ORAL LIQUIDS 1 Contents v Emulsion as oral

ORAL LIQUIDS 1

Contents v. Emulsion as oral ØMicro emulsion ØNano emulsion ØMultiple emulsion ØDry emulsion v Suspension as oral ØNano suspension ØMicro suspension 2

liquids Ø Definition This is a general term used to describe a solution, suspension or emulsion in which the active ingredient is dissolved or dispersed in a suitable liquid vehicle. “A solution is a liquid-preparation that contains one or more soluble chemical substances dissolved in a specified solvent. ” Ø Advantages ü ü Immediately available for absorption. Administration convenient, particularly for infants, psychotic patients. Easy to color, flavor & sweeten. Liquids are easier to swallow than solids and are therefore particularly acceptable for pediatric patient. ü A solution is an homogeneous system and therefore the drug will be uniformly distributed throughout the preparation. ü Some drugs like aspirin, KCl can irritate gastric mucosa if used orally as a solid dosage forms. But this effect can be reduce by solution system. 3

Ø Disadvantages ü Bulky than tablets or capsule, so difficult to carry transport. ü Less stable in aqueous system. Incompatibility is faster in solution than solid dosage form. ü Patients have no accurate measuring device. ü Accident breakage of container results in complete loss. ü Solution often provide suitable media for the growth of microorganisms. ü The taste of a drug, which is often unpleasant, is always more pronounced when in solution than in a solid form. 4

Classification of liquids LIQUID Monophasic Oral use Solution Draught Drops Linctuses Syrups Elixirs External use Parenteral Used in Oral cavity Biphasic Special use Liquid in liquid Oral use Used in other than oral cavity Solids in liquid External use Parenteral Oral External EMULSION THROAT PAINTS GLYCERITES MOUTH WASHES THROATSPRAY S DOUCHES ENEMAS EYE DROPS EYE LOTIONS NASAL DROPS INHALANTS Liniments Lotion SUSPENSION 5

Emulsion as Oral MICROEMULSION NANOEMULSION MULTIPLE EMULSION DRY EMULSION 6

EMULSION Ø An emulsion is a mixture of two or more liquids that are normally immiscible (nonmixable or unblendable). Ø In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase). Ø Examples of emulsions include vinaigrettes, milk, and some cutting fluids for metal working. Ø The word "emulsion" comes from the Latin word for "to milk", as milk is (among other things) an emulsion of milk fat and water. 7

MICROEMULSION • Microemulsions are clear, stable, liquid mixtures of oil, water and surfactant, frequently in combination with a co surfactant like short chain alcohol or amine. • Diameter of the droplets in a microemulsion is in the range of 0. 1 to 10 µm. • The two basic types of microemulsions are (1) o/w (oil dispersed in water) and (2) w/o (water dispersed in oil). 8

Difference between Ordinary emulsion and Microemulsion: Ordinary emulsion Microemulsion Size of globule: 0. 5 -50 µm 0. 1 -10 µm Appearance: Turbid Clear Thermodynamically: Stable but coalesce finally. More stable Viscosity: - Less compared to other emulsion. Preparation: It require high shear condition By simple mixing of the component and do not require high shear condition Surfactant concentration: Phases: 2 -3 %Weight 2 6 -8 %Weight 2 9

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Ø Advantages Of Microemulsion Over Other Dosage Forms • • • Increase the rate of absorption. Eliminates variability in absorption. Helps solublize lipophilic drug. Provides a aqueous dosage form for water insoluble drugs. Increases bioavailability. Various routes like topical, oral and intravenous can be used to deliver the product. Rapid and efficient penetration of the drug moiety. Helpful in taste masking. Provides protection from hydrolysis and oxidation as drug in oil phase in O/W microemulsion is not exposed to attack by water and air. Liquid dosage form increases patient compliance. Less amount of energy requirement. 11

Component of Microemulsion System Ø A large number of oils and surfactant are available but their use in the microemulsion formulation is restricted due to their toxicity, irritation potential and unclear mechanism of action. Ø Oils and surfactant which will be used for the formulation of microemulsion should be biocompatible, non-toxic, clinically acceptable, and use emulsifiers in an appropriate concentration range that will result in mild and nonaggressive microemulsion. Ø The emphasis is, excipients should be generally regarded as safe. 12

Main three components 1. Oil phase 2. Surfactant 3. Aqueous Component Ø If a cosurfactant is used, it may sometimes be represented at a fixed ratio "pseudo-component". Ø The relative amounts of these three components can be represented in a ternary phase diagram. Ø Gibbs phase diagrams can be used to show the influence of changes in the volume fractions the of different phases on the phase behavior of the system. 13

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contd…. Ø In case turbidity appears followed by a phase separation, the samples shall be considered as biphasic. Ø In case monophasic, clear and transparent mixtures are visualized after stirring; the samples shall be marked as points in the phase diagram. Ø The area covered by these points is considered as the microemulsion region of existence. 16

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Types of microemulsion systems v According to Winsor, there are four types of microemulsion phases exists in equilibria , these phases are referred as Winsor phases. They are, Ø Winsor I: With two phases, the lower (o/w) Microemulsion phases in equilibrium with the upper excess oil. Ø Winsor II: With two phases, the upper (w/o) Microemulsion phase in equilibrium with lower excess water. Ø Winsor III: With three phases, middle Microemulsion phase (o/w plus w/o, called bi continous) in equilibrium with upper excess oil and lower excess water. Ø Winsor IV: In single phase, with oil, water and Surfactant homogenously mixed. 18

Oil Component Ø The oil component influences curvature by its ability to penetrate and swell the tail group region of the surfactant monolayer. Ø Following are the different oil are mainly used for the formulation of microemulsion: Saturated fatty acid-lauric acid, myristic acid, capric acid Unsaturated fatty acid-oleic acid, linolenic acid Fatty acid ester-ethyl or methyl esters of lauric, myristic and oleic acid. Ø The main criterion for the selection of oil is that the drug should have high solubility in it. Ø This will minimize the volume of the formulation to deliver therapeutic dose of the drug in an encapsulated form. 19

Surfactants Ø The role of surfactant in the formulation of microemulsion is to lower the interfacial tension. Ø The surfactant should have appropriate lipophilic character to provide the correct curvature at the interfacial region. Ø Generally, low HLB surfactants are suitable for w/o microemulsion, whereas high HLB (>12) are suitable for o/w microemulsion. Ø Following are the different surfactants are mainly used for microemulsion Polysorbate (Tween 80 and Tween 20), Lecithins, Decyl polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6 -dioleate (Plurol Oleique), Dioctyl sodium sulfosuccinate (Aersol OT), PEG-8 caprylic /capril glyceride (Labrasol). 20

Co surfactants Ø Cosurfactants are mainly used in microemulsion formulation for following reasons: Ø They allow the interfacial film sufficient flexible to take up different curvatures required to form microemulsion over a wide range of composition. 1. Short to medium chain length alcohols (C 3 -C 8) reduce the interfacial tension and increase the fluidity of the interface. 2. Surfactant having HLB greater than 20 often require the presence of cosurfactant to reduce their effective HLB to a value within the range required for microemulsion formulation. Ø Following are the different co surfactant mainly used for microemulsion: v sorbitan monoleate, sorbitan monosterate, propylene glycol monocaprylate (Capryol 90), 2 -(2 ethoxy)ethanol (Transcutol) and ethanol. 21

Preparation of Microemulsion q Following are the different methods are used for the preparation of microemulsion: 1. Phase titration method (self emulsification) 2. Phase inversion method 22

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Phase Titration method (SEDDS) Ø Microemulsions are thermodynamically stable, so they can prepared simply by blending oil, water, surfactant and cosurfactant with mild agitation or mild heat. Ø Titrating the mixer of surfactant, cosurfactant and oil against the water till the clear solution is obtained. Ø If solution is still slight turbid then add some more amount of cosurfactant to get the clear solution. 24

Phase inversion method Ø Phase inversion of microemulsion is carried out upon addition of excess of the dispersed phase or in response to temperature. Ø During phase inversion drastic physical changes occur including changes in particle size that can ultimately affect drug release both in vitro and in vivo. Ø For non-ionic surfactants, this can be achieved by changing the temperature of the system, Ø forcing a transition from an o/w microemulsion at low temperature to a w/o microemulsion at higher temperatures (transitional phase inversion). 25

Contd… Ø During cooling, the system crosses a point zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets. Ø Apart from temperature, salt concentration or p. H value may also be considered. Ø A transition in the radius of curvature can be obtained by changing the water volume fraction. Ø Initially water droplets are formed in a continuous oil phase by successively adding water into oil. Increasing the water volume fraction changes the spontaneous curvature of the surfactant from initially stabilizing a w/o microemulsion to an o/w microemulsion at the inversion. 26

Contd. . Ø Many examples of microemulsion based formulations are now on the market ; ØAmong them, the performances of microemulsions are well demonstrated in the reformulation of Cyclosporin A by Novartis into a microemulsion based formulation marketed under the trade mark Neoral® 27

Characterization Of Microemulsion 1. 2. 3. 4. 5. 6. 7. The droplet size, viscosity, density, turbidity, refractive index, phase separation and p. H measurements shall be performed to characterize the microemulsion. 28

The droplet size Ø The droplet size distribution of microemulsion vesicles can be determined by either light scattering technique or electron microscopy. Ø This technique has been advocated as the best method for predicting microemulsion stability. Ø Dynamic light-scattering measurements. ØThe DLS measurements are taken at 90° in a dynamic light-scattering spectrophotometer which uses a neon laser of wavelength 632 nm. The data processing is done in the built-in computer with the instrument. 29

Phase analysis and viscosity measurement Ø Polydispersity Ø Studied using Abbe refractometer. Ø Viscosity measurement Ø The viscosity of microemulsions of several compositions can be measured at different shear rates at different temperatures using Brookfield type rotary viscometer. Ø The sample room of the instrument must be maintained at 37 ± 0. 2°C by a thermobath, and the samples for the measurement are to be immersed in it before testing. 30

ØPhase analysis ØTo determine the type of microemulsion that has formed, the phase system (o/w or w/o) of the microemulsions is determined by measuring the electrical conductivity using a conductometer. Emulsion Bulb glows with O/W Emulsion Bulb doesn’t glow with W/O 31

Stability Studies Ø The physical stability of the microemulsion must be determined under different storage conditions (4°C, 25°C and 40 °C) during 12 months. Ø Depending on different regulatory agency requirement it’ll vary according to them. Ø Fresh preparations as well as those that have been kept under various stress conditions for extended period of time is subjected to droplet size distribution analysis. Ø Effect of surfactant and their concentration on size of droplet is also be studied. 32

Application of microemulsion in delivery of drug Ø Oral delivery Ø Microemulsions have the potential to enhance the solubilization of poorly soluble drugs (particularly BCS class II or class IV) and overcome the dissolution related bioavailability problems. Ø These systems have been protecting the incorporated drugs against oxidation, enzymatic degradation and enhance membrane permeability. Ø Presently, Sandimmune Neoral(R) (Cyclosporine A), Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are the commercially available microemulsion formulations. Ø Microemulsion formulation can be potentially useful to improve the oral bioavailability of poorly water soluble drugs by enhancing their solubility in gastrointestinal fluid. 33

Topical delivery Ø Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first-pass metabolism of the drug and related toxicity effects. Ø Another is the direct delivery and target ability of the drug to affected areas of the skin or eyes. Ø Now a day, there have been a number of studies in the area of drug penetration into the skin. Ø They are able to incorporate both hydrophilic (5 -flurouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide) and enhance their permeation. 34

Evaluation of Microemulsion 1)Percentage Transmittance: Transparency of microemulsion formulation was determined by measuring percentage transmittance through U. V. Spectrophotometer. 2)Droplet Size Analysis: By microscopic method 3)Zeta-Potential Determination: 4)Viscosity 5)Stability Studies: The optimized ME was stored at three different temperature ranges for 6 months i. e. , refrigerating condition (20 C – 80 C), room temperature and elevated temperature (50 ± 20 C) and shelf life of the stored microemulsion system was evaluated by visual inspection (phase separation), % transmittance, Particle size and % Assay. 35

Research Work carried out on Microemulsions Drug Name Route Purpose/Result Flurbiprofen Parenteral Increased the solubility Apormorphine HCl Transdermal Increased the permeability Ketoprofen Transdermal Enhancement of permeability Prilocainne-HCL Transdermal Increased the solubility Estradiol Transdermal Improvement in solubilization Aceclofenac Dermatological Increased the solubility Piroxicam Oral Increased the solubility Diclofenac Transdermal Permeability enhancement Dexamethasone Topical Ocular Enhanced the Bioavailability Chloramphenicol Ocular Increased the solubility Ibuprofen Parenteral Increased the solubility Sumatriptan Intranasal Enhanced the Bioavailability Ibuprofen Topical Increasing the solubility 36

NANOEMULSION • Nanoscale emulsion having size less than 100 nm. • Due to their small droplet size, nano-emulsions may appear transparent, and Brownian motion prevents sedimentation or creaming, hence offering increased stability. • In contrast to microemulsions, nanoemulsions are metastable and can be diluted with water without changing the droplet size distribution. • Nanoemulsion are thermodynamically stable system in which the two immisible liquid (water and oil)are mix to form a single phase by means of appropriate surfactant. 37

Method of preparation 1)High pressure homoginization: • By high pressure homoginizer or piston homoginizer which produce NEs of exrtemly low particle size upto 1 nm. 2)Microfluidization: • This make use of microfluidizer. • This device use high pressure positive displacement pump(500 -20000 psi) which force the product through the interaction chamber which consist of small micro channel. • Product flow through the micro channel on to the impingement resulting in the formation of nano size droplet. 38

CHARACTERIZATION OF NANOPARTICALS • Nano-emulsions are not thermodynamically stable, and because of that, their characteristics will depend on preparation method. Here some parameters are discussed which should be analysed at the time of preparation of nanoemulsion. • Phase Behavior Study This study is necessary in characterization and optimization of ingredients. This is used in case of NE formulation prepared by phase inversion temperature method and self-emulsification method. • Particle Size Analysis Generally Dynamic Light Scattering(DLS) method are used. • Surface Charge Measurement Surface zeta potential of NE droplets should be measured with the help of mini electrode to predict the surface properties of NEs. . 39

Contd… • Transmission Electron Microscopy TEM is used to observe the morphology in Nano-emulsion. • Viscosity should be measured to ensure the better delivery of the formulation. • Morphology & structure Morphology and structure of nanoemulsion can be studied using TEM. The study of globule shape and surface can be observed by TEM. To perform TEM observations, a drop of the nanoemulsion is deposited on the holey film grid and observed after drying. 40

Ø Advantages of nanoemulsion • Reduction of globules: Increase surface area, Enhance solubility, Increase bioavailability • They do not show the problems of flocculation, coalescence and sedimentation. • They are non-toxic , non-irritant 41

Limitations Of Nanoemulsions • The manufacturing of nanoemulsion formulation is an expensive process because size reduction of droplets is very difficult as it required a special kind of instruments and process methods. • For example, homogenizer (instruments required for the nanoemulsion formulation) arrangements is an expensive process. Again microfluidization and ultrasonication (manufacturing process) required high amount of financial support. • Stability of nanoemulsion is quite unacceptable and creates a big problem during the storage of formulation for longer time of period. Ostwald ripening is the main factor associated with unacceptability of nanoemulsion formulations. This is due to high rate of curvature of small droplets show greater solubility as compared to large drop with a low radius of curvature. 42

APPLICATIONS OF NANO-EMULSIONS Ø The compositional flexibility of nanoemulsions offers a wide range of applications. Ø The incorporation of fluorescent dyes and other molecules into nanoemulsions makes the interesting probes for exploring properties of living cells and for drug delivery. Ø Nanoemulsion vaccine could inactivate and kill the virus and then subsequently induce immunity to the virus that includes cellular immunity, antibody immunity and mucosal immunity. Ø The deformable and liquid nature of the droplets may lead to discoveries of new pathways for cellular uptake and dispersal. Both oil-soluble and watersoluble drug molecules can be incorporated into the nanodroplets of direct and inverse nanoemulsions for potential pharmaceutical uses. Ø In the printing and data storage industries, one may imagine the resolution of droplets. 43

Contd… Ø In the personal care and food industries, nanoemulsions may provide interesting alternatives as pleasantly transparent and soft solids that possess plastic-like rheological properties. While being appealing from an optical and rheological point of view, nanoemulsion also can deliver moisturizers to the skin quite efficiently and also block ultraviolet light without leaving a white residue. Ø The small size of the nano droplets will likely increase transport efficiency of any active drugs or other molecules inside the droplets across biological membranes, including the skin. Thus, nanoemulsions may have significant applications in medical patches. Ø High-throughput production methodologies make nanoemulsions a realistic commercial-scale alternative for diverse areas, including lotions and pharmaceuticals. 44

Marketed products: Drug Brand Manufacturer Indication Propofol Diprivan Astra zeneca Anesthatic Dexamethazone Limethasonn Mitsubishi pharmaceutical, Japan Steroids Palmitate alprostadil Liple Mitsubishi pharmaceutical, Japan Vasodilator Flubriprofen axetil Ropion Kaken pharmaceutical, Japan NSAIDS Vitamines A, D, E, K Vitalipid Fresenius kabi, Europe Parenteral nutrition 45

Multiple emulsion 46

Introduction Ø Multiple emulsion systems are novel developments in the field of emulsion technology and are more complex type of dispersed system. Ø These are the emulsion systems in which the dispersed phase contain smaller droplets that have the same compositon as the external phase. Ø These made possible by the double emulsification hence the systems are also called as “double emulsion”. Ø Diameter of the droplets in a Multiple emulsion is in the range of 0. 5 to 3µm. Ø Multiple emulsions are defined as emulsions in which both types of emulsions, i. e. water-in-oil (w/o) and oil-in-water (o/w) exist simultaneously. Ø They combine the properties of both w/o and o/w emulsions Ø These two liquids forming a system are characterized by their low thermodynamic stability. 47

Ø Like simple emulsion multiple emulsion are classified into two type. 1)O/W/O type 2)W/O/W type Ø The immiscible phase , which separates the two miscible phase is known as “liquid membrane” and act as a diffusion barrier and semipermeable membrane for drugs or moities entrapped in the internal aqueous phase. 48

Preparation Ø Multiple emulsions, either W/O/W or O/W/O emulsions, are generally prepared using a 2 -step procedure. Ø For W/O/W emulsions, the primary emulsion (W/O) is first prepared using water and a low-HLB surfactant solution in oil. In the second step, the primary emulsion (W/O) is re-emulsified in an aqueous solution of a high-HLB surfactant to produce a W/O/W multiple emulsion. Ø The first step is usually carried out in a high-shear device to produce very fine droplets. The second emulsification step is carried out in a low-shear device to avoid rupturing the multiple droplets. 49

Multiple emulsion (w/o/w or o/w/o), Prepared by two step procedure First step (o/w) Primary emulsion Second step (o/w/o) Secondary emulsification phase Oil + Aqueous phase Low HLB surfactant + Oil Blend and heat up to 70 -80º C Formation of very fine droplets Heat and blend with low shear Oil Blend with low shear Multiple emulsion At different phase volume ratio of oil and primary emulsion as shown in table 1 50

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EVALUATION OF MULTIPLE EMULSION Ø Viscosity Ø surface tension Ø conductivity Ø p. H Ø Globule size Ø Test for sterility Ø Microscopic method Ø Particle size distribution 57

Multiple Emulsion 58

Application : Ø Ø Ø Controlled and sustained drug delivery. Vaccine adjuvant. Cosmetic application. As a preparative tool for microencapsulation technology. Miscellaneous. Protection action. Taste masking. Absorption enhancement through GIT. 59

Dry emulsion Ø A novel oral dosage formulation of insulin consisting of a surfactant, a vegetable oil, and a p. H-responsive polymer has been developed. First, a solid -in-oil (S/O) suspension containing a surfactant–insulin complex was prepared. Ø Solid-in-oil-in-water (S/O/W) emulsions were obtained by homogenizing the S/O suspension and the aqueous solution of hydroxy propyl methyl cellulose phthalate (HPMCP). Ø A micro-particulate solid emulsion formulation was successfully prepared from the S/O/W emulsions by extruding them to an acidic aqueous solution, followed by lyophilization. Ø The insulin release from the resultant dry emulsion responded to the change in external environment simulated by gastrointestinal conditions, suggesting that the new enteric coated dry emulsion formulation is potentially applicable for the oral delivery of peptide and protein drugs. 60

Homogenization and membrane emulsification Dropwise extrusion through a syringe Recovery and lyophilization. 61

SUSPENSION AS ORAL Nano suspension Micro suspension 62

NANOSUSPENSION INTRODUCTION PREPARATION EVALUATION APPLICATIONS 63

Suspension Ø Mixture of two substances, one of which is finely divided and dispersed in the other. Ø Suspensions: S-S, L-S (OR S-L), G-S Ø Colloidal suspension 1 nm to 0. 5 µm Ø Coarse suspension 1 to 100 µm Ø A suspension of liquid droplets or fine solid particles in a gas is called an aerosol. Ø Blood is an example of suspensions Ø Suspensions are useful for administering insoluble or poorly soluble drugs or in situations when the presence of a finely divided for the material in the GI tract is required. 64

The Difference Between Solution & Suspensions Ø When the 2 substances totally mix it is called a solution. Ø E. g. Solute + Solvent = Solution (sugar) + (water) = Solution Ø Then, We can say sugar is soluble in water, it has dissolved. 65

Contd… Ø Suspensions Ø Sometimes when we mix substances they stay in clusters. We therefore say it is insoluble in water. Ø E. g. Chalk + Water = Suspension Ø Eventually the particles sink to the bottom to form sediment. 66

More than 40% of drugs are poorly soluble in water, so they show problems in formulating them in conventional dosage forms. For class II drugs (e. g. -Itraconazole & carbamazepine), WHICH ARE POORLY 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 therapy with respect to pharmacokinetics. 11

Nanosuspension Ø 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. Ø 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. Ø 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. 68

Nanosuspension preparation Top down Media Milling (Nanocrystals) HPH in water (Dissocubes) HPH in non aqueous media (Nanopure) Bottom up Combination of precipitation and HPH (Nanoedge) Precipitation 69

Bottom Up technology Added to non -solvent Precipitation Of Crystals Drug dissolved in the solvent 70

ØMain advantage is the use of simple and low cost equipments. Ø 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. Ø 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. 71

Top Down Approaches 72

Ø The nanosuspensions are prepared by using high shear media mills. The milling chamber charged with milling media, water, drug & stabilizer is rotated at very high shear rate under controlled temp. for 2 -7 days. Ø The major concern with this method is the residues of milling media remaining in the finished product could be problematic for administration. Principle Ø The high energy and shear forces generated as a result of the impaction of the milling media with the drug provide the energy input to break the micro particulate drug into nano-sized particles. Ø The milling medium is composed of glass, zirconium oxide or highly cross-linked polystyrene resin. 73

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Coolant Large drug crystals Charged with drug, water and stabilizer Re-circulation chamber Milling chamber Screen retaining milling media in chamber Milling shaft Nanocrystals Milling media Motor 75

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 1 mg/ml to 400 mg/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. 76

The instrument can be operated at pressure varying from 100 – 1500 bars (2800 – 21300 psi) and up to 2000 bars with volume capacity of 40 ml (for laboratory scale). Have to be started with micronized drug particle size less than 25μ to prevent blocking of homogenization gap. So it is essential to prepare a presuspension of the micronized drug in a surfactant solution using high speed stirrer. 77

-Cavitation, High shear forces and collision of particles against each other -The drug suspension, contained in a cylinder of diameter about 3 mm, passes suddenly through a very narrow homogenization gap of 25 μm, which leads to a high streaming velocity. High pressure homogenizer -In the homogenization gap, according to Bernoulli’s equation, the dynamic pressure of the fluid increases with the simultaneous decrease in static pressure below the boiling point of water at room temperature. 78

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- water starts boiling at room temperature, leading to the formation of gas bubbles, which implode when the suspension leaves the gap (called Cavitation) and normal air pressure is reached again. - The implosion forces are sufficiently high to break down the drug microparticles into nanoparticles. - Additionally, the collision of the particles at high speed helps to achieve the nano-sizing of the drug. 80

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 400 mg/m. L, 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 homogenization. 81

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), PEG 1000 etc. The homogenization can be done at room temperature, 0 o C and below freezing point (-20 o C). 82

Combined Precipitation And Homogenization (Nanoedege) Precipitated drug particles (nanosize desired) Continues to grow till microcrystal size So the precipitated particle suspension is subsequently homogenized which preserve the particle size obtained after the precipitation step. 83

Evaluation of Nanosuspensions ØIn-Vitro Evaluation -Particle size & Size Distribution -Particle Charge (Zeta potential) -Crystalline state & Morphology -Saturation Solubility & Dissolution Velocity ØIn- Vivo Evaluation -Surface Hydrophobicity -Interaction with Body Protein 85

3 nm to 3 μm Photon correlation Spectroscopy 0. 0 0 5– 2 m Atomic Force Microscopy 00 μ Mean particle size and size distribution Laser Diffractometry 86

Particle Charge ( zeta potential) “Potential difference between the ions in the tightly bound layer and the electroneutral region, referred to as zeta potential. ” Gives idea about physical stability of the Nanosuspension Electrostatically stabilized nanosuspension Electrostatic & Steric stabilization >+30 e. V >+20 e. V 87

Crystalline State and Particle Morphology Differential Scanning Calorimetry Crystalline Structure X- Ray Diffraction Change in physical state and extent of amorphous drug. SCANNING ELECTRON MICROSCOPY 88

Saturation solubility & Dissolution Velocity Help to anticipate In-vivo performance blood profiles, plasma peaks, bioavailability 89

APPLICATIONS Oral applications: ↑ Bioavailability (↓drug dose, ↑cost-effectiveness, No undue drug dumping in the body. ) ↑concentration gradient between the GI lumen and blood, ↑dissolution velocity. adhesiveness of the drug NS, increased surface area 90

e. g. : IMPROVED BIOAVAILABILITY 1) Atovaquone 10 -15% bioavailable high dose (750 mg, twice a day) NANOSUSPENSION 2. 5 FOLD INCREASE IN BIOAVAILABILITY 2) Danazole poorly soluble gonadotropin inhibitor Marketed Suspension(Danocrine) 5. 2% Bioavailability NANOSUSPENSION 82. 5% BIOAVAILABILITY QUICK ONSET OF ACTION: 3) NAPROXEN, an NSAID Nanosuspension • Tmax= 1. 69 hr Naprosyn (Suspension) • Tmax= 3. 33 hr Anaprox (Tablet) • Tmax= 3. 2 hr 91

v Patented technologies for Preparation: 92

MARKETED NANOSUSPENSIONS: 93

MICROSUSPENSION (? ) Ø Microsuspension® is a registered trademark used for Aqueous Solutions Sold As a Component of Veterinary Pharmaceutical Preparations For Use In the Treatment of Respiratory Disease In Livestock and owned by G. C. Hanford Manufacturing Company. Ø Drug is in micro size range. Ø No significant advantages over the macrosuspension or Nanosuspension. Ø Same methods of preparation as the Nanosuspension. 94

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REFERENCES Jiraporn CHINGUNPITUK, Nanosuspension Technology for Drug Delivery, Walailak J Sci & Tech 2007; 4(2): 139 -153. V. B. Patravale, Abhijit A. Date and R. M. Kulkarni, Nanosuspensions: a promising drug delivery strategy JPP 2004, 56: 827– 840 Rong Liu Water-Insoluble Drug Formulation Second Edition, page no. 122 -123 Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and Uday B. Kompella 96

Advances in controlled and novel drug delivery. By N. K. Jain. Targeted and controlled drug delivery By S. P. Vyas and R. K. Khar Nano emulsion: A pharmaceuticle review. http: /www. sysrevpharm. org Review Article : Microemulsions: a novel drug carrier system. International Journal of Drug Delivery Technology 2009; 1(2): 39 -41 www. ijddt. com TOPICAL REVIEW: nanoemulsions: Formation, structure, and physical properties. Journal of physics: condensed matter 18 (2006) r 635–r 666 Stacks. Iop. Org/jphyscm/18/R 633 97

Thank You 98