-
AAPS PharmSciTech Oct 2019The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving... (Review)
Review
The deployment of oral multi-unit pellet formulation has gained significant attention in recent years conferring to numerous applications, especially in achieving modified release and acid resistance property. The fluidized bed coating, specifically Wurster technique is commercially utilized for pellet manufacturing, which is a complex process involving too many variables. Risk assessment tools can be employed to determine the critical variables affecting the pre-defined quality profile and screen out important parameters out of literally hundreds of variables to develop a robust product. The present review aims to describe possibly all the variables involved in Wurster coating process and application of FMEA in pellet manufacturing. A brief case study regarding applicability of FMEA to study the effects of critical factors is outlined. Risk assessment tools assist to reduce number of trials to manageable levels with aid of prior art, literature, and preliminary trials to develop an optimized product.
Topics: Chemistry, Pharmaceutical; Drug Implants; Pharmaceutical Preparations; Technology, Pharmaceutical
PubMed: 31654266
DOI: 10.1208/s12249-019-1516-7 -
Pflugers Archiv : European Journal of... Sep 2021The second messengers, cGMP and Ca, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor... (Review)
Review
The second messengers, cGMP and Ca, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca-dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications.
Topics: Animals; Calcium Signaling; Cell Death; Cyclic GMP; Drug Delivery Systems; Drug Implants; Humans; Nanoparticles; Photoreceptor Cells; Retinal Degeneration
PubMed: 33864120
DOI: 10.1007/s00424-021-02556-9 -
International Journal of Pharmaceutics Mar 2023Ozurdex is a biodegradable implant formulated for sustained-release delivery of the corticosteroid dexamethasone to the posterior segment of the eye. The small,...
Ozurdex is a biodegradable implant formulated for sustained-release delivery of the corticosteroid dexamethasone to the posterior segment of the eye. The small, rod-shaped implant is administered directly to the vitreous using a dedicated applicator, and releases drug for up to 6 months after administration. Sustained release is achieved by embedding dexamethasone in a matrix of 50:50 poly(lactic-co-glycolic acid) (PLGA). In this work, the Ozurdex implant was thoroughly characterized to enable the reverse engineering of a compositionally and structurally equivalent implant. Advanced imaging techniques such as scanning electron microscopy (SEM) and microcomputed tomography (microCT) revealed that the Ozurdex implant exhibits an irregular surface and an internal porosity of 6% due to a large number of discrete voids approximately 3 μm in diameter. Thermal and spectroscopic analyses showed limited interaction between the drug and the polymer, resulting in a two-phase system of dexamethasone crystals embedded within a PLGA matrix. Reverse-engineered implants with properties similar to Ozurdex were prepared using a two-step hot-melt extrusion process. The reverse-engineered implants exhibited a triphasic drug release profile similar to Ozurdex. This work seeks to provide insight into the manufacturing process and characterization of PLGA-based solid implants to support future generic product development.
Topics: X-Ray Microtomography; Drug Implants; Dexamethasone; Glucocorticoids; Intravitreal Injections
PubMed: 36690129
DOI: 10.1016/j.ijpharm.2023.122625 -
Drug Development and Industrial Pharmacy Nov 2021The stages of preparing high drug loaded pellets were investigated using static and dynamic imaging techniques to provide a greater understanding and ease the scale up...
OBJECTIVE
The stages of preparing high drug loaded pellets were investigated using static and dynamic imaging techniques to provide a greater understanding and ease the scale up process.
SIGNIFICANCE
An example of a real case laboratory and production scale quality by design (QbD) based development of pellets is demonstrated. Potential process analytical technology (PAT) approaches by dynamic image analysis (DIA) are presented in various process phases.
METHODS
Pellets were prepared at laboratory and production scale (high shear granulation, extrusion/spheronization, drying, and coating). The influence of process parameters on pellet properties (aspect ratio (AR), yield, pellet size, and their distribution) was investigated using static and DIA. During coating, we focused on the coating thickness and identification of potential agglomeration.
RESULTS AND CONCLUSION
The effects of kneading time, amount of water, extrusion screen plate (ESP) opening diameter and thickness on pellet properties were confirmed in accordance with literature. In terms of screw speed, spheronization speed and time, no considerable influence on pellet properties was observed in the range of studied process parameters, thereby confirming the design space. In addition to the ESP thickness and opening diameter, quality of the ESP impacts the pellet properties. Lastly, coating thickness measurements with dynamic and static image analysis were comparable and an exemplary case of in-line agglomeration detection was presented. Real-time evaluation with PATVIS APA is an effective PAT tool for the evaluation of spheronization (pellet size distribution, AR, and yield) and coating (coating thickness, agglomeration detection).
Topics: Desiccation; Drug Implants; Particle Size; Water
PubMed: 35389314
DOI: 10.1080/03639045.2022.2063880 -
European Journal of Pharmaceutical... Dec 2023FDA's initiative Pharmaceutical CGMPs for the 21st century opened the door for introduction of several risk based approaches in pharmaceutical industry. One significant...
FDA's initiative Pharmaceutical CGMPs for the 21st century opened the door for introduction of several risk based approaches in pharmaceutical industry. One significant advancement that has emerged is the implementation of process analytical technology (PAT), which has opened doors for understanding and controlling complex technological processes. Two such processes, radial extrusion and pellet coating, offer a solid foundation for the application of PAT tools due to their numerous critical process parameters. The aim of the first part of the study was to optimize the neutral pellet production to produce the pellets with properties desired for successful film coating using design of experiments (DoE). In the second part the optimized pellets underwent film coating and the coating quantity was predicted in real or near real-time using in-line and at-line NIR probes and the performance of both probes was compared. The desired properties of the pellets, narrow particle size distribution, high sphericity and high process yield, were successfully achieved. Models for film coating quantity prediction using in-line and at-line NIR probe were successfully calibrated and tested by coating two additional batches. Despite the limited sample size for model calibration, at-line NIR exhibited excellent prediction performance and enabled accurate determination of process end-point. The coating quantity determined by UV/VIS spectroscopy in both test batches deviated by less than 2.0 % from the target value. However, the in-line NIR probe, primarily due to its inferior spectral resolution, displayed a slightly lower quality of the calibrated model and notable overprediction for the tested batches.
Topics: Spectroscopy, Near-Infrared; Technology, Pharmaceutical; Technology; Drug Implants; Drug Industry
PubMed: 37770005
DOI: 10.1016/j.ejps.2023.106595 -
Acta Biomaterialia Jan 2015Fragility fractures can cause significant morbidity and mortality in patients with osteoporosis and inflict a considerable medical and socioeconomic burden. Moreover,... (Review)
Review
Fragility fractures can cause significant morbidity and mortality in patients with osteoporosis and inflict a considerable medical and socioeconomic burden. Moreover, treatment of an osteoporotic fracture is challenging due to the decreased strength of the surrounding bone and suboptimal healing capacity, predisposing both to fixation failure and non-union. Whereas a systemic osteoporosis treatment acts slowly, local release of osteogenic agents in osteoporotic fracture would act rapidly to increase bone strength and quality, as well as to reduce the bone healing period and prevent development of a problematic non-union. The identification of agents with potential to stimulate bone formation and improve implant fixation strength in osteoporotic bone has raised hope for the fast augmentation of osteoporotic fractures. Stimulation of bone formation by local delivery of growth factors is an approach already in clinical use for the treatment of non-unions, and could be utilized for osteoporotic fractures as well. Small molecules have also gained ground as stable and inexpensive compounds to enhance bone formation and tackle osteoporosis. The aim of this paper is to present the state of the art on local drug delivery in osteoporotic fractures. Advantages, disadvantages and underlying molecular mechanisms of different active species for local bone healing in osteoporotic bone are discussed. This review also identifies promising new candidate molecules and innovative approaches for the local drug delivery in osteoporotic bone.
Topics: Bone Morphogenetic Protein 2; Drug Implants; Fibroblast Growth Factor 2; Fracture Healing; Humans; Nanocapsules; Osteoporotic Fractures
PubMed: 25218339
DOI: 10.1016/j.actbio.2014.09.006 -
Molecules (Basel, Switzerland) Dec 2022This work aimed to develop a new one-pot and readily scaled-up formulation capable of retaining 5-fluorouracil and prolonging its release to obtain a site-specific...
This work aimed to develop a new one-pot and readily scaled-up formulation capable of retaining 5-fluorouracil and prolonging its release to obtain a site-specific medication delivery for the potential treatment of colorectal cancer. Six polymer-based formulations were successfully produced using a thermal bulk polymerization method and loaded with 5-fluorouracil, which is a chemotherapeutic agent used in the treatment of colorectal carcinoma. The pellets produced were characterized by measuring the glass transition temperature, tensile strength, Young's modulus, and tensile elongation at break. Studies on in vitro swelling and release were carried out in phosphate-buffered saline to evaluate the behaviour of the developed system. The Young's modulus, glass transition temperature, and tensile strength all increased significantly as the crosslinker concentration increased, but the fracture strain value reduced significantly. The in vitro swelling profile of the produced formulations was significantly reduced by increasing crosslinking density. Less than 27% cumulative drug release was achieved for all formulations after 5 h of starting the release study. The highest cumulative drug release reached after 24 h was 69%. The developed drug delivery system demonstrated the ability to delay the release of 5-fluorouracil in upper gastrointestinal tract-mimicking conditions, while permitting its release in a controlled way afterward, which makes it promising for the potential delivery of 5-fluorouracil to the colon.
Topics: Fluorouracil; Drug Delivery Systems; Drug Implants; Polymers; Colon
PubMed: 36615499
DOI: 10.3390/molecules28010306 -
Clinical Obstetrics and Gynecology Dec 2014Intrauterine contraceptive devices and the progestin implant are the most effective long-acting reversible contraception (LARC) methods available for preventing... (Review)
Review
Intrauterine contraceptive devices and the progestin implant are the most effective long-acting reversible contraception (LARC) methods available for preventing unintended pregnancy. LARC devices are safe, non-user-dependent methods that have the highest rates of continuation and satisfaction of all reversible contraceptives. Use of these contraceptives remains low in the United States due to several barriers including: misperceptions among both providers and patients; cost barriers; and patient access to the devices. Increasing the opportunities for women to access LARC methods in the primary care, postabortion, and postpartum setting can be achieved by addressing the system, provider, and patient barriers that exist.
Topics: Attitude of Health Personnel; Contraceptive Agents, Female; Desogestrel; Drug Implants; Family Planning Services; Female; Health Knowledge, Attitudes, Practice; Humans; Intrauterine Devices, Medicated; Levonorgestrel; Progestins
PubMed: 25314089
DOI: 10.1097/GRF.0000000000000071 -
Acta Biomaterialia Jul 2019Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory cytokine that inhibits IL-1 activity and has been proposed to treat a wide variety... (Review)
Review
Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring anti-inflammatory cytokine that inhibits IL-1 activity and has been proposed to treat a wide variety of systemic and local inflammatory pathologies for multiple decades. However, the short half-life and high concentration required to inhibit IL-1 activity has limited its use in clinical applications. Many strategies have been developed with the goal of improving the therapeutic efficacy of IL-1Ra for a variety of pathologies, including fusing IL-1Ra to protein/peptide/polymer partners, releasing IL-1Ra from injectable polymer or mineral particles, and release of IL-1Ra from injectable coacervates and gels. This literature review examines injectable biomaterials engineered to improve IL-1Ra delivery, both locally and systemically, to increase its efficacy and ease of use in clinic. STATEMENT OF SIGNIFICANCE: Interleukin-1 receptor antagonist (IL-1Ra) is a therapeutic protein with the potential to treat numerous inflammatory conditions and diseases. However, its short biological half-life and high therapeutic concentration may limit its utility in all but a few clinical scenarios. In this review, we present the biomaterial based delivery strategies which have been explored to deliver IL-1Ra to improve its efficacy and applicability to treat inflammation.
Topics: Animals; Biocompatible Materials; Drug Implants; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Recombinant Fusion Proteins
PubMed: 31029831
DOI: 10.1016/j.actbio.2019.04.051 -
Pediatric Clinics of North America Apr 2017Long-acting reversible contraception (LARC) methods are 20% more effective than traditional contraceptives and are recommended by the American Academy of Pediatrics and... (Review)
Review
Long-acting reversible contraception (LARC) methods are 20% more effective than traditional contraceptives and are recommended by the American Academy of Pediatrics and American College of Obstetrics and Gynecology as first-line contraception for adolescent girls. Large studies show that LARC use reduces unintended pregnancies, increases user satisfaction, and prolongs duration of use. This article prepares the primary care provider (PCP) with knowledge on safety, efficacy, eligibility, confidentiality, anticipatory guidance, how to find a LARC provider, and guidance on common side effects so the PCP can confidently counsel adolescent patients on LARC methods.
Topics: Adolescent; Contraception; Contraceptive Agents, Female; Delayed-Action Preparations; Drug Implants; Family Planning Services; Female; Humans; Intrauterine Devices, Medicated; Pregnancy; Pregnancy, Unplanned; United States
PubMed: 28292451
DOI: 10.1016/j.pcl.2016.11.014