Novel Drug Delivery Systems PDF

Pharmaceutical Technology-I COURSE PD – 705  COURSE OUTLINE 1. Principles of Pharmaceutical formulation and dosag form design. 2.Advanced Granulation Technology (Design an Practice) 3. Advance formulation Technique 4. Polymers used in drug delivery systems 5....

Pharmaceutical Technology-I COURSE PD – 705  COURSE OUTLINE 1. Principles of Pharmaceutical formulation and dosag form design. 2.Advanced Granulation Technology (Design an Practice) 3. Advance formulation Technique 4. Polymers used in drug delivery systems 5. Novel DDS  NOVEL DRUG DELIVERY SYSTEM: i) The concept of sustained release, First order releas approximation, Multiple dosing, Implementation o designing, approaches based upon dosage form modificatio product evaluation and testing, Matrices tablets, Contr release technology. ii) Developmental aspects of Matrix and Reservoir Systems iii) Sustained/ Controlled Release Drug Delivery Systems a) Microencapsulation technique Coacervation Solvent evaporation Interfacial polymerization Spray drying RECOMMEDED BOOKS: 1. M. E. Aulton, Pharmaceutics: Science of dosage form design, ELBS / Churchill Livingston, London 2. Banker, Modern Pharmaceutics, Marchell Dakker In New York, 3. Ansel, Pharmaceutical Dosage form in Drug Deliver System, Lee & Febiger, London. 4. Lachman L, Theory and Practice of Industri Pharmacy, Lee & Febiger, Philadeiphia  Learning Objectives Understand what is modified release dosage form. Elaborate the need for development of sustained release formulation. Describe zero order release kinetics and mechanism of SR products by implementation of designing. Learn the factor influence SR formulation development. Understand SR formulation evaluation and testing. Discuss process approaches of SR oral dosage form and dosage form modification. Conventional oral drug delivery systems are known to provide an immediate release of drug, in which one cannot control the release of the drug and effective concentration at the target site, therefore alteration of drug release is required.  Novel drug delivery systems have emerged and advanced the concept of drug delivery from a simple pill to a programmable, time controlled smart system  Rationale For Development Of Modified Release System: The main objectives of any drug delivery system are to ensure safety and to improve efficacy of drugs as well as patient compliance. This is achieved by better control of plasma drug levels and less frequent dosing.  Conventional dosage forms are not able to control the rate of drug delivery and provide rapid drug release, to maintain a therapeutic level required frequent drug administration, which leads to fluctuated level of drug in blood and tissues.  In contrast, Modified release dosage forms are not only able to maintain therapeutic levels of drug with narrow fluctuations but they also make it possible to reduce the frequency of drug administration.  On administrating the drug by either IV or an oral route (Immediate release dosage form), the drug blood levels are not achieved within the therapeutic range for an extended period of time. On the contrary, to overcome this, therapeutic efficacy and safety of drugs can be improved by more precise spatial and chronological placement within the body, thereby reducing both the size as well as the number of doses. The text mentions that this can be achieved by placing medication at a specific location within the body and at a particular time.  Classification: The modified release system, i.e. non-immediate release systems, may be divided conveniently in following categories: 1) Delayed release 2) Extended release 3) Orally disintegrating tablets (ODT 4) Sustained release 4.1. Controlled release, 4.2. Prolong release 5) Site specific and receptor release (Targeted Release) 6) Repeat action 1) Delayed release: Delayed release systems are those systems that use repetitive, intermittent dosing of a drug Repeat action tablets and capsules are the classical examples. A delayed release dosage form does not produce or maintain uniform drug blood levels within the therapeutic range. Typical drug blood levels versus time profiles for delayed release  The delay may be time-based or based on the influence of environmental conditions such as GI. pH, enzyme, pressure, etc 2. Extended release: At least two fold reduction in dosing frequency. 3. Orally disintegrating tablets (ODT): disintegrate rapidly in the saliva after oral administration 4. Sustained release: It includes all drug delivery systems that achieve slow release of drug over an extended period of time. A sustained release oral dosage form is designed to rapidly release pre-determined fraction of the total dose (loading dose) into gastrointestinal tract, which will produce the desired pharmacological response as promptly as possible and the remaining fraction of the total dose (maintenance dose) is then released at a controlled rate 4.1 Controlled release: Drug product is designed so that the release rate of maintenance dose is equal to the elimination rate. The constant blood levels can be achieved from controlled release system. Designed to release their medication in controlled manner, at pre-determined rate, duration and location in the body to achieve and maintain optimum therapeutic blood levels of drug. Predictability and reproducibility 4.2 Prolonged release: Prolonged release dosage forms reduce fluctuation in plasma drug levels by slowing down the absorption rate due to slower drug release rate. It extends the period of time the drug concentration is in the therapeutic range but does not maintain constant blood levels as controlled release systems. Drug blood level versus time profile showing the relationship between controlled release (A), Prolonged release (B), & conventional release (C) 5. Site specific and receptor release (Targeted release): In the case of site specific release, the target is a certain organ or tissue (e.g. in the treatment of arthritis or gout). While for receptor release, the target is the particular receptor for a drug within an organ or tissue (e.g. H1 and H2 antagonists located in tumor cells). 6.Repeat action : These are dosage forms usually containing 2 single doses of medication, one for immediate and the second for delayed release e.g. bilayered tablets.  Advantages Of Modified Release Dosage Form: 1. Avoid patient compliance problems 2. Better drug utilization and employed less total drug a. Minimize or eliminate local side effects and systemic side effects b. Reduction in drug activity with chronic use c. Minimize drug accumulation with chronic dosing that's why MR are use for chronic conditions rather than acute 3. Improve efficiency in treatment 4. Cure or control condition more promptly 5. Improve control of condition i.e. reduce fluctuation in drug level 6. Improve bioavailability of some drugs 7. Make use of special effects e.g. Sustained release aspirin for morning relief of arthritis by dosing before bedtime 8. Economical  Limitations of modified release system 1. Drug with following characteristics cannot be given by modified release dosage form. a. Drugs with very narrow therapeutic index. b. Drugs with irregular/erratic absorption from gastrointestinal track c. Drugs with long biological half life d. Drugs which needs to adjust dose regime e. Drugs with very high dose 2. The dose cannot be subdivided as in conventional dosage form 3. Difficult to provide antidote for sustained release formulations  Sustained Release Dosage Form (SRDF) Sustained release, sustained action, prolonged action controlled release, extended release, depot release these are the various terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over a long period of time after administration of a single dose of drug.  The Goals of SRDF’s is to obtain Zero order release from the dosage form.  Zero order release is a release which is independent of the amount of drug present in the dosage form.  Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion.  Disadvantages Of Sustained Release Drug Delivery 1. Increased cost. 2. Toxicity due to dose dumping. 3. Unpredictable and often poor in vitro-in vivo Corelation. 4. Risk of side effects or toxicity upon fast release of contained drug (mechanical failure, chewing or masticating, alcohol intake). 5. Need for additional patient education and counseling. --------------------------------------- --------------------------- ---------------------------------------------------- as low dose given ----------------------------- ---------------------------- Classification Of Sustained Release System 1. Dissolution Controlled The drugs with slow solubility are suitable candidates for this system and for the drugs having high solubility the dissolution is decreased by conversion into a suitable salt or Derivative. mathematical model that describes the relationship between the dissolution rate of a drug and several factors affecting it. The equation is useful for understanding and predicting the dissolution rate of drugs in various formulations.  Drug present in this system may be of two types: Drugs with inherently slow dissolution rate. e.g. griseofulvin, digoxin, nifedipine etc. Drugs that transforms into a slow dissolving form on coming in contact with GI fluids. e.g. Ferrous sulphate.These are the drugs having high aqueous solubility and dissolution rate.  These systems can further be categorized as: i. Coating dissolution system: In this type of system the drug particles are coated with polymers like cellulose, polymethacrylates, PEGs etc. The resulting pellets are compressed as tablets. The dissolution rate of the coat depends upon thickness and solubility of coat. Masks color, odor, taste, minimising GI irritation. One of the method used is microencapsulation ii. Soluble matrix system: single porous structure These systems are also known as monoliths as the drug is homogenously dispersed in a rate controlling medium. Waxes like bee wax, carnauba wax etc. are used for controlling the dissolution rate. The rate of dissolution is controlled by either of following mechanisms: i. Altering the rate of fluid penetration into tablet by altering the porosity of tablet. ii. Decreasing the wettability of tablet. iii. Slow dissolution rate of polymer Altering Porosity: Changes in tablet porosity influence fluid penetration, with higher porosity speeding up dissolution and lower porosity slowing it down. Decreasing Wettability: Using hydrophobic materials or coatings can reduce wettability, thereby controlling the rate of dissolution. Slow Dissolution Polymers: Employing polymers that dissolve slowly can regulate drug release by forming a matrix or coating that controls the dissolution rate.  Diffusion Theory  Diffusion is a process by which molecules transfer spontaneously from one region to another.  The migrating molecules are termed diffusants (also called permeants or penetrants).  The membrane or matrix in which the diffusant migrates is called the diffusional barrier.  The external phase is called the medium. The concentration gradient or profile of the diffusant within the diffusional barrier is the driving force for diffusion.  The theory of diffusion in isotropic (identical in all direction) substances therefore, is based on the hypothesis which is that the flux J or rate of diffusion (amount Qt in time t) through a unit area of a barrier section is proportional to the concentration gradient (x is change in distance); that is, The change in concentration (dC) over a change in distance (dx). This gradient drives the diffusion process.  This is Fick’s first law, with the proportionality constant d termed diffusivity or diffusion coefficient. The negative sign arises because the direction of molecular movement is opposite to the increase in the concentration.  2. Diffusion Sustained System These systems are those where the rate controlling step is not the dissolution rate of the drug but diffusion of the dissolved drug molecule. Depending upon the mechanism such system can be classified as: i. Porous membrane controlled system ii. Porous matrix controlled system i. Porous Membrane Controlled System OR Reservoir system /Laminated matrix device In these type of system the rate controlling element is a water insoluble non swellable polymer like ethyl cellulose, polymethaacrylate etc. which controls the drug release through the micro pores present in their membrane or matrix structure. Advantages: Can provide zero order drug release. Disadvantages: High cost per dosage unit. In case of dose dumping toxicity can take place. ii. Porous Matrix Controlled System  In these type of system the rate controlling element is a water swellable material ( hydrophilic polymers and gums) like alginates, xanthan gum, locust bean gum, HPMC etc.  Also called as Glassy hydrogels. Popular for sustaining the release of highly water soluble drugs. the Higuchi equation is a key tool in pharmaceutical science for modeling the release of drugs from solid matrices where diffusion is the primary The Higuchi equation is a fundamental mechanism of drug release. model used to describe the release of drugs from solid matrices. It is especially applicable to systems where the drug release is controlled by diffusion through a porous matrix. The equation provides a relationship between the amount of drug released and time, considering a system where the initial drug concentration is much higher than the drug solubility. Advantages: Cost effective. Easy to fabricate. Drug could be protected from hydrolysis or other changes in GIT, so enhanced stability. Compounds with high molecular weight could be formulated. Disadvantages: Release rate is affected by presence of food. Matrix must be removed after the release of drug.  Sustained release formulation’s describes the retard release of a drug substance from a dosage form to maintain therapeutic response for extended period (8-24 hrs and Parenteral from days to months) of time. Examples are…   Bioerodible And Combination Diffusion And Dissolution In this kind of system, the drug is enclosed in a membrane which is partially water soluble. The dissolution of the membrane take place due to which pores are formed and these pores allows aqueous medium to enter in the membrane. This results in the dissolution of the drug in membrane followed by the diffusion of the dissolved drug from the system. Example of such coating is combination of ethyl cellulose with PVP or methyl cellulose.  synthetic polymer: polyesters, poly(orthoesters), polyhydrides, polyphosphazenes natural polymers: chitosan, Hyaluronic acid, alginic acid  Osmotically Controlled Systems Drug surrounded by semi-permeable membrane and release governed by osmotic pressure. Zero order release obtainable. Release of drug independent on environment of system.  Ion Exchange Resins Based upon the principle that GIT has a relatively constant level of ions, this type of system has developed for controlling the rate of delivery of ionisable or ionic drugs. Such a system can be prepared by incubating the drug resin solution or by passing the drug solution through a column containing exchange resin.  A cationic drug is complexed with a resin containing SO3 - group and for anionic drug resin containing N(CH3)3 group is used. In the GIT hydronium and chloride ions diffuses into the sustained release tablet and interact with drug resin compex to trigger the release of drug. (+) drug --- resin containing SO3 (-) drug --- resin containing N(CH3)3  Resin+ – Drug– + Cl– --------- > >> resin+ Cl– + Drug– Resin– – Drug+ + Na+ -------- > >> resin– Na+ + Drug Water insoluble cross linked polymer compounds are used for this system.  These systems prevent dose dumping as they have better drug retaining properties. So, chances of toxicity are reduced. The polymeric and ionic property of ion exchange resin makes the drug release more uniform than that of simple matrices. IER= ion exchange resin As SO3 group is attached to the resin than this means it contained a cationic drug resinate combination of resin with drug  EVALUATION  Drug release is evaluated based on drug dissolution from dosage form at different time intervals.  Two types 1.In vitro evaluation 2.In vivo evaluation 1. In vitro dissolution studies:  The test is carried out to measure the amount of time required for certain percentage of drug to go into the solution under the specific test conditions.  Rotating paddle type and rotating basket type apparatus can be used as per pharmacopoeial standards or as mentioned in monograph of particular drug.  Modified dissolution testing apparatus (apparatus 3) at a specified time intervals measurement of drug is made in simulated gastric fluid / intestinal fluid. - 2 hrs in gastric fluid and 6 hrs in intestinal fluid  The test is passed if for each of the five tablets, the amount of active ingredient in solution is not less than 70% of the stated amount or as specified in the monograph of the API in pharmacopoeia.  Data Analysis For i. Dose dumping i.e., Maintenance dose is released before the time period for drug release is completed. ii. Dose that is unavailable is not released in G.I.T. iii. Release of loading dose. iv. Unit to unit variation, predictability of release properties.  Sensitivity of the drug to the process variables like:  Composition of the simulated fluid  Rate of agitation  Stability of the formulation  Ultimately does the observed profile fit expectations. Model Dependent Method  based on presented kinetic models for drug release for instance i. Zero order release kinetics ii. First order release kinetics iii. Higuchi model iv. Hixon-crowel cube root law v. Korsemeyer peppas etc. Model Independent Method  Analysis of release profile for i. Similarity Factor (f2) : The similarity factor (f2 ) is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves. ii. Difference Factor (f1) : – The difference factor calculates the percent (%) difference between the two curves at each time point and is measure of relative error between the two curves: – where n is the number of time points, Rt is the dissolution value of the reference (prechange) batch at time t, and Tt is the dissolution value of the test (postchange) batch at time t.  In Vivo Evaluation Preliminary in vivo testing of formulation carried out in a limited number of carefully selected subjects based on: Similar body wt, occupation, diet, activity, sex, and other variable control. A single dose administered and measure profile (24 hrs) Test may or may not be blind and cross over design. In vivo Bioavailability data to be determined include: i. Pharmacokinetic profiles ii. Bioavailability data iii. Either comparable or not, to reference dosage form iv. Reproducibility of in vivo performance Kinetics of Drug release  Drug release from conventional dosage forms, like the other processes of ADME, are governed by the first- order kinetics model.  In First-order model, drug release is dependent on the amount of drug available for release and therefore the rate of release declines exponentially with time.  Extended release dosage forms are governed by zero- order kinetics in which the rate of release is independent of amount of drug remaining in the dosage form.  Therefore a constant amount of drug will be released over time from extended release dosage forms  Zero-order Release Approximation  The release pattern (how drug release i.e slow or very slow) becomes independent of the magnitude of the maintenance dose and does not change during effective maintenance period.  System that delivers drug at a constant rate. The best example of zero-order input are intravenous infusions.  Pharmaceutical scientists have focused on zero-order delivery system Pharmaceutical scientists have focused on zero-order delivery systems because these systems achieve relatively stable Cp levels there by helping to minimize side effects due to peak drug concentrations and lack of efficacy due to sub-therapeutic trough drug concentrations.  A zero-order system delivers the same amount of drug per unit time from its initiation to termination Zero Order Release Approximation Rate of drug release Maintenance portion of dosage form (Zero Order ) drug at absorption site remain constant  Number of available formulation do not follow this basic lay out  availability of drug do not constant  drug conc. Fluctuate  therapeutic activity do not constant ……… so develop SR/CR formulations.  Factors Influencing SR Dosage Form Design 1. Biological Factors:  Half Life  Absorption  Metabolism 2. Physico-chemical Factors Dose size Ionization, Pka & Aqueous solubility. Partition coefficient Stability Half Life: Drugs with short half lives are good candidate for SR preparation since this can reduce dosing frequency. Drugs with half life shorter than 2 hrs (furosemide & levodapa) and greater than 8 hrs (digoxin, warfarin & phenytoin) are not considered good candidate. 2-8 hr OK Absorption: Compound with poor absorption rate constants are poor candidate for SR formulations. Certain drug absorbed in specific regions like Ferrous sulfate where absorption occur at jejunum and deuodenum, desired SR product must release ferrous sulfate before passing out this region. Gastric floating is also an approach for delayed release and increase sustained effect (p amino benzoic acid: drug with limited GI absorption; by increasing retention available more for absorption) Another approach is bioadhesive. Alternate to retention is penetration enhancers. Disadvantage is associated toxicity. Metabolism: Drug that frequently metabolized in intestine may not be the good candidate for SR products. (saturable enzymatic system will completely metabolize drug from slow available drug into its metabolite) For instance aloprenolol extensively metabolized in intestine when given in SR form. Levodopa metabolized by dopa-decarboxylase in intestine and may be formulated with dopa-decarboxylase supressing agent. Formulation of enzymatic susceptible drugs as prodrug is another approach.  Physico-chemical Factor Dose size: SR products can not be formulated with a relatively large dose size. Usual IR dosage is 0.5 – 1 gm for oral administration. Ionization, Pka and aquous solubility: Drug in uncharged forms are prefrentially permeate across lipid membrane while drug solubility decrease in uncharged form. Compounds with very low solubility (0.01 mg/mL) are inherently sustained. The lower limit of solubility for a SR system is 0.1 mg/ml. So, it is obvious that solubility of compound will limit choice of mechanism for SR system. Diffusion system will be poor choices for least soluble drugs as the driving force for the system that is drug concentration in solution form, will be low due to less solubility. Partition Coefficient: compound with high partition coefficient are lipid soluble and retain in body for longer period because they retain in lipid membrane of cell. Eg Phenothiazine. Stability: Drugs those are unstable in stomach, prolong delivery of drug for the entire course of transit in GIT is beneficial until the dosage form reaches to small intestine. Compounds unstable in small intestine subject to degradation e.g. Propentheline and Probanthine.