Bioabsorbable Polymers for Implantable Therapeutic Systems

Abstract

For a long time, subcutaneous implantable drug pellets using nondegradable polymers have been used for long-term, continuous drug administration. The procedure requires surgical implantation and removal of the drug-containing devices or polymeric matrices, which has a significant negative impact on the acceptability of the product candidate. In addition, the release profile from such devices is neither constant nor readily controlled in terms of precision of rate of release and duration of action. These facts have led to the research and development of novel, controllable, nonirritating, noncarcino genie, biocompatible, and bioabsorbable drug delivery systems for overcoming the drawbacks of nondegradable implantable pellets for prolonged continuous release. Biodegradable implantable systems release the drug over a long period of time with simultaneous or subsequent degradation in the tissue of the polymer to harmless constituents, thus avoiding removal once the therapy is complete. This approach has considerably improved patient acceptability and patient compliance. Various bioabsorbable polymers have been evaluated for controlled implantable drug delivery, including hydrogels, copolymers ofpolylactic and polyglycolic acids, polylactic acid, poly(orthoesters), polyanhydrides, poly(E-capro-lactone), and polyurethanes. Their characteristics have been studied using a variety of drugs, like anticancer agents, hormone agonists and antagonists, nonsteroidal anti-inflammatory agents, neuroleptics, contraceptives, and others. The present paper describes the current research on implantable therapeutic systems, the bioabsorbable polymers, and the biologically active agents being used in this approach.     

Chitosan: A Unique Polysaccharide for Drug Delivery

Abstract

The aim of this review is to give an insight into the many potential applications of chitosan as a pharmaceutical drug carrier. The first part of this review concerns the principal uses of chitosan as an excipient in oral formulations (particularly as a direct tableting agent) and as a vehicle for parenteral drug delivery devices. The use of chitosan to manufacture sustained-release systems deliverable by other routes (nasal, ophthalmic, transdermal, and implantable devices) is discussed in the second part.     

Miniaturized,Battery‐Free Optofluidic Systems with Potential for Wireless Pharmacology and Optogenetics

Combination of optogenetics and pharmacology represents a unique approach to dissect neural circuitry with high specificity and versatility. However, conventional tools available to perform these experiments, such as optical fibers and metal cannula, are limited due to their tethered operation and lack of biomechanical compatibility. To address these issues, a miniaturized, battery‐free, soft optofluidic system that can provide wireless drug delivery and optical stimulation for spatiotemporal control of the targeted neural circuit in freely behaving animals is reported. The device integrates microscale inorganic light‐emitting diodes and microfluidic drug delivery systems with a tiny stretchable multichannel radiofrequency antenna, which not only eliminates the need for bulky batteries but also offers fully wireless, independent control of light and fluid delivery. This design enables a miniature (125 mm³), lightweight (220 mg), soft, and flexible platform, thus facilitating seamless implantation and operation in the body without causing disturbance of naturalistic behavior. The proof‐of‐principle experiments and analytical studies validate the feasibility and reliability of the fully implantable optofluidic systems for use in freely moving animals, demonstrating its potential for wireless in vivo pharmacology and optogenetics.     

Advanced applications for materials implanted within the human body

Abstract

Biomaterials are materials that are used in medical devices that are intended to interact with biological systems. These medical devices include the now common hip replacements and prosthetic heart valves, and the less common neurological prostheses and implantable drug delivery systems. Biomaterials include the traditional stainless steel, titanium, polyethylene, and polymethyl methacrylate and the more biologically sophisticated calcium hydroxyapatite, surface modified polymers, and glass ceramics. In this paper, some of the principles that are involved in the selection and use of these materials in present and future medical devices are discussed.

MST/663     

Simultaneous In Vitro Release of Levodopa and Carbidopa from Biocompatible Core-in-Cup Implants

Most implantable drug delivery systems do not release drug at a zero-order rate of release due to their geometry of a decreasing releasing surface. Microcapsules which can release drug at a zero-order rate are very difficult to produce and are prone to dose dumping. The purpose of this study was to test the in vitro release of levodopa and carbidopa from a new core-in-cup bioerodible implantable tablet. Core-in-cup implantable tablets with cups of Resomer® 207, and cores of Resomer RG 746 and Resomer RG 858 were tested. The core-in-cup implantable tablets were tested as to whether they released levodopa or carbidopa at a zeroorder rate. Their rate and extent of erosion in normal saline were also examined. The results indicate that levodopa and carbidopa were released at a zero-order rate in vitro for up to 100 days depending on the inherent viscosity of the polymer used in the core of the implant. It was also found that the rate and extent of erosion of the cup portion of the core-in-cup implantable tablet did not adversely affect the zero-order release of the drugs.     

PEI-CDs复合物的制备及其在药物传输中的应用研究

癌症是21世纪威胁人类健康的三大杀手之一。目前,治疗癌症的药物由于缺乏靶向性和选择性对正常细胞和组织也会造成严重损害。靶向性载药体系的构建是解决这一难题的关键。碳点(Cardon dots,CDs)是近年来发展起来的一种新型荧光纳米材料,因其具有无毒性、优良的生物兼容性、良好的发光性能等优点,在肿瘤标记及药物的靶向输送中具有重大的应用潜力。本实验以枸杞为碳源,采用水热法制备碳量子点,通过静电作用将聚乙烯亚胺(PEI)修饰在碳量子点表面,形成PEI-CDs复合物,在室温下通过物理吸附的手段使盐酸阿霉素(Dox)组装到PEI-CDs复合物表面,形成PEI-CDs-Dox型荧光载药系统,并对该载药体系进行体外释放模拟实验。实验结果表明,阿霉素的负载显著增强了碳点复合物的荧光性能,24 h释放率可达90%,随着药物的释放,体系的荧光强度逐渐下降,据此可以将其进一步应用于细胞靶向成像及药物靶向监测。     

Development and Evaluation of Transdermal Salbutamol Delivering Systems

Abstract

The transdermal drug delivery systems based on polymeric pseudolatex and matrix diffusion controlled systems for salbutamol were prepared and compared for in vitro skin permeation profile and in vivo performances. Poly (isobutylene) was used as release controlling polymer in both the systems. In vitro skin permeation was studied using the human cadavar skin in franz diffusion cell. Permeation rate constants for matrix diffusion controlled system and pseudolatices were 10.625 and 13.750 mcg/hr/cm² respectively. The prepared transdermal systems were tested on human volunteers having chronic reversible airways obstruction and compared with oral treatments (Asthaline). The in vivo drug plasma profiles following transdermal and oral treatments reveal that although peak plasma level by oral administration was higher in comparison with the transdermal treatments, troughs and peaks were discernible at dosing times. In the case of transdermal treatments, constant drug plasma and FEV₁ levels were recorded indicating controlled and systemic delivery of drug spaced over 30 hours. Among the prepared transdermal drug delivery systems, pseudolatices demonstrated better drug plasma profile, maintained at relatively higher level and flatter in appearance. The relative performance of the systems was noted to reflect in AUC and FEV₁.     

Self‐Powered Multifunctional Transient Bioelectronics

Controllable degradation and excellent biocompatibility during/after a lifetime endow emerging transient electronics with special superiority in implantable biomedical applications. Currently, most of these devices need external power sources, limiting their real‐world utilizations. Optimizing existing bioresorbable electronic devices requires natural‐material‐based construction and, more importantly, diverse or even all‐in‐one multifunctionalization. Herein, silk‐based implantable, biodegradable, and multifunctional systems, self‐powered with transient triboelectric nanogenerators (T²ENGs), for real‐time in vivo monitoring and therapeutic treatments of epileptic seizures, are reported. These T²ENGs are of customizable in vitro/in vivo operating life and biomechanical sensitivity via the adjustments of silk molecular size, surface structuralization, and device configuration. Functions, such as drug delivery and structural‐integrity optical readout (parallel to electronic signals), are enabled for localized anti‐infection and noninvasive degradation indication, respectively. A proof‐of‐principle wireless system is built with mobile‐device readout and “smart” treatment triggered by specific symptoms (i.e., epilepsy), exhibiting the practical potential of these silk T²ENGs as self‐powered, transient, and multifunctional implantable bioelectronic platforms.     

Ocular Preparations: The Formulation Approach

ABSTRACT

The main aim of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: the barriers that decrease the bioavailability of an ophthalmic drug; the objectives to be considered in producing optimal formulations; and the approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addition, the review attempts to give various analytical procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems.

The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aqueous suspensions; (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase solubility of various drugs, vesicular systems, and chemical delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resolution of the above-mentioned technological suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.     

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability

Objective: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients.

Methods: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems.

Results: The optimum formulations were composed of different ratios of Capryol? 90 as an oil phase, Cremophor^® RH40 as a surfactant, and Transcutol^® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19?nm and emulsification time not exceeding 1?min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6–2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies.

Conclusions: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.     

MEDICAL AEROSOLS: TECHNIQUES FOR PARTICLE SIZE EVALUATION

ABSTRACT

Methods for the in-vitro measurement of the particle size distribution of aerosols from medical aerosol delivery systems, including pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs) and nebulizers, are reviewed with emphasis on their applicability both for compendial testing and for simulation of patient use. The importance of real-time measurement techniques, particularly for routine quality control testing, is also discussed, despite the current lack of a means to obtain absolute measurements of drug mass with these systems.     

Controlled release systems based on poly(lactic acid). An in vitro and in vivo study

A new biodegradable delivery system based on poly(lactic acid) has been formulated, with potential applications in sustained antibiotic release against bone infection. The in vitro release of a new quinolone (pefloxacin) from low molecular weight poly(D,L-lactic acid) Mw = 2×10³ lasted for 56 d whereas the in vivo delivery lasted 33 d. In both cases, the release rate is controlled by the drug diffusion and the polymer degradation, which seems to be the predominant factor. For the release experiments, discs were prepared from poly (D,L-lactide) Mw = 2×10⁴ with drug loadings of 2% and 10% w/w. It was concluded that pefloxacin concentration remains higher than the Minimum Inhibitory Concentration (MIC) against the major causative bacteria of bone infection. The results indicate that the two different types of poly(lactic acid) can be used effectively in an implantable antibiotic release system. ©2000 Kluwer Academic Publishers     

Feasibility of obtaining in situ nanocapsules through modified self-microemulsifying drug delivery systems. A new manufacturing approach for oral route administration

Nanocapsules (NCs) are submicron-sized core shell systems which present important advantages such as improvement of drug efficacy and bioavailability, prevention of drug degradation, and provision of controlled-release delivery. The available methods for NC production require expensive recovery and purification steps which compromised the morphology of NCs. Industrial applications of NCs have been avoided due to the aforementioned issues. In this study, we developed a new method based on a modified self-microemulsifying drug delivery system (SMEDDS) for in situ NCs production within the gastrointestinal tract. This new methodology does not require purification and recovery steps and can preserve the morphology and the functionality of NCs. The in situ formed NCs of Eudragit^® RL PO were compared with nanospheres (NEs) in order to obtain evidence of their core-shell structure. NCs presented a spherical morphology with a size of 126.2?±?13.1?nm, an ibuprofen encapsulation efficiency of 31.3% and a zeta-potential of 37.4?mV. Additionally, NC density and release profile (zero order) showed physical evidence of the feasibility of NCs in situ creation.     

A Contribution to Transfer of Matter Through a Polymer Membrane

Abstract

Controlled release of the active ingredient from a drug delivery system may be obtained by means of an enclosure (wall) consisting of a permeable polymer membrane. When creating similar drug delivery systems, prior selection of the film-forming material is unavoidable. From physical viewpoints, the most important film property in such selection is its coefficient of permeation P. This property can within the scope of preformulation studies be followed in the system model membrane - drug (either real or model one).     

Implementation of wireless power transfer and communications for an implantable ocular drug delivery system

A wireless power transfer and communication system based on near-field inductive coupling has been designed and implemented. The feasibility of using such a system to remotely control drug release from an implantable drug delivery system is addressed. The architecture of the wireless system is described and the signal attenuation over distance in both water and phosphate buffered saline is studied. Additionally, the health risk due to exposure to radio frequency (RF) radiation is examined using a biological model. The experimental results demonstrate that the system can trigger the release of drug within 5 s, and that such short exposure to RF radiation does not produce any significant (_1 8C) heating in the biological model. The conclusion of the work is that this system could replace a chemical battery in an implantable system, eliminating the risks associated with battery failure and leakage and also allowing more compact designs for applications such as drug delivery.     

Controlled Transdermal Occlusive Delivery Device of Primaquine

Abstract

Primaquine an antimalarial drug was studied for its permeation behavior across the human cadaver skin. Ethylene vinyl acetate copolymer (E.V.A. cop) was used for the preparation of drug reservoir. To optimize the drug delivery from the drug reservoir E.V.A. cop of different vinyl acetate mole content (40%, 25%, 18%) was used. To achieve an enhanced skin permeation an occlusive face adhesive type delivery system was fabricated. The prepared systems were characterized for in-vitro studies. The system that delivered the drug in accordance with the theortically calculated required delivery rate was selected for in-vivo performance evaluation. The prepared system functions over an predicted definite time period in an uniform and defined fashion. The drug transdermal application has therapeutic potential.     

Electrospun nanofibrous materials for tissue engineering and drug delivery

Abstract

The electrospinning technique, which was invented about 100 years ago, has attracted more attention in recent years due to its possible biomedical applications. Electrospun fibers with high surface area to volume ratio and structures mimicking extracellular matrix (ECM) have shown great potential in tissue engineering and drug delivery. In order to develop electrospun fibers for these applications, different biocompatible materials have been used to fabricate fibers with different structures and morphologies, such as single fibers with different composition and structures (blending and core-shell composite fibers) and fiber assemblies (fiber bundles, membranes and scaffolds). This review summarizes the electrospinning techniques which control the composition and structures of the nanofibrous materials. It also outlines possible applications of these fibrous materials in skin, blood vessels, nervous system and bone tissue engineering, as well as in drug delivery.     

Development and gamma-scintigraphy study of Hibiscus rosasinensis polysaccharide-based microspheres for nasal drug delivery

Objective: This work describes the application of natural plant polysaccharide as pharmaceutical mucoadhesive excipients in delivery systems to reduce the clearance rate through nasal cavity.

Methods: Novel natural polysaccharide (Hibiscus rosasinensis)-based mucoadhesive microspheres were prepared by using emulsion crosslinking method for the delivery of rizatriptan benzoate (RB) through nasal route. Mucoadhesive microspheres were characterized for different parameters and nasal clearance of technetium-99m (^99mTc)-radiolabeled microspheres was determined by using gamma-scintigraphy.

Results: Their Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) studies showed that the drug was stable during preparation of microspheres. Aerodynamic diameter of microspheres was in the range 13.23?±?1.83–33.57?±?3.69?µm. Change in drug and polysaccharide ratio influenced the mucoadhesion, encapsulation efficiency and in-vitro release property. Scintigraphs taken at regular interval indicate that control solution was cleared rapidly from nasal cavity, whereas microspheres showed slower clearance (p?Conclusion: Natural polysaccharide-based microspheres achieved extended residence by minimizing effect of mucociliary clearance with opportunity of sustained delivery for longer duration.     

Microemulsions as transdermal drug delivery systems for nonsteroidal anti-inflammatory drugs (NSAIDs): a literature review

Abstract

Pain is a global crisis and significant efforts have gone into the development of drugs that can be used to treat pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of analgesics that act to selectively relieve pain and inflammation without significantly altering consciousness. Although there have been many advancements with NSAIDs drug development; these drugs still present with severe adverse effects and toxicities, which often limits their use in many patients. Moreover, others are inadequate in relieving specific types of pain such as localized or nerve pain because of poor systemic absorption with conventional delivery systems. The topical route of drug delivery has been used to avoid many of these effects, but not without challenges of its own. The skin acts as an impermeable barrier to most polar drug candidate and absorption across the dermal membranes is often too slow and incomplete to produce meaningful therapeutic benefit. Nevertheless, the use of microemulsions as topical delivery systems for small molecule drug candidates like NSAIDs has been posited as a solution to this problem for years. This review focuses on the recent use of microemulsions as a probable solution to the challenges of transdermal drug delivery of NSAIDs and how microemulsions may be used to enhance the development of more effective but safer analgesic drug products for patients.     

Characterization of silicone pressure-sensitive adhesive episcleral implant for drug delivery

The development of an effective sustained ocular drug delivery system remains a challenging task. The objective of the present study was to characterize a silicone pressure sensitive adhesive (PSA) episcleral implant system for transscleral drug delivery. Silicone PSA implants for dexamethasone, atenolol, and bovine serum albumin (BSA) were prepared at different polymer-to-drug mass ratios. Implant adhesion to human cadaver sclera was measured. Drug release experiments were conducted in well-stirred containers in vitro. The results were then analyzed using a pharmacokinetic model and in vitro–in vivo data comparison from previous studies. The silicone PSA episcleral implants in the present study had an average diameter of 3.5?mm and a thickness of 0.8?mm. Drug release from the silicone PSA implants was influenced by drug solubility, implant polymer content, and implant coating. Drug release from the implants was observed to follow the receding boundary release mechanism and was solubility dependent with the higher water solubility drug showing higher release rate than the low-solubility drug. Increasing polymer content in the implants led to a significant decrease in the drug release rate. Coated implants reduced the initial burst effect and provided lower release rates than the uncoated implants. These implants provided sustained drug release that could last up to several months in vitro and demonstrated the potential to offer drug delivery for chronic ocular diseases via the transscleral route.