Abstracts


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Development of Dry Powder Inhalers
Mahavir B. Chougule, Bijay K. Padhi, Kaustubh A. Jinturkar and Ambikanandan Misra

Development of dry powder inhalers involves powder recrystallization, formulation, dispersion, delivery, and deposition of the therapeutic agent in different regions of the airways in prophylaxis/ treatment/ diagnosis of pulmonary and systemic disorders. Conventional powder production by crystallization and milling has many limitations resulting into development of alternative techniques to overcome the problems. In the last decade many patents have been filed claiming improvement in aerosol performance of dry powder inhalers through the use of (i) incorporation of fines of carrier particles to occupy active sites on the surface and use of hydrophobic carriers to facilitate deaggregation through reduced surface energy and particle interaction (ii) reducing aerodynamic diameters through particle engineering and incorporating drug into porous or low particle density, and/or (iii) preparing less cohesive and adhesive particles through corrugated surfaces, low bulk density, reduced surface energy and particle interaction and hydrophobic additives. Moisture within dry powder inhaler (DPI) products has also been shown to influence aerosol performance via capillary force and electrostatic interaction. Better understanding of particle forces and surface energy has been achieved by the use of sophisticated analytical techniques. Understanding the intricacies of particle shape and surface properties influencing specific lung deposition has been further facilitated by the availability of newer and advanced softwares. A critical review of recent patents claiming different approaches to improve lung deposition of dry powder inhalers will help in deciding the focus of the research in the area of technological gaps.

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Engineered Nanoparticles in Cancer Therapy
Natalie P. Praetorius and Tarun K. Mandal

Intense research has led to a more comprehensive understanding of cancer at the genetic, molecular, and cellular levels providing an avenue for methods of increasing antitumor efficacy of drugs while reducing systemic side effects. Nanoparticulate technology is of particular use in developing a new generation of more effective cancer therapies capable of overcoming the many biological, biophysical, and biomedical barriers that the body stages against a standard intervention. Nanoparticles show much promise in cancer therapy by selectively gaining access to tumor due to their small size and modifiability. Typically, though not exclusively, nanoparticles are defined as submicroscopic particles between 1 and 100 nm. Nanoparticles are formulated out of a variety of substances and engineered to carry an array of substances in a controlled and targeted manner. Nanoparticles are prepared to take advantage of fundamental cancer morphology and modes of development such as rapid proliferation of cells, antigen expression, and leaky tumor vasculature. In cancer treatment and detection nanoparticles serve many targeted functions in chemotherapy, radiotherapy, immunotherapy, immunodetection, thermotherapy, imaging, photodynamic therapy, and anti-angiogenesis. Not only are modifying agents allowing for greater and more accurate tumor targeting, they are also aiding in the crossing of biophysical barriers such as the blood brain barrier there by reducing peripheral effects and increasing the relative amount of drug reaching in the brain. Moreover, multifunctional nanoparticles perform many of these tasks simultaneously such as targeted delivery of a potent anticancer drug at the same time as an imaging material to visualize the effectiveness of the drug utilized for treatment follow-up. In this review, several recent US and World patents developing and modifying nanoparticles for the detection, analysis, and treatment of cancer are discussed.

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Smart Polymer Based Delivery Systems for Peptides and Proteins
Khaled Al-Tahami and Jagdish Singh

Biodegradable polymeric systems represent promising means for delivering many bioactive agents, including peptide and protein drugs. The importance of these systems grew with the advancement in the understanding of peptide and protein pharmacology as well as the ability to mass-produce these compounds. Some polymers undergo sol-gel transition once administered. In situ gel formation happens in response to one or a combination of two or more stimuli. These stimuli include UV-irradiation, pH change, temperature change, and solvent exchange. These smart polymeric systems have several advantages over conventional methods, such as ease of manufacturing, ease of administration, biodegradability, and the ability to alter release profiles of the incorporated agents. In the past few years, an increasing number of in situ gel-forming systems have been investigated and many patents for their use in various biomedical applications, including drug delivery, have been reported. In this article, we introduce the different strategies that have been developed and patented for the use of smart polymers in delivering peptide and protein drugs. The advantage, disadvantages, possibilities, and limitations of each of the smart polymer systems have been discussed.

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Nanocarriers for Systemic and Mucosal Vaccine Delivery
Aliasgar Shahiwala, Tushar K. Vyas and Mansoor M. Amiji

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT 1 receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT1 receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT1 receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT1 receptor enhances the activation of nuclear factor NF-κB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT1 receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT1 receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.

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Modified-Release Solid Formulations for Colonic Delivery
Brahma N. Singh

Solid formulations intended for targeted drug release into the lower gastrointestinal (GI) tract are beneficial for the localized treatment of several diseases and conditions, mainly inflammatory bowel diseases, irritable bowel syndrome and colon cancer. Also, because of their inherent potential to delay or avoid systemic drug absorption from the small intestine, colonic formulations can be utilized for chronotherapy of diseases which are affected by circadian biorhythms (e.g., asthma, hypertension and arthritis), and to achieve clinically relevant bioavailability of drugs that are poorly absorbed from the upper parts of the GI tract because of their polar nature and/or susceptibility to chemical and enzymatic degradation in the small intestine (e.g., proteins and peptides). The purpose of this review is to summarize the recent patent literature concerning various modified-release (MR) formulation technologies that are claimed to provide colonic delivery for a wide array of therapeutic molecules. These technologies either utilize a single or a combination of two or more physiological characteristics of the colon, which includes pH, microflora (enterobacteria), transit time, and luminal pressure. Accordingly, these technologies may be grouped under four distinct classes: pH-controlled (or delayed-release) system, time-controlled (or time-dependent) system, microbially-controlled system, and pressure-controlled system. Among these, formulations that release drugs in response to colonic pH, enterobacteria, or both are most common and promising.

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Chitosan and Its Use in Design of Insulin Delivery System
Tin W. Wong

The global burden of diabetes is estimated to escalate from about 171 million in 2000 to 366 million people in 2030. The routine of diabetes treatment by injection of insulin incurs pain and has been one major factor negating the quality of life of diabetic patients. The possibility of administering insulin via alternative routes such as oral and nasal pathways has been investigated over the years, but with insulin experiencing risks of enzymatic degradation and poor transmucosal absorption. This leads to the rising needs to develop new formulation strategies emphasizing on the assembly of insulin and excipients into a physical structure to maintain the stability and increase the bioavailability of insulin. Chitosan and its derivatives or salts have been widely investigated as functional excipients of delivering insulin via oral, nasal and transdermal routes. The overview of various recent patented strategies on non-injection insulin delivery denotes the significance of chitosan for its mucoadhesive and able to protect the insulin from enzymatic degradation, prolong the retention time of insulin, as well as, open the inter-epithelial tight junction to facilitate systemic insulin transport. The chitosan can be employed to strengthen the physicochemical stability of insulin and multi-particulate matrix. The introduction of chitosan coat or co-formulation of chitosan with cationic gelatin or electrolytes which provide solidified or partially crosslinked structures retain and/or enhance the positive charges of dosage form necessary to induce mucoadhesiveness. The chitosan is modifiable chemically to produce water-soluble low molecular weight polymer which renders insulin able to be processed under mild conditions, and sulphated chitosan which markedly opens the paracellular channels for insulin transport. Combination of chitosan and fatty acid as hydrophobic nanoparticles promotes the insulin absorption via lymphoid tissue. Attainment of optimized formulations with higher levels of pharmacological bioavailability is deemed possible in future through targeted delivery of insulin using chitosan with specific adhesiveness to the intended absorption mucosa.

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Orally Disintegrating Systems: Innovations in Formulation and Technology
Honey Goel, Parshuram Rai, Vikas Rana and Ashok K. Tiwary

Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due to the highest component of compliance they enjoy in patients especially the geriatrics and pediatrics. In addition, patients suffering from dysphagia, motion sickness, repeated emesis and mental disorders prefer these medications because they cannot swallow large quantity of water. Further, drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated in these dosage forms. However, the requirements of formulating these dosage forms with mechanical strength sufficient to with stand the rigors of handling and capable of disintegrating within a few seconds on contact with saliva are inextricable. Therefore, research in developing orally disintegrating systems has been aimed at investigating different excipients as well as techniques to meet these challenges. A variety of dosage forms like tablets, films, wafers, chewing gums, microparticles, nanoparticles etc. have been developed for enhancing the performance attributes in the orally disintegrating systems. Advancements in the technology arena for manufacturing these systems include the use of freeze drying, cotton candy, melt extrusion, sublimation, direct compression besides the classical wet granulation processes. Taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Fluid bed coating, agglomeration, pelletization and infusion methods have proven useful for this purpose. It is important to note that although, freeze dried and effervescent disintegrating systems rapidly disintegrate in contact with fluids, they do not generally exhibit the required mechanical strength. Similarly, the candy process cannot be used for thermolabile drugs. In the light of the paradoxical nature of the attributes desired in orally disintegrating systems (high mechanical strength and rapid disintegration), it becomes essential to study the innovations in this field and understand the intricacies of the different processes used for manufacturing these systems. This article attempts at discussing the patents relating to orally disintegrating systems with respect to the use of different formulation ingredients and technologies.

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Microemulsions: A Novel Approach to Enhanced Drug Delivery
Sushama Talegaonkar, Adnan Azeem, Farhan J. Ahmad, Roop K. Khar, Shadab A. Pathan and Zeenat I. Khan

Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. They can be classified as oil-in-water (o/w), water-in-oil (w/o) or bicontinuous systems depending on their structure and are characterized by ultra low interfacial tension between oil and water phases. These versatile systems are currently of great technological and scientific interest to the researchers because of their potential to incorporate a wide range of drug molecules (hydrophilic and hydrophobic) due to the presence of both lipophilic and hydrophilic domains. These adaptable delivery systems provide protection against oxidation, enzymatic hydrolysis and improve the solubilization of lipophilic drugs and hence enhance their bioavailability. In addition to oral and intravenous delivery, they are amenable for sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes. Microemulsions are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. They have been used to improve the oral bioavailability of various poorly soluble drugs including cyclosporine and paclitaxel as professed by Hauer et al., US patent 7235248, and Gao et al., US patent 7115565, respectively. Furthermore, they can be employed for challenging tasks such as carrying chemotherapeutic agents to neoplastic cells and oral delivery of insulin as diligently described by Maranhao, US patent 5578583 and Burnside et al., US patent 5824638 respectively. The recent commercial success of Sandimmune Neoral^® (Cyclosporine A), Fortovase^® (Saquinavir), Norvir^® (Ritonavir), etc. also reflects the tremendous potential of these newer drug therapeutic systems. A critical evaluation of recent patents claiming different approaches to improve the drug delivery is the focus of the current review.

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Recent Advances and Patents on Solid Lipid Nanoparticles
Krutika K. Sawant and Shamsunder S. Dodiya

Solid Lipid Nanoparticles (SLNs) have attracted increasing scientific and commercial attention as colloidal drug carriers during the last decade. They have emerged as a potential alternative compared to other colloidal systems like polymeric nanoparticles, liposomes and fat emulsions, as they have been claimed to combine their advantages but successfully overcome their drawbacks. SLN formulations are extensively developed and characterized for their in vitro and in vivo applications by various routes like parenteral, oral, pulmonary, ocular, and dermal. SLNs are being widely investigated as carriers for delivery of macromolecules like proteins, oligonucleotides and DNA. SLNs have already been taken up for medium and large scale production using two of its reported production methods. In fact, the first SLN based product has recently been introduced in the Poland market as a topically applied moisturizer. Newer methods for production of SLNs and their applications are being reported and patented. Nanostructured lipid carriers (NLC) are mixture of solid lipid and liquid lipid while Lipid Drug Conjugates (LDC) are water insoluble lipid carrier for loading of poorly lipid soluble drugs. These new generation of lipid nanoparticles have been claimed to overcome the shortcomings of SLNs. This article reviews the formulation, characterization, applications, and patents on the advances and research on SLNs, NLC and LDC.

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CNS Drug Delivery Systems: Novel Approaches
Shadab A. Pathan, Zeenat Iqbal, Syed M.A. Zaidi, Sushma Talegaonkar, Divya Vohra, Gaurav K. Jain, Adnan Azeem, Nitin Jain, Jigar R. Lalani, Roop K. Khar and Farhan J. Ahmad

The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by discussing the recent patents available.