Search

Over the past several years, immunization and treatment of infectious diseases has undergone a paradigm shift. Stemming from the vaccine research and development, not only a large number of disease-specific vaccines have been developed, but also enormous efforts have been made to improve the effectiveness of vaccines in order to provide optimal immunization. Introduction of nanotechnology and the development of nanocarrier-based vaccines have started to receive a lot of attention in order to provide effective immunization through better targeting and by triggering antibody response at the cellular level. Also, in the past several years, attention is placed on routes of vaccine administration in order to induce both mucosal and systemic immunity against the pathogen. Through judicious selection of the nanocarrier systems and the vaccine antigen, an optimal immunization and protection can be induced. This review article focuses on the patented applications of nanocarrier-based vaccine formulations and delivery. We have examined the United States patent literature to select inventions that specifically address this strategic approach for prevention of infectious diseases.

Epidermal growth factor [EGF] mediated stimulation of its receptor in endothelial cell [EC] is accompanied by phosphorylation of the EGF-receptor [EGFR] and activation of phospholipase C-γ, resulting in the breakdown of phosphatidylinositol(4,5)-bisphosphate and generating inositol (1,4,5)-trisphosphate [IP3] and diacylglycerol. IP3 thus formed can be further converted to inositol (1,3,4,5)-tetrakisphosphate [IP4] by an enzyme called IP3-kinase [IP3K]. In this study we have investigated the effect of modulation of intracellular IP3K activity by the use of an inhibitor, 2-trifluoromethyl [6-(4-nitrobenzyl)-purine] [IP3KI] and siRNA against IP3KB on EGF-induced ERK-phosphorylation and cell motility. EGF stimulated ERK-phosphorylation that has been implicated in EGF-stimulated cell migration was inhibited by both IP3KI and siRNA against IP3KB. Inhibition of ERK-phosphorylation was accompanied by decreased cell migration in the presence of IP3KI.

The purpose of the study was to investigate the nasal route as a non-invasive alternative for delivery of leuprorelin acetate (leuprolide acetate, LEU) and to achieve an effective concentration of leuprorelin acetate in blood after nasal administration for contraception in rats. The plain drug solution, physical mixture (plain drug along with constituents of liposomes), or drug encapsulated in either neutral or charged liposomes containing 5 μg leuprorelin acetate were administered to rats through the nasal route. The plain drug solution was administered subcutaneously (s.c.). Simultaneous evaluation was performed on the influence of a mucoadhesive agent (chitosan) on nasal absorption of the plain drug and the liposome-encapsulated drug. Blood samples were taken at regular time intervals and subjected to luteinising hormone (LH) analysis using a specific immunoassay kit. The plasma luteinising hormone concentration vs time data of nasal and subcutaneous treatments were plotted and compared with that of subcutaneous administration. Relative percentage of bioavailability (F) for nasal treatments was calculated from plasma concentration vs time plots. Sperm count and fertility performance studies were carried out for selected formulations in rats. Neutral liposomes (LLEU) and negatively-charged liposomes (LLEUn) showed higher relative percentage of bioavailability (F 27.83 and 21.30%, respectively) as compared with the plain drug and the physical mixture (F 10.89 and 10.96%, respectively) after nasal administration. Hence, work on neutral liposomes was continued. F was further improved after incorporation of chitosan i.e. 10.89 to 49.13% for plain leuprorelin acetate and 27.83 to 88.90% for liposomal leuprorelin acetate formulations. Liposomal chitosan formulation administered nasally and leuprorelin acetate solution subcutaneously achieved complete azoospermia. No implantation sites were observed after the mating of female rats with treated males. It was observed that in the treated female rats, the estrous cycles ceased with the same formulations from the first treatment cycle. The findings of these investigations demonstrated that the bioavailability of the nasally-administered liposomal leuprorelin acetate with chitosan formulation was comparable with that of the subcutaneously administered drug. Complete contraception was obtained in male and female rats that had been treated with either the nasally administered liposomal leuprorelin acetate with chitosan or the subcutaneously administered drug.

The developed liposomal DPI of LEU (LLEUn-DPI) demonstrated approximately 50% bioavailability compared with SC route. The studies justify the role of the pulmonary route as a promising alternative to the presently available SC route. The components of liposomal vesicles may be suitably changed to achieve higher bioavailability. Pulmonary delivery of LEU is expected to help in improving patient compliance, self-administration and avoiding the complications related to injection procedure. The developed LEU-DPI may be employed for both male and female contraception and treatment of prostate cancer in men and early puberty in children. In women it may be used for ovarian, endometrial, pancreas, and breast cancer; endometriosis; Uterine Leiomyoma; and anemia due to uterine fibroid tumors. However, the role of LEU-DPI in clinical practice can only be justified only after in vivo studies on 2 species of animals followed by extensive clinical trials.

Oral-controlled and modified-release drug delivery systems with zero-order sustained-release kinetics have been developed and proven suitable for meeting increasingly sophisticated therapeutic needs. Nevertheless, the impact of basic chronobiology concepts on the practice of medicine is still ongoing and to address chronotherapy needs, various types of pulsatile drug delivery systems have been innovated. The purpose of this review is to highlight these innovations in the field of chronotherapy.The present review discusses in depth on recent patents and developments related to pulsatile drug delivery systems with eroding, soluble or rupturable barrier coatings, and systems with capsular structures. Besides focusing on all recent innovations, the review addresses the novelty and feasibility of all upcoming technologies being exploited considering pulsatile drug delivery systems.There has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable and well-defined lag phase from the time of administration. From 1981 until the present date, patent publications related to pulsatile drug delivery have shown more promising systems with numerous developments in arena of drug delivery. Future development of chronotherapeutic medications requires proper assessment and integration with other emerging disciplines such as hydrogel and transdermal delivery systems. The selection of the appropriate chronopharmaceutical technology should take into considerations with the ease of manufacturing and the cost-effectiveness.

Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.

Disease management of outdoor patients is mainly affected by patient compliance to the drug therapy, which in turn is governed by patient convenience. Failure to follow through with a treatment decision is one of the biggest causes of unsuccessful medical care. At present, different formulation options are available for various drugs, and hence, the decision is based on the most convenient dosage form for the patient, along with optimum therapeutic benefits.This paper reviews various available formulation approaches, in the hope of improving patient convenience, compliance and the overall outcome of oral drug therapy.While parenterals are valued for their speed and efficiency of delivery, these systems generally score low on patient satisfaction surveys. The oral route is the preferred route for drug delivery, although it renders multiple obstacles to formulate a patient-convenient platform, such as unfavorable taste and swallowing difficulties. Transdermal drug delivery also provides high patient satisfaction, but is effective only for the delivery of smaller, lipophilic molecules. The increasing development of biopharmaceutical therapies renders an increasing number of challenges for formulation scientists to develop a more patient-convenient means of drug delivery.

With the advancement of tablet manufacturing process, the demand of excipients with improved functionalities, mainly in terms of flow and compression properties, has increased. Coprocessed excipients are a mixture of two or more existing excipients at subparticle level, offer substantial benefits of the incorporated excipients and minimize their drawbacks. These multipurpose excipients have dramatically reduced the number of incorporating excipients in the tablet. The present review discusses the potential advantages of coprocessing and coprocessed excipients, material characteristics required for coprocessing, methods of coprocessing and various coprocessed excipients for direct compression available in the market.

In the body under physiological conditions, many vital functions are regulated by transient release of bioactive substances at a specific time and site. Thus, to mimic the function of living systems and in view of emerging chronotherapeutic approaches, pulsatile delivery, which is meant to release a drug following programmed lag phase, has attracted increasing interest in recent years. In pursuit of pulsatile release, various design strategies have been proposed, broadly categorized into single-unit and multiple-unit systems. However, in recent pharmaceutical applications involving pulsatile delivery, multiparticulate dosage forms are gaining much favor over single-unit dosage forms because of their potential benefits like predictable gastric emptying, no risk of dose dumping, flexible release patterns and increased bioavailability with less inter- and intra-subject variability. Based on these premises, the aim of the present review is to survey the main multiparticulate pulsatile delivery systems, for which the swelling and rupturing; dissolution or erosion; and changed permeability of the coating membrane are primarily involved in the control of release. The development of low density floating multiparticulate pulsed-release dosage forms possessing gastric retention capabilities has also been addressed with increasing focus on the upcoming multiparticulate-pulsatile technologies being exploited on an industrial scale.

The objective of this study was to develop and evaluate squalane oil-containing water-in-oil-in-water (W/O/W) multiple emulsion for mucosal administration of ovalbumin (OVA) as a model candidate vaccine in BALB/c mice. Control and optimized OVA-containing W/O/W emulsion (OVA-Emul) and chitosan-modified W/O/W emulsion (OVA-Emul-Chi) formulations were administered intranasally and orally at an OVA dose of 100 mug. The mucosal and systemic immune responses were evaluated after the first and second immunization. The OVA-Emul formulations resulted in higher immunoglobulin-G (IgG) and immunoglobulin-A (IgA) responses as compared with aqueous solution. In addition, significant IgG and IgA responses were observed after the second immunization dose using the emulsions with both routes of administration. Intranasal vaccination was more effective in generating the systemic OVA-specific IgG response than the mucosal OVA-specific IgA response. Oral immunizations, on the other hand, showed a much higher systemic IgG and mucosal IgA responses as compared with the nasally treated groups. The results of this study show that squalane oil-containing W/O/W multiple emulsion formulations can significantly enhance the local and systemic immune responses, especially after oral administration, and may be adopted as a better alternative in mucosal delivery of prophylactic and therapeutic vaccines.

Nanotechnology has shown tremendous promise in target-specific delivery of drugs and genes in the body. Although passive and active targeted-drug delivery has addressed a number of important issues, additional properties that can be included in nanocarrier systems to enhance the bioavailability of drugs at the disease site, and especially upon cellular internalization, are very important. A nanocarrier system incorporated with stimuli-responsive property (e.g., pH, temperature, or redox potential), for instance, would be amenable to address some of the systemic and intracellular delivery barriers. In this review, we discuss the role of stimuli-responsive nanocarrier systems for drug and gene delivery. The advancement in material science has led to design of a variety of materials, which are used for development of nanocarrier systems that can respond to biological stimuli. Temperature, pH, and hypoxia are examples of “triggers” at the diseased site that could be exploited with stimuli-responsive nanocarriers. With greater understanding of the difference between normal and pathological tissues and cells and parallel developments in material design, there is a highly promising role of stimuli-responsive nanocarriers for drug and gene delivery in the future.

The aim of this investigation was to develop novel oil-in-water (o/w) nanoemulsions containing Saquinavir (SQV), an anti-HIV protease inhibitor, for enhanced oral bioavailability and brain disposition. SQV was dissolved in different types of edible oils rich in essential polyunsaturated fatty acids (PUFA) to constitute the internal oil phase of the nanoemulsions. The external phase consisted of surfactants Lipoid-80 and deoxycholic acid dissolved in water. The nanoemulsions with an average oil droplet size of 100-200 nm, containing tritiated [(3)H]-SQV, were administered orally and intravenously to male Balb/c mice. The SQV bioavailability as well as distribution in different organ systems was examined. SQV concentrations in the systemic circulation administered in flax-seed oil nanoemulsions were threefold higher as compared to the control aqueous suspension. The oral bioavailability and distribution to the brain, a potential sanctuary site for HIV, were significantly enhanced with SQV delivered in nanoemulsion formulations. In comparing SQV in flax-seed oil nanoemulsion with aqueous suspension, the maximum concentration (C(max)) and the area-under-the-curve (AUC) values were found to be five- and threefold higher in the brain, respectively, suggesting enhanced rate and extent of SQV absorption following oral administration of nanoemulsions. The results of this study show that oil-in-water nanoemulsions made with PUFA-rich oils may be very promising for HIV/AIDS therapy, in particular, for reducing the viral load in important anatomical reservoir sites.

Many drugs are not being effectively and efficiently delivered using conventional drug delivery approach to brain or central nervous system (CNS) due to its complexity. The brain and the central nervous system both have limited accessibility to blood compartment due to a number of barriers. Many advanced and effective approaches to brain delivery of drugs have emerged in recent years. Intranasal drug delivery is one of the focused delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Realization of nose to brain transport and the therapeutic viability of this route can be traced from the ancient times and has been investigated for rapid and effective transport in the last two decades. Various models have been designed and studied by scientists to establish the qualitative and quantitative transport through nasal mucosa to brain. The development of nasal drug products for brain targeting is still faced with enormous challenges. A better understanding in terms of properties of the drug candidate, nose to brain transport mechanism, and transport to and within the brain is of utmost importance. This review will discuss some pertinent issues to be considered and challenges to brain targeted intranasal drug delivery. A few marketed and investigational drug formulations will also be discussed.

The brain is a delicate organ, and evolution built very efficient ways to protect it. Unfortunately, the same mechanisms that protect it against intrusive chemicals can also frustrate therapeutic interventions. Many existing pharmaceuticals are rendered ineffective in the treatment of cerebral diseases due to our inability to effectively deliver and sustain them within the brain. General methods that can enhance drug delivery to the brain are, therefore, of great interest. Despite aggressive research, patients suffering from fatal and/or debilitating central nervous system (CNS) diseases, such as brain tumors, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of systemic cancer or heart disease. The clinical failure of much potentially effective therapeutics is often not due to a lack of drug potency but rather to shortcomings in the method by which the drug is delivered. Treating CNS diseases is particularly challenging because a variety of formidable obstacles often impede drug delivery to the brain and spinal cord. By localizing drugs at their desired site of action one can reduce toxicity and increase treatment efficiency. In response to the insufficiency in conventional delivery mechanisms, aggressive research efforts have recently focused on the development of new strategies to more effectively deliver drug molecules to the CNS. This review intends to detail the recent advances in the field of brain-targeting, rational drug design approach and drug delivery to CNS. To illustrate the complexity of the problems that have to be overcome for successful brain targeting, a brief intercellular characterization of the blood-brain barrier (BBB) is also included.

Objective To ascertain the nasal bioavailability of Levonorgestrel and change formulation components to provide long-term effective concentrations of the drug in blood. An experimental study was conducted on rats to reduce dose and/or frequency of drug administration to reduce expected side effects reported in humans. Design In vivo study in rats. Setting Centre of Relevance & Excellence in new drug delivery systems, Pharmacy Dept., G.H. Patel Budg., Faculty of Technology and Engineering, M.S. University of Baruda, Fatehgunj, Vadodara, Gujarat, India. Animal(s) Rats of proven fertility. Intervention(s) Formulations containing 10-μg of levonorgestrel were administered in rats via the nasal route. Similarly, a 10-μg drug suspension was administered orally. The influence of the mucoadhesive agents chitosan and carbopol 934p on nasal absorption of the drug was also evaluated. Main outcome measure(s) Plasma drug concentration and pharmacokinetics. Result(s) Relative bioavailabilities of 29.93%, 32.14%, and 25.97% were observed after nasal administration of plain drug, physical mixture, and liposomal formulations, respectively. Mucoadhesive agents in nasal formulations were found to produce a threefold increase in drug bioavailability. Bioavailability was improved from 29.93% to 101.70% and 99.42%, respectively, for chitosan (0.5%) and carbopol 934p (0.5%) formulations, with a significantly improved plasma half life from 7.0 hours to 55.7 hours and 52.9 hours, respectively. Pharmacodynamic studies indicate that the dosing interval can be changed from daily oral administration to nasal administration once every 2 days without changing the dose. Conclusion(s) Levonorgestrel with mucoadhesive agents administered nasally in rats is superior for maintaining effective drug concentrations over an extended period of time when compared with the presently available orally administered form.

A niosome based transdermal drug delivery system of Nimesulide (NIM) was developed and extensively characterized and evaluated for in-vitro performance followed by in-vivo evaluation in rats by carrageenan induced rat paw edema method.Niosomes were prepared by lipid film hydration technique using tweens and spans. Preparation of niosomes was optimized for highest percent drug entrapment (PDE). The prepared niosomes were incorporated into 1 percent carbopol gel base and the system was evaluated for drug diffusion across human cadaver skin (HCS) using modified validated diffusion cell. The drug retention studies in niosomes were performed at refrigerated temperature (2 degrees C - 8 degrees C) and at room temperature (25 degrees C+/-2 degrees C) for the period of 2 months. In-vivo performance of plain drug gel, niosomally-entrapped drug in carbopol gel base and marketed formulation were evaluated using acute rat paw edema method.Highest mean percentage edema inhibition (PEI) was observed for niosomal nimesulide gel after 24 hours i.e. 66.68 percent +/- 5.19 percent compared to plain drug gel i.e. 12.57 percent +/- 1.78 percent and marketed NIM formulation i.e. 20.49 percent +/- 0.91 percent.Findings of this investigation conclusively demonstrate prolongation of drug release and increase in amount of drug retention into the skin and permeation across the skin after niosomal encapsulation of NIM. Developed nimesulide niosomal gel formulation has also demonstrated enhanced anti-inflammatory activity compared to plain drug gel and marketed formulation.

Introduction: Common cold is the most frequently recurring disease in the world and is a leading cause of doctor visits and missed days from school and work. Cold reliever medicated chewing gum (MCG) will be a definitive patient acceptable solution for this condition. Anti-allergic, cetirizine (CTZ) is a BCS class-I (highly soluble and highly permeable) non-sedating antihistaminic drug and this study was based on the hypothesis that CTZ as a BCS class I drug will be easily released from chewing gum into the salivary fluid within few minutes of chewing and can be easily permeated from oral mucosa by the pressure created by the chewing action and absorbed to a larger extent into the systemic circulation. Therefore, ultimately patients will get quick relief from symptoms of common cold with greater compliance compared to other conventional dosage forms. Materials and Methods: This study mainly focuses on taste masking of CTZ by inclusion complexation method, its formulation development in the MCG form and its quality and performance evaluation with the study of potential factors affecting drug release by 32 full factorial experimental design. A “chew out” study is carried out to assess in vivo drug release from MCG, in which residual amount is extracted from the chewed sample. Results: Formulation ingredients, such as elastomers, softeners, bulking agents, play an important role in the feel of the final product and its consistency; while sweeteners and flavors play a very essential character in its sensory properties. Conclusion: Interindividual variation in chewing frequency and chewing intensity is the main factor which affects release of active ingredient from MCG; while salivary dilution and involuntary swallowing are main reasons for variability in the absorption site, i.e., either from buccal mucosa or from gastrointestinal tract.

Sumit Patil1, Swati Pund2, Amita Joshi2, Chamanlal J Shishoo2, Aliasgar Shahiwala11Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, India; 2Department of Pharmaceutics, BV Patel PERD Centre, Ahmedabad, IndiaBackground: The objective of this study was to develop and evaluate a press-coated pulsatile drug delivery system intended for treatment of early morning stiffness and symptomatic relief from pain in patients with rheumatoid arthritis.Methods: The formulation involved press coating of a rupturable coat around a rapidly disintegrating core tablet of aceclofenac. A three-factor, two-level, full factorial design was used to investigate the influence of amount of glyceryl behenate, amount of sodium chloride in the coating composition, and the coating level on the responses, ie, lag time to release and amount of aceclofenac released in 450 minutes.Results: Glyceryl behenate and the coating level had a significant influence on lag time, while sodium chloride helped in the rupture of the coat by acting as a channeling agent. After the coat was ruptured, the core tablet showed a rapid release of aceclofenac due to the presence of Ac-Di-Sol®. Graphical analysis of effects by Lenth's method and Bayesian analysis of coefficients enabled identification of variables active on the selected responses. The optimized formulation comprised 20% w/w glyceryl behenate and 2.2% w/w sodium chloride with a 650 mg coating level, and showed a desired lag time of 358.23 minutes, which mimics the fluctuating symptoms of rheumatoid arthritis, followed by rapid release of aceclofenac.Keywords: chronotherapy, pulsatile delivery, rupturable coat, aceclofenac&nbsp

The purpose of these studies was to achieve desired bioavailability after pulmonary administration of Levonorgestrel (LN) and to provide prolonged effective concentration of the drug in plasma and to reduce reported side effects of orally administered drug. The plain drug suspension, physical mixture (plain drug with liposomal constituents), and drug-encapsulated liposomes containing 10 micro g of drug were instilled intratracheally in rats. Similarly, 10- micro g drug suspension (LO) was administered orally. The blood samples were withdrawn at specific time intervals and were subjected to LN analysis by spectrofluorimetric technique. The plasma drug concentration data of both the treatments were plotted, and pharmacokinetics data were calculated and compared with that of oral administration. Percentage relative bioavailability (F*) of 97.6%, 98.6%, and 109.9% were observed after pulmonary administration of plain drug formulation (LP1), physical mixture (plain drug along with constituents of liposomes [LP2]), and liposomal (LP3) formulations of the drug, respectively. Following oral administration, Cmax of 14.4 +/- 0.6 ng/mL was observed at 2.1 +/- 0.2 hours followed by subtherapeutic concentration beyond 30 +/- 0.2 hours, while after pulmonary administration of LP1, LP2, and LP3 formulations, Cmax of 4.4 +/- 0.4 ng/mL, 4.2 +/- 0.5 ng/mL, and 4.4 +/- 0.6 ng/mL were observed at 6.0 +/- 0.2 hours, 7.0 +/- 0.2 hours, and 6.8 +/- 0.2 hours, respectively, followed by maintenance of effective plasma drug concentration up to 60 +/- 2 hours. These studies demonstrate superiority of pulmonary drug delivery with regards to maintenance of effective therapeutic concentration of the LN in the plasma over a period of 6 to 60 hours. Hence, the pulmonary delivery is expected to reduce frequency of dosing and systemic side effects associated with oral administration of LN.