Modified Drug Release Research Articles

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Emerging Lipid Based Drug Delivery Systems

In the past decade, research in the area of nanodrug delivery has reached a new height with the advent of lipid based nanodrug delivery systems. Lipids being biocompatible and possessing diverse physicochemical properties have tremendous potential to enhance oral bioavailability of water insoluble drugs. Incorporation of a drug in lipid carriers is a smart approach to overcome problems related with conventional oral therapy. In recent years, two lipid based nanoparticles, namely solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are widely explored. SLN are spherical nanoparticles with a drug-containing solid lipid core stabilized with surfactants and formulated mainly to improve bioavailability of the drug molecules. Despite several advantages of SLNs, their major drawbacks include limited drug loading, drug leakage, and crystallization during storage. These drawbacks were avoided or reduced by the development of a new generation of lipid nanoparticles, the NLC, wherein a solid lipid is blended with liquid lipid. Modulation of drug release was added advantage with NLC formulations. The present review focuses on production techniques, characterization, release characteristics, stability, toxicity and potential applications of SLNs and NLCs.

Comparison of the coating process and in vitro dissolution of 3 mm gastro-resistant minitablets and 5 mm gastro-resistant tablets with pantoprazole.

Minitablets are solid oral forms, which, due to their size (1-3 mm), may be easily swallowed by children. The administration of minitablets in a certain number of units allows for flexible dosing for a broad age group of paediatric patients, which is particularly important for modified-release drugs. In this study, enteric-coated minitablets (3 mm) with pantoprazole were developed and compared to conventional tablets (5 mm). Eudragit L 30D 55® and Acryl Eze II® films, which were 50 and 80 μm thick, respectively, were applied using two different fluid bed systems. The increase in the pantoprazole release rate occurred not only due to the application of a thinner film but also due to the reduction in the size of the core independent of the coating apparatus that was used. In contrast to minitablets, the thin film's thickness was insufficient for 5 mm tablets and a loss of gastro-resistance was observed. The insertion of minitablets into a hard gelatine capsule did not affect drug release from the minitablets under in vitro conditions.

Excipient-excipient interactions in the development of nanocarriers: an innovative statistical approach for formulation decisions

Excipient interaction has become essential knowledge for rational formulation design of nanoparticles. Nanostructured lipid carriers (NLCs) include at least three types of excipient, which enhance excipient interaction possibilities and relevance. The present article introduces an alternative approach for evaluating a great number of excipients with few samples, using NLC as a model delivery system. This approach is based on two sequential experiments using Hall-2 experimental design and analysis of excipient interactions in respect to their physicochemical properties by multilevel statistics. NLCs were prepared using a hot emulsification-ultrasonication method with lidocaine and nine excipients (solid lipids, oils and surfactants). The evaluated parameters were z-average size (DLS), dispersity (DLS), zeta potential (electrophoretic mobility) and entrapment efficiency (HPLC). Cetyl palmitate, beeswax, castor oil, capric/caprylic acid and polysorbate 80 all presented larger effects amongst the studied factors as well as a clear pattern of synergistic interactions. Following the verified trends, we produced an optimized NLC that exhibited all desirable physicochemical characteristics and a modified drug release profile. Our results demonstrate the methodology’s robustness, which can be applied to other nanoparticles and establish a cost-effective excipient evaluation.

Synthesis of Pectin Graft Drug to Treatment the Wounds and Inflammations

This idea of this work included preparation new adhesive drug polymers to treatment the wounds and inflammations, new drug polymers were prepared as bio adhesive, which have high viscosity and treatment the wounds by the adhesion of both ends of the wound when it put as well as the speed of the treatment of external inflammation, because it remains inherent to the position of injury fast time, because of the property for it viscosity. A new bio adhesive polymer was prepared by modification of Pectin structure with acrylic acid (P1) as a spacer by using ceric ammonium nitrate (CAN) as an initiator, and new graft copolymer was substituted with amino drugs such as amoxicilli produced amide polymer. This design carries controlled delivery of therapeutic agents which could release the entrapped drug over an extended period of time due to its biodegradable, nontoxic and slow digesting nature. All prepared adhesive drug polymers were characterized by FTIR, 1H-NMR spectroscopes, thermo gravimetric analysis TGA and DSC were studied. intrinsic viscosities and physical properties of all prepared polymers were measured, biological activity was studied for all adhesive drug polymers this new adhesive drug biological polymers were applied on different infected mice and wounds, It gave outstanding results and compliance mice infected with a full recovery by a short period of time. The prepared drug copolymer was analyzed in different pH values at 37 °C in vitro study and controlled drug release was compared at zero time and after three days. The rate of hydrolysis in basic medium was found higher than acidic medium. It was concluded that modified drug release with extended drug action via slow release and in vivo performance was noted to be promising.

How to Modify Drug Release in Paediatric Dosage Forms? Novel Technologies and Modern Approaches with Regard to Children's Population.

In the pharmaceutical technology, paediatric population still presents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. As for many medicines, there is a lack of paediatric dosage forms adequate for a child’s age; it is a prevailing practice to use off label formulations. Children need balanced and personalized treatment, patient-friendly preparations, as well as therapy that facilitates dosing and thus eliminates frequent drug administration, which can be ensured by modified release (MR) forms. MR formulations are commonly used in adult therapy, while rarely available for children. The aim of this article is to elucidate how to modify drug release in paediatric oral dosage forms, discuss the already accessible technologies and to introduce novel approaches of manufacturing with regard to paediatric population.

Substantiation of manufacture technology development for the tablets of isosorbide dinitrate with modified release

Isosorbide dinitrate belongs to the group of organic nitrates, the oldest representatives of antianginal drugs, and today is the first-choice drug for purchase and prevention of strokes. High prophylactic efficacy of prolonged forms of nitrates should be noted. The modified-release drugs based on isosorbide dinitrate can combine high pharmacological activity, a long period of therapeutic action, and the absence of serious side effects typical of all nitrate group drugs. The need for modern cardiological preparations with a high level of efficacy and safety creates the need for further development of drugs with modified release, especially for oral administration.The purpose of the work is to choose the concept of a modern solid oral dosage form of isosorbide dinitrate and the technological approach for its implementation.Materials and methods. Data analysis of domestic and foreign scientific literature.Results. The analysis of the advantages and disadvantages of oral dosage forms with traditional immediate and modified release. Modified-release preparations are more technologically sophisticated, but provide a high level of safety, efficacy and convenience for the patient.Conclusion. In the course of the study, the concept of a multidose pellet dosage form was selected to develop modified release isosorbide dinitrate tablets. To obtain pellets containing isosorbide dinitrate, the optimal technological solution is the method of extrusion-spheronization.

Modulated transdermal delivery of nonsteroidal anti-inflammatory drug by macroporous poly(vinyl alcohol)-graphene oxide nanocomposite films

In this study, a facile, economically feasible, and scalable approach to fabricate macroporous poly(vinyl alcohol)-GO (PVA-GO) nanocomposite films with varying filler loadings was demonstrated. The nanocomposite films were prepared using a solvent casting process and employed as a diffusion layer for modulating the transdermal delivery of an anti-inflammatory drug (i.e., ketoprofen). The diffusion membrane was assembled in a three-layer structure with PVA/PVA-GO films between ketoprofen-loaded cellulose and cellulose acetate to mimic skin barrier. Through the incorporation of GO sheets into PVA matrix, the mass diffusion and drug release rate of ketoprofen could be modulated to attain a controlled-release system within period in comparison to that of neat PVA film, which showed more rapid release. It was observed that the dispersion level of GO sheets in the polymer matrix played a crucial role to slow the diffusion rate and drug release, where 3 wt% filler loading gave the slowest rate of release. The results from the present study shed light on the mechanism of and may provide guidelines for modulating drug release rates of NSAID in film-based delivery vehicles for transdermal delivery applications.

Vascular Nanomedicine: Current Status, Opportunities, and Challenges.

The term "nanotechnology" was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10-9) scale, and the term "nanomedicine" was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

Pulsatile Discharge from Polymeric Scaffolds: A Novel Method for Modulated Drug Release

Abstract Controlled drug release holds promise to revolutionize medicine, particularly if short-term and long-term release can be combined in a single system. We present here a new pulsatile release system, in which the pulses were achieved using 3D scaffolds of poly(l-lactic acid), PLLA. From a morphological characterization of the scaffold’s surfaces, before and after releasing experiments at distinct pHs, we infer that release is governed by electrostatic interactions and the fractal geometry of the scaffolds. Furthermore, the scaffold can present short-term (within hours) or long-term (several days long) releasing profiles by varying the pH, which opens the way for unprecedented drug release control.

Formulation and antibacterial properties of clay mineral-tetracycline and -doxycycline composites

Clay minerals have been used as adsorbents for decades but research into their use within healthcare as drug-carriers and modified drug release materials is an increasingly common area of interest. In current clinical practice the management of acute bacterial skin and skin-structure infections (ABSSSIs) requires patients to take systemic antibacterial treatment due to a lack of appropriate topical options. In this research tetracycline (TC) and doxycycline (DC) were adsorbed onto a range of clay minerals (kaolinite, montmorillonite, acid-activated montmorillonite, Laponite® RD and Laponite® XL21) to evaluate their potential as materials for the delivery of these antibiotics to infected wounds. A dispersion pH that favoured the zwitterionic form of the antibiotic molecules was shown to favour adsorption onto the clay minerals. FTIR and pXRD showed that positively charged groups on the antibiotic molecules interacted with the negatively charged clay mineral surface, whilst negatively charged groups on the antibiotic molecules could interact with the positively charged edge-sites of the clay minerals. Swelling clays such as the two Laponites® were able to adsorb much more TC and DC due to their structure and chemistry. The clay minerals alone did not have any antibacterial effects against Staphylococcus epidermidis, Cutibacterium acnes, and Pseudomonas aeruginosa. Antibiotic containing composites successfully released TC and DC, exhibiting activity against the three bacterial strains proportional to the antibiotic-loading on the composites. This research demonstrates the ability of these clay minerals to deliver TC and DC against common skin pathogens and their potential for future development towards clinical applications.

Palygorskite sheets prepared via tape casting for wound healing applications

AbstractThe main objective was to increase the applicability of palygorskite by palygorskite sheets using a tape casting method. The stability of the suspension was investigated and the tapes were characterized by TGA/DTA, XRD, and SEM‐FEG. The antimicrobial activity was analyzed in order to test the applicability of a newly modified drug release system that incorporates neomycin in palygorskite. Preliminary results showed that the palygorskite sheet prepared via the tape casting is promising for wound healing applications.

Near-infrared light-responsive, pramipexole-loaded biodegradable PLGA microspheres for therapeutic use in Parkinson's disease

Parkinson’s disease (PD) is associated with symptoms such as tremor and bradykinesia which, together with a rigorous dosing regimen, can place an untenable burden on patients. These issues underscore the need for triggerable, modulated drug delivery systems. Currently, pramipexole (PRX) is the most widely used non-ergot dopamine agonist for the treatment of PD. In this study, near-infrared light-responsive PRX and hollow gold nanospheres (HGNS)-loaded biodegradable poly (D, L-lactide-co-glycolide) (PLGA) microspheres (PRX/HGNS MS) were fabricated using solid-in-oil-in-water (S/O/W) and water-in-oil-in-water (W/O/W) emulsion-solvent evaporation techniques to achieve modulated drug release. The PRX/HGNS MS were uniform, with an average diameter of approximately 24 µm, favorable PRX and HGNS encapsulation efficiencies (51.71 ± 0.54% and 65.15 ± 2.30%, respectively) and rapid, controllable drug release both in vitro and in vivo. Cytotoxicity tests revealed no significant differences between HGNS and PRX/HGNS MS when compared with a negative control. Pharmacodynamics and immunohistochemistry studies revealed a more rapid recovery of striatum in the group treated with PRX/HGNS MS produced using the S/O/W method. The results clearly demonstrate that light-responsive PRX/HGNS MS produced using the S/O/W method have the potential to address PD patients’ mobility problems in a smart, controllable and remotely triggerable manner.

Decision Science for Generic Drug Development and Review.

Decision Science for Generic Drug Development and Review.

Mixed solvent system as binder for the production of silicified microcrystalline cellulose‐based pellets

ABSTRACTSilicified microcrystalline cellulose pellets with hydroxypropyl methylcellullose (HPMC) as modifier were prepared using a mixed solvent as liquid binder. Pellets were produced using extrusion‐spheronization with a mixed solvent consisting of water and isopropanol as liquid binder. The key spheronization aid was Prosolv® SMCC 90. Low viscosity grade HPMC was incorporated aiming to modify release of indometacin. Physical characteristics including breaking load, apparent density and flow properties, particle size distribution and shape were determined. Drug loaded pellets were also tested for dissolution profiles. By adjusting liquid binder property, at isopropanol to water ratio of 3.5 to 6.5, pellets of desirable size and shape with reasonable yields were obtained. Pellets exhibited good flow property and they were mechanically strong. Pellet with higher HPMC content displayed a faster drug dissolution profile. This was because low viscosity grade HPMC was not enough to create strong gel. Instead hydration of HPMC molecules increased matrix's hydrophilicity and weakened the structure of pellet faster. The release of indometacin was partly based on the erosion of hydrated matrix. The presence of HPMC in the pellets would require a mixed solvent to produce desirable shape. Incorporation of HPMC had modified drug release from the pellets without further coating. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 47924.

Hierarchical silica monolithic tablets as novel carriers for drug delivery

This paper proposes the use of carriers with hierarchical porous structures as novel monolithic tablets for modified drug release. The influence of pore structure on the tamsulosin release profile is presented. The hierarchical arrangement of porous structure in monolithic tablets and the deposition of tamsulosin inside the silica carrier enable to control the kinetic of release and the amount of tamsulosin released. We developed a mathematical model of tamsulosin release from two carriers with different hierarchy of meso- and macropores. A model of this nature will allow to predict the release of tamsulosin from other carriers with a similar pore structure. We hope this research will improve the design process of novel carriers, and thus, will allow to tailor the porous structure of a carrier to achieve the desired release profile.

Release Profile of Gentamicin Sulfate from Polylactide-co-Polycaprolactone Electrospun Nanofiber Matrices.

The advent and growth of resistance phenomena to antibiotics has reached critical levels, invalidating the action of a majority of antibiotic drugs currently used in the clinical field. Several innovative techniques, such as the nanotechnology, can be applied for creating innovative drug delivery systems designed to modify drug release itself and/or drug administration route; moreover, they have proved suitable for overcoming the phenomenon of antibiotic resistance. Electrospun nanofibers, due to their useful structural properties, are showing promising results as antibiotic release devices for preventing bacteria biofilm formation after surgical operation and for limiting resistance phenomena. In this work gentamicin sulfate (GS) was loaded into polylactide-co-polycaprolactone (PLA-PCL) electrospun nanofibers; quantification and in vitro drug release profiles in static and dynamic conditions were investigated; GS kinetic release from nanofibers was studied using mathematical models. A preliminary microbiological test was carried out towards Staphylococcus aureus and Escherichia coli bacteria.

The Digital Pharmacies Era: How 3D Printing Technology Using Fused Deposition Modeling Can Become a Reality.

The pharmaceutical industry is set to join the fourth industrial revolution with the 3D printing of medicines. The application of 3D printers in compounding pharmacies will turn them into digital pharmacies, wrapping up the telemedicine care cycle and definitively modifying the pharmacotherapeutic treatment of patients. Fused deposition modeling 3D printing technology melts extruded drug-loaded filaments into any dosage form; and allows the obtainment of flexible dosages with different shapes, multiple active pharmaceutical ingredients and modulated drug release kinetics—in other words, offering customized medicine. This work aimed to present an update on this technology, discussing its challenges. The co-participation of the pharmaceutical industry and compounding pharmacies seems to be the best way to turn this technology into reality. The pharmaceutical industry can produce drug-loaded filaments on a large scale with the necessary quality and safety guarantees; while digital pharmacies can transform the filaments into personalized medicine according to specific prescriptions. For this to occur, adaptations in commercial 3D printers will need to meet health requirements for drug products preparation, and it will be necessary to make advances in regulatory gaps and discussions on patent protection. Thus, despite the conservatism of the sector, 3D drug printing has the potential to become the biggest technological leap ever seen in the pharmaceutical segment, and according to the most optimistic prognostics, it will soon be within reach.

Development of MCM-41 mesoporous silica nanoparticles as a platform for pramipexole delivery

Herein, we present development of new pH-responsive drug delivery systems for D3-dopamine receptor agonist pramipexole, based on its encapsulation in MCM-41 mesoporous silica particles. Pramipexole loaded particles were further coated with chitosan and/or sodium alginate in order to modify drug release. The prepared pramipexole loaded nanoparticles were characterized by using X-ray diffraction (XRD), N2-physisorption, dynamic light scattering (DLS), TEM and attenuated total reflection infrared (ATR-FTIR) spectra. The post-coating of pramipexole loaded MCM-41 with chitosan/sodium alginate polymers changed dramatically physicochemical properties of the particles. The release profile showed that combination of both polymers led to significant reduction by approximately 50% in the initial burst-release effect at both tested pH values (1.2 and 6.8). Uncoated MCM-41 released the total amount of pramipexole within the first 15 min, whereas double-coated particles reached full release after 300 min. Interestingly, we found that pramipexole loaded MCM-41 particles showed a higher potential in preventing H2O2-induced oxidative damage in human neuroblastoma SH-SY5Y cells, compared to the free drug. In conclusion, pramipexole loading in chitosan/sodium alginate coated MCM-41 might represent a promising drug delivery strategy for modified release and neuronal protection against oxidative damage, observed in Parkinson's disease.

Approval of modified-release products by FDA without clinical efficacy/safety studies: A retrospective survey from 2008 to 2017

In principle, approval of a modified-release (MR) drug product is based on evidence from pharmacokinetic (PK) and/or pharmacodynamic studies and clinical efficacy/safety studies. The purpose of this survey is (i) to explore the number of new drug applications (NDAs) of MR drug products, approved by the FDA, employ the PK study as a bridge to already-approved immediate-release drug products without conducting their own clinical efficacy/safety studies; and (ii) to understand the type of PK studies are required for such NDAs. To this end, we surveyed the approved records of MR drug products from 2008 to 2017 from the Drug@FDA website, and filtered pertinent information from FDA's assessment reports. A total of five out of 79 products were found. A single dose PK study was conducted to investigate the underlying drug release mechanisms in four of these products. For these products, the applicants also performed multiple dose PK equivalence studies, but the PK parameters used to support the equivalence were different among studies. Information regarding the exposure-response relationship was available for all selected products, which is fundamental for such cases. Although the difference in PK curve shapes is recognized as being critical for the clinical effectiveness, this evaluation was not performed in all selected cases, as indicated in FDA's assessment reports.

Modulation of drug release by decoration with Pluronic F127 to improve anti-colon cancer activity of electrospun fibrous meshes

Applications of fibrous meshes for localized chemotherapy have been limited by the lack of optimal carriers that are capable of releasing sufficient drug locally. To overcome this obstacle, we introduced Pluronic F127 (PF127) to the camptothecin (CPT)-loaded poly(lactic acid/glycolic acid) (PLGA) electrospun fibrous meshes, abbreviated as PPC, for modulation of drug release. These PPC meshes had smooth surface and high drug loading (5.6–6.8%). Addition of PF127 obviously improved the hydrophilicity of the meshes. Interestingly, the CPT release rate of PPC meshes was significantly higher than that of CPT-loaded PLGA (PLGA-CPT) meshes. Most importantly, incorporation of PF127 in the meshes led to significant reduction in the CT-26 viability compared to PLGA-CPT mesh. The improved anticancer effects of PPC meshes were mainly due to the induction of apoptosis in CT-26 cells. These findings suggest that PPC mesh could be a promising implantable system that may enhance the therapeutic efficacy and prevent tumor recurrence after surgical resection.