Modified Release Dosage Forms - WSU EACPHS

WSU – EACPHS DOCTOR OF PHARMACY PROGRAM PSC-4115 Modified Release dosage forms Course Coordinator: Arun Iyer, Ph.D. Associate Professor EACPHS Room 3601 [email protected] Modified Solid dosage forms Required Texts: Ansel's Pharmaceutical Dosage Forms and Drug Delivery S...

WSU – EACPHS DOCTOR OF PHARMACY PROGRAM PSC-4115 Modified Release dosage forms Course Coordinator: Arun Iyer, Ph.D. Associate Professor EACPHS Room 3601 [email protected] Modified Solid dosage forms Required Texts: Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 10th Edition, Lippincott Williams & Wilkins, 2014. Other references: Physical_pharmacy David Attwood 1st Ed. , Pharmaceutical Press. 2008; Martin's Physical Pharmacy and Pharmaceutical Sciences, International Edition. 2010.  Contents 3 I- Introduction to Modified Release Dosage forms (MRDFs) II- Modified Release Dosage forms classification III- Advantages and Disadvantages of Controlled release dosage forms IV- Oral controlled drug delivery systems: 1- Diffusion controlled A- Reservoir devices B- Matrix devices 2- Dissolution controlled 3- Osmotically controlled systems 4- Ion-Exchange resins  I. Introduction to Modified Release Dosage forms (MRDF) 4 A drug prepared in a suitable form for administration = dosage form = delivery system. Dosage form type may alter the bioavailability of the drug.  Terminology MRDFs are drug products designed to alter the time and rate of release of the drug. MRDFs achieve therapeutic objectives that conventional dosage forms can’t.  II. Classification 5 1. Delayed release dosage forms:  A dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration  Ex: Repeat-action (release of 2 doses successively = immediate release then delayed release) Prolonged action (initial dose plus a replenishment) Enteric coated tablets (timed release is achieved by a certain polymer barrier coating) Modified enteric coated tablets (additional drug is applied over the enteric coat and is released in the stomach, while the remainder is released further down the GI tract)  II. Modified Release Dosage forms classification 6 2. Controlled release dosage forms: Releases the drug over an extended period of time. Avoids the undesirable sawtooth characteristics of the plasma concentration vs. time profiles of the conventional drug products. The rate of release is controlled to a constant drug concentrations at the target tissue or cells. https://doi.org/10.1016/B978-0-08-101997-9.00001-1  II. Modified Release Dosage forms classification 7 3. Sustained release dosage forms:  = initial release of sufficient amount of drug to provide an immediate therapeutic dose then gradual release over an extended period.  II. Modified Release Dosage forms classification 8 4. Targeted dosage forms: Site specific targeting: The drug release is at the organ or site of absorption, Receptor targeting: The drug release is at the receptor for the drug action. III- A- Advantages 9 1. Increase efficacy by maintaining constant plasma drug level in the therapeutic window range for an extended period of time. 2. Reduce dosing frequency and eliminate drug accumulation in the body = minimizing untoward effects. 3. Increases patient compliance. 4. The cost of treatment for chronic diseases may be reduced.  III-B- Disadvantages 10 1. Dose dumping = release of > usual dose of drug or at a greater rate than the amount of drug per dosing interval = potential adverse plasma levels may be reached. Occurs if the MRDFs were not properly formulated because they contain the equivalent of 2 or more drug doses present in a conventional dosage form. 2. Once administered, the withdrawal of the drug from the body may be difficult, if not impossible. 3. Orally administered MRDF may yield erratic or variable drug absorption owing to interactions with the contents of GIT and changes in GI motility = drug ineffectiveness.  IV- Oral controlled release drug delivery systems 11 The basic principle in the design of oral controlled-release drug delivery systems that controls the availability of the drug is the kinetics of drug release, rather than the kinetics of drug absorption. These oral controlled release dosage forms are classified based on the mechanism that controls the release of the drug incorporated in the system. 1. Diffusion Controlled Systems  Polymers function as physical barriers to drug transport to control the rate of release of a drug when administered orally.  Generally = 2 types: reservoir devices and matrix devices. Reservoir Devices with Microporous Membranes Reservoir Devices with Microporous Membranes  A. Reservoir Devices The drug core is enclosed by a water-insoluble polymer. 15  Drug release: 1. Water, gastric juices, or intestinal juices penetrate the coating & dissolves the drug to produce a saturated solution, assuming the amount of drug present is enough to achieve this condition; 2. The drug molecules diffuse though the polymeric coating. A constant rate of drug release occurs if the concentration of drug in the polymeric coating (core) remains at saturation. The nature of the polymeric material controls the rate of drug release from reservoir.  To enhance the polymer coating permeability: 16 1. Plasticizers are added to increase fluid uptake into the polymer coating. 2. Water-soluble additives (pore-formers) are added = form a disperse phase in the polymer coating. When placed in an aqueous environment, the water-soluble additives dissolve to leave pores in the coating = allows both lipophillic and hydrophilic drugs, including ions, to pass through. The release of drugs from Reservoir Devices is based on Fick's law. Fick's first Law of diffusion M  D C S t x  The rate of transfer of a diffusing substance (mass = M = g, mole) = (dM/dt) per unit area of a section (S = cm2) is proportional to the concentration gradient (dC/dx), (J= dM/S.δt) = Flux D = proportionality constant or diffusion Diffusion cell. coefficient of a penetrant in cm2/sec, The donor compartment contains C = concentration in g/cm3, diffusant (drug) at concentration C dx = distance in cm. The –ve sign = diffusion occurs in the direction of decreasing concentration of diffusant. Diffusion will stop when the concentration gradient no longer exists (i.e., when dC/dx = 0). Sink To reach a steady state, the solution in the receptor compartment is constantly replaced Source with fresh solvent to keep the concentration at a low level = sink conditions. Drug diffuses through the membrane to solvent side Steady diffusion across a thin film of thickness x.  In this case the diffusion coefficient is constant.  The concentrations on both sides of the film, Cd and Cr, are kept constant and both sides are well mixed.  Diffusion occurs in the direction from the higher M C  D concentration (Cd) to the lower concentration (Cr). S t x  After sufficient time, steady state is achieved, and the concentrations are constant at all points in the film.  At steady state fick’s first law became It is normal for the concentration curve to increase or decrease sharply at the boundaries of the barrier. C1 = Cd, only if K = C1/Cd had a value of unity. x  Methods for preparing Reservoir Devices i. Coated Beads or Pellets 19 The first step: coating of a drug solution onto preformed cores = nonpareil seeds or beads. Prepared using slurry of starch, sucrose, lactose & Microcrystalline cellulose. The second step: covering of the core (beads) by an insoluble but permeable coat (using pan coating or air-suspension techniques) to sustain the release of the drug. EX: of coat materials = cross-linked poly(vinyl alcohol), hydroxypropyl cellulose, polyvinyl acetate, ethyl cellulose, polyethylene glycol, beeswax, and cetyl alcohol. Plasticizers and other additives such as pore-formers may be added to the coating solution. ii. Microencapsulation 20 Used to encapsulate small particles of drug, solution of drug, or even gases in a coat, usually a polymer coat via: A. Coacervation: 1- Simple 1- The liquid or solid to be encapsulated is dispersed in a solution of polymer with which it is miscible. 2- The nonsolvent for the polymer is added to form a polymer coacervate (polymer-rich) layer around the disperse phase – cool = crosslinking = form capsule walls.  2- Complex 2 oppositely charged polymers in solution (under certain conditions). The interaction of the two polymers decreases their solubility = deposition of the polymer layer (coacervate) at the particle-solution interface = then crosslinked. Ex of polymers used for coacervation: gelatin, gum Arabic (acacia), hydroxyethylcellulose, starch, poly(vinyl alcohol), and cellulose nitrate.  B.Interfacial polymerization 21 Based on the reaction between oil-soluble and water-soluble monomers at the oil- water interface of w/o or o/w emulsions. The monomers diffuse to the oil-water interface & react to form a polymeric membrane; hence, the term interfacial polymerization. The drug is dissolved in the disperse phase. The size of the microcapsules depends on the size of the emulsion droplets. EX: The polyamide coat is formed by interfacial condensation of water-soluble alkyldiamines with oil-soluble acid dichlorides. C. Solvent evaporation The polymer + drug are dissolved or suspended in a water-immiscible volatile solvent. The yield is dispersed in an aqueous solution + surfactant, to form an emulsion. Evaporate the organic solvent = small polymer microcapsules ppt from the emulsion. B. Matrix Devices = inert polymeric matrix in which a drug is dissolved or uniformly dispersed. 22 A. Homogeneous matrix. Drug = dissolved or dispersed to form a homogeneous matrix. The release of drugs depends on square root of time for a homogeneous (monolith) matrix. The amount of drug released per unit area: Determine by Higuchi's equation, Assumed that the solid drug dissolves from the surface layer Mt = [CsD(2A-Cs)t]1/2 and that this layer becomes Mt = amount of drug released per unit area. exhausted of dispersed particles. A = Total amount of drug present per unit volume in matrix. Cs = drug saturation solubility per unit volume in the matrix. D = diffusion coefficient in the matrix,  B. Porous (Heterogeneous) The matrix is made of a hydrophobic polymer with negligible drug permeation. Matrix 23 Release of drug is triggered by the ingress of water or GI fluids into the pores and channels, followed by dissolution and diffusion of drug molecules. Ex of polymers used in porous matrix: copolymers of methylmethacrylate and methyl acrylate, poly(vinyl chloride), and polyethylene. C. Hydrophilic matrix The drug release occurs by gelation and diffusion. The size and shape of the matrix change as water penetrates into the system. Ex of polymers; sodium alginate, carboxymethylcellulose, sodium carboxymethyl- cellulose, and hydroxypropyl methylcellulose.  2. Dissolution Controlled Systems A. Matrix Dissolution controlled systems 24 The matrix system can be prepared as follow:  The drug is dispersed or dissolved within a slowly soluble polymeric matrix or via direct compression (drug + polymer + other excipients) into tablets.  The drug is released as the matrix is eroded & the rate of release is controlled by the rate of penetration of the gastric fluid into the matrix.  The rate of penetration depends on the porosity of the matrix among other factors.  B. Encapsulated Dissolution Controlled System 25 Prepared by coating the drug with slowly dissolving polymeric materials. Once this membrane has dissolved, the drug core is available for immediate release and absorption. Controlled drug release is achieved by adjusting the thickness and hence the dissolution rate of the polymeric membrane. Consequently, by compressing multiple particles of drug with varying thickness, which results in varying erosion times, into a tablet, it is possible to obtain a uniform sustained release. Drug particles without a polymeric barrier are often included for immediate release of the drug. Examples of materials used for coating of particles are cellulose acetate butyrate, cellulose acetate phtalate, ethylcellulose, shellac, gelatin, and carnuba wax.  Polymer membrane permeation controlled DDS  Reservoir is solid drug or dispersion of solid drug in liquid or solid medium.  Drug enclosed in reservoir and reservoir is enclosed in rate limiting polymeric membrane. nonporous Polymeric microporous membrane semipermeable Spansules (Sustained Release Capsules)  3. Osmotically Controlled Systems Osmotic pump 28 The osmotic device consists of: A core of a drug alone or drug + osmotic agent. Surrounded by a semipermeable polymer membrane with an orifice for delivery of the drug. Ex of polymers used to make semipermeable membranes: cellulose acetate, ethylcellulose, polyvinyl chloride, and polyvinyl alcohol. Mechanism: Device + body fluids= the osmotic agent draws in water through the semipermeable membrane & increase volume =develops pressure inside the device. The flow of saturated solution of drug out of the device through the delivery orifice relieves the pressure inside. This process continues at a constant rate (releasing a constant amount of drug per unit time) until the entire solid agent has been dissolved.  Osmosis-Controlled Drug Release smogen: Sucrose, Mannitol  The drug release rate is virtually unaffected by the pH of the environment and is essentially constant as long as the osmotic gradient remains constant (i.e., until the excess undissolved drug is depleted, at which time the release rate decreases to zero). The pioneer oral osmotic pump drug delivery system is the Oros developed by Alza. 30 The drug release is affected by: saturated solubility of the drug, osmotic pressure, size of the delivery orifice, and type of membrane. The release rate = zero-order as long as the concentration of drug solution (Cs) is above saturation.  4. Ion-Exchange Resins Controlled Systems 32 Crosslinked polymer networks with ionizable groups capable of exchanging ions of the same charge present in solution. They are often prepared as beads or particles. They are insoluble in water. EX: cation exchangers or anion exchangers The drug-resin complex may be tableted, encapsulated, or suspended in an aqueous solution for oral administration. The drug-resin complex may be coated with a suitable polymer to further control the release of drug.  The mechanism of action of drug release from ion exchange resins may be depicted as follows: 33 Ions must diffuse into and out of the resin for exchange to occur. The release rate is affected by:  the diameter of the resin beads,  the degree of crosslinking within the resin,  the pKa of the ionizable resin group, and  electrolyte concentration in the microenvironment of drug release. THANK YOU FOR YOUR ATTENTION