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CONTENTS Novel drug delivery systems - Controlled and novel drug delivery edited by N.K.Jain -definition -types Transdermal drug delivery systems - controlled and drug delivery concepts by S.P.Vyas,R.K.Khar -definition- p.g.no: 411 -evaluation of transdermal drug delivery systems-p.g.no:443 Liposomes - Controlled and novel drug delivery edited by N.K.Jain -definition - p.g.no:304 -characterization – p.g.no:321 to 326 2

Novel drug delivery system: 

Novel drug delivery system Definition It is advance drug delivery system which improve drug potency, control drug release to give a sustained therapeutic effect, provide greater safety, finally it is to target a drug specifically to a desired tissue. 3


TYPES Oral Transmucosal drug delivery Ocular drug delivery Nano particles Resealed erythrocytes Trandermal drug delivery Liposomes Niosomes 4

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Oral transmucosal drug delivery The drug is penetrated through the oral sublingual mucosa in sufficient quantities to achieve desired therapeutic effect Ocular drug delivery The drug is diffused through the eye.The dosage forms used are conventional, ophthalmic inserts(occusert),contact lens etc. Nano particles These are particulate dispersions or solid particles with a size in the range of 10-1000nm Resealed erythrocytes Drugs are loaded into erythrocytes and after resealing they are used for parenteral drug delivery 5

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Transdermal drug delivery The drug is delivered through the intact skin at a controlled rate to systemic circulation Liposomes These are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecules Niosomes Niosomes are non ionic surfactant vesicles that can entrap both hydrophilic and lipophilic drugs 6

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Transdermal drug delivery system DEFINITION Transdermal drug delivery systems are self contained, discrete dosage form which when applied to the intact skin deliver the drug through skin at a controlled rate to systemic circulation . 7

Multi layer transdermal system: 

Multi layer transdermal system 8

Examples : 

Examples Nicotine : to quit tobacco smoking Fentanyl : analgesic for severe pain Estrogen : menopause and osteoporosis Nitroglycerin : angina 9


EVALUATION OF TRANSDERMAL DRUG DELIVERY SYSTEMS MONOGRAPHIC METHODS 1.DISSOLUTION TEST U.S.P i.)APPARATUS 5(The Paddle over Disc) The transdermal system is attached to a disc or cell resting at the bottom of the vessel which contains medium at 32 ±0.5°C. The dissolution medium is a buffered solution so that its PH is within 0.05 unit of the PH specified in the individual monograph 10


INTERPRETATION LEVEL NUMBER TESTED CRITERIA L1 6 No individual value lies out side the stated range. L2 6 The average value of the L2 units(L1+L2) lies with in the stated range. No individual value is out side the stated range by more than 10%of the average of stated range. L3 12 The average value of the 24 units(L1+L2+L3) lies with in the stated range. Not more than two of the 24 units are outside. the average of the stated range and none of the units is outside the stated range by more than 20% of the average of the stated range. 11

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APPARATUS 6(The Cylinder modified USP Basket) The TDD system is attached to the surface of a hollow cylinder immersed in medium at 32 ±0.5°C. Interpretation The requirements are met if the quantities of active ingredient released from the system conform to above table. APPARATUS 7(The reciprocating disc) In this method patches attached to holders are oscillated in small volumes of medium, allowing the apparatus to be useful for systems delivering low concentration of drug. In addition paddle over extraction cell method may be used. Interpretation The requirements are met if the quantities of active ingredient released from the system confirm to above table . 12

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2.B.P DISC ASSEMBLY METHOD CELL METHOD ROTATING CYLINDER METHOD Interpretation: Perform the assay on each sample as directed in the individual monograph. Repeat the test with additional patches. The requirements are met if the quantity of the active ingredient released from the patch is with in the prescribed limit at the defined sampling times B.UNIFORMITY OF CONTENT 10 patches are selected and content is determined for individual patches. If 9 out of 10 patches have content between 90% and 110% of the specified value and one has content not less than 75% to 125% of the specified value, then transdermal patches pass the test of content uniformity 13

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NON MONOGRAPHIC METHODS Physicochemical Evaluation Thickness The thickness of transdermal film is determined by traveling microscope,  dial gauge, screw gauge or micrometer at different points of the film Uniformity of weight Weight variation is studied by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight Moisture content The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 hrs. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula 14

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% Moisture content = Initial wt –final w t x100                                      final wt Drug content determination   An accurately weighed portion of film (about 100 mg) is dissolved in 100 mL of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 hrs in shaker incubator . Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution Moisture Uptake Weighed films are kept in a desiccator at room temperature for 24 h . These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below. % moisture uptake = Final weight – Initial weight X 100                                                 Initial weight 15

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. Flatness A transdermal patch should possess a smooth surface and should not constrict with time. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness. % constriction = I 1 – I 2    X 100                                                                  I 1 I 2 = Final length of each strip I 1 = Initial length of each strip Folding Endurance Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value. 16

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Microscopic studies Distribution of drug and polymer in the film can be studied using scanning electron microscope. Tensile strength Tensile strength of the film was determined with the help of texture analyzer. The force and elongation were measured when the films broke. 17

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2.Evaluation of adhesive The pressure-sensitive adhesives are evaluated for general adhesive properties as well as for thermal toxicity and human wear.An adhesive laminate consists of backing sheet or membrane,an adhesive film and a release liner A ) Peel Adhesion properties The force required to remove an adhesive coating from a test substrate is referred to as peel adhesion. Adequate adhesion to skin and non traumatic removal of TDD systems from skin, depend on the peel adhesion properties. A single tape is applied to stainless steel plate or a backing membrane of choice and then tape is pulled from the substrate at a 180 angle, and the force required for tape removed is measured. The force is expressed in ounces {gm}/inch width of tape, with higher values indicating greater bond strength. If the pulled tape does not leave any residue on the plate, it indicates “adhesive failure”, which is desirable for most of the applications, especially for TDD system. If some residue is left behind, it suggests “cohesive failure”, which often signifies a lack of cohesive strength. 18

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B) Tack properties Tack is the ability of a polymer to adhere to a substrate with little contact pressure. In the case of TDD systems, which a applied with finger pressure, tack is an important property. There are 4 generally used tests for tack determination namely thumb, rolling ball, quick-stick (peel-tack), and probe tack test. 1.Thumb tack test It is a qualitative test applied for tack property determination of adhesive. In this test, the thumb is simply pressed on the adhesive and the relative tack property is detected. By experience one can differentiate between relative degree of tack. 2.Rolling ball tack test This test measures the softness of a polymer that relates to tack. In this test a stainless steel ball of 7/16 inches in diameter is released on an inclined tack so that it roles down and comes into contact with horizontal, upward-facing adhesive. The distance the ball travels along the adhesive provides the measurement of tack, which is usually expressed in inch. The less tacky the adhesive, the farther the ball will travel . 20

Rolling ball tack test: 

Rolling ball tack test 21

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3.Quick-stick(peel-tack) test In this test, the tape is pulled away from the substrate at 90 at a speed of 12 inches/min. The peel force required to break the bond between adhesive and substrate is measured and recorded as tack value, which is expressed in ounces (or gms) per inch width. The higher values of force required indicates the higher degree of tack. 4.Probe tack test In this test probe tack tester is used. The tip of a clean probe with a defined surface roughness is brought into contact with adhesive, and when a bond is formed between probe and adhesive. The subsequent removal of the probe mechanically breaks it. The force required to pull the probe away from the adhesive at fixed rate is recorded as tack( expressed in gms). 22

Probe tack test: 

Probe tack test 23

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C.) Shear strength properties Shear strength is the measurement of the cohesive strength of an adhesive polymer. If transdermal device has adequate cohesive strength, it will not slip after application and will leave no residue upon removal. In this particular test the adhesive coated tape is applied on to a stainless steel plate. A specified weight is hung from the tape, to affect its pulling in a direction parallel to the plate. Shear strength is determined by measuring the time it takes to pull the tape off the plate. The longer the time taken for removal, the greater is the shear strength 24

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3. Kinetic evaluation of Transdermal drug delivery systems Classification of different diffusion cells 1 . Physical design of diffusion cell Horizontal type Vertical type Flow through type 2. Method of sampling and measurement Continuous system Fluid circulation type Non fluid circulation type b) Intermittent system Rotary agitation system Transdermal drug delivery systems can be evaluated for their drug release and permeation kinetics by using a two-compartment diffusion cell assembly, placed under identical conditions. The different types of diffusion cells can be summarized on the basis of their physical design and method of sampling and measurement. Among various diffusion cells developed “Franz-diffusion cell“ is being widely used for studying skin permeation profile by finite dosing technique 25

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The full thickness abdominal skin (human cadaver or hairless mouse) is mounted between the donor and receptor compartment. The drug delivery systems are then applied with their drug releasing surface being in intimate contact with the stratum corneum surface of the skin. The skin permeation profile of the drug is assessed by sampling the receptor solution at pre determined intervals for definite duration and assaying the drug concentrations in the samples using a sensitive analytical method The release profile of the drug from these transdermal therapeutic systems can also be investigated by using the same experimental setup with out the skin . 26

A.) In vitro drug evaluation: 

A .) In vitro drug evaluation In vitro release kinetics Controlled release kinetics of drug from technologically- different transdermal therapeutic systems can be evaluated and compared by using Franz- diffusion cell assembly. For e.g. in the case of nitroglycerin TDD systems, the release of nitroglycerine from Transderm-Nitro (a membrane moderated transdermal system) and Deponit ( an adhesive diffusion controlled system) can be compared by plotting the data for cumulative amount of drug release from these systems as a function of time( Q vs. t) Keshery et al., 1985 found that the release of nitroglycerin from the Transderm-Nitro is almost 3 times greater than that from the Deponit system. So they suggested that the rate controlling adhesive layers in Deponit system play a greater rate controlling role for release of nitroglycerine than does the rate controlling membrane in the case of Transderm-Nitro system. 27

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In vitro permeation kinetics It can be performed on hairless mouse skin or human cadaver skin by using Franz-diffusion cell or 2 reservoir diffusion cell . In 2 reservoir diffusion cell, sink conditions can be maintained . The permeation of nitro glycerins across human cadaver and hairless mouse skin from different transdermal drug delivery therapeutic system was compared for their kinetics . It was noted that the rates of skin permeation generated from the excised skins of hairless mouse agree fairly with the data obtained from human cadaver skin, suggesting that hairless mouse skin could be an acceptable animal modes for human skin permeation kinetics studies. 28

b.) In-vivo evaluation : 

b .) In-vivo evaluation Animal model In vivo animal models are preferred because considerable time and resource are required to carry out studies in human. Some of the animal are used to in vivo studies are mouse, rat, guinea pig, rabbit, hairless mouse, hairless rat, hairless dog, cat, dog, miniature pig, pig, horse, goat, squirrel, monkey, etc. Human model The final stage in the development of transdermal device involves the collection of pharmacokinetic and pharmacodynamic data following application of the device to human volunteers. Determination of absorption following topical administration requires the investigator to know the amount of radioactivity retained in the body, or excreted by routes not monitored (assayed). This necessitates measurement of elimination following parenteral (ideally i.v.) administration of the compound. 29

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The percentage of dose absorbed transdermally is then calculated as % dose absorbed = 100 × Total radioactivity excreted after administration Total radioactivity excreted after intravenous administration c .)Cutaneous toxicological evaluations The following tests are conducted a .) Contact irritant dermatitis Contact irritant dermatitis results from direct toxic injury to cell membranes, cytoplasm or nuclei. This is generally manifested by inflammation, cutaneous erythema and itching, and can occur from the drug, vehicle, absorption enhancers and from the adhesive used to secure the system. Screening of new systems for contact irritant dermatitis involves use of animals like rabbits or guinea pigs. b) Evaporative water loss measurements Contact irritation also disrupts the stratum corneum barrier and causes an excessive water loss from the damaged surface that can be measured by means of evaporimetry. 30


liposomes Definition Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of a lipid molecule Structural components -phospholipids -cholesterol Advantages Provides selective passive targeting to tumour tissues. E.g.Liposomal Doxorubicin Increased efficacy and therapeutic index Increased stability of encapsulated drug Site avoidance effect Improved pharmacokinetic effects 31

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CHARACTERIZATION OF LIPOSOMES 1.PHYSICAL PROPERTIES Size and its Distribution - Microscopic Methods - Laser light scattering - Gel permeation Surface Charge Percent Capture (entrapment) Entrapped Volume Lamellarity Phase behavior of liposomes Drug release 33

a) Size and its distribution : 

a) Size and its distribution Microscopic methods Light microscopy has been utilized to examine the gross size distribution of large vesicles If the bilayers are having fluorescent hydrophilic probes, the liposomes are examined under a fluorescent microscope N egative stain electron microscopy can obtain an estimation of the lower end of the size distribution Freeze fracture electron microscopy studies the vesicle size and structure Laser light scattering Using this technique one can measure particles in the size range of about 3nm to 3 um When a ray of laser light is incident on a particle it gets diffracted at an angle. This diffraction causes the light to bend and change in its path length A high sensitivity detector can then record the time varying signal caused by scattered light and compared to the constant signal emitted when no molecules are present.This process is known as Dynamic light scattering 34

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GEL PERMEATION Gel exclusion chromatography on large pure gels was introduced to separate SUVs from radial MLV s However large vesicles of 1-3 um diameter usually fail to enter the gel and are retained on the top of column. A thin layer chromatography system using agarose beads has been introduced as a convenient, fast technique for obtaining a rough estimation of the size distribution of a liposome preparation. B) SURFACE CHARGE A method using free flow electrophoresis is used to determine the surface the surface charge of MLVs. The lipid samples ( 5 moles) are applied to the plate and electrophoresis is carried out at a 4 degrees c elsius on a flat bed apparatus for 30 mints at 18 v/cm. The plate is dried and the phospholipids are visualized by the molybdenum blue reagent. Liposomes up to 0.2 um in diameter can migrate on this support and with this technique as little as 2 mole % of charged lipids can be detected in a liposomal bilayer. 35

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C. PERCENT CAPTURE( ENTRAPMENT ) It is essential to measure the quantity of material entrapped inside liposomes. One may assume that the quantity of material remaining is 100% entrapped, but the preparation may change upon storage. In general 2 methods may be used- Mini column centrifugation Protamine aggregation Mini column centifugation method In this method, the hydrated gel (sephadex G‐50) is filled in a barrel of 1mL syringe without plunger which is plugged with a whatman GF/B filter pad. This barrel is rested in a centrifuge tube. This tube is spun at 2000rpm for 3 mints to remove excess saline solution from the gel. After centrifugation the gel column should be dried and have come away from the side of the barrel. Then , eluted saline is removed from the collection tube Liposome suspension( 0.2mL undiluted is applied drop wise to the top of the gel bed and the column is spun at 2000rpm for 3 min to expel the void volume containing the liposomes into the centrifuge tube. The elute is then removed and set aside for assay. 36

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The Protamine aggregation method The protamine aggregation method may be used for liposomes of any composition( both +vely and –vely charged materials). However, a preliminary test should be carried out before to check that the solute material entrapped does not itself precipitate in presence of protamine after release from liposome. In this method, liposome suspension( 20 mg/ml in normal saline) is placed inn conical glass centrifuge tube, 0.1mL of protamine solution(10 mg/ml) is added with mixing, and allowed to stand for 3 min. 30 mL of saline is added and then the spun for 20 min at 2000rpm at room temperature. The supernatant is removed and assayed for free, untrapped compound by standard methods. The suspended pellet is re-suspended in 0.6mL of 10% triton X-100 and the material completely dissolved. The volume is made up to the desired value and then assayed for entrapped material by standard methods. 37

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D. ENTRAPPED VOLUME The entrapped volume of a population of liposomes(in uL/mg) can often be deduced from measurements of the total quantity of solute entrapped inside liposomes assuring that the concentration of solute in the aqueous medium inside liposome is the same as that in the solution used to start with, and assuming that no solute has leaked out of the liposomes after separation from unentrapped material The best way to measure internal volume is to measure the quantity of water directly, and this may be done very conveniently by replacing the external medium(water) with a spectroscopically inert fluid(D2O), and then measuring the water signal, for e.g. by NMR. In this method liposomes prepared in aqueous solution consisting of ordinary water are spun at high centrifugal force to give a tight pellet. The pellet is the resuspended in deuterium oxide. The permeability of membrane to the water is such that D2O and H2O equilibrate very rapidly through out the whole of the volume of the medium. A small aliquot is removed for quantification of phospholipid and the remainder is used to obtain an NMR scan of H2O, the peak height of which can be related to concentration by comparison with standards containing known amount of H2O in D2O. 38

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E . LAMELLARITY The average number of bilayers present in a liposome can be found by freeze electron microscopy and by 31P-NMR. In 31P-NMR the signals are recorded before and after the addition of broadening agent such as manganese ions which interact with the outer leaflet of the outermost bilayers. Thus, a 50% reduction in NMR signal means that the liposome preparation is unilamellar and 25% reduction in the intensity of the original NMR signal means that there are 2 bilayers in the liposome. 39



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F.PHASE BEHAVIOUR OF LIPOSOMES A n important feature of lipid membrane is the existence of a temperature dependent, reversible phase transition, where the hydrocarbon chains of the phospholipid undergo a transformation from an ordered(gel ) state to a more disordered fluid(liquid crystalline state ). These changes have been documented by freeze fracture electron microscopy, but most easily demonstrated by differential scanning calorimetery. The phase transition temperature is a function of phospholipid content of the bilayers. It gives information regarding liposomal stability, permeability and whether drug is entrapped in the bilayers or the aqueous compartment. 41

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G.DRUG RELEASE The mechanism of the drug release from the liposomes can be assessed by the use of a well calibrated in vitro diffusion cell. In vitro assays to predict pharmacokinetics and bioavailability of the drug. 2. CHEMICAL PROPERTIES Quantitative determination of phospholipids Phospholipids hydrolysis Phospholipids oxidation Cholesterol analysis A Quantitative determination of phospholipids It is difficult to measure directly the phospholipids concentration, since dried lipids can often contain considerable quantities of residual solvent. Consequently the method most widely used for determination of phospholipid is an indirect one in which the phosphate content of the sample is first measured. The phospholipids are measured either using Bartlett assay or Stewart assay. 42

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B. PHOSPHOLIPID HYDROLYSIS The major product of phospholipid( lecithin)hydrolysis is lyso-phospholipid( lysolecithin) where one fatty acid chain is lost by de-esterification. Ideally, estimation of phospholipids hydrolysis by quantitation of lysolecithin could be carried out by HPLC where the column outflow can be monitored continuously by UV absorbance to obtain a quantitative record of the eluted components. 43

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C. PHOSPHOLIPID OXIDATION Oxidation of fatty acids of phospholipids in the absence of specific oxidants occurs via a free radical chain mechanism . The initiation step is abstraction of a hydrogen atom from the lipid chain that can occur most commonly as a result of exposure to electro-magnetic radiation or trace amount of contamination with the transition metal ions . Poly chain- saturated lipids are particularly prone to oxidative degradation . A number of techniques are available for determining the oxidative of phospholipids at different stages i.e., UV absorbance method, iodometric method ( for hyper oxides) and GLC method. 44

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D. CHOLESTEROL ANALYSIS Cholesterol is qualitatively analyzed using capillary column of flexible fused silica. Where as it is quantitatively estimated (in the range of 0-8ug) by measuring the absorbance of purple complex produced with iron upon reaction with a combined reagent containing ferric perchlorate, ethyl acetate and sulfuric acid at 610nm. 45


references Indian pharmacopoeia 2007 USP,BP Controlled and novel drug delivery, edited by N.K.JAIN . Targeted and controlled drug delivery- novel carrier systems, S.P.VYAS and R.K.KHAR . Advances in controlled and novel drug delivery, edited by N.K.JAIN . Novel drug delivery systems- second edition, revised and explained, by YIE.W.CHIEN Bio pharmaceutics and pharmacokinetics a treatise, by D.M.BRAHMANKAR and SUNIL.B.JAISWAL . 46

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