Review of prolonged local anesthetic action

Importance of the field: Pain following surgery is often treated by local anesthetic agents. Duration of the analgesia can be extended safely following administration of encapsulated large doses of local anesthetic agents.

Areas covered in this review: This review considers formulations used for encapsulation of local anesthetic agents for prolonged anesthesia effect. All studies describing encapsulation of a commercial local anesthetic agent for providing prolonged analgesia were considered using the NCBI Medline site. of local anesthetic, prolonged anesthesia, polymers and liposomes were entered in order to retrieve appropriate articles and reviews from 1966 to 2010, with emphasis on the last 10 years. Reference pages were searched manually for other relevant articles. The topics covered include an overview of local anesthetic agents and a review of local anesthetic carrier agents, with emphasis on liposomes and polymer carriers. Articles were limited to the English language.

What the reader will gain: The current research areas for prolongation of local anesthetic effect are evaluated, along with their limitations. Each topic has been summarized, and the review has attempted to cover all current laboratory and clinical studies in a simple manner that should also be useful for readers without a pharmacology background. The direction of research is promising and exciting, and this review should be a useful up-to-date reference.

Take home message: Many formulations including polymer and liposome carriers have facilitated prolonged local anesthetic action for several days, although few clinical studies have been performed. This field promises a safe way to deliver local anesthetics for effect far beyond that of commercially available agents, with potential cost and health benefits for patients suffering chronic or postoperative pain     

Strategies for delivering local anesthetics to the skin: focus on liposomes,solid lipid nanoparticles,hydrogels and patches

Introduction: Dermal and transdermal drug delivery systems offer the possibility to control the release of the drug for an extended period of time. In particular, skin-delivery of local anesthetics (LA) is one of the most important strategies to increase the local drug concentration and to reduce systemic adverse reactions.

Areas covered: During the development phase of new formulations for skin-delivery of LA one should consider a set of desirable features such providing suitable adhesion, easy application/removal and also to be biocompatible, biodegradable and non-toxic. This review emphasizes the main strategies for skin-delivery of LA considering those features in relation to the composition of the delivery systems described. The topics highlight the relationships between physico-chemical studies and pharmaceutical applications for liposomes and solid lipid nanoparticles as well as the formulation and clinical applications for hydrogels and patches.

Expert opinion: The development of LA skin-delivery systems using hydrogels and different permeation enhancers, liposomes or lipid nanoparticles (as isolated carrier systems or as their dispersion in a gel-base) and patches have been explored as alternatives to commercial formulations, modifying the release rate of LA, increasing bioadhesive properties and reducing toxicity, resulting in an improved therapeutic efficacy. This review should provide to the reader a special emphasis on four delivery-systems, comprising the group of liposomes and lipid nanoparticles, hydrogels and patches technologies looking forward their application for skin anesthesia.     

Adverse effects of topical anesthetics for dermatologic procedures

Introduction : Topical anesthetics are frequently used to decrease the pain associated with a variety of procedures including cutaneous surgery, cosmetic treatments and laser surgery. They are also routinely used in children prior to invasive procedures, such as venipuncture. The ideal topical anesthetic should safely increase patient comfort associated with these procedures with minimal potential for adverse effects.

Areas covered : Topical anesthetic formulations have evolved over the past several decades to include formulations with improved efficacy and side effect profiles [1 – 3]. However, significant adverse events are still possible.

Expert opinion : Medical practitioners can mitigate the risk of side effects and toxicity with careful selection of anesthetic type, concentration, body location and dermatologic procedure. Compounded formulations should be used with caution in medical settings only on limited body surface areas without occlusion. This review presents a detailed analysis of products available, reported complications and an outline for appropriate use of topical anesthetics in combination with dermatologic procedures.     

New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine

Introduction: Although generally considered both safe and effective, local anesthetics are often used in conjunction with opioids postoperatively in part because of the limited duration of drug action of local anesthetics. Much interest exists in extending the duration of local anesthetics’ effects, which may reduce the requirement for opioid pain medications that are frequently associated with side effects, including nausea and vomiting, pruritus and respiratory depression.

Areas covered: This article introduces liposomal bupivacaine and SABER®-Bupivacaine, two new formulations of bupivacaine that increase the duration of analgesia postoperatively through two novel slow-release technologies. The pharmacodynamics, pharmacokinetics, efficacy and safety of both preparations of bupivacaine are reviewed. An electronic database search conducted using the Cochrane Central Register of Controlled Trials and MEDLINE/PubMed with the following search terms: ‘bupivacaine,’ ‘liposomal bupivacaine’, ‘liposome bupivacaine’, ‘Exparel’, ‘SABER-Bupivacaine’, ‘SABER Bupivacaine’, and ‘SABER’ yielded 90 articles (no language or date of publication restrictions were imposed).

Expert opinion: Clinical trials involving liposomal bupivacaine and SABER-Bupivacaine indicate that both safely prolong analgesia, while decreasing opioid requirements when compared with placebo. However, additional clinical studies are necessary to better determine the efficacy and cost-effectiveness of these long-acting local anesthetic formulations.     

The discovery of new anesthetics by targeting GABAA receptors

Introduction: Many of the general anesthetics, currently used in clinical practice, work through interactions with GABA_A receptors. The last 2 decades has witnessed substantial progress in defining the molecular mechanisms by which general anesthetics interact with GABA_A receptor sites. However, despite progress in the basic scientific understanding of the mechanism of action of general anesthetics, introduction of novel general anesthetic agents into clinical practice has proven quite challenging.

Areas covered: The focus of this review is on the potential for translating basic science advances into the design of new and improved anesthetics. The authors review general anesthetics in current practice as well as anesthetic drug candidates in development and discuss the potential for novel anesthetic drug development.

Expert opinion: Opportunities for the discovery of new anesthetics include: computational-based ligand-design, structure-based design, re-exploration of old structure–activity data, absorption, distribution, metabolism, excretion and toxicity predictions and high-throughput screening. The authors believe a lack of high-resolution three-dimensional structures of mammalian GABA_A receptors remains a significant limiting factor in structure-based anesthetic drug design.     

Topical drug delivery systems: a patent review

Introduction: Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration.

Areas covered: This review summarizes innovations from the past 3 years (2012–2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically.

Expert opinion: Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.     

Potential of polymeric nanoparticles in AIDS treatment and prevention

Importance of the field: Acquired immunodeficiency syndrome (AIDS) remains one of the greatest challenges in public health. The AIDS virus is now responsible for > 2.5 million new infections worldwide each year. Despite significant advances in understanding the mechanism of viral infection and identifying effective treatment approaches, the search for optimum treatment strategies for AIDS remains a major challenge. Recent advances in the field of drug delivery have provided evidence that engineered nanosystems may contribute to the enhancement of current antiretroviral therapy.

Areas covered in this review: This review describes the potential of polymeric nanoparticle-based drug delivery systems in the future treatment of AIDS. Polymeric nanoparticles have been developed to improve physicochemical drug characteristics (by increasing drug solubility and stability), to achieve sustained drug release profile, to provide targeting to the cellular and anatomic human immunodeficiency virus (HIV) latent reservoirs and to be applied as an adjuvant in anti-HIV vaccine formulations.

What the reader will gain: The insight that will be gained is knowledge about the progress in the development of polymeric nanoparticle-based drug delivery systems for antiretroviral drugs as alternative for AIDS treatment and prevention.

Take home message: The advances in the field of targeted drug delivery can result in more efficient strategies for AIDS treatment and prevention.     

Printing technologies in fabrication of drug delivery systems

Introduction: There has been increased activity in the field recently regarding the development and research on various printing techniques in fabrication of dosage forms and drug delivery systems. These technologies may offer benefits and flexibility in manufacturing, potentially paving the way for personalized dosing and tailor-made dosage forms.

Areas covered: In this review, the most recent observations and advancements in fabrication of drug delivery systems by utilizing printing technologies are summarized. A general overview of 2D printing techniques is presented including a review of the most recent literature where printing techniques are used in fabrication of drug delivery systems. The future perspectives and possible impacts on formulation strategies, flexible dosing and personalized medication of using printing techniques for fabrication of drug delivery systems are discussed.

Expert opinion: It is evident that there is an urgent need to meet the challenges of rapidly growing trend of personalization of medicines through development of flexible drug-manufacturing approaches. In this context, various printing technologies, such as inkjet and flexography, can play an important role. Challenges on different levels exist and include: i) technological development of printers and production lines; ii) printable formulations and carrier substrates; iii) quality control and characterization; and iv) regulatory perspectives.     

Future of nanomedicines for treating respiratory diseases

Introduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?

Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.

Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.     

Safety of amide local anesthetics: new trends

Importance of the field: Local anesthetics have become one of the most common drugs used in daily practice worldwide. Neurologic and cardiovascular events are the most frequent adverse reactions related to local anesthetics use. Recently, new trends have been developed on this topic.

Areas covered in this review: We performed an overview of the data available so far on local anesthetics adverse reactions. Relevant literature was identified using PubMed search of articles published up to November 2009, including experimental studies, case reports or clinical studies when available. Search terms included: ‘local anaesthetics’, ‘adverse drug reaction’, ‘pharmacovigilance’ and ‘complication’.

What the reader will gain: Neurologic, cardiovascular and allergic reactions remain the most frequent adverse drug reactions related to local anesthetics in the literature. Studies based on pharmacovigilance systems have highlighted the frequency of adverse reactions little known until now, such as failure of block. Lipid emulsions are included into algorithm for cardiac resuscitation. Recent studies have demonstrated the myotoxicity and chondrotoxic effects of long-acting local anesthetics.

Take home message: Physicians must keep in mind all these adverse reactions to better prevent their occurrence and give the most appropriate treatment.     

Innovations in bioadhesive vaginal drug delivery system

Introduction: Vagina, due to its anatomical position and physiological characteristics is increasingly being explored as a site for drug delivery in recent years. This route coupled with bioadhesion phenomena has born fruitful results in delivering drugs both locally as well as systemically.

Areas covered: Bioadhesive vaginal drug delivery system has been used for the treatment of local diseases affecting the vagina like candidiasis, STD, vaginal dryness, and so on. Also, research has demonstrated that drugs can be successfully delivered to systemic circulation via vaginal mucosa for treatment of various diseases like migraine and osteoporosis. Besides, this vaginal route has also been used for uterine targeting of drugs. This review focuses on these recent innovations that have been patented in the area of bioadhesive vaginal drug delivery systems. The review also highlights certain physicochemical characteristics of bioadhesive polymers that affect drug delivery through this route.

Expert opinion: An in-depth study of this review will give an insight into the potential areas that can be explored while designing a bioadhesive vaginal drug delivery system. Also, the in vitro and in vivo experimental results discussed in the review will help stimulate research in development and optimization of newer formulations.     

Local anesthetic lidocaine delivery system: chitosan and hyaluronic acid-modified layer-by-layer lipid nanoparticles

Context: Transdermal local anesthesia is one of the most applied strategies to avoid systemic adverse effects; there is an appealing need for a prolonged local anesthetic that would provide better bioavailability and longer pain relief with a single administration.

Objective: Layer-by-layer (LBL) technique was used in this study to explore a nanosized drug delivery system for local anesthetic therapy.

Materials and methods: LBL-coated lidocaine-loaded nanostructured lipid nanoparticles (LBL-LA/NLCs) were prepared and characterized in terms of particle size (PS), zeta potential, drug encapsulation efficiency (EE), in vitro skin permeation and in vivo local anesthetic studies.

Results: Evaluation of the in vitro skin permeation and in vivo anesthesia effect illustrated that LBL-LA/NLCs can enhance and prolong the anesthetic effect of LA.

Discussion and conclusion: LBL-LA/NLCs could function as a promising drug delivery strategy for overcoming the barrier function of the skin and could deliver anesthetic through the skin with sustained release behavior for local anesthetic therapy.     

Drug delivery from gelatin-based systems

Introduction: Carriers for controlled drug release offer many advantages compared with conventional dosage forms. Gelatin has been investigated extensively as a drug delivery carrier, due to its properties and history of safe use in a wide range of medical applications.

Areas covered: Gelatin was shown to be versatile due to its intrinsic features that enable the design of different carrier systems, such as microparticles and nanoparticles, fibers and even hydrogels. Gelatin microparticles can serve as vehicles for cell amplification and for delivery of large bioactive molecules, whereas gelatin nanoparticles are better suited for intravenous delivery or for drug delivery to the brain. Gelatin fibers contain a high surface area-to-volume ratio, whereas gelatin hydrogels can trap molecules between the polymer’s crosslink gaps, allowing these molecules to diffuse into the blood stream. Another interesting area is the combination of tissue bioadhesive-based gelatin with controlled drug release for pain management and wound healing.

Expert opinion: The modification of gelatin and its combinations with other biomaterials have demonstrated the flexibility of these systems and can be employed for meeting the challenges of finding ideal carrier systems that enable specific, targeted and controlled release in response to demands in the body.     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Challenges in SN38 drug delivery: current success and future directions

Introduction: Clinical use of SN38 is limited by its poor aqueous solubility and hydrolysis of the lactone ring at pH > 6 to inactive carboxylate form. A variety of drug delivery systems have been developed to improve the solubility and stability of SN38, and reduce its toxicity. A few noteworthy formulations with some success in initial phases of clinical trials are reported.

Areas covered: This work aims to provide a comprehensive review on the various techniques and strategies employed (physical, chemical and biological methods) to improve physicochemical properties and to deliver the drug efficiently to the cancer cells. Physical methods such as nanoparticle encapsulation, cyclodextrin complexation; chemical methods such as prodrugs, polymer-, albumin- and immunoconjugates; and enzyme activated prodrug therapy are discussed.

Expert opinion: The challenges in SN38 drug delivery may be overcome by two ways: ensuring multiple layers of protection against degradation and slow but sustained release of therapeutically effective drug concentrations. It may also be achieved by preparing a polymer–drug conjugate and further encapsulating the conjugate in suitable carrier system; tumor-targeted SN38 delivery by using immunoconjugates, enzyme-activated prodrug therapy and antibody-directed nanoparticle delivery. However, selection of a suitable ligand for tumor targeting and use of safe and biocompatible nanoparticle systems play an important role in realizing this goal.     

Biomaterial-based scaffolds – current status and future directions

Introduction: Biomaterial-based scaffold formulations (three-dimensional Porous matrix, nano-fibre mesh, hydrogels and microspheres) are the major components that are used to deliver the bioactive molecules into the body organs through different routes for an effective treatment of various diseases.

Areas covered: Various fabrication techniques such as freeze-drying, polymerisation, spray drying, gas foaming, supercritical fluid technology, etc., are successfully used for fabrication of scaffold formulations. Due to their unique characteristics, these formulations are widely used against various diseases such as tuberculosis, bone defects, cartilage repair, skin diseases, cardiovascular diseases, periodontal diseases, wound dressing, etc.

Expert opinion: The study of biomaterial-based scaffold formulations is exhilarating with novel approaches to drug/cell/gene delivery being developed all the time. At present, there is a huge extent of research being performed worldwide on all aspects of tissue engineering/drug or gene delivery. In the future, the main focus will be on the development of more patient compliant, sustained and controlled delivery systems against various diseases by modification of polymers, manufacturing technologies as well as carrier systems.     

Nasal route: an alternative approach for antiemetic drug delivery

Introduction: Antiemetic drugs are used in the treatment of nausea and emesis. Development of novel delivery systems for antiemetic drugs, as an alternative to conventional preparations, is important in terms of good patient compliance and improving bioavailability. The nasal route offers unique superiorities, such as fast and high drug absorption, and high patient compliance. Therefore, a considerable amount of research has been carried out on the development of nasal delivery systems for antiemetic drugs.

Areas covered: This review deals with the importance of nasal delivery of antiemetic drugs and the studies performed on this subject. The first part of this review summarizes the properties of the nasal route, its advantages and limitations, parameters affecting drug absorption through nasal mucosa, nasal passage pathways and general approaches to improve nasal transport. The second part reviews the studies conducted on the development of nasal delivery systems.

Expert opinion: Due to its superiorities, the nasal route could be considered as an attractive alternative to oral and parenteral routes. To overcome the barrier properties of the nasal epithelium and to enhance transport of antiemetic drugs, several approaches, including permeation enhancers, in situ gel formulations and micro- and nanoparticulate systems, have been evaluated. The results obtained are promising and indicate that nasal formulations of some antiemetic drugs may enter the market in the near future.     

Development of cytarabine prodrugs and delivery systems for leukemia treatment

Importance of the field: Cytarabine is a polar nucleoside drug used for the treatment of myeloid leukemia and non-Hodgkin's lymphoma. The drug has a short plasma half-life, low stability and limited bioavailability. Overdosing of patients with continuous infusions may lead to side effects. Thus, various prodrug strategies and delivery systems have been explored extensively to enhance the half-life, stability and delivery of cytarabine. Among the recent cytarabine prodrugs, amino acid conjugate ValCytarabine and fatty acid derivative CP-4055 (in Phase III trials) have been investigated for the treatment of leukemia and solid tumors, respectively. Alternatively, delivery systems of cytarabine have emerged for the treatment of different cancers. The liposomal-cytarabine formulation (DepoCyt, Pacira Pharmaceuticals Inc., New Jersey, USA) has been approved for the treatment of lymphomatous meningitis.

Areas covered in this review: Various prodrug strategies evaluated for cytarabine are discussed. Then, the review summarizes the drug delivery systems that have been used for more effective cancer therapy.

What the reader will gain: This review provides in-depth discussion of the prodrug strategy and delivery systems of cytarabine derivatives for the treatment of cancer. The design of cytarabine prodrugs and delivery systems provides insights for designing the next generation of more effective anticancer agents with enhanced delivery and stability.

Take home message: Strategies on designing cytarabine prodrug and delivery formulations showed great promise in developing effective anticancer agents with better therapeutic profile. Similar studies with other anticancer nucleosides can be an alternative approach to gaining access to more effective anticancer agents.     

Cationic nanoparticles for cancer therapy

Importance of the field: The lack of selective delivery of therapeutic molecules to cancer cells remains a problem in cancer therapy. As a result of this non-selectivity, cytotoxic agents are delivered to both healthy and cancerous cells, resulting in severe side effects for the patient, eventually causing termination of therapy or ineffective therapy resulting in progression or recurrence of the disease. In this context, cationic polymers with net positive surface charge emerge as a promising option owing to their very strong cellular interaction properties and good cellular uptake.

Areas covered in this review: In this review, the structure, characteristics and preparation techniques for cationic nanoparticulate drug delivery systems are discussed in the light of cytotoxicity associated with cationic polymers and strong complement activation properties of cationic carrier systems on injection. In vivo behavior and biodistribution of cationic nanoparticles are also reviewed for a better understanding of biological interaction of cationic nanoparticles.

What the reader will gain: This review will give an insight to the properties of cationic polymers, including their advantages and drawbacks and drug/gene delivery systems based on cationic polymers intended for cancer therapy.

Take home message: Cationic polymer-based nanoparticles emerge as a promising group of nanosize carrier systems to the tumor cell level with a wide range of modification and application possibilities.