Extended Release Profile Research Articles

Development of rosuvastatin flexible lipid-based nanoparticles: promising nanocarriers for improving intestinal cells cytotoxicity

BackgroundRosuvastatin (RSV) is a poorly water-soluble drug that has an absolute oral bioavailability of only 20%. The aim of this work was to prepare a positively charged chitosan coated flexible lipid-based vesicles (chitosomes) and compare their characteristics to the corresponding negatively charged flexible liposomal nanoparticles (NPs) in order to develop new RSV nanocarrier systems.MethodsThree formulation factors affecting the development of chitosomes nano-formulation were optimized for their effects on the particles size, entrapment efficiency (EE) and zeta potential. The optimized flexible chitosomes and their corresponding liposomal NPs were characterized for morphology, in vitro release, flexibility and intestinal cell viability. The half maximum inhibitory concentrations (IC50) for both formulations were calculated.ResultsThe drug to lipid molar ratio, edge activator percent and the chitosan concentration were significantly affecting the characteristics of NPs. The optimized chitosomes nano-formulation exhibited larger size, higher EE and greater zeta potential value when compared to the corresponding liposomal NPs. Both formulations showed a spherical shape nanostructure with a marked outer shell for the chitosomes nano-formulation. Chitosomes illustrated an extended drug release profile when compared with the corresponding liposomal NPs and the prepared drug suspension. Flexibility of both vesicles was confirmed with superiority of liposomal NPs over chitosomes. RSV loaded chitosomes nano-formulation exhibited lower IC50 values and higher therapeutic window while liposomal NPs were compatible with the intestinal cells.ConclusionsRSV loaded chitosomes nano-formulation could be considered as a promising nanocarrier system with a marked cytotoxic activity while, RSV loaded liposomal NPs are suitable nanocarrier to improve RSV activity in treatment of cardiovascular disorders.

The Effect of Solvent Vapor Annealing on Drug-Loaded Electrospun Polymer Fibers.

Electrospinning has emerged as a powerful strategy to develop controlled release drug delivery systems but the effects of post-fabrication solvent vapor annealing on drug-loaded electrospun fibers have not been explored to date. In this work, electrospun poly(ε-caprolactone) (PCL) fibers loaded with the hydrophobic small-molecule spironolactone (SPL) were explored. Immediately after fabrication, the fibers are smooth and cylindrical. However, during storage the PCL crystallinity in the fibers is observed to increase, demonstrating a lack of stability. When freshly-prepared fibers are annealed with acetone vapor, the amorphous PCL chains recrystallize, resulting in the fiber surfaces becoming wrinkled and yielding shish-kebab like structures. This effect does not arise after the fibers have been aged. SPL is found to be amorphously dispersed in the PCL matrix both immediately after electrospinning and after annealing. In vitro dissolution studies revealed that while the fresh fibers show a rapid burst of SPL release, after annealing more extended release profiles are observed. Both the rate and extent of release can be varied through changing the annealing time. Further, the annealed formulations are shown to be stable upon storage.

Improvement of Ocular Efficacy of Levofloxacin by Bioadhesive Chitosan Coated PLGA Nanoparticles: Box-behnken Design, In-vitro Characterization, Antibacterial Evaluation and Scintigraphy Study.

Conjunctivitis is considered as a common infection of ocular surfaces. Eye drop is most commonly used for treatment of conjunctivitis, but has some drawback like 95% drug eliminated after administration. Administration of levofloxacin to the anterior site in form of chitosan coated poly (lactic-co-glycolic acid) nanoparticles (LFV-CS-PLGA-NPs) expected to overcome these problem and increasing corneal contact time and permeability for effective treatment of bacterial conjunctivitis. The Nanoparticles were developed by single emulsion solvent evaporation technique and optimized for different variables (chitosan, poly (lactide-co-glycolic acid) and polyvinyl alcohol concentration) by employing three factors, three levels Box–Behnken statistical design. The nanoparticles were evaluated for particle size, drug loading, entrapment efficiency, drug release, ex-vivo permeation, ocular tolerance, antimicrobial study, confocal laser microscopy, and Gamma scintigraphy study. The particle size and PdI of the optimized nanoparticles were 169.968 ± 15.23 nm and 0.13 ± 0.03, respectively, where as entrapment efficiency and drug loading is 49.54 ± 2.43% and 11.29 ± 2.13% with extended release profile and strong mucoadhesion. DSC data indicated levofloxacin formed molecular dispersion within coated nanoparticles. Corneal flux showed significantly (P < 0.05) higher permeation as compared to marketed formulation. Formulation was nonirritant and possessed good antibacterial activity. Gamma Scintigraphy showed slow drainage compared to drug solution, indicating reduction in nasolachrymal drainage. The Gamma Scintigraphy study indicated the CS coated PLGA-NPs have high corneal residence time as compared to drug solution. So, it is revealed that LFV-CS-PLGA-NPs increase the drug concentration over ocular tissue and potential usefulness for sustained drug delivery.

Solid lipid nanoparticles self-assembled from spray dried microparticles.

We report the self-assembly of drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (IMC) and hydrophilic (5-FU) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spray-dried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations.

Development and evaluation of performance characteristics of timolol-loaded composite ocular films as potential delivery platforms for treatment of glaucoma

Thin and erodible polymeric films were developed as potential ocular drug delivery systems to increase drug retention on the eye with the aim of improving bioavailability and achieving controlled drug release. Two biocompatible film forming polymers, hyaluronic acid (HA) and hydroxypropyl methylcellulose (HPMC), which are currently used as thickening agents in eye drops were employed. Two different films were prepared (i) as single polymer and (ii) as composite formulations by solvent casting method, incorporating glycerol (GLY) as plasticizer and timolol maleate (TM) as model glaucoma drug. After preliminary optimization of transparency and ease of handling, the formulations were further characterized for their physicochemical properties. No indication of significant drug-polymer or polymer-polymer (in composite films) interaction was observed from FTIR results while evaluation by IR mapping revealed uniform distribution of drug throughout the films. Amorphization of TM in the film matrix was confirmed by both DSC and XRD. Swelling studies illustrated remarkable swelling capacity of HA in comparison with HPMC which directly affected the drug release profiles, making HA a suitable polymer for controlled ocular drug delivery. Tensile and mucoadhesion properties confirmed higher elasticity and adhesiveness of HA while HPMC produced stronger films. The effect of sterilization by UV radiation on mechanical properties was also evaluated and showed no significant difference between the sterilized and non-sterilized films. The SEM results confirmed smoothness and homogeneity of film surfaces for all the formulations studied. The in vitro drug dissolution studies showed more extended release profiles of formulations containing HA. Cytotoxicity study (cell viability) using MTT assay on HeLa cells, confirmed that the single polymer and composite films are generally safe for ocular administration. The present work shows excellent film forming ability of HA and HPMC which can be used as single polymer or combined in composite formulations as potential topical ocular drug delivery platform to enhance drug retention on the ocular surface and therefore potential improved bioavailability.

Natamycin solid lipid nanoparticles - sustained ocular delivery system of higher corneal penetration against deep fungal keratitis: preparation and optimization.

BackgroundFungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis.PurposeThe objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration.MethodsNAT-SLNs were prepared using the emulsification-ultrasonication technique. Box– Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X1], surfactant concentration [X2], and sonication frequency [X3]) on particle size (R1), zeta potential (ZP; R2), and drug entrapment efficiency (EE%) (R3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated.ResultsThe optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (Papp) and steady-state flux (Jss) reached 11.59×10−2 cm h−1 and 3.94 mol h−1, respectively, in comparison with 7.28×10−2 cm h−1 and 2.48 mol h−1 for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate, that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues.ConclusionThus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.

Amination degree of gelatin is critical for establishing structure-property-function relationships of biodegradable thermogels as intracameral drug delivery systems

Glaucoma is a lifelong disorder that necessitates continuous medical therapy to manage its symptoms and preserve the vision of patients; accordingly, it is highly beneficial to develop a long-acting injectable depot system that can exhibit better drug delivery capability. This study aims to investigate the effect of the amination degree of gelatin on the carbodiimide-mediated grafting of thermo-responsive poly(N-isopropylacrylamide) segments onto biodegradable protein backbone molecules. Moreover, the potential applications of these carrier materials for intracameral pilocarpine administration in glaucomatous subjects will be considered. The gelatins with different amination degrees that are prepared by controlling the feed amount of adipic acid dihydrazide are further used for the synthesis of graft copolymers. The results of chemical characterization and electron microscopy studies showed that both grafting reaction effectiveness and gelling carrier ultrastructure vary in response to biomaterial amination. Compared to unmodified biopolymer thermogel without gel formation, graft copolymers that are composed of aminated gelatin networks showed a more remarkable temperature-triggered pilocarpine capture under physiological conditions. This could create more stable depot-forming carrier systems with improved in vivo pharmacological efficacy. Although the increase in amination degree enhances the biodegradation resistance of graft copolymers for achieving extended drug release profiles and provides significant therapeutic benefits, carriers with excess positive charges may potentiate the cytotoxic actions of oxidative stress signals and may cause damage in cellular barrier integrity. Consequently, unfavorable ocular tissue responses and poor treatment outcomes are observed in glaucomatous rabbits. For the first time, our findings suggest that the amination degree of gelatin performs a crucial function in guiding the development of structure-property-function relationships of biodegradable thermogels as intracameral drug delivery systems.

Formulation Development and Evaluation of Sodium Valproate and Valproic acid Extended Release Tablets

The objective of the present study was to formulate and develop extended release drug delivery system of antiepileptic drug Sodium valproate (VAS) and Valproic acid (VA) in the ratio of 70: 30 with extended release profile. Preliminary studies with different polymers such as HPMC K15M, PVP K90, Ethyl cellulose N50, Carbopol were performed. The results of in-vitro release data showed that HPMC K15M can sustain the drug release upto 24hr. From these studies HPMC K15M has been selected for further studies. HPMCK15M was used along with HEC 250HX to retard the drug release. VAS and VA extended release tablets were prepared by wet granulation method. The hardness of these extended release tablets was within the range between 5.63±0.42 to 6.92±0.33 kg/cm2. The drug content was within the range, 97.23±0.25 to 102.03±2.45%. The in-vitro VAS and VA release from the tablets was found sustained over 24 hours with Higuchi kinetics of drug release and release pattern followed anomalous (Non-Fickian) diffusion. The Fourier transform Infrared spectroscopy analyses indicated that there was absence of chemical interaction between the drug and the excipients. The dissolution profiles of the developed formulation and the commercial tablet formulation, Encorate, were compared using the similarity factor (f2) and difference factor (f1). The released profile of tablet containing 15% HPMC K15M and 15% HEC 250HX by weight was similar to that of Encorate® providing the values of similarity factor (f2) and difference factor (f1) of 88.20 and 3.22 respectively.

Dissolution improvement of an active pharmaceutical ingredient in a polymer melt by hot melt extrusion

Abstract Dissolution of poorly water-soluble active pharmaceutical ingredients (APIs) in polymeric melts plays an important role in the manufacturing of solid dispersions and solid solutions. The understanding of the dissolution is essential for selecting the processing equipment, the operating conditions, and the polymer excipients. The methodology presented in this work for ketoprofen (KTO) and polymer excipients serves as a screening process to select the best API-polymer formulation for hot melt extrusion (HME) to target a specific release profile. KTO dispersion within the polymer was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), and dissolution tests. Thermal characterization shows that a single phase amorphous solid solution (one glass transition temperature [Tg]) was achieved under the HME processing conditions and screw configuration; and with the combination of polymer excipients, an extended release profile of KTO was accomplished, releasing 100% of KTO in 24 h.

ENCAPSULATED 3,4,3-LI(1,2-HOPO) IN CHITOSAN NANOPARTICLES FOR DECORPORATION VIA INHALATION.

3,4,3-LI(1,2-HOPO) has been identified as an excellent alternative for DTPA for decorporating actinides, such as Pu and Am, after internal contamination. Efforts have been focused on its application through oral administration. When 3,4,3-LI(1,2-HOPO) was encapsulated with biocompatible, biodegradable nanoparticles made of chitosan, its release from the nanoparticles to lung fluid, observed in in vitro experiments, exhibited an extended release profile. These observations were very encouraging, as this nanomedicine could lead to a reduction in the dosing frequency required to achieve the decorporation efficacy of unformulated 3,4,3-LI(1,2-HOPO) itself. In vivo release tests as well as actinide decorporation experiments, using an inhalation exposure animal model, will follow.

Advanced Drug Delivery Systems for Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs: A Review

Transdermal route of delivery of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) has several advantages over other routes like reduced adverse effects, less systemic absorption, and avoidance of first-pass effect and degradation in the gastrointestinal tract (GIT). Transdermal route is also beneficial for drugs having a narrow therapeutic index. The skin acts as the primary barrier for transdermal delivery of various therapeutic molecules. Various advanced nanocarrier systems offer several advantages like improved dermal penetration along with an extended drug release profile due to their smaller size and high surface area. Various nanocarriers explored for transdermal delivery of NSAIDs are liposomes, niosomes, ethosomes, polymeric nanoparticles (NPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), dendrimers, nanosuspensions/nanoemulsion, and nanofibers. In the present review, our major aim was to explore the therapeutic potential of advanced nanocarrier systems enlisted above for transdermal delivery of NSAIDs. All literature search regarding advanced nanocarrier systems for transdermal delivery of NSAIDs was done using Google Scholar and Pubmed. Advanced nanocarriers have shown various advantages like reduced side effect, low dosing frequency, high skin permeation, and ease of application over conventional transdermal delivery systems of NSAIDs in various preclinical studies. However, clinical exploration of advanced nanocarrier systems for transdermal delivery of NSAIDs is still a challenge.

Abstract 3713: Targeting β-catenin pathway by nanoparticle-mediated delivery of norcantharidin impairs the stemness of triple negative breast cancer cells

Abstract Background Norcantharidin (NCTD) is known as an inhibitor of serine/threonine protein phosphatase types 1 and 2A (PP1/PP2A) and exhibits potent anticancer efficacies. Our preliminary study identified NCTD interfering with the interaction between phospho-β-catenin and PP1/PP2A could downregulate the levels of non-phospho β-catenin in the cytoplasm in Triple Negative Breast Cancer (TNBC) cells. As β-catenin pathway plays an important role in cancer stemness, we hypothesize that NCTD could prevent β-catenin nuclear translocation, impair the stemness and reduce the metastasis of TNBC. However, the inherent features of short half-life and nephrotoxicity hinder NCTD's further in vivo application. The goal of this study was to test the therapeutic effect of targeting β-catenin pathway by nanoparticle-mediated delivery of NCTD against TNBC. Experimental Design NCTD was loaded into an integrin α5 targeting nanoparticle (NP) (RGD-LPH) via complexing with polyethyleneimine. The targeting efficiency of RGD-LPH was tested by the in vivo imaging of RGD-LPH labeled by cyanine 7.5 (cy7.5). The effects of NP-mediated delivery NCTD on TNBC cell malignant behaviors and tumor metastasis were tested in various in vitro and in vivo models. Results We found that RGD-LPH NP-mediated delivery of NCTD significantly reduced the active and total β-catenin levels as evidenced by Western Blot. The self-renewal capacity was remarkably blocked by RGD-LPH, as examined by sphere formation. RGD-LPH also suppressed features of cancer cells related to proliferation, as examined by MTT, clonogenic assay and soft agar colony formation. In particular, compared to free NCTD, RGD-LPH demonstrated extended-release profile and long-last effect in the long-term experiments such as clonogenic assay and soft agar colony formation assay. In vivo, systemic delivery of RGD-LPH(cy7.5) indicated a preferential uptake in primary tumor and lung of the tumor-bearing mice. Efficacy studies indicated reduced metastasis of mice from RGD-LPH treatment. Conclusion: Collectively, our results strongly suggest that NCTD being encapsulated in RGD-LPH, which warrants further development for preclinical and clinical studies as a novel TNBC therapeutic approach, is a robust modulator of Wnt signaling with anti-metastasis activity. Citation Format: Yunfei Li, Zhishan Wang, Yajuan Xiao, Chengfeng Yang. Targeting β-catenin pathway by nanoparticle-mediated delivery of norcantharidin impairs the stemness of triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3713.

Microsuspension of fatty acid esters of entecavir for parenteral sustained delivery

Entecavir (EV), an anti-viral agent for hepatitis B infection, should be administered under fasted state, as intestinal absorption of this hydrophilic compound is markedly decreased under post-prandial conditions. Herein, in order to improve therapeutic adherence, a parenteral sustained delivery system was constructed, by synthesizing water-insoluble ester prodrugs of the nucleotide analogous with fatty acids. EV-3-palmitate (named EV-P), exhibited the lowest solubility in phosphate buffered saline (pH 7.4, 1.1 μg/ml), with extended release profile compared with EV, EV-3-myristate, and EV-3-stearate, was selected as a candidate to formulate drug suspension. The crystalline suspension was fabricated using anti-solvent crystallization technique, with a mean particle size of 7.7 μm. After subcutaneous (SC) injection in beagle dogs (0.43 mg/kg as EV), the plasma concentrations of EV were markedly protracted with lowered maximum plasma concentration (Cmax, 4.7 ng/ml), extended time required to reach Cmax (Tmax, 9.0 days), and lengthened elimination half-life (T1/2, 129.3 h) compared with those after oral administration (0.0154 mg/kg, Cmax, 15.4 ng/ml; Tmax, 0.01 days; T1/2, 4.1 h). The systemic exposure of the lipidic prodrug was below 0.1% compared with that of EV following SC injection, denoting that EV-P was rapidly converted into the parent compound in blood. Therefore, SC delivery of EV-P microsuspension can be an alternative to oral EV therapy, offering prolonged pharmacokinetic profile after single injection.

Tamarind seed gum-hydrolyzed polymethacrylamide-g–gellan beads for extended release of diclofenac sodium using 32 full factorial design

Development of tamarind seed gum (TSG)-hydrolyzed polymethacrylamide-g-gellan (h-Pmaa-g-GG) composite beads for extended release of diclofenac sodium using 32 full factorial design is the main purpose of this study. The ratio of h-Pmaa-g-GG and TSG and concentration of cross-linker CaCl2 were taken as independent factors with three different levels of each. Effects of polymer ratio and CaCl2 on drug entrapment efficiency (DEE), drug release, bead size and swelling were investigated. Responses such as DEE and different drug release parameters were statistically analyzed by 32 full factorial design using Design-Expert software and finally the formulation factors were optimized to obtain USP-reference release profile. Drug release rate was found to decrease with decrease in the ratio of h-Pmaa-g-GG:TSG and increase in the concentration of Ca2+ ions in cross-linking medium. The optimized formulation showed DEE of 93.25% and an extended drug release profile over a period of 10h with f2=80.13. Kinetic modeling unveiled case-I-Fickian diffusion based drug release mechanism.

Intranasal Pharmacokinetics of Morphine ARER, a Novel Abuse-Deterrent Formulation: Results from a Randomized, Double-Blind, Four-Way Crossover Study in Nondependent, Opioid-Experienced Subjects.

Objective To investigate the pharmacokinetics (PK) of Morphine ARER, an extended-release (ER), abuse-deterrent formulation of morphine sulfate after oral and intranasal administration. Methods This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study assessed the PK of morphine and its active metabolite, M6G, from crushed intranasal Morphine ARER and intact oral Morphine ARER compared with crushed intranasal ER morphine following administration to nondependent, recreational opioid users. The correlation between morphine PK and the pharmacodynamic parameter of drug liking, a measure of abuse potential, was also evaluated. Results Mean maximum observed plasma concentration (Cmax) for morphine was lower with crushed intranasal Morphine ARER (26.2 ng/mL) and intact oral Morphine ARER (18.6 ng/mL), compared with crushed intranasal ER morphine (49.5 ng/mL). The time to Cmax (Tmax) was the same for intact oral and crushed intranasal Morphine ARER (1.6 hours) and longer for crushed intranasal morphine ER (1.1 hours). Higher mean maximum morphine Cmax, Tmax, and abuse quotient (Cmax/Tmax) were positively correlated with maximum effect for drug liking (R2 ≥ 0.9795). Conclusion These data suggest that Morphine ARER maintains its ER profile despite physical manipulation and intranasal administration, which may be predictive of a lower intranasal abuse potential compared with ER morphine.

Abuse-deterrent features of an extended-release morphine drug product developed using a novel injection-molding technology for oral drug delivery.

A novel technology platform (Guardian™ Technology, Egalet Corporation, Wayne, PA) was used to manufacture morphine abuse-deterrent (AD), extended-release (ER), injection-molded tablets (morphine-ADER-IMT; ARYMO® ER [morphine sulfate] ER tablets; Egalet Corporation), a recently approved morphine product with AD labeling. The aim of this article is to highlight how the features of Guardian™ Technology are linked to the ER profile and AD characteristics of morphine-ADER-IMT. The ER profile of morphine-ADER-IMT is attributed to the precise release of morphine from the polymer matrix. The approved dosage strengths of morphine-ADER-IMT are bioequivalent to corresponding dosage strengths of morphine ER (MS Contin®; Purdue Pharma LP, Stamford, CT). Morphine-ADER-IMT was very resistant to physical manipulations intended to reduce particle size, with <10 percent of particles being reduced to <500µm, regarded by the US Food and Drug Administration as a relevant cutoff for potential insufflation in their generic solid oral AD opioid guidance. Furthermore, morphine was not readily extracted from the polymer matrix of morphine-ADER-IMT in small- or large-volume solvent extraction studies that evaluated the potential for intravenous and oral abuse. The ER profile and AD characteristics of morphine-ADER-IMT are a result of Guardian™ Technology. The combination of the polyethylene oxide matrix and the use of injection molding differentiate morphine-ADER-IMT from other approved AD opioids that deter abuse using physical and chemical barriers. The high degree of flexibility of the Guardian™ Technology enables the development of products that can be tailored to almost any desired release profile; as such, it is a technology platform that may be useful for the development of a wide range of pharmaceutical products.

Synthesis and melt processing of cellulose esters for preparation of thermoforming materials and extended drug release tablets

Using softwood pulp as the starting material, the synthesis of regioselectively substituted mixed cellulose esters with varying degree of substitution and ratio of short/long chains was successfully completed. The structures of the cellulose esters were characterised. The impact of the structural changes and the degree of substitution of the cellulose esters on thermal properties and processability were investigated. The study shows that the sequential esterification is a promising modification route for cellulose to improve its thermal processability and mechanical properties without the use of external processing aids such as plasticisers. In particular, the hexanoate group in the C6 position on the cellulose backbone acts as an internal plasticiser and improves thermal processability and increases the strength and stiffness of the cellulose ester. The properties of sequentially esterified cellulose promote its practical use in plastics, coatings, films and drug delivery. Sequentially esterified cellulose hexanoate-acetate was used successfully in a coating formulation for the preparation of tablets and showed a stable extended release profile for three water-insoluble drugs in this context. The pH of the release medium had no notable effect on the release properties.

Evaluations of the Effect of Sodium Metabisulphite on the Stability and Dissolution Rates of Various Model Drugs from the Extended Release Polyethylene Oxide Matrices

PurposeThis study examines the effect of sodium metabisulphite (SMB) as an antioxidant on the stability and release of various model drugs, namely, propranolol HCl, theophylline and zonisamide from the polyethylene oxide (PEO) tablets. The antioxidant was used to minimise degradation and instability of the manufactured tablets when stored at 40 °C (55 ± 5% RH) over 8 weeks.MethodMultiple batches of tablets weighing 240 mg (50% w/w) with a ratio of 1:1 drug/polymer and 1% (w/w) sodium metabisulphite containing different model drugs and various molecular weights of PEO 750 and 303 were produced.ResultsThe results indicated that the use of sodium metabisulphite marginally assisted in reducing drug release and degradation via oxidation in propranolol HCl tablets containing both PEO 750 and 303. In the case of poorly and semi-soluble drugs (zonisamide and theophylline), the formulations with both PEO showed entirely superimposable phenomenon and different release profiles compared to control samples (matrices without SMB). DSC study demonstrated the modifications of the polymer due to degradation and observed the effect of SMB on the thermal degradation of the PEO matrices.ConclusionThe use of antioxidant has assisted in retaining the stability of the manufactured tablets with different model drugs especially those with the highly soluble drug that are susceptible to rapid degradation. This has been reflected by an extended release profile of various drugs used at various stages of the storage time up to 8 weeks.

The role of hyaluronan as a drug carrier to enhance the bioavailability of extended release ophthalmic formulations. Hyaluronan-timolol ionic complexes as a model case

The aim of this work was to obtain information concerning the properties of ophthalmic formulations based on hyaluronic-drug ionic complexes, to identify the factors that determine the onset, intensity and duration of the pharmacotherapeutic effect.Dispersions of a complex of 0.5% w/v of sodium hyaluronate (HyNa) loaded with 0.5% w/v of timolol maleate (TM) were obtained and presented a counterionic condensation higher than 75%. For comparison a similar complex obtained with hyaluronic acid (HyH) was also prepared. Although the viscosity of HyNa-TM was significantly higher than that of HyH-TM, in vitro release of TM from both complexes showed a similar extended drug release profile (20–31% over 5h) controlled by diffusion and ionic exchange.Ocular pharmacokinetic study performed in normotensive rabbits showed that HyNa-TM complex exhibited attractive bioavailability properties in the aqueous humor (AUC and Cmax significantly higher and later Tmax) compared to commercial TM eye-drops. Moreover, a more prolonged period of lowered intra-ocular pressure (10h) and a more intense hypotensive activity was observed after instillation of a drop of HyNa-TM as compared to the eye-drops. Such behavior was related to the longer pre-corneal residence times (400%) observed with HyNa-TM complex. No significant changes in rabbit transcorneal permeation were detected upon complexation.These results demonstrate that the ability of HyNa to modulate TM release, together with its mucoadhesiveness related to the viscosity, affected both the pharmacokinetic and pharmacodynamic parameters. The HyNa-TM complex is a potentially useful carrier for ocular drug delivery, which could improve the TM efficacy and reduce the frequency of administration to improve patient compliance.

In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone.

The need for pain medication which will not lead to abuse is well recognized. Ensysce has designed prodrug analogs of the commonly used pain medications including hydromorphone, oxycodone (OC), hydrocodone, and morphine that limit their use to oral delivery, two of which are in clinical development. This study was undertaken to demonstrate that PF614, an extended-release prodrug of OC, allows the release of OC as designed when delivered orally, yet it resists ex vivo extraction with household chemicals and is pharmacologically inactive when administered by nonoral routes (nasal and parenteral), thereby substantially reducing its intravenous (IV) and intranasal abuse potential. In vitro and in vivo methods were used to determine release of OC from PF614 and to show potential µ-opioid receptor activity. Plasma and cerebral spinal fluid levels of OC were evaluated following in vivo IV administration of PF614 in rats. In vitro extraction of OC from PF614 was explored using enzymes, common solvents, and household chemicals at room temperature and elevated temperature over time to determine release of OC from the prodrug. PF614 was stable with in vitro exposure to human plasma, saliva, and liver microsomes or culinary enzyme preparations. PF614 was stable (≥90 percent remaining as intact prodrug) under all room temperature conditions evaluated for 24 hours. At 80°C for 1 hour, no OC was released. Incubation at 80°C for 24 hours in vinegar or vodka produced a conversion to OC of 6 percent. Incubation with trypsin at 37°C converted PF614 approximately stoichiometric to OC with half-life of 4 hours. PF614's penetration of the central nervous system was 83-fold lower than OC and it had a 6.5-fold reduced potency as a µ-opioid agonist. Finally, oral PF614 delivers OC into plasma with an extended-release profile in dogs (reduced Cmax; delayed Tmax). The Bio-Activated Molecular Delivery prodrug design limits the use of PF614 to the intended oral route of delivery with reduced potential for IV or nasal abuse, as it cannot be activated intravenously or nasally to provide an active opioid. Unlike existing opioid formulations, the extended-release profile of PF614 cannot be accelerated by chewing or ex vivo extraction to pharmacologically active substances.