Approach to Target Retention – disadvantage of the gastric retention initiate the need to target retention for the sustained release of the drug in the intestine where preferential absorption takes palce.Bio adhesive technology – rely on the chemical interaction of the mucous to slow down the transit of the drug. Mucous membrane ranging from few micron to several hundred, coat the epithelial layer of stomach and intestine, and orally administered drug has to pass through this layer to reach the epithelial lining.Specific targeting agent - The polymers developed to facilitate this interaction have been primarily hydrophilic, anionic, high molecular weight polymers that exhibit a variety of non-specific interactions within the mucus layer.
However, the human gastrointestinal tract is a formidable barrier against the intact absorption of macromolecules, making oral delivery, in general, an ineffective method for delivering these therapeutics. Chemical instability, susceptibility to proteolysis, and the inability to cross biological barriers due to their large size restrict the bioavailability of the peptides and proteins. Various methods have been explored to improve the oral bioavailability of proteins. These include strategies described above that couple protected, sustained release with an approach for improving device retention, with the additional requirement of enhancing absorption across the epithelium. One common method has been the use of permeation enhancers, which open the tight intercellular junctions, thereby increasing the transport of proteins such as insulin across the intestinal membrane.
Bottom up: The principle of this method is based on the dissolution of the active drug substance in an organic solvent which is then added into a non solvent (miscible with the organic solvent). In the presence of stabilizers, thereafter, the Nano crystals are precipitated.
What is Nanotechnology?• Nanotechnology is the engineering of functional systems at the molecular scale.• Nanotechnology refers to the projected ability to construct items from the bottom up, Top Down & Spray Drying, using techniques and tools being developed today to make complete, high performance products.• Preparation of drug Nano crystal for oral delivery is of the Important application.
APPLICATION CHEMICLES MEDICAL & TEXTTILES PHARMA CEUTICLE AGRICULTURE AUTOMATIVE APPLICATION OFENVIRONMENT DEFENCE NANO TECHNOLOGY ENERGY PRODUCTION AEROSPACE & DISTRIBUTION INFORMATION MATERIAL TECHNOLOGY TELECOME
SOME SIGNIFICANT ACHIEVEMENTS OF NANODEVICES• Development of one dose a day ciprofloxacin using nanotechnology• Tumor targeted taxol delivery using nanoparticles in Phase 2 clinical trial stage• Improved ophthalmic delivery formulation using smart hydrogel nanoparticles• Oral insulin formulation using nanoparticles carriers.• Liposomal based Amphotericin B formulation
CHALLENGES• Prevention of drug from biological degradation• Effective Targeting• Patient Compliance• Cost effectiveness• Product life extension
IMPROVING DRUG RETENTION• Major challenge involved in the Oral drug delivery is proving the systemic therapeutic level of given drug without reaching the toxic level.• To provide a sustained release profile over time and reducing the number of dose required while maintaining the level of drug above the therapeutic level.• Most of approach use polymer based technology.• Two of the main approaches to achieving retention of the sustained-release system: – Gastric Retention – Targeted Retention
Gastric Retention• The basic idea is the Drug-encapsulating material is retained within the stomach and allows slow elution of drug.• Specific approaches to achieving gastric retention include: – Swelling polymer systems that are effectively trapped in the stomach; – Floating polymer systems that float on the gastric juices and do not get emptied with the stomach contents; – High-density systems that are trapped within the rugae of the stomach; and – Bio adhesive systems designed to bind primarily to components of the gastric mucosae.• Drawback: – Unsuitability for certain pH sensitive molecules. – This approach does not help to improve the absorption of poorly absorbed drug.
Targeted Retention• Approach to Target Retention.• Bio adhesive Technology.• Specific Targeting agents have been investigated, like – polymer based strategies or lactins that binds to the glycoprotein of the mucous & epithelium.• Challenge: – Non specific nature of this targeting approach within mucus layer. – Enzymatic degradation that occur within the mucus layer.
PEPTIDE DELIVERY• All most all currently available protein based therapeutics are delivered parenterally. E.g.: Insulin – current market 15 billion.• Thus significant development effort are aimed to develop orally available dosage forms for this class of dosage forms.• GIT bioavailability problem due to chemical instability, susceptibility to proteolysis, and inability to cross biological barrier due to large size.• Various approach to increase the oral bioavailability of proteins and insulin like macromolecules.• The potential for toxicity and damage to epithelia is a major concern.
Ideal Improved Delivery• Provide a sustained release profile typified by polymeric microsphere technologies that allow significant drug loading and controlled release;• Provide a means of retaining that device at the site of optimal absorption, ideally by binding directly to the epithelial surface to reduce device loss due to intestinal transit or mucus turnover; and• Provide a mechanism by which larger molecules can effectively permeate the epithelial lining into the bloodstream.
DRUG DELIVERY CARRIERS• When developing Nanotechnology, the goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity.• E.g. : – Liposomes – Niosomes – Micelle – Dendrimers – Polymeric Nanoparticles – Carbon 60
LIPOSOMES • Their exterior lipid bilayer is very chemically reactive, thereby providing a means to conveniently couple “tags” on a covalent basis. • With diameters ranging in size from approximately 50 nm to 800 nm, their aqueous core encapsulates up to millions of molecules of signal generating “markers” that can be detected in a variety of different way. • E.g. : • Visually detectable dye, • Optically & fluorometrically detectable dye, • Enzyme, • Electro active compound
NIOSOMES • Widely studied as a alternative of the Liposomes. • Niosomes are prepared by the same way as Liposomes under the variety of condition, from unilamellar or multilamellar structures. • Niosomes alleviate the problem associate with Liposomes, such as chemical instability, variable quality of phospholipid and high cost. • Have potential of controlled and targeted drug delivery. • Also, enhance the penetration of drug.
MICELLE• Micelle is an aggregate of amphipathic molecules in water, with the nonpolar portions in the interior and the polar portions at the exterior surface, exposed to water.• Micelles are known to have an anisotropic water distribution within their structure, means water concentration decreases from the surface towards the core of the micelle, with a completely hydrophobic (water-excluded) core.• Hydrophobic drugs can be encapsulated into inner core.• Position of the solubilized drug is depends on the polarity of drug.
DENDRIMERS • Dendrimers have a high degree of molecular uniformity, narrow molecular weight distribution, specific size and shape characteristics, and a highly functionalized terminal surface. • The manufacturing process is a series of repetitive steps starting with a central initiator core. Each subsequent growth step represents a new "generation" of polymer with a larger molecular diameter, twice the number of reactive surface sites, and approximately double the molecular weight of the preceding generation.
POLYMERIC NANOPARTICLES • In recent years, Biodegradable polymeric nanoparticles have attracted considerable attention as potential drug delivery devices in view of their applications in drug targeting to particular organs/tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through as per oral route of administration.
CARBON 60• C60 are spherical molecules about 1nm in diameter, comprising 60 carbon atoms arranged as 20 hexagons and 12 pentagons: the configuration of a football.• Hence they find application as Nano Pharmaceuticals with large drug payload in their cage like structure.• On the other hand with development of various chemical substitutes for C60, it is possible to develop functionalized C60 with better drug targeting properties
PREPARATION Homogenization Top Down Milling Nano Bottom Up precipitationPREPARATION Top Down & Bottom Up Spray Drying
Bottom Up• This technology reside on Precipitation.• API dissolved in the Organic Solvent which is then added into a nonsolvent and in the presence of Stabilizer Nano crystals are precipitated.• E.g. : Hydrosols, Nano morphs.
Top Down• This technology either applied by Milling or Homogenizer.• Milling: – Pearl, Bead or Ball mill method used. – API and stabilizer are dispersed in dispersion medium and this mixture is put into grinding chamber. – Various Parameters effect the particle size. – Problem: Contamination of the product as a result of erosion of ball.• Homogenizer: – Ultasonification used to decrease particle size in liquid & solid medium. – In High Pressure Homogenization 2 type of homogenizer is used: • Micro fluidizer. • Piston gap Homogenizer.
Top Down & Bottom Up• In “top down and bottom up” technology, both methods are used together.• NanoEdge is a product obtained by such a combination technology.• Here, precipitation is followed by high pressure homogenization in this technology.
Spray Drying• This method is usually used for drying of solution and suspension.• In cylindrical cyclone, solution droplet are sprayed from top to bottom, dried by hot air and spherical particles are obtained.
Special Features• Switchable System Delivers Drug Inside Cells• Nano particle delivery is based on natural pathway of cellular uptake.• By synthesizing nanoparticles within cavity of ferritin, a natural iron storage and delivery protein.• Cell uptake of nanoparticles can be switched off – This can be carry out by blocking the cell surface receptors.
CHARACTERISATION• Characterization is necessary to understand nanoparticle synthesis and application.• It is done by various technique: – Electron microscopy – Atomic force microscopy – Dynamic light scattering – X-ray photoelectron spectroscopy – Powder X-ray diffraction – FTIR – NMR
Insulin – phospholipid complex for Oral delivery• Oral administration of the Peptide drug like INSULIN is the greatest challenge in the pharmaceutical technology.• Problem: – Substance is too large and hydrophilic to readily cross the intestinal mucosa. – Extensive protein degradation by proteases.• Insulin – phospholipid complex were prepared by novel reverse micelle solvent evaporation method.• Material used: – Porcine Insulin – Soybean phosphotidylcholine(SPC) – Bio degradable polyester like PLA, PGA, PLGA – Organic Solvent like DCM, Ethyl Acetate, EtOH.
Formulation Method: Preparation of Insulin – phospholipid Complex: By anhydrous lyophilization technique. Solution was freeze-dried Insulin & SPC dissolved in Agitate the solution until overnight at a temperature ofDMSO containing 5% glacial formation of clear mixture −40 C and under a vacuum acetic acid of 10 Pa. Solubilization study: Organic solvent with a range of polarity were used to evaluate the altered solubility of insulin after it was combined with SPC. Aliquot of organic solvent introduced into complexes with different molar ratio of SPC vs Insulin. Transmittance of each system was recorded by UV spectrophotometer.
Determination of interaction of insulin and SPC: Fourier transform infrared spectrophotometry was used to study the interaction between insulin and SPC. Preparation and characterization of nanoparticles: DCM containing complex &polymer Evaporate organic 2% polymer was gradually solvent with precipitated in the added to gentle stirring emulsion droplets INS-SPC Formation of Agitation until Formation of nanoparticles clear micellar stable loaded with solution o/w emulsion INS–SPC comp. Solution poured Recovered by in to aq. Solution Sonication for ultracentrifugatio containing 10s ice water bath n followed by 2%PVA lyophilization
In Vitro Study• In vitro drug release from the nanoparticles was performed in simulated gastric medium and intestinal medium without enzymes at 37 C with continuous orbital mixing .• At appropriate intervals, duplicate suspensions were withdrawn and replaced with equal volume of fresh release medium.• One sample was treated with 2% triton X-100 and subjected to ultracentrifugation.• amount of SPC and total insulin released in the supernatant was evaluated by ammonium ferrothiocyanate method & RP-HPLC analysis respectively.• Another was added into the reservoir of ultrafiltration centrifuge filter, the filtrate that contains free insulin was collected after centrifuging the dispersion to determine the amount of SPC–uncombined insulin released.• The amount of SPC–combined insulin released was calculated as the difference between that of total and free insulin.
In Vivo Study• Streptozotocin-induced male diabetic rats were fasted overnight.• Diabetic rats were divided into 3 groups. – Group 1: Control with oral administration of insulin solution. – Group 2: Given insulin loaded Nano particulate suspensions. – Group 3: Injected subcutaneously with insulin solution.• Blood samples were collected from the retro orbital plexus of the rats prior to oral administration to establish baseline glucose levels and, at different times after dosing.• Plasma was separated by centrifugation to determine the plasma glucose level using the glucose oxidase method and the insulin concentration using radioimmunoassay.• Relative bioavailability after Intragastric administration was calculated.
Characterization• Solubilization study, IR and X-ray diffraction analysis were employed to prove the complex formation.• Effect of key parameter like polymer/SPC weight ratio, organic phase and polymer type on the properties of the nanoparticles were investigated.• The drug entrapment efficiency was up to 90%.• The specific modality of drug release, i.e., free or SPC–combined, was investigated in the aid of ultracentrifugation and ultrafiltration methods.• The pharmacological effects of the nanoparticles were further evaluated to confirm their potential suitability for oral delivery.• Intragastric administration of the 20 IU/kg nanoparticles reduced plasma glucose levels to 57.4% within the first 8 h of administration.• 7.7% of oral bioavailability relative to subcutaneous injection was obtained.