. When a drug is poorly soluble, their bioavailability will be affected. However, the solubility of the drug can be enhanced by using various methods like pharmaceutical approach, pharmacokinetic approach and biological approach. It can also be improved by formulating a lipid based drug delivery system. In the present study, nanoemulsion has been developed by using oil, surfactant and a co-surfactant in order to increase the solubility of poorly soluble BCS Class II and Class IV drugs. Nanoemulsions can be prepared by different techniques. In the current study, nanoemulsion has been formulated by using simple spontaneous emulsification approach. Artesunate was used as a choice of drug and capryol 90 was used as oil in the present study. Pseudo-ternary phase diagrams were used in order to determine the oil and Smix ratio. After the formulation, the product was subjected to various evaluation studies like droplet size, zeta potential, PDI and viscosity etc. Further, the in-vitro dissolution test was carried out for the formulated product, marketed formulation and the pure drug. And it was observed that the formulated product showed an improved drug release. In addition to these evaluation tests, accelerated stability studies according to the ICH guidelines were also carried in order to determine the shelf life as well as the effect of added ingredients on the stability of the product. The shelf life of the product was observed to be 2.38 years at room temperature.

The enhancement of surface activity and nanoparticle stability through the alteration of charged amino acids of HGFI.

HGFI (hydrophobin found in Grifola frondosa) is a small surface-active protein, belonging to class I hydrophobins, and can form amphipathic protein films at hydrophobic- hydrophilic material interfaces. HGFI has a low isoelectric point (pI) because no basic amino acids are present in its sequence. Here we constructed two HGFI mutants using a site-directed mutation method. The two mutants were named MGF3 (E24K/D35K/D37K) and MGF6 (E12K/D19K/E24K/D35K/D37K/D66K). MGF3 was generated by replacing three acidic amino acids, namely Glu24, Asp35 and Asp37, with the basic amino acid Lys. MGF6 was obtained by substituting Glu12, Asp19, Glu24, Asp35, Asp37 and Asp66 with six Lyses. Zeta-potential analysis showed that the pI values of MGF3 and MGF6 were between 5 and 6. The water contact angle (WCA) and quartz-crystal microbalance (QCM) analyses revealed enhanced adsorption capacity of these two mutants. Circular dichroism measurements (CD), Thioflavin T (THT) assays and atomic force microscopy (AFM) tests indicated that neither MGF3 nor MGF6 have the ability to form rodlets. An in vitro drug release assay showed the water solubility of the indometacin (IND) nano-particles (NPs) was improved by both MGF3 and MGF6 modification. Furthermore, the mutant hydrophobin-modified NPs were more stable and exhibited a lower release rate in solutions at pH 1.2 and 7 at 37 °C. The MGF6-IND NPs showed a particularly improved drug release behavior. These results suggest new applications of the mutated hydrophobins in sustained delivery of oral drugs in the gastrointestinal tract.

Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases

Transdermal drug delivery (TDDS) has been highly explored in the past couple of decades due to benefits such as increased patient compliance, improved drug release, tissue targeting, avoiding the presystemic metabolism in the liver etc. However, the stratum corneum poses as the rate limiting barrier to the permeation of drugs through the skin, which has been a continuous challenge in TDDS. This review covers the various types of nanoparticles and nanoemulsions that are currently being investigated for TDDS applications, desirable physical and chemical characteristics of these systems, their routes of penetration through the skin, and summarizes recent advances using these systems in treating conditions such as alopecia, wound healing, psoriasis, and melanoma. Additionally, synergistic effect of iontophoresis and mechanical force mediated drug delivery will be reviewed.

Formulation of aripiprazole-loaded pH-modulated solid dispersions via hot-melt extrusion technology: In vitro and in vivo studies

The objective of this study was to formulate aripiprazole (ARI)-loaded pH-modulated solid dispersions (SD) to enhance solubility, dissolution, and bioavailability via hot-melt extrusion (HME) technology. Kollidon® 12 PF (PVP) and succinic acid (SA) were selected after solubility screenings of various polymers and acidifiers. Several formulations, varying in screw speed and drug/polymer/acidifier ratios, were extruded using an 11 mm twin-screw extruder and were investigated for the effect of these variables. Scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to perform solid-state characterizations of the pure drug and extrudates. The aqueous solubility and dissolution were evaluated for the pure drug and milled extrudates. Among the prepared formulations, N6 was chosen for in vivo absorption studies. Solid-state characterization demonstrated the transformation of the crystalline ARI to an amorphous state in the formulations. Each formulation showed increased solubility and dissolution compared to the drug powder. The oral bioavailability (Cmax and AUC0–12) of N6 was significantly improved when compared to the pure ARI. This novel study not only discusses the incorporation of acidifiers in SDs but also the preparation of SDs using HME technology as effective techniques to improve drug release and bioavailability.

Biodegradable Simvastatin-Containing Polymeric Prodrugs with Improved Drug Release.

Simvastatin was previously converted to a polymeric prodrug with higher drug loading, but the hydrophobic nature of the poly(simvastatin) component of the block copolymer led to slow release of the drug in vitro. In this study, we hypothesized that degradation could be accelerated by chemically modifying the polymer backbone by introducing glycolide and lactide comonomers. Copolymers were formed by ring-opening polymerization using 5 kDa monomethyl ether poly(ethylene glycol) as the microinitiator in presence of triazabicyclodecene catalyst. In addition to simvastatin, modified reaction mixtures contained lactide or glycolide. Incorporation of the less hydrophobic glycolide comonomer led to in vitro degradation of up to two times greater mass loss, release of up to ~7 times more simvastatin, and a 2-3 times increase in compressive modulus compared to the lactide-containing and parent polymers.

The relevance of co-amorphous formulations to develop supersaturated dosage forms: In-vitro, and ex-vivo investigation of Ritonavir-Lopinavir co-amorphous materials

Ritonavir and Lopinavir have previously been demonstrated to decrease the maximum solubility advantage and flux in the presence of each other. The present study investigated the ability of Ritonavir and Lopinavir co-amorphous materials to generate a supersaturated state. Further, it explored the precipitation and flux behavior of co-amorphous materials. The co-amorphous materials of Ritonavir and Lopinavir were prepared by quench cool method and characterized in the solid state using XRPD, DSC, FTIR. The solubility studies were conducted in USP phosphate buffer (pH 6.8) for 12 h. The supersaturation potential and precipitation behavior were studied employing pH shift method. Further, the diffusion behavior was explored in vitro and ex-vivo using a semipermeable membrane and intestinal everted sac method, respectively. The results showed that the co-amorphous materials have the potential to generate a supersaturated state. However, the reduction in the amorphous solubility was observed for both the drug(s) and the degree of reduction was found proportionate with the mole fraction of the compound in the co-amorphous material. Interestingly, the flux of both the drugs from co-amorphous material of 2:1 M ratio (Ritonavir 2: Lopinavir 1) was found exceeding the flux of the individual drugs in the amorphous form. The significant increase in the flux was attributed to the improved drug release properties due to precipitation of drug rich phase of nano/micro dimensions.

Formulation optimization and pharmacokinetics evaluation of oral self-microemulsifying drug delivery system for poorly water soluble drug cinacalcet and no food effect

The present research indicated that a new self-microemulsifying drug delivery systems (SMEDDS) were used to reduce the food effect of poorly water-soluble drug cinacalcet and enhance the bioavailability in beagle dogs by oral gavage. Ethyl oleate, OP-10, and PEG-200 was selected as the oil phase, surfactant and co-surfactant of cinacalcet-SMEDDS by the solubility and phase diagram studies. Central Composite Design-Response Surface Methodology was used to determine the ratio of surfactant and co-surfactant, the amount of oil for optimizing the SMEDDS formation. The prepared formulations were further characterized by the droplet size, self-microemulsifying time, zeta potential, polydispersity index (PDI), and robustness to dilution. The in vitro release profile of cinacalcet-SMEDDS was determined in four different release medium and in fasted state and fed state of simulated gastrointestinal fluid. Cinaclcet-SMEDDS were implemented under fed and fasted state in dogs and product REGPARA® was used as a comparison to the prepared formulation in the pharmacokinetics. The result showed the components of SMEDDS, the amount of oil, the ratio of surfactant, and co-surfactant was optimized using solubility, pseudo-ternary phase diagram studies, and response surface methodology. In vitro drug release studies indicated that the cinacalcet-SMEDDS eliminated the effect of pH variability in release medium and variational gastroenteric environments with improved drug release performance. Pharmacokinetic studies revealed that the profiles of cinacalcet-SMEDDS were similar both in the fasted and fed state compared with commercial product, indicating the formulation significantly promoted the absorption, enhanced bioavailability and had no food effect essentially. It is concluded that poorly water-soluble drug cinacalcet was improved in the solubility and bioavailability by using a successful oral dosage form the SMEDDS, and eliminated food effect as well.