Controlled Release Tablets - L7 PDF

Controlled release tablets Parijat Kanaujia, PhD Vice President, Injectable Product Development Clinuvel Pharmaceuticals Singapore 08 Oct 2024 Learning outcomes Motivation for altering the release profile of drugs Various types of tablets based on the release rate Ways of controlling the rel...

Controlled release tablets Parijat Kanaujia, PhD Vice President, Injectable Product Development Clinuvel Pharmaceuticals Singapore 08 Oct 2024 Learning outcomes Motivation for altering the release profile of drugs Various types of tablets based on the release rate Ways of controlling the release of drugs from tablets Impact on the patient’s compliance and improved therapeutic outcomes. Tablet classification based on Drug release USP classifies the tablet dosage forms in two groups: Conventional (Immediate release) tablet Modified release tablets Delayed Release tablets Controlled Release tablets Sustained Release tablets Drug release from a tablet Drug release Pharm Res. 2017; 34(5): 890–917 Modified drug release from a tablet Modified release: suggests release rates which are different from fast- release. Controlled release: suggests true control of drug release rates Sustained/prolonged release: suggests prolonged release and prolonged plasma levels Pulsatile release: means the release of more than one dose of drug from a given system Timed/delayed release: suggests release of drug after a specified period of time Triggered release: applies to systems from which drug release is stimulated by an external or endogenous signal Delayed release/Enteric coated tablets A delayed-release dosage form is designed to release the drug at a time other than promptly after administration. The delay may be time based or based on the influence of environmental conditions, like gastrointestinal pH. Release is triggered by a change in pH GIT-pH and residence time Delayed release/Enteric coated tablets: Why? To protect the acid-labile drug substances from the acidic pH of gastric acid. Such drug substances include diclofenac, erythromycin, mesalamine, omeprazole etc. To prevent gastric distress/ulceration or nausea due to irritation caused by certain drugs such as aspirin and certain nonsteroidal anti-inflammatory compounds. To deliver drugs that are optimally absorbed in the small intestine to their primary absorption site in their most concentrated form. To provide a delayed release component to repeat action tablets. Delayed release/Enteric coated tablets-Polymers Delayed release tablets are IR tablets coated with polymer which exhibit pH solubility. These polymers are insoluble at pH 6 or below (stomach) but above pH 6 (intestine), the functional group ionized thus solubilizing the polymer. These polymers are known as enteric polymer and tablets coated with these polymer are known as enteric coated tablets. Polymers used are Cellulose acetate phthalate (CAP) Hydroxypropyl methyl cellulose phthalate (HPMCP) Hydroxypropyl methyl cellulose acetate-succinate (HPMCAS) Polyvinyl acetate phthalate (PVAP) Methacrylic acid copolymers (Eudragit ® NE 30 D, L100, S100) Delayed release/Enteric coated tablets- Drug release Controlled release tablets US Pharmacopoeia defined modified release dosage “the one for which the drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms.” The terms “controlled release (CR)”, “prolonged release”, “sustained or slow release (SR)” and “long-acting (LA)” have been used synonymously with “extended release”.  Controlled release Vs sustained release Controlled drug delivery- which delivers the drug at a predetermined rate for a specified period of time. Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration. Sustain release dosage form- is defined as the type of dosage form in which a portion i.e. (initial dose) of the drug is released immediately (loading dose), in order to achieve desired therapeutic response more promptly, and the remaining (maintenance dose) is then released slowly there by achieving a therapeutic level which is prolonged, but not maintained constant. Sustained release implies slow release of the drug over a time period. It may or may not be controlled release. Controlled release Vs Immediate release Terminology: MEC, MTC, therapeutic window half-life Controlled release Vs Immediate release SAW TOOTH PATTERN Why Controlled release ? Clinical Advantages Reduction in frequency of drug administration Improved patient compliance Reduction in drug level fluctuation in blood Reduction in total drug usage when compared with conventional therapy Reduction in drug accumulation with chronic therapy Reduction in drug toxicity (local/systemic) Stabilization of medical condition (because of more uniform drug levels) Improvement in bioavailability of some drugs because of spatial control (drug release at the site absorption) Economical to the health care providers and the patient Why Controlled release ? Commercial / Industrial Advantages Illustration of innovative/technological leadership Product life-cycle extension Product differentiation Market expansion Patent extension Problems associated with Controlled release tablets Delay in onset of drug action Possibility of dose dumping in the case of a poor formulation strategy Increased potential for first pass metabolism Greater dependence on GI residence time of dosage form Possibility of less accurate dose adjustment in some cases Cost per unit dose is higher when compared with conventional doses Not all drugs are suitable for formulating into ER dosage form Drug Selection: Biopharmaceutics and pharmacokinetics factors Biological half-life (t ½): The shorter the t ½ of a drug the larger will be the fluctuations between the maximum steady state concentration and maximum steady state concentration upon repetitive dosing. Thus drug product needs to be administered more frequently. Minimum effective concentration (MEC) : If a minimum effective concentration, MEC is required either frequent dosing of a conventional drug product is necessary or a controlled release preparation may be chosen. Dose size and Extent of duration: The longer the extent of duration the larger the total dose per unit delivery system needs to be. Hence there is a limitation to the amount of drug that can be practically incorporated into such a system. Relatively long t1/2 or fluctuation desired at steady state: It is the belief of some that neither a SR nor a CR delivery system is needed or useful for drugs having a t½ of 12 hours or more. A drug having a t ½ between 12 and 72 hours may be designed for a CR delivery system permitting application for every two to three days. Pharmacokinetic phases of a drug Molecules 2021, 26, 5905  Properties of ideal drug candidate for Controlled release Physico-chemical Properties of ideal drug candidate Properties Range Molecular weight/ size < 1000Da Solubility >0.1 μg/ml for pH 1 to pH 7.8 pKa Non ionized moiety > 0.1% at pH 1 to pH 7.8 Apparent partition coefficient High Release Should not be influenced by pH and enzymes Stability Stable in pH 1-6 Dose Low to moderate  Properties of ideal drug candidate for Controlled release Biological Properties of ideal drug candidate Properties Range Half life Short half life Metabolism Should not have hepatic first pass metabolism Absorption mechanism Passive Diffusion General absorbability All segments of GIT Absolute Bioavailability Very high(>75%) Therapeutic window Wide Steady state concentration (Css) lower Css and smaller Vd Mechanisms for controlling the release Several approaches have been developed for the formulation of controlled release dosage form including: Dissolution controlled release ❖ Reservoir system ❖ Matrix system Diffusion controlled release ❖ Reservoir type devices ❖ Matrix type devices Diffusion and Dissolution controlled systems Ion exchange resins Osmotically controlled release Gastroretentive system Ultra long acting oral systems Dissolution controlled formulations Dissolution is defined as solid substance solubilized in a given solvent. The rate of dissolution of the drug is controlled by slowly dissolving polymers or by micro encapsulation. Dissolution CRSs designed as reservoirs or matrix systems using slowly dissolving polymers whereby dissolution rate defines the release rate of drugs. Microencapsulated Particles/Coated Compress the drug with a slow granules compressed as tablet dissolving carrier Noyes-Whitney equation for drug dissolution dm/dt = solute dissolution rate (kg.s-1 ) m = mass of dissolved material (kg) t = time (s) A = surface area of the solute particle (m2 ) d = thickness of the concentration gradient (m), D = diffusion coefficient (m.s-1 ), which is related, in part, to the viscosity of the solvent Cs = particle surface (saturation) concentration (kg or moles/L) Cb = concentration in the bulk solution (kg or moles/L)  Reservoir dissolution controlled formulation: Coating These systems method involves coating of individual particles (or) granules of drug with a slow dissolving material. The coated particles can be compressed directly into tablets (or) placed in capsules. The rate of dissolution of the drug (and thereby availability for absorption) is controlled by micro encapsulation. Once the coating is dissolved, the drug becomes available for dissolution. By varying the thicknesses of the coat and its composition, the rate of drug release can be controlled. Effect of coating on release rate In vitro release patterns of [14c] dextro-amphetamine sulfate pellets pan-coated with various amounts of a fat-wax coating. A, 17% coating; B, 15% coating; C, 13% coating; D, 11% coating; E, 9% coating; F, 7% coating; G, selected blend of uncoated and coated pellets. Controlled Drug Delivery, Robinson J.R. and Lee VHL, Page 384 Reservoir dissolution controlled formulation: Microencapsulaton Microencapsulation is the protective technology of encapsulating solid, liquid or gas materials into micro particles with a diameter of 1– 1000 μm, forming a core shell structure. The coating material can be selected from a wide variety of natural and synthetic polymers, depending on the material to be coated and the release characteristics desired. Process Type of material for coating Shell Coacervation/phase separation Water soluble polymers (polymer) Core Interfacial polymerization Water soluble and insoluble monomers (Drug) Electrostatic method Oppositely charged aerosols Precipitation Water or solvent soluble polymers Hot melt Low molecular weight lipids Salting out Water soluble polymers Solvent evaporation Solvent soluble polymers  Reservoir dissolution controlled formulation: Microencapsulaton Process Type of material for coating Coacervation/phase separation Water soluble polymers Interfacial polymerization Water soluble and insoluble monomers Electrostatic method Oppositely charged aerosols Precipitation Water or solvent soluble polymers Hot melt Low molecular weight lipids Salting out Water soluble polymers Solvent evaporation Solvent soluble polymers  Matrix dissolution controlled formulation: Monolithic system Drug is compressed with a slowly dissolving carrier into a tablet form. Drug dissolution rate is controlled by the rate of penetration of the dissolution fluid into the matrix which is controlled by porosity of the tablet matrix, the presence of hydrophobic additives, and the wettability of the tablet and particle surface. The porosity of the tablet / surface area available, can be altered in a compressed tablet by compression force, adhesion between adjacent particles as well as size and shape of the particles In addition, hydrophobic fillers can be added to decrease the effective porosity by limiting the number of pores that can be penetrated by the eluting fluid. Black color drug particles dispersed in slowly dissolving polymer Comparative release from IR and CR (matrix) formulations Plasma concentrations of procainamide after repeated doses of slow release tablets every 8 hr (o) and conventional tablets every 4 hr ( ) (mean and SEM). Controlled Drug Delivery, Robinson J.R. and Lee VHL, Page 389 Meltrex Technology® for controlled release Hot melt extrusion to tablet technology Well established process in polymer, food and plastic industry Suitable for pharmaceutical formulations Solvent free green formulation technology In line PAT can be used to monitor product quality Easily scalable Meltrex Technology® for controlled release Alcohol induced dose dumping The sustained release formulations contain more active than normal formulations. The integrity of the barrier controlling the release rate is very critical. Breaching this barrier can result in an increased exposure to the active drug (dose dumping) resulting in possible safety issues, and changes in clinical efficacy Impact of concomitant intake of ethanol on the in vivo release of drugs from modified release oral formulations has become an increasing concern. Meltrex Technology® for controlled release Alcohol induced dose dumping Verapamil retard® 240mg Meltrex Technology® for controlled release Alcohol induced dose dumping Verapamil Meltrex® 240mg W. Roth et al. / International Journal of Pharmaceutics 368 (2009) 72–75 Dissolution controlled formulations: Limitations A major disadvantage of matrix devices is that drug release rate continuously decreases with time. This is a consequence of increased diffusional distance and decreased surface area at the penetrating solvent front. In order to achieve zero order release from matrix devices, it will be necessary to select a geometry that compensates the increase in diffusional distance with a corresponding increase in surface area for dissolution. Diffusion controlled release formulations It is a major process for absorption in which no energy is required. Drug molecules diffuse from a region of higher concentration to lower concentration until equilibrium is attained and it is directly proportional to the concentration gradient across the membrane. Release rate is determined by its diffusion through a water-insoluble polymer. There are two types of diffusion devices: o Reservoir diffusion system o Matrix diffusion system  Diffusion controlled release formulations Diffusion controlled release Diffusion controlled release formulations: Reservoir Devices In this system, a water-insoluble polymeric material encases a core of drug. Drug will partition into the membrane and exchange with the fluid surrounding the particle or tablet. Additional drug will enter the membrane, diffuse to the periphery, and exchange with the surrounding media. The amount of drug released, the release rate dM/dt is given by equation: dM/dt = ADK C/ ℓ where A is the area, D is the diffusion coefficient, K is the partition coefficient of drug between the membrane and drug core, ℓ is the diffusional path length (thickness of coat in the ideal case), and C is the concentration difference across the membrane. To obtain a constant drug release rate from a reservoir device it is necessary to maintain constant area, diffusional path length, concentration, and diffusion coefficient. Diffusion CR formulations: Reservoir Devices preparation Drug containing cores in tablets Compression coating of drug cores Air suspension coating of drug pellets Drug particles: Microencapsulation of drug particles to be incorporated into tablets or capsules. In most cases, drug is incorporated in the coating film as well as in the core of the microcapsule so as to provide the initial and sustaining doses, respectively. Diffusion CR formulations: Reservoir Devices release rate Several factors which can affect the release rate are: Partition of drug between membrane and core Thickness of the coating Polymer ratio in the coating Hardness of microcapsules A combination of dissolution and diffusion may be involved in drug release from microencapsulated material. However, if the material used for encapsulation is chosen properly, diffusion control will predominate over dissolution. Diffusion CR formulations: Reservoir Devices release rate A comparison of the release relationship of microcapsular tablets of three different hardnesses in 0.1 M phosphate media. o, 8 hardness; , 5 hardness; □, 2 hardness. Controlled Drug Delivery, Robinson J.R. and Lee VHL, Page 396 Diffusion controlled release formulations: Matrix devices Rigid Matrix Diffusion: Materials used are insoluble plastics such as PVP & fatty acids. Swellable Matrix Diffusion: Also called as Glassy hydrogels and popular for sustaining the release of highly water soluble drugs. The materials used are hydrophilic gums- Natural- Guar gum, Tragacanth. Semi-synthetic -HPMC, CMC, Xanthan gum. Synthetic -Polyacrylamides Diffusion controlled release formulations In this system, a solid drug is dispersed in an insoluble matrix. The rate of drug release is dependent on the rate of drug diffusion but not on the rate of solid dissolution. The Higuchi equation describes the drug release from this system Q = [D/(2A −  Cs )Cs t]1/2 where Q = weight in grams of drug released per unit surface area; D = diffusion coefficient of drug in the release medium;  = porosity of the matrix;  = tortuosity of the matrix; Cs = solubility of drug in the release medium; and A = concentration of drug in the tablet, expressed as g/ml. The assumptions made in deriving are as follows. 1. A pseudo-steady state is maintained during release. 2. A » Cs , i. e. , excess solute is present. 3. C = 0 in solution at all times (perfect sink). 4. Drug particles are much smaller than those in the matrix. 5. The diffusion coefficient remains constant. 6. No interaction between the drug and the matrix occurs. For purposes of data treatment, the above equation is usually reduced to: Q = k t 1/2 Therefore, a plot of amount of drug released versus the square root of time should be linear if drug release from the matrix is diffusion controlled. Diffusion controlled release formulations: Matrix devices The release of drug from a homogeneous matrix diffusion CR formulations can be control by varying the following parameters: 1. Initial concentration of drug in the matrix 2. Drug solubility 3. Porosity 4. Tortuosity 5. Leaching solvent composition 6. Polymer system making up matrix Zero-order release is not commonly achieved in vivo using these systems. The most common explanation in this problem is changing diffusional path lengths. Skyepharma’s Geomatrix® Technology Geomatrix® is highly versatile and can be applied to a wide range of different drugs to achieve a variety of different release profiles. The modulation of the drug release profile is achieved by using a multi-layered tablet that combines two key features :  Use of highly swellable hydrophilic polymers.  Dynamic control of the surface of the layer containing the drug that is exposed to surrounding fluids. Skyepharma’s Geomatrix® Technology: Applications Geomatrix® is a highly versatile platform that can be used to create a wide variety of different release profiles. Application of Geomatrix® include:  A wide range of sustained release profiles  Controlled release of both poorly and highly soluble drugs  Zero order and bi-phasic release of drugs (either rapid then slow or ascending profiles)  Release of two or more drugs at different rates  Simultaneous or phased release of several drugs at individualised release rates from a single tablet  Skyepharma’s Geomatrix® Technology: Requip® XL REQUIP XL Extended-Release Tablets are formulated as a three-layered tablet. A central, Ropinirole-containing, slow-release layer, and 2 placebo outer layers acting as barrier layers which control the surface area available for drug release. Inactive ingredients consist of carboxymethylcellulose sodium, glyceryl behenate, hydrogenated, hypromellose, lactose monohydrate, maltodextrin, mannitol, povidone Diffusion and dissolution controlled release formulations The drug core is enclosed with a partially Ethyl cellulose soluble membrane. membrane Drug Pores are created due to dissolution of parts of membrane. It permits entry of aqueous medium into core & drug is dissolved or diffused out of the system. Ex- Ethyl cellulose & methyl cellulose mixture where methyl cellulose dissolves in water & Pores formed by creates pores of insoluble ethyl cellulose. methyl cellulose  Zolpidem tartrate extended-release tablets: Ambien® Zolpidem tartrate is a sedative, also called a hypnotic. It affects neurochemicals in brain that may become unbalanced and cause sleep problems (insomnia). Half life is 2.8 hours and metabolized in the liver Ambien CR (zolpidem tartrate extended-release tablets) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. AMBIEN CR consists of a coated two-layer tablet: one layer that releases its drug content immediately and another layer that allows a slower release of additional drug content. The release of API is controlled by matrix using HPMC polymer. Immediate release layer Controlled release layer Pharmacokinetics of Ambien CR Ion Exchange resins (IER) Ion exchange resins are water-insoluble materials containing anionic or cationic groups in repeating positions on the resin chain. The drug-charged resin is prepared by Batch technique – after suitable pretreatment, a specific quantity of the granular IER is agitated with the drug solution until the equilibrium is established (b) Column technique – resinate is formed by passing a concentrated solution of drug through the IER- packed column until the effluent concentration is the same as the eluent concentration. The drug-resin is then washed to remove contaminant ions and dried to form particles or beads and then coated with a semi permeable coating material such as Ethyl Cellulose. This system reduced the degradation of drug in GIT. Drug release characteristics depends only on the ionic environment of the resin containing drug and should therefore be less susceptible to environmental conditions, such as enzyme content and pH, at the site of absorption. This approach not suitable for skin due to lack of ions and parenteral delivery due to biodegradation of resins. Ion Exchange resins When a high concentration of an appropriately charged ion is in contact with the ion-exchange group, the drug molecule is exchanged and diffuses out of the resin to the bulk solution according to the following scheme. Anion exchange resin [N(CH3)]+ X~ + Z~ ------------> Resin [N(CH3)]+Z ~ + X~ or Cation exchange resin (SO3 ) ~ A+ + B+ ---------------> Resin (SO3 ) ~ B+ + A+ where X~ and A+ are drug ions. Ion Exchange resins Mechanism of drug release from resinate Drug discovery today Vol. 6, No. 17 September 2001 Ion exchange resins used in pharmaceuticals Resin Properties Cholestyramine Quaternary ammonium anion exchange resin Used in reducing blood cholesterol level Colestipol Anion exchange resin with copolymer of diethylenetriamine Used to remove bile acids from the body Sulfonated Cation exchange resin with copolymer of styrene sulfonated styrene and divinylbenzene Hydrocodone and Chlorpheniramine resinate Osmotic controlled delivery systems In these types of systems osmotic pressure is the driving force that generates constant drug release. Osmotic tablets are not affected by physiological factors that result from type of food intake, gastric pH, and patient-to-patient variability. The delivery strategy and release profile for this system can be customized to suit various APIs with a wide range of thermodynamic properties. Due to this uniqueness, osmotic systems have witnessed increasing interest and the number of marketed products has doubled in the past decades. Osmotic controlled delivery systems: Basic principles When an osmotic system is exposed to water or any body fluid, water will flow into the core due to an osmotic pressure difference across the coating membrane. Under this osmotic pressure gradient, the volume flow of water into the core reservoir, dV/dt, is expressed as: dV/dt = (Ak/h) ( - P) where A, k and h are the area, membrane permeability, and thickness, respectively,  is the osmotic pressure difference, and P is the hydrostatic pressure difference. If the orifice is sufficiently large, the hydrostatic pressure difference will be small compared to the osmotic pressure difference, and equation becomes: dV/dt = (Ak/h)  The drug will be pumped out of the system through the orifice at a controlled rate, dM/dt, which is equal to the volume flow rate of water into the core multiplied by the drug concentration, Cs. Thus, dM/dt = (dV/dt)Cs Osmotic controlled delivery systems: Basic principles Trends in Biotechnology, May 2022, Vol. 40, No. 5, 605-619  Osmotic controlled delivery systems: Polymers for coating By design, the coating membrane is rigid and non-swelling so that it is able to maintain the structural integrity of the system during the course of drug release. The coating is impermeable to drug solutes, but is permeable to gastrointestinal fluid. The permeability of the rate controlling membrane is a governed by diffusion coefficient and solubility of water in the polymeric membrane, structure of the polymer, relative pressure difference across the membrane, thickness of the membrane, as well as temperature. The flux of water through a semipermeable membrane can be determined and be expressed as water vapor transmission rate (WVTR). WVTR The steady state rate at which water vapor permeates through a film at specified conditions of temperature and relative humidity. Values are expressed in g/100 in2/24 h Osmotic controlled delivery systems: Polymers for coating WVTR (g/100in2/24h/ Polymer 1mm thick film) Cellulose acetate 40-75 Cellulose acetate butyrate 50 Ethylcellulose 75 Ethylene vinyl acetate 1-3 Methylcellulose 70 Polyvinyl alcohol 100 Polypropylene 0.7 Polyurethane 30-150 Polycarbonate 8 Osmotic controlled delivery systems: Elementary osmotic pump (EOP) ALZA corporation’s first-generation oral osmotic tablets, called the elementary osmotic pump (EOP) is a single-layer tablet coated with semipermeable polymer and a laser-drilled exit hole. Indomethacin, Osmosin®, and phenylpropanolamine, AcutrimTM were launched in the early 1980s but unexpectedly recalled and withdrawn from the market due to severe side effects, such as GI irritation and perforation of the intestinal wall. Osmotic controlled delivery systems: Controlled porosity osmotic pump (CPOP) To improve the EOP design and minimize the risk of drug-induced local irritation, single-layer tablet, the controlled-porosity osmotic pump (CPOP) designed. CPOP differs in its release mechanism as there is no preformed orifice on the membrane, but instead, the CPOP’s semipermeable membrane creates pores when the tablet is in contact with water, thereby allowing the release of the drug. Best suited for water-soluble APIs.  Osmotic controlled delivery systems: Push pull osmotic systems (PPOP) EOP exhibits an incomplete and first-order release for insoluble drugs, while CPOP requires the drugs to be solubilized within the core for an effective release through the pores. PPOP has an additional internal layer, called the ‘push layer’, which would help push the drug layer suspension out of the orifice at a controlled rate. The push layer is made up of swellable polymer (such as polyethylene oxide) that expands upon contact with water. The drug delivery system that incorporated this multilayer design was termed the push– pull osmotic pump (PPOP). Initial During operation  Osmotic controlled delivery systems: Polymers as Swelling agents Swelling agents employed in the design of multilayer osmotic tablets are typically hydrophilic crosslinked or entangled polymers, which exhibit swelling from 10 to 1000 times their original size upon contact with an aqueous medium.  Osmotic controlled delivery systems: Push stick osmotic systems (PSOP) To develop an ideal delivery system that could deliver methylphenidate, an API used to treat attention deficit hyperactivity disorder in children and characterized by a short half-life. This led to the development of the push-stick osmotic pump (PSOP), a modified version of the PPOP technology that combined immediate and sustained drug release phases. Ideally suitable for delivering poorly water-soluble or highly water-soluble drug candidates at a constant rate and can accommodate low to moderate drug doses. Trends in Biotechnology, May 2022, Vol. 40, No. 5 Osmotic controlled delivery systems: Sandwiched osmotic tablet (SOTS) A tablet core consisting of a middle push layer and two attached drug layers is coated with a SPM. Initial During operation  Osmotic controlled delivery systems Factors affecting drug release from oral osmotic pumps Release rate directly proportional to the solubility of drug within the core. Both highly and poorly water soluble drugs, per se, are not good candidates for osmotic Drug solubility delivery. Number of approaches available to deliver drugs having extremes of solubility. Release rate directly proportional to the osmotic pressure of the core formulation. Osmotic Additional osmagent required if drug does not possess suitable osmotic pressure. pressure Should be within the desired range to control the drug release. Delivery orifice Number of approaches available to create orifice within the membrane. Release rate affected by the type and nature of membrane- forming polymer, thickness of the membrane, and presence of other additives (type and Coating nature of plasticizer, flux additives, etc.). membrane Membrane permeability can be increased or decreased by proper choice of membrane- forming polymers and other additives. Viscosity Both drug layer and push layer viscosity affect the release rate  Osmotic controlled delivery systems: Selection of system Single-composition osmotic tablet (SCOT) is a modified elementary osmotic pump (EOP) (single layer) with a highly porous membrane that accommodates high drug-loading. Self-emulsifying elementary osmotic pump (SEOP) Trends in Biotechnology, May 2022, Vol. 40, No. 5 Osmotic controlled delivery systems: Advantages ▪ Zero order release ▪ Pulsed or delayed release function can be achieved ▪ Release is independent of gastric pH and other physiological conditions ▪ Release mechanism is independent of properties of drug ▪ High degree of in vitro-in vivo corelation in performance Osmotic controlled delivery systems: Marketed products Trends in Biotechnology, May 2022, Vol. 40, No. 5 Osmotic controlled delivery systems: Marketed products Trends in Biotechnology, May 2022, Vol. 40, No. 5 Procardia XL: PPOS Name of Drug: Nifedipine Nifedipine is an antihypertensive drug having half-life of 2 hrs. It is practically insoluble in water. Comparative pharmacokinetic of Procardia XL Tegretol® XR- SEOP Carbamazepine self emulsifying osmotic pump Name of Drug: Carbamazepine Carbamazepine is an anticonvulsant drug having half-life of 30 hrs. It is poorly soluble in water.  Tegretol® XR- Pharmacokinetics Subjects were seated and administered 400-mg oral doses every 12 h (at approximately 0700 and 1900 h) for 4 days, and once (at approximately 0700 h) on the 5th day.  Methylphenidate HCL Triple layer Osmotic pump: Concerta® Osmotically active trilayer core surrounded by a semipermeable membrane with an immediate- release drug overcoat. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There is a precision-laser drilled orifice on the drug- layer end of the tablet. In an aqueous environment, such as the gastrointestinal tract, the drug overcoat dissolves within one hour, providing an initial dose of methylphenidate. Water permeates through the membrane into the tablet core. As the osmotically active polymer excipients expand, methylphenidate is released through the orifice. Methylphenidate HCl Triple layer Osmotic pump: Concerta® Name of Drug: Methylphenidate HCl Carbamazepine is a CNS stimulant drug used to treat attention deficit hyperactivity disorder (ADHD). The drug has half-life of 2-3 hrs and It is freely soluble in water. Gastroretentive systems The maximum achievable sustained drug release is subject to inter individual variations, with an average gastrointestinal (GI) transit time of around 24 h in humans. The retention of oral dosage forms in the upper GIT causes prolonged contact time of drug with the GI mucosa, leading to higher bioavailability, and hence therapeutic efficacy, reduced time intervals for drug administration, potentially reduced dose size and thus improved patient compliance. Gastroretentive systems : Selection of APIs Gastroretentive DDSs exhibiting controlled drug release are significantly important for drugs which are: Acting locally in the stomach (e.g. antibiotics against Helicobacter Pylori, antacids and misoprostol. Absorbed incompletely due to a relatively narrow window of absorption in the GIT, such as cyclosporin, ciprofloxacin, furosemide, L-DOPA, p-aminobenzoic acid and riboflavin. Unstable in the intestinal or colonic environment such as captopril or Exhibit low solubility at high pH values such as verapamil HCl, diazepam and chlordiazepoxide. Gastroretentive DDS, are not suitable for drugs that may cause gastric lesions, e.g., non-steroidal anti-inflammatory agents drug substances that are unstable in the strong acidic pH of the stomach or which are absorbed throughout the gastrointestinal tract Gastroretentive systems : Types The most common approaches used to increase the gastric residence time of pharmaceutical dosage forms include a) Co-administration of the DDS with pharmacological agents that slow gastric motility- ingestion of indigestible polymers or fatty acid salts which change the motility pattern of the stomach to a fed state, thereby decreasing the gastric emptying rate b) Bioadhesive systems- use of bioadhesive polymers that can adhere to the epithelial surface of the stomach like crosslinked polyacrylic acids, sodium carboxymethyl cellulose (CMC), sodium alginate and carrageenan c) Size increasing systems, which are either due to expansion and shape modification or swelling- involves retaining the dosage form in the stomach by increasing its size above that of the pyloric sphincter d) Density controlled systems which are either, high density systems or low density systems Gastroretentive systems: Size increasing systems To facilitate swallowing, the dosage form should have an initially small size. Once in the stomach, the dosage forms should quickly increase in size, to prevent premature emptying through the pylorus. To avoid accumulation following multiple administrations, the system should be cleared from the stomach after a predetermined time interval. The dosage form should have no effect on gastric motility or emptying process The increase in the systems’ size can be based on several principles, including expansion due to swellable excipients or unfolding and/ or shape modification (to complex geometric shapes) in the stomach. Gastroretentive systems: Effervescent Floating The inner layer of effervescent agents containing sodium bicarbonate and tartaric acid is divided into 2 sublayers to avoid direct contact between the 2 agents. These sublayers are surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. When this system is immersed in the buffer at 37ºC, it settles down and the solution permeates into the effervescent layer through the outer swellable membrane. CO2 is generated, producing swollen pills (like balloons) with a density less than 1.0 g/mL. The system has good floating ability independent of pH and viscosity and the drug (para-amino benzoic acid) is released in a sustained manner AAPS PharmSciTech 2005; 6 (3) Gastroretentive systems: Swellable Triple layer system HPMC and poly (ethylene oxide) are rate-controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple-layer matrix for controlled delivery, while bismuth salt was included in one of the outer layers for instant release. The floatation was accomplished by incorporating a gas-generating layer consisting of sodium bicarbonate: calcium carbonate (1:2 ratios) along with the polymers. Used to prolong the gastric residence time of triple drug regimen (tetracycline, metronidazole, and clarithromycin) in Helicobacter pylori–associated peptic ulcers. AAPS PharmSciTech 2005; 6 (3)  Gastroretentive systems : Swellable floating system Hydrodynamically balanced sustained release tablets containing drug and hydrophilic hydrocolloids, which on contact with gastric fluids at body temperature formed a soft gelatinous mass on the surface of the tablet and provided a water-impermeable colloid gel barrier on the surface of the tablets. The drug slowly released from the surface of the gelatinous mass that remained buoyant on gastric fluids AAPS PharmSciTech 2005; 6 (3) Gastroretentive systems : Marketed products Product Active ingredient Technology Madopar HBS Levodopa and benserzide HBS floating tech Valrease Diazepam HBS floating tech Liquid Gaviscon Alginic acid and sodium HBS floating tech bicarbonate Topalkan Aluminum magnesium antacid HBS floating tech Almagate Antacid HBS floating tech flotcoat Glumetza Metformin Size increasing Proquin Ciprofloxacin Size increasing Ultra long acting oral systems Treatment of diseases like malaria, TB and HIV is limited by the logistic challenges of reaching large rural populations and ensuring patient adherence to adequate pharmacologic treatment. An oral, ultra–long-acting capsule that dissolves in the stomach and deploys a star-shaped dosage form that releases drug while assuming a geometry that prevents passage through the pylorus yet allows passage of food, enabling prolonged gastric residence is under development. This gastric-resident, drug delivery dosage form releases small-molecule drugs for days to weeks and potentially longer. Upon dissolution of the macrostructure, the components can safely pass through the gastrointestinal tract. Ultra long acting oral systems Sci Transl Med. 2016 Nov 16;8(365):365ra157 Ultra long acting oral systems Sci Transl Med. 2016 Nov 16;8(365):365ra157 Ultra long acting oral systems: release of ivermectin Sci Transl Med. 2016 Nov 16;8(365):365ra157 Ultra long acting oral systems: Pharmacokinetics Sci Transl Med. 2016 Nov 16;8(365):365ra157 Selected readings Thank you [email protected]