This invention relates to a method for deliveringdrugs sublimable in a vaporizationvehicle. The method involves combining a sufficient amount of a vaporizationvehicle to sublime the drug and the drug to be delivered, heating the vaporizationvehicle to substantially its boiling point and administering the vapor by inhalation to a subject.
Various methods are known to improve water solubility and drug release, among which the liquisolid technology is one of the most promising approaches. With this technology liquids such as solutions or suspensions of poorly solubledrugs in a non-volatile liquid vehicle are converted into acceptably flowing and compressible powders by simple physical blending with selected excipients named the carrier and the coating material. As highest drug release rates are observed with liquisolid compacts containing a drug solution as liquid portion, liquisolid compacts may be optimized by selection of the liquid vehicle and the carrier and coating materials. The addition of disintegrants may further accelerate drug release from liquisolid compacts. The liquisolid technology may also be used for the preparation of sustained release formulations with zero order release pattern. Thus, a constant plasma level will be reached, which is maintained throughout the dosing interval. For sustained release liquisolid compacts, the selection and the concentration of the excipients such as liquid vehicle, retarding agent (matrix forming material) as well as carrier and coating material play an important role. The liquisolid approach is a promising technology because of the simple manufacturing process, low production costs and the possibility of industrial manufacture due to the good flow and compaction properties of liquisolid formulations.
The most challenging task for research scientist is to formulate a successful drug product of a poorly soluble drug. This occurs mainly because of poor bioavailability. Improving oral bioavailability of the drugs which are given as solid dosage forms remains a challenge for the formulation scientists due to solubility problems 1 . Limited drug absorption resulting in poor bioavailability is paramount amongst the potential problems that can be encountered when delivering an active agent via the oral route 2 . Poorly water-solubledrugs often show poor bioavailability because of low and erratic levels of absorption. The rate limiting process for absorption of poorly solubledrugs from the solid dosage form could be a slow dissolution rate. Various factors affecting the drug absorption from gastrointestinal tract are poor aqueous solubility or poor membrane permeability. Therefore, slow dissolution rate can be overcome by adopting various solubility enhancement techniques such as such as use of surfactants, complexation, polymorphism, salt formation, size reduction and emulsification. Among various approaches applied for solubility and bioavailability enhancement of poorly water solubledrugs solid dispersion is one of the most successful method for increasing the drug dissolution rate of the drug.
The delivery of therapeutics in a cell-specific manner is a highly promising application of nanotechnology. Delivery vehicles composed of smart materials having tunable physical and biological properties will improve current therapeutic strategies by encapsulating toxic agents thereby limiting off-target interactions; improving the bioavailability of poorly solubledrugs imparting tissue or cell specificity and improving or enabling intracellular delivery. 27 Nanoemulsions are colloidal dispersions composed of an oil phase, aqueous phase, surfactant and co-surfactant at appropriate ratios. Unlike coarse emulsions micronized with external energy. Nanoemulsions are based on low interfacial tension. This is achieved by adding a co-surfactant, which leads to spontaneous formation of a thermodynamically stable nanoemulsion. The term ‗Nanoemulsions‘ is often used to designate emulsions with the internal phase droplets smaller than 1000 nm. The nanoemulsions are also referred as mini emulsions, ultrafine emulsions and submicron emulsions. Phase behavior studies have shown that the size of the droplets is governed by the surfactant phase structure (bicontinuous microemulsion or lamellar) at the inversion point induced by either temperature or composition. Studies on nanoemulsion formation by the phase inversion temperature method have shown a relationship between minimum droplet size and complete solubilisation of the oil in a microemulsion bicontinuous phase independently of whether the initial phase equilibrium is single or multiphase. Due to their small droplet size, nanoemulsions possess stability against sedimentation or creaming with Ostwald ripening forming the main mechanism of Nanoemulsion breakdown. 28 The major difference between emulsion and nanoemulsion even though emulsion are kinetically stable but thermodynamically unstable, emulsion are cloudy and nanoemulsion is very clear in physical appearance. 1
Nanoemulsions have the potential in pharmaceutical industries because of the transparency at high droplet volume fraction, higher rate of bioavailability or diffusion and increased shelf life of the pharmaceuticals. Nanoemulsions are clear, thermodynamically stable, isotropic liquid mixtures of oil, water, surfactant and co-surfactant. These are oil-in-water (o/w) type of emulsions with the average droplet size ranging from 5nm to 100 nm. Reduction in droplet size to nanoscale leads to change in physical properties such as optical transparency & unusual elastic behavior. Nanoemulsions have widespread applications in different fields such as pharmaceutics, food technology. Nanoemulsion offers a promising vehicle for increasing the aqueous solubility of poorly water-solubledrugs. Nanoemulsions have many advantages; for instance, enhance drug solubility, perfect thermodynamic stability, ease of manufacturing and permeation over conventional formulations that convert them to important drug delivery systems. The design & development of nanoemulsions aimed at controlling or improving required bioavailability levels of therapeutic agents. This review mainly discussed about the importance of nanoemulsions over other dosage forms, preparation methods, characterization of nanoemulsions and applications.
bioavailability. Solid dispersions have been widely reported as an effective method for enhancing the dissolution rate and bioavailability of poorly water solubledrugs.  The dissolution rate is directly proportional to solubility of drug.  The term „solid dispersion‟ refers to the dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the fusion, solvent evaporation and melt solvent methods.  The release mechanism of drug from a variety of solid dispersions depends on the physical properties of carriers as well as drug substances and preparation methods.  Lercanidipine was used as a model drug, which is an anti‐hypertensive agent with topical and systemic
In aqueous nanosuspension can be nebulised utilized an ultrasonic nebulizer or mechanical for lung conveyance. In their little size, all things considered in every aerosol droplet at least one drug particles are contained, prompting an increasing uniform distribution of the drug in the lung. The nanoparticles nature of the drug permits the quick dispersion and the dissolution of the drug at the site of action. E.g. budesonide a poorly water- soluble corticosteroid has been successfully formulated as a nanosuspension for pulmonary conveyance. 36,37
high-frequency focused acoustic energy into heat to ablate tumors. Imaging guidance is usually used to plan and perform HIFU. Clinical trials investigating the effectiveness of HIFU for the treatment of pancreatic cancer  are under way. Because the increased local temperature may elevate tumor permeability, recent research has focused on the role of HIFU in improving drug delivery and triggering the release of drugs from nanocarriers . NPs carrying extrinsic contrast agents such as MRI contrast agents may enable MRI imaging within the tumor that allows for dose quantification to optimize HIFU treatment . In an interesting study, HIFU was shown to cause tissue cavitation and enhance the tumor delivery of doxorubicin intravenously injected into KPC (KrasLSL.G12D/+; p53R172H/+; PdxCretg/+) transgenic mice with spontaneous PDAC that have dense stroma and poor blood permeability . Ultrasound has also been shown to enhance the delivery of NPs and microparticle drug carriers. Tinkov et al.  observed a 12-fold higher concentration of doxorubicin in a subcutaneous PDAC model in rats after intravenous injection of doxorubicin-loaded microbubbles. Rapoport et al.  used HIFU to mediate the delivery of paclitaxel-loaded nanodroplets in a subcutaneous PDAC model in mice. In that study, HIFU was applied under MRI guidance in both continuous wave and pulsed wave modes at a sub-ablative energy level. The continuous wave mode had higher drug delivery to tumor cells than the pulsed wave mode, and this was accompanied by better tumor ablation effects. The ultrasound parameters and timing of the NP injections will need to be optimized to improve the therapeutic effects of HIFU combined with NPs.
The second part of the proposed approach improves the solutions obtained by the genetic algorithm. This part is based on a metaheuristic called variable neighborhood search (VNS), where the principle is the change of neighborhoods during the search. Our algorithm based on VNS to solve the problem is inspired from the work of Geiger (2004), who presents a Multiobjective Variable Neighborhood Search Algorithms for a Single Machine Scheduling Problem with Distinct due Windows (MOVNS). In our algorithm, we use the nomdominated solutions from the set A2 as initial solutions, and we use tree neighborhood structures for generating neighbor solutions by swap operator, interchange operator and insert operator. At the beginning, we randomly choose a solution X from A2, then, at each iteration, a neighbor X1 is generated using the neighborhood structure N1, and we apply 2 opt on X1 to get X2. If X2 is a dominant solution, we will insert it into A2, and we evaluate another neighbor generated by the same neighborhood structure. Otherwise, we move to another neighboor generated by the other neighborhood structure, up to a maximum number of iterations. This process is repeated n times with change of X which is randomly selected from set A2. The procedure of VNS applied to our problem is detailed in the following paragraphs. The description consists of building an initial solution, shaking phase, local search method, and acceptance decision.
 Jinjing Che., Quingfang Meng., Zhinang Chen., Chengpi San., Yunan Hou and Yuanguo Cheng., validation of a sensitive LC/MS/MS method for simultaneous quantitation of Flupenthixol and Melitracen in Human Plasma.,AMMS, Dongda Street, Fengtai District, Beijing, PR China., 2007:20.
Increasing the aqueous solubility of Insoluble and slightly solubledrugs has been done by various methods to avoid the usage of organic solvents. Because of toxicity, volatility, and also high cost of organic solvents, an alternative method has been developed. Mixed solvency concept is one of the methods to enhance the aqueous solubility of less water solubledrugs. Mixed solvency concept may be a proper choice to preclude the use of organic solvents. So there is a broad scope for mixed solvency concept in quantitative estimation of other less water solubledrugs. By application of this concept, innumerable solvent system can be developed. Maheshwari [1-6] is one of the opinions that each substance possesses solubilizing power. He has given several ecofriendly methods in the area of drug estimations and formulations precluding the use of toxic organic solvents. The solubility of large number of poorly solubledrugs has been enhanced by mixed solvency concept. [1-31]
Hupu gum is a naturally occurring polysaccharide derived as an exudate from the tree. Hupu gum is a polymer of galacturonic acid, b-D galactopyranose, rhamnose, a-D arabinose, mannose and fructose with sugar linkage. Modified hupu gum were characterized for swelling index, viscosity and water retention capacity. The modified hupu gum gives tremendous changes in structural bonding, crystallinity, cohesive and adhesive forces of attraction of drug, at different temperature, which help to lower the viscosity and swelling index and this reacts to increases water holding capacity which improves the wettability of drug and helps to dissolve the poorly water soluble drug (24).
Recent scientific advances have provided a map of the human genome along with a better understanding of the processes that transform healthy cells into diseased cells. This has led to the emergence of a new class of drugs called targeted therapies. 2 The goal of targeted therapy for cancer treatment is to selectively treat cancer cells without harming healthy tissue by acting on pathways that are unique to cancer cells. 3 They achieve their specificity by targeting differences in cancer cells on a molecular level. It also referred to as molecular-targeted drugs or molecularly-targeted therapies. 4 Cancer is a genetic disease involving multiple and sequential genetic changes that affect oncogenes, tumor suppressor genes and modifier genes. In addition, there is interplay of various cells in the body which are important in immune surveillance, responsible for removing abnormal cells from the body. The three conventional modalities of treatment of cancer – surgery, radiotherapy and chemotherapy are often unsuccessful in treating cancer, 5-
Successful treatment of most of the diseases is limited by a lack of safe and effective methods of drug delivery. Drug delivery methods have significant effects on the pharmacological efficacy of a drug. Every drug has an optimum con- centration range within which maximum benefit is derived; and concentrations above or below the range can be toxic or provide no therapeutic benefits at all. Therefore, development of an efficient drug delivery system remains an im- portant challenge in medicine, and this can be achieved only through multidisciplinary approaches to the mechanisms of delivery of drugs to targets in tissues. Thus, several drug delivery and drug targeting systems are currently being developed. Targeting is an ability to direct the drug(s) to the desired site. There are two major mechanisms, viz., active and passive for drug targeting. Controlled drug release and subsequent biodegradation are also indispensable for de- veloping successful formulations. Colloidal drug vehicles such as micelles, vesicles, liquid crystal dispersions, and nanomaterials consisting of miniscule nanoparticles of 5 - 200 nm diameter have shown great promise as drug delivery systems. In this context, past decades have witnessed certain major advancements. This review article emphasizes on these advances in the field of drug delivery systems.
Floating Granules is a novel approach for dissolution enhancement of ibuprofen (a weekly acidic, non- steroidal anti-inflammatory drug) by preparing floating formulation. Drug having high permeability through stomach because it remain 99.9 % unionize in stomach (pKa of Ibuprofen - 4.43, pH of gastric fluid - 1.2) and mostly permeable through stomach but due to its solubility limitation it can’t enter in to systemic circulation and gastric empting time is 30 min to 2 hr. After this time ibuprofen goes in to small intestine where it is solubilized but can’t permeate through its membrane. It was logically decided to design such formulations which retain in stomach for more than 2 hrs because drug was not completely soluble within 2 hrs hence to dissolve completely in stomach region, this can be achieved by making floating dosage form. Floating ibuprofen granules were prepared by fusion method. Ibuprofen(200 mg divided in to 50 mg and 150 mg), gelucire 44/14 (350 mg melted) and ibuprofen (50 mg) added, disperse with glass road for uniform distribution of drug in tomolted carrier, remaining 150 mg ibuprofen added in to molted
However, there still remains an unmet need to equip the pharmaceutical industry with particle engineering technologies capable of formulating the poorly solubledrugs to improve their efficacy and to optimize therapy with respect to pharmacoeconomics. One such novel technology is nanosuspension technology. Nanosuspensions are sub-micron colloidal dispersions of nanosized drug particles stabilized by surfactants 14 . Nanosuspensions consist of the poorly water- soluble drug without any matrix material suspended in dispersion 15 . These can be used to enhance the solubility of drugs that are poorly soluble in aqueous as well as lipid media. As a result of increased solubility, the rate of flooding of the active compound increases and the maximum plasma level is reached faster.
Solubility can be also enhanced by alteration in molecular level of physical form of drug 4 . Solid dispersions are the most attractive method for improving of bioavailability of poorly water solubledrugs. Solid dispersions are defined as the dispersion of one or more active substance in matrix at solid state by different method like-fusion or melting solvent method. Solid dispersions are classified in to six category; solid solutions, eutectic mixture, glass suspensions, precipitations, complexes and combinations of above five.
cosolvents. Co-solvents are mixtures of water and one or more water miscible solvents used to create a solution with enhanced solubility for poorly soluble compounds. Co- solvent formulations of poorly solubledrugs can be administered orally and parenterals. The pharmaceutical form is always liquid. Poorly soluble compounds which are lipophilic or highly crystalline that have a high solubility in the solvent mixture may be suited to a co-solvent approach. Commonmly used cosolvents Glycerol, propylene glycol, PEG 400, Dimethyl Sulfoxide, Dimethyl Acetamide, Ethanol, n- Octanol are the commonly used cosolvents.