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MISR University for Science and Technology Access Provided by: Shargel and Yu's Applied Biopharmaceutics and Pharmacokinetics, 8e CHAPTER OBJECTIVES Define modified release drug products...

MISR University for Science and Technology Access Provided by: Shargel and Yu's Applied Biopharmaceutics and Pharmacokinetics, 8e CHAPTER OBJECTIVES Define modified release drug products. Differentiate between conventional, immediate release, extended release, delayed release, and targeted drug products. Explain the advantages and disadvantages of extended release drug products. Describe the kinetics of extended release drug products compared to immediate release drug products. Explain when an extended release drug product should contain an immediate release drug dose. Explain why extended release beads in capsule formulation may have a different bioavailability profile compared to an extended release tablet formulation of the same drug. Describe several approaches for the formulation of an oral extended release drug product. Explain why a transdermal drug product (patch) may be considered an extended release drug product. Describe the components of a transdermal drug delivery system. Explain why an extended release formulation of a drug may have a different efficacy profile compared to the same dose of drug given in as a conventional, immediate release, oral dosage form in multiple doses. List the studies that might be required for the development of an extended release drug product. List the several advantages of drug devices based on modified release drug design. MODIFIED-RELEASE DRUG PRODUCTS AND CONVENTIONAL (IMMEDIATE-RELEASE) DRUG PRODUCTS Most conventional (also called immediate release [IR]) oral drug products, such as tablets, capsules, and solutions, are formulated to release the active pharmaceutical ingredient (API) immediately after oral administration. In the formulation of conventional drug products, no deliberate effort is made to modify the drug release rate. IR products generally provide relatively rapid drug absorption and onset of accompanying pharmacodynamic (PD) effects, but not always. In the case of conventional oral products containing prodrugs, the PD activity may be altered due to the time for conversion from prodrugs to the active drug by hepatic or intestinal metabolism or by chemical hydrolysis. Alternatively, in the case of conventional oral products containing poorly soluble (lipophilic drugs), drug absorption may be gradual due to slow dissolution in or selective absorption across the GI tract, also resulting in a delayed onset time. The term modified release (MR) drug product is used to describe products that are formulated to alter the timing and/or rate of release of the drug and/or site of release. An MR dosage form is a formulation in which the drug release characteristics of the time course and/or location are chosen to accomplish therapeutic or convenience objectives, which is not offered by conventional dosage forms. To achieve a desired therapeutic objective and/or better patient compliance, the pattern of drug release from modified release (MR) dosage forms is deliberately changed from that of a conventional (also called immediate release, IR) dosage formulation. MR drug products are often a more effective therapeutic alternative to conventional or IR dosage forms. The objective of MR drug products for oral administration is to prolong the therapeutic effect of the active drug by controlling the rate of drug absorption from the gastrointestinal (GI) tract. MR formulations release a drug in a controlled manner during the absorption period, so they have advantages over IR formulas such as fewer pills to be taken and less peak−trough fluctuations of Chapter 9: Modified Release Drug Products and Drug Devices, Hong Ding ©2022 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 1 / 56  MISR University for Science and Technology Access Provided by: drug concentration in serum which may be associated with decreased adverse effects. Modified drug delivery p r o d u c t s a n d a d v a n c e d d o s a g e f o r m s c a n p r o v id e cli n i c a l be n e f i t s , t h e r a p e u ti c b e n e f it s , s a f e t y b e n e fi t s a n d e c o n o m i c b e n e fi t s. Clinical benefits: Improvement of patient's compliance, Improved outcomes, Allowing the patients to receive medications at home. Therapeutic benefits: Optimization of the duration of action of the drug, Decreasing dosage frequency, Controlling the site of release, Maintaining constant drug levels. Safety benefits: Reducing adverse effects, Decreasing the number of concomitant medication that the patient must take. Economic benefits: Simplifying administration regimen, A reduction in the overall use of medicinal resources, An overall reduction of health care expenses. Several types of MR oral drug products are as follows. 1. Extended release (ER) drug products. A dosage form that allows at least a 2-fold reduction in dosage frequency as compared to that drug presented as an IR (conventional) dosage form. ER drug products are formulated so that the active drug is available over an extended period of time following administration. ER products can be used for reducing fluctuations in plasma concentrations. Several terms have been used to describe ER formulations. Examples of ER dosage forms include controlled release (CR), sustained release (SR), prolonged release, long-acting (LA), and time release drug products. 2. Delayed release (DR) drug products. A dosage form that releases a discrete portion/portions of drugs at a time later than immediately after administration (USP-NF). An initial portion may be released promptly after administration. The delayed release may be time sensitive or dependent on the environment (eg, GI pH). Enteric coated dosage forms are common DR products (eg, enteric coated aspirin and other NSAID products) that do not dissolve in the acid conditions in the stomach but release the drug in the higher pH of the duodenum. Some manufacturers have combined a delayed release drug product with an ER component. Esomeprazole magnesium (Nexium® 24) capsules contain enteric coated beads with an ER core. Esomeprazole is not stable in acid. The enteric coating prevents the release of esomeprazole in the stomach. In the duodenum, the enteric coating dissolves and the bead’s inner core slowly releases esomerprazole in an extended period. 3. Targeted release (TR) drug products. A dosage form that releases drug at or near the intended physiologic site of action (see Chapter 10). TR dosage forms may have either immediate or extended release characteristics. 4. Repeat action tablet. A type of MR drug product that is designed to release one dose of drug initially, followed by a second or more doses of drug at a later time. It provides the required dosage initially and then maintains or repeats it at desired intervals. This ER drug product delivers an initial therapeutic dose, followed by a slower and constant release. The immediate release component acts as a loading dose is to provide Chapter 9: Modified Release Drug Products and Drug Devices, Hong Ding ©2022 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 2 / 56  MISR University for Science and Technology Access Provided by: immediate or fast drug release to quickly provide therapeutic drug concentrations in the plasma. The rate of release of the maintenance dose is designed so that the amount of drug loss from the body by elimination is constantly replaced. 5. Orally disintegrating tablets (ODTs). ODTs disintegrate rapidly in the saliva after oral administration. ODTs may be used without the addition of water. The drug is dispersed in saliva and swallowed with little or no water. MR drug products are designed for different routes of administration based on the physicochemical, PD, and pharmacokinetic (PK) properties of the drug and on the properties of the materials used in the dosage form (Table 9-1). Several different terms are now defined to describe the available types of MR drug products based on the drug release characteristics of the products. TABLE 9-1 Modified Drug Delivery P r o d u c t s Route of Drug Pr od u ct Examples Comments Admini st rat ion Oral drug products Extended release Diltiazem HCl extended release Once-a-day dosing. Delayed release Diclofenac sodium delayed Enteric-coated tablet for drug delivery into small intestine. release Delayed (targeted) Mesalamine delayed release Coated for drug release in terminal ileum. drug release Oral mucosal drug Oral transmucosal fentanyl Fentanyl citrate is in the form of a flavored sugar lozenge that delivery citrate dissolves slowly in the mouth. Oral soluble film Ondansetron The film is placed top of the tongue. Film will dissolve in 4 to 20 Chapter 9: Modified Release Drug Products and Drug Devices, Hong Ding ©2022 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 3 / 56  MISR University for Science and Technology Access Provided by: seconds. Orally disintegrating Aripiprazole ODT is placed on the tongue. Tablet disintegration occurs rapidly in tablets (ODT) saliva. Transdermal drug Transdermal Clonidine transdermal Clonidine TTS is applied every 7 days to intact skin on the upper arm delivery systems therapeutic system therapeutic system or chest. (TTS) Iontophoretic drug Small electric current moves charged molecules across the skin. delivery Ophthalmic drug Insert Controlled-release pilocarpine Elliptically shaped insert designed for continuous release of delivery pilocarpine following placement in the cul-de-sac of the eye. Intravaginal drug Insert Dinoprostone vaginal insert Hydrogel pouch containing prostaglandin within a polyester retrieval delivery system. Parenteral drug Intramuscular drug Depot injections Lyophylized microspheres containing leuprolide acetate for depot delivery products suspension. Water-immiscible injections (eg, Medroxyprogesterone acetate (Depo-Provera). oil) Subcutaneous drug Controlled-release insulin Basulin is a controlled-release, recombinant human insulin delivered products by nanoparticulate technology. Targeted delivery IV injection Daunorubicin citrate liposome Liposomal preparation to maximize the selectivity of daunorubicin for systems injection solid tumors in situ. Implants Brain tumor Polifeprosan 20 with Implant designed to deliver carmustine directly into the surgical cavity carmustine implant (Gliadel when a brain tumor is resected. wafer) Intravitreal implant Fluocinolone acetonide Sterile implant designed to release fluocinolone acetonide locally to intravitreal implant the posterior segment of the eye. Chapter 9: Modified Release Drug Products and Drug Devices, Hong Ding ©2022 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Page 4 / 56 1 Time-Controlled Drug Delivery Systems Juergen Siepmann and Florence Siepmann Department of Pharmaceutical Technology, College of Pharmacy, Universite´ Lille Nord de France, Lille, France INTRODUCTION The success of a pharmaco-treatment essentially depends on (i) the availability of the drug at the site of action in the living body. It is mandatory that (ii) the intact drug reaches its target site (e.g., a specific receptor in the central nervous system) at concentrations greater than the minimal effective concentration (MEC) are provided. If these two prerequisites are not fulfilled, the therapy fails in vivo, even if the drug has an ideal chemical structure to allow for optimal interactions with the target structure and pharmacodynamic effects. Some of the potential reasons for the inability of a drug to reach its site of action are (i) poor aqueous solubility, (ii) poor permeability across biological barriers, and (iii) rapid clearance out of the living body. In the first case, the drug remains at the site of administration or—in the case of oral administration—is not absorbed from the contents of the gastrointestinal tract (GIT). This is because only dissolved (individualized) drug molecules are able to diffuse and cross the major natural barriers in a living body (e.g., the GIT mucosa or blood-brain barrier). Poor permeability through biological barriers can, for example, be caused by a high molecular weight of the drug (hindering, for instance, diffusional mass transport), poor partitioning into the barrier (membrane), and/or effective efflux systems (e.g., P-glycoprotein pumps). Rapid drug inactivation can be due to fast drug metabolism and/or elimination and can also preventmany drugs from becoming active in vivo, despite of a great therapeutic potential. Furthermore, in various cases, the undesired side effects of a drug, caused in other parts of the living body, can be so severe that the administered dose must be limited, eventually to an extent that does not allow for therapeutic drug concentrations at the site of action. Also in these cases the therapy fails in vivo, since the drug is distributed throughout the living body, and not specifically delivered to the target site. To overcome these restrictions, an ideal drug delivery system should be able (i) to release the drug at a rate that perfectly matches the real need in vivo for the duration ofthe therapy, and (ii) to deliver the drug exclusively to its target site. The term “controlled drug delivery” encompasses both aspects: time and rate of drug release. In this chapter, only time-controlled drug delivery systems are addressed; the reader is referred to chapter 9of this volume (“Target-Oriented Drug Delivery Systems”). 1 2 Siepmann and Siepmann The use of time-controlled drug delivery systems can provide tremendousadvantages for a pharmaco-treatment including the following: 1. The optimization of the resulting drug concentration–time profiles at the site of action in the living body over prolonged periods of time (1–3). Each drug has a characteristic, so-called “minimal effective concentration” (MEC), below which no therapeutic effect occurs, even if the drug is present at the site of action. In addition, each drug has a so-called “minimal toxic concentration” (MTC), above which undesired side effects occur. The range in-between these two concentrations is called “therapeutic range,” or “therapeutic window.” Depending on the type of drug, this concentration range can be more or less narrow. Ideally, the drug concentration remains within the therapeutic window during the treatment period. However, if a conventional (immediate-release) dosage form is used to administer a highly potent drug exhibiting a narrow therapeutic range (e.g., an anticancer drug), the entire drug dose is generally rapidly released. In the case of oral administration, the drug is subsequently absorbed into the blood stream, distributed throughout the living body, and reaches its site of action. Depending on the administered dose and therapeutic range of the drug, the risk can be considerable to achieve toxic concentrations, which might necessitate the interruption/termination of the drug treatment (thin curve in Fig. 1). In addition, as the entire drug dose is rapidly released, there is no further drug supply. Thus, the elimination of the drug out of the living body leads to decreasing drug concentrations at the site of action. In many cases, therapeutic drug concentrations are achieved only during short periods of time (thin curve in Fig. 1). Importantly, time-controlled drug delivery systems can allow overcoming these restrictions: If the rate at which the drug enters the living body can be adjusted, the rate at which the drug appears at the site of action (and in the rest of the organism) can be controlled, avoiding both toxic as well as subtherapeutic drug concentrations. For instance, a constant drug supply might be provided, which compensates the drug elimination out of the body, resulting in about constant drug concentrations within the therapeutic range (thick curve in Fig. 1). However, it must be pointed out that constant drug levels Figure 1 Schematic presentation of the “therapeutic window” of a drug and potential drug concentration–time profiles upon administration of oral immediate- and controlled-release dosage forms (thin and bold curve) (c denotes the drug concentration at the site of action in the living body, t the time after administration). Time-Controlled Drug Delivery Systems 3 are not optimal for all types of pharmaco-treatments. For instance, due to circadian fluctuations in certain hormone concentrations, daytime-dependent drug concentrations might be needed (chrono-pharmacology). 2. The reduction of the administration frequency of the drugs. This is particularly important for drugs with short in vivo half-lives. In the case of oral administration, for instance, a three to four times daily administration might be replaced by a once-daily administration only. In the case of parenteral administration, the injection of a drug solution every day might be replaced by a once a month injection of a suspension only. These simplifications of the administration schedule do not only help save time and financial resources, but most importantly, improve patient compliance. The inappropriate/inaccurate administration of many drugs still limits the success of various pharmaco- therapies in practice. Many patients are elderly people with multiple, complicated drug treatments. 3. The simulation of night time dosing. Certain diseases require high drug concentrations at the site of action in the very early morning. For instance, the risk of asthma attacks is particularly elevated at this time of the day. Thus, the patient should wake up in the night and take a conventional dosage form to be protected in the very early morning. Alternatively, a controlled-release dosage form with a so-called “pulsatile” drug-release profile can be administered in the late evening, before going to bed. In the first part of the night, no drug is released, but after a predetermined lag time, the entire dose is rapidly released. Time-controlled drug delivery systems can be classified according to different principles, for example, with respect to the route of administration, field of application, and/or underlying drug-release mechanisms.  4 Siepmann and Siepmann CONTROLLED DRUG DELIVERY SYSTEMS According to their inner structure, three types of diffusion-controlled drug delivery systems can be distinguished (Fig. 2): reservoir systems, monolithic systems, and miscellaneous systems. Reservoir / Non-Erodible Controlled Drug Delivery Systems In these cases, the drug and the release rate–controlling material/membrane (generally a polymer or lipid) are physically separated: The drug is located at the center of the dosage form, constituting the “reservoir” or “drug depot,” and the polymer or lipid surrounds this reservoir as a “release rate–controlling membrane.” The release rates in these systems are dependent on the pore sizes and numbers present in the rate controlling membrane. These systems usually follows zero-order kinetics. The rate controlling membranes are usually formed of Ethyl Vinyl Acetate (EVA) either solely or combined with anther polymer(s). Monolithic/Erosion Controlled Drug Delivery Systems In these cases, the drug and matrix former are not clearly physically separated with a core-shell structure, but more or less homogeneously mixed (Fig. 2). In contrast to the reservoir devices described above, the resulting drug release depend on the rate of polymer degradation. Fick’s second law and Higuchi equation can be used to describe drug-release kinetics from these systems. Generally,polymers used to formulate these systems are Hydroxypropyl methylcellulose (HPMC) poly(lactic acid) (PLA) and poly(lacticco-glycolic acid) (PLGA). Miscellaneous Systems This can, for instance, be a coated pellet, capsule, or tablet, containing the drug in the core as well as in the coating. Alternatively, the device might consist of a monolithic drug polymer/lipid core, which is surrounded by an additional polymer/lipid coating, with both the core as well as the coating being involved in the control of drug release. Time-Controlled Drug Delivery Systems 5 Figure 2 Classification scheme for predominantly diffusion-controlled drug delivery systems. Only spherical dosage forms are illustrated, but the scheme is applicable to any type of geometry. Stars represent dissolved (individual) drug molecules, whereas black circles represent undissolved drug excess (e.g., crystals and/or amorphous aggregates).  6 Siepmann and Siepmann Implants They are small sterile solid masses consisting of a highly purified drug and either or non-biodegradable polymers. Biodegradable implants are usually formed of poly lactic acid (PLA) or poly glycolic acid (PGA) polymers while non-biodegradable polymers are usually formed of polyvinyl alcohol (PVA) polymer and ethylene vinyl acetate (EVA) copolymer. Implants are drug delivery systems, which provide continuous sustained or controlled delivery of drugs over a long period of time ranging from months to years. Implants are classified into: A- Injectable implants These implants are injected using certain injectable devices. They are usually placed subcutaneously to produce long-term systemic effect. B- Surgical implants They are surgically placed inside the body, either in a specific organ or in a specific region to produce local effect. Here are some examples of both injectable and surgical implants. 1- Nexplanon® It is a small, thin, and flexible contraceptive arm implant. It is placed under the skin of the inner upper arm. Nexplanon is long-term birth control option that lasts for up to 3 years. It is a non-biodegradable implant; it contains the active ingredient etonogestrel, which is a synthetic form of the progesterone hormone and ethylene vinyl acetate (EVA) copolymer. The drug release is controlled by no and size of pores in the RCM This implant will be removed after 3 years. 2- Gliadel Wafer Carmustine wafer implants (Gliadel®) is a sterile, wafer that provided a way of delivering chemotherapy into the area of tumors. Gliadel consisted of a polyanhydride biodegradable polymer matrix containing carmustine as the active ingredient. Gliadel® wafers are directly implanted into the surgical cavity created when a brain tumor is surgically removed. The wafers will slowly degrade (when exposed to the aqueous environment in the resection cavity, the anhydride bonds in the copolymers are hydrolyzed) releasing carmustine over two to three weeks. Carmustine, is then diffuses into the surrounding brain tissue, producing an antineoplastic effect by alkylating DNA and RNA. Gliadel® Wafer therapy is used in conjunction with surgery and radiation to treat certain kinds of brain tumors. Polymers used in different controlled delivery systems Three Dimensional (3D) Macromolecules Polymers They are highly branched structures in which all bonds converge to a core or focal point and a multiplicity of reactive chain ends. There are two types of three dimensional macromolecules polymers, namely dendrimers and hyperbranched polymers. Dendrimers Dendrimers are highly ordered synthetic spheroid polymeric nanostructures consisting of three regions: a focal moiety or core, branched repeat units (branched monomers) emerging from the core, and functional end groups (Fig. 3). The branched monomer units are layered around the core molecule to build up an onion-like structure where each layer is called a generation. Dendrimers are produced in multistep reactions (synthesized by the stepwise incorporation of repetitive units). The size of the dendrimers is relatively small, diameter is lower than 100 nm. In addition, the highly branched dendrimers provide an enormous surface area. Dendrimers can be employed as a carrier of both hydrophobic drug (loaded in cavity in hydrophobic core) and hydrophilic drug (attached by covalent conjugation or electrostatic interaction to multivalent dendrimers surface). Also, different ligands can be attached to it’s surface. These properties make dendrimers attractive for delivery of different AI(s). Dendrimers can be used for delivery of DNA, siRNA, antiviral and antimicrobial therapeutics. VivaGel® is a dendrimer based nanoparticulate product developed for prevention and treatment of bacterial vaginosis (BV). The effects of this product are also extended for the prevention of genital herpes (HSV-2), HIV and other sexually transmitted infections (STIs). VivaGel® is a water based vaginal gel (3% wt/wt) of SPL7013 (active ingredient by StarPharma), formulated using Carbopol. Figure 3 Dendrimers Structure Time-Controlled Drug Delivery Systems 7 Hyperbranched Polymers (HPs) They are three-dimensional structure that is highly branched with a large number of modified terminal functional groups. Hyperbranched polymers possess both the multi- terminal structure of dendritic macromolecules and the large molecular weight of linear polymers. Their globular and dendritic architectures endow them with unique structures and properties such as abundant functional groups, intramolecular cavities, low viscosity, and high solubility. HPs can be facilely synthesized via a one-step polymerization of traditional small molecular monomers or emerging macromonomers. They are less ordered than dendrimersbut more easier in synthesis. HPs have been widely applied in various fields such as lightemitting materials, nanoscience and technology, supramolecular chemistry, biomaterials, hybrid materials and composites, coatings, adhesives, and modifiers. In addition, these polymers have antibacterial effect especially with gram-positive bacterial cells as compared to gram-negative cells. HP–drug complexes can improve drug solubility and prolong duration of action. They can easily penetrate cell membranes and selectively accumulate, as well as be retained at tumor sites. Figure 4 Hyperbranched Polymer  8 Siepmann and Siepmann Stimuli Responsive Polymers (SRP)s Stimuli responsive polymers (smart polymers) are polymers that adapt to physical, chemical and biological stimuli, such as temperature, light, pH, electrical signal, magnetic field, mechanical energy, ions, enzymes and antigens, which give rise to a response such as a change in shape, permeability, phase, mechanical properties, optical properties and electrical properties (Fig. 5). The response may be temporary or reversible; as such the original properties may be reverted towhen the stimuli is removed or changed. Some of the polymers may respond to more than one stimulus simultaneously and in a predictive manner. Such stimuli responsive polymers are often referred to as smart polymers, polymer chameleons and adaptive materials. Figure 5: Different stimuli and response for smart polymers Time-Controlled Drug Delivery Systems 9 In-situ gels/ Gel forming solutions They are polymer‐based liquid preparations. They exhibit sol to gel transition when exposed to certain physicochemical parameters changes. The transition of the liquid (sol) to gel is dependent on the type of polymer(s) involved in preparing the in-situ gel. According to the type of polymer(s) used, the factors that triggers the sol to gel transition will vary as follows: 1) pH triggered in-situ gelation: Cellulose acetate phthalate (CAP) is a polymer that form gelation when the original pH of the solution (4.5) is raised to 7.4. 2) Temperature triggered in-situ gelation: Poloxamer‐407 is a polymer that form gelation when the solution temperature is raised to (32°C). N.B: this type always requires storage in refrigerator. 3) Ion activated in-situ gelation: Gellan gum, is a polymer that form gelation in the presence of mono or divalent cations. Timolol GFS and Timoptic-XE, are commercial ophthalmic in- situ gels of timolol using xanthan gum as in-situ gel forming polymer. They are used to reduce the IOP as in case of glaucoma.