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DOLTODE M.Pharm(Pharmaceutics) First Semester Under the Guidance of PROFESSOR S.N.DHOLE Modern College of Pharmacy(For Ladies),Moshicontent: content Introduction Preparation methods Evaluation parameters Applications Marketed preparations Literature References INTRODUCTION: INTRODUCTION More than 40% of drugs are poorely soluble in water, so they show problems in formulating them in conventional dosage forms. for class ii drugs which are poorely soluble in aqueous and organic media, the problem is more complex. Various approaches to resolve problems of low solubility and low bioavailability micronization , co- solvancy , oily solution, salt formation- some other techniques are liposomes , emulsions, microemulsion , solid dispersion, ß- cyclodextrin inclusion complex etc. Many of these techniques are not universally applicable to all drugs or are not applicable to drugs which are not soluble in both aqueous & organic media. A different but simple approach is needed to tackle the formulation problem to improve their efficacy and to optimize the therapy with respect to pharmacokinetics.NANOSUSPENSION: NANOSUSPENSION A pharmaceutical nanosuspension is defined as very finely dispersed solid drug particles in an aqueous or organic vehicle for either oral and topical use or parenteral and pulmonary administration . The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm . Nanosuspensions differ from nanoparticles . Nanoparticles are commonly polymeric colloidal carriers of drugs whereas solid lipid nanoparticles are lipidic carriers of drugs. In nanosuspension technology, the drug is maintained in the required crystalline state with reduced particle size, leading to an increased dissolution rate and therefore improved bioavailability.PowerPoint Presentation: METHOD OF PREPARATION OF NANOSUSPENSION BOTTOM UP TECHNOLOGY TOP DOWN TECHNOLOGY NANOPRECIPITATION MEDIA MILLING DISSCUBES NANOPURE NANOEDEGEBottom up Technology : Bottom up Technology Bottom up Technology In Bottom up technology the drug is dissolved in a solvent, which is then added to non‐solvent that causes precipitation of the fine drug particles. Simple and low expenditure. In this technique, the drug needs to be soluble in at least one solvent which is miscible with nonsolvent.PowerPoint Presentation: Main advantage is the use of simple and low cost equipments . Basic challenge is that during the precipitation procedure growing of the crystals need to be controlled by addition of surfactant to avoid formation of microparticles . Limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and the solvent needs to be miscible with non-solvent . Moreover,It is not applicable to the drugs, which are poorly soluble in both aqueous and non-aqueous media.PowerPoint Presentation: TOP DOWN APPROCHESMedia Milling: Media Milling The nanosuspensions are prepared by using high shear media mills . The milling chamber charged with milling media, water, drug & stabilizer is rotataed at very high shear rate under controlled temp. The milling medium is composed of glass, zirconium oxide or highly cross-linked polystyrene resin. The high energy shear forces are generated as a result of impaction of milling media with the drug resulting into breaking of microparticulate drug to nanosized particles. The major concern with this method is the residues of milling media remaining in the finished product could be problematic for administrationPowerPoint Presentation: ADVANTAGES OF MEDIA MILLING 1. Applicable to the drugs that are poorly soluble in both aqueous and organic media . 2. Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/ml to 400mg/ml drug quantity . DISADVANTAGES OF MEDIA MILLING 1. Nanosuspensions contaminated with materials eroded from balls may be problematic when it is used for long therapy. 2. The media milling technique is time consuming. 3. Some fractions of particles are in the micrometer range. 4. Scale up is not easy due to mill size and weight.High pressure Homogenisation in Water (Dissocubes): High pressure Homogenisation in Water (Dissocubes) Homogenization involves the forcing of the suspension under pressure through a valve having a narrow aperture . Most of the cases require multiple passes or cycles through the homogenizer Examples of Commercial homogenizers : APV micron LAB 40 (APV Deutschland GmbH, Lubeck, Germany) Piston‐gap homogenizers from Avestin (Avestin Inc., Ottawa, Canada ) Stansted (Stansted Fluid Power Ltd, Stansted, UK) 11PowerPoint Presentation: Advantages Drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions. Ease of scale-up and little batch-to-batch variation Narrow size distribution of the nanoparticulate drug present in the final product. Allows aseptic production of nanosuspensions for parenteral administration. Flexibility in handling the drug quantity, ranging from 1 to 400mg/mL, thus enabling formulation of very dilute as well as highly concentrated nanosuspensions . Disadvantages Prerequisite of micronized drug particles. Prerequisite of suspension formation using high-speed mixers before subjecting it to homogenizationHomogenisation In Nonaqueous Media (Nanopure) : Homogenisation In Nonaqueous Media (Nanopure) The drugs that are chemically labile can be processed in such non-aqueous media or water-miscible liquids like polyethyleneglycol-400 (PEG), PEG1000 etc. The homogenization can be done at room temperature, 0 o C and below freezing point (-20o C).Combined Precipitation And Homogenization (Nanoedege) : Combined Precipitation And Homogenization (Nanoedege) So the precipitated particle suspension is subsequently homogenized which preserve the particle size obtained after the precipitation step. Precipitated drug particle (nanosize ) Contineous to grow till microcrystal size Evaluation Parameters: : Evaluation Parameters: Evaluation Parameters In-vitro Evaluation 1. Particle size and size distribution 2. Zeta potential 3. Crystalline state and morphology 4. Saturation solubility and dissolution velocityMean particle size and Size Distribution: : Mean particle size and Size Distribution: Mean particle size and Size Distribution;- The most important characterization parameter Governs the physicochemical properties like saturation solubility, dissolution velocity, physical stability and even biological performance. Methods for determining particle size distribution: Photon correlation spectroscopy (PCS), Laser diffraction (LD), Coulter counter multisizer .Zeta Potential (particle charge): : Zeta Potential (particle charge): Zeta Potential (particle charge) Determines the physical stability of nanosuspension . In order to obtain a nanosuspension exhibiting good stability, for an electrostatically stabilized nanosuspension a minimum zeta potential of ± 30mv is required.Crystalline state and Particle Morphology: : Crystalline state and Particle Morphology: The X-Ray Diffraction (XRD) is also used for determining change in physical state and extent of amorphous drug . Differential Scanning Calorimetry (DSC) determines the crystalline structure. When nanosuspensions are prepared drug particles get converted to amorphous form hence it is essential to measure the extent of amorphous drug generated during the production of nanosuspensionsSaturation solubility and Dissolution rate: : Saturation solubility and Dissolution rate: Nanosuspension increases the dissolution velocity and saturation solubility . An increase in solubility that occurs with relatively low particle size reduction may be mainly due to a change in surface tension leading to increased saturation solubility . Depend upon temperature and properties of dissolution medium APPLICATIONS: APPLICATIONSPowerPoint Presentation: Bioavailability enhancement Ocular administration Intravenous administration Pulmonary administration Targeted drug deliver Topical formulationsPatented technologies for Preparation:: Patented technologies for Preparation: NANOCRYSTAL COMPANY PATENT/PATENT APPLICATION EXAMPLE HODROSOL NOVATIS(prev.sandoz) GB 22 69 536 NANOMORPH SOLIGS/ABBOTT GB 22 00 048 D 1963 7517 NANOCRYSTAL ELAN NANOSYSTEM US 5,145, 684 DISSOCUBES SKYPHARMA US 5,858,410 NANOPURE PHARMASOL PCT/EPOO/0635 NANOEDGE BAXTER US 6,884,436MARKETED NANOSUSPENSIONS:: MARKETED NANOSUSPENSIONS: PRODUCT DRUG COMPOUND INDICATION COMPANY NANOPARTICE TECHNOLOGY RAPAMUNE® Sirolimus Immunosuppresant Wyeth ELAN DRUG DELIVARY NANOCRYSTAL EMEND® Aprepitant Antiemetic Merck ELAN DRUG DELIVARY NANOCRYSTAL TRICOR® Fenofibrate Treatment of hypercholesterolemia Abbott ELAN DRUG DELIVARY NANOCRYSTAL MEGACE®ES Megestrol acetate Appetite stimulant PAR Pharmaceuticals ELAN DRUG DELIVARY NANOCRYSTAL TRIGLIDE™ Fenofibrate Treatment of hypercholesterolemia First horizon pharmaceuticals SKYEPHARMA IDD ®-P TECHNOLOGYLITERATURE: LITERATURE SR NO AUTHOR NAME WORK DONE MATERIAL AND METHOD RESULT 1 Kassem MA ,et.al ophthalmic delivery system for certain glucocorticoid drugs. High pressure homogenization method Enhance the rate and extent of ophthalmic drug absorption as well as the intensity of drug action. 2 Thakkar HP et.al nanosuspensions of olmesartan medoxomil for bioavailability enhancement media milling technique bioavailability enhancement 3 Detroja C et al Antihypertensive activity of candesartan cilexetil nanosuspension: media milling enhancement in antihypertensive activity of candesartanPowerPoint Presentation: SR NO AUTHOR NAME WORK DONE MATERIAL AND METHOD RESULT 4 Kim JH ,et al a novel ophthalmic ciclosporin Aloaded nanosuspension. top down media milling method promising candidate for causing less ocular irritation 5 Wang Y ,et al paclitaxel for intravenous delivery high-pressure homogenization. Paclitaxel dissolution was also enhanced 6 Lou H ,et al Oridonin nanosuspension high-pressure homogenization apromising approach for treating tumors.PowerPoint Presentation: SR NO AUTHOR NAME WORK DONE MATERIAL AND METHOD RESULT 7 Zheng D ,et al In vitro antitumor activity of silybin high pressure homogenization treatment of human prostate cancer. 8 Sun M ,et al for oral delivery of quercetin high pressure homogenization poorly water-soluble QT toenhance the bioavailabiliy. 9 Li W , et al revaprazan hydrochloride nanosuspension high pressure homogenization absorption in gastrointestinal tract and enhance oral bioavailability of RH in ratsPowerPoint Presentation: SR NO AUTHOR NAME WORK DONE MATERIAL AND METHOD RESULT 10 Nakarani M ,et al Cyclosporine a-nanosuspension milling media, Enhance bioavailability and stability 11 Wang Y ,et al deacety mycoepoxydiene nanosuspension. high-pressure homogenization treatment anti-prostate cancer 12 Muthu MS ,et al risperidone for parenteral delivery: nanoprecipitation method treatment of psychotic disordersREFERENCES: REFERENCES 1. 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