Advanced Drug Delivery Systems PDF

Advanced Drug Delivery Systems Polymers in Controlled Release Drug Delivery Rania Hamed PhD Professor Faculty of Pharmacy Al-Zaytoonah University of Jordan Introduction The drug concentration in the plasma does not remain constant and fluctuates between maximum therapeutic conc...

Advanced Drug Delivery Systems Polymers in Controlled Release Drug Delivery Rania Hamed PhD Professor Faculty of Pharmacy Al-Zaytoonah University of Jordan Introduction The drug concentration in the plasma does not remain constant and fluctuates between maximum therapeutic concentration (MTC) and minimum effective concentration (MEC). Therefore, the drug level may rise too high leading to toxic side effects or fall too low resulting into the lack of efficacy Frequent dosing is needed to maintain therapeutic effective plasma drug level, particularly for drugs with short half- lives, which is likely to result into toxic side effects and poor patient compliance Controlled drug delivery involves delivering drug either locally or systemically at a predetermined rate Introduction The ability to control the release of therapeutics and the extremely versatile nature of polymeric drug delivery platforms offer numerous advantages:  Ability to tune physicochemical properties of the drug delivery systems (DDSs)  Temporal control of payload release for hours, days, months, or even years (e.g. contraceptive implants)  Pulsatile drug release (Exercise #1)  Ability to deliver macromolecular therapeutics, combinations of drugs, and both hydrophilic and hydrophobic drugs  Protection of the payload against proteolytic enzymes and plasma components Introduction  Opportunities to widen the drug therapeutic index  Organ, tissue, cell, or subcellular compartment specific- targeting  Improved pharmacokinetics and biodistribution of the therapeutic payload  Reduction of off-target effects and toxicity due to targeted or localized delivery  Biodegradable due to in vivo biological activity of incorporated biological units  Availability of a range of clinically validated polymers  Minimization of frequent repeat dosing while maintaining therapeutic drug concentration leading to improvement in patient compliance and clinical outcome  Existing approved polymeric drug delivery systems Biodegradable polymers Biodegradation: the breakdown of polymers due to cellular or in vivo biological actions to nontoxic natural byproducts such as water and carbon dioxide, which can be easily eliminated The majority of degradable polymers used in drug delivery applications are based on hydrolysable ester bonds The development of biodegradable polymers has lead to significant biotechnological advancements in drug delivery, biomaterials, tissue engineering, and medical device development Biocompatibility means not having toxic or injurious effects on biological systems Good biocompatibility does not ensure good biodegradability Biodegradable polymers The applications of synthetic biodegradable polymers dates back to the 1960s and 1970s, when the polyesters poly(glycolic acid) (PGA), poly(D,L-lactic acid) (PLA), and poly(D,L-lactic-co glycolic acid) (PLGA) were developed for use as biodegradable sutures Polymers such as poly(ε-caprolactone) (PCL), PLA, and PLGA are FDA-approved and well known for their biodegradability, biocompatibility and nontoxic properties, which make them suitable as matrices for controlled release drug delivery systems Biodegradable polymers The development of polymeric drug delivery platforms was motivated by:  Discovery of more potent therapeutics peptides, proteins, nucleic acids, and other bioactive molecules  The short half-lives of many therapeutics  Nonspecific distribution and toxicity of previously identified small drug molecules General polymer properties Degradable polymers are classified according to their source into natural or synthetic Synthetic degradable polymers are favored in tissue- engineering scaffolds, drug delivery systems, implants, and surgical materials as they have less batch-to-batch variability and less immunogenicity, as compared to degradable polymers from natural sources Polymers can be degradable through the inclusion of labile ester, anhydride, and amide chemical linkages, which are susceptible to degradation mechanisms involving hydrolysis or enzymatic cleavage leading to the breaking of chemical bonds of polymer chains Commonly used degradable and biodegradable polymers Factors affecting drug release from polymeric systems Polymer crystallinity Describes the degree of crystalline regions within a polymer in relation to amorphous regions, thus polymers never reach 100% crystallinity and are therefore semicrystalline Only amorphous regions are permeable and therefore accessible to water molecules Crystallinity affects polymer mechanical strength, swelling, and hydrolytic and biodegradation rates A high degree of crystallinity causes slower drug release E.g. the rate of drug release is higher in polyesters with a low degree of crystallinity because of higher macromolecular chain mobility Polymer glass transition Tg is the temperature at which the glassy state to rubbery state transition occurs Tg is determined using differential scanning calorimetry (DSC) Below Tg, the polymer is in a glassy state; it has limited mobility and low diffusion rates Above Tg, the polymer is in a rubbery state, which facilitates water penetration and drug diffusion throughout the matrix In drug delivery applications, a balance between amorphous and crystalline states is necessary, as these parameters have direct effects on the degree of mechanical toughness and rate of drug release Polymer hydrophilicity and hydrophobicity Solubility is a key concept in the design of degradable polymeric drug delivery systems Solubility is dependent on the chemical nature, structure, and degree of crystallinity within the polymer When the polymer used is hydrophobic, drug release is controlled by surface erosion When there are hydrophilic functionalities in the polymer backbone, degradation can occur by bulk erosion Blending of hydrophilic polymers with hydrophobic polymers can increase pore formation, rate of polymer degradation, and drug release Bulk erosion vs surface erosion A: Bulk erosion B: Surface erosion Polymer molecular weight Low-MW polymers degrade more rapidly The MW of degradable polymers has a significant impact on  Drug-release profile  Biological properties of polymeric drug delivery systems such as elimination, phagocytosis, and biological activity Low-MW polymers produce smaller nanoparticles (NPs), resulting in altered drug release kinetics, enhanced blood circulation times, reduced accumulation in organs such as liver and spleen, and therefore enhanced biological efficacy due to longer duration of drug exposure PLGA Polymers Are polyesters with ester bond linkages in the carbon backbone The aliphatic polyesters include PGA, PLA, and PLGA PLGA is synthesized from ring-opening polymerization (ROP) of cyclic lactide and glycolide monomers PLGA degrades via hydrolysis of its ester bonds in water PLGA can be obtained in a variety of MWs and lactide-to- glycolide ratios (L/G) When the ratio of L/G monomer decreases, the degradation rate of PLGA decreases PLGA Polymers E.g. the degradation times of PLGA polymer with 50:50, 75:25, and 85:15 (L:G) were 1–2, 4–5, and 5–6 months in aqueous conditions PLGA is  is the most utilized degradable polymers, due to its long history of clinical use and favorable controlled-release and degradation behavior  can be used for the entrapment of therapeutics with a wide range of MWs and can be fabricated into particles of various sizes and shapes  drug release capabilities can be tuned by varying MW, L/G ratio, and drug concentration Radiolabeling studies of PLGA NP degradation have shown that all the polymer is degraded in vivo and cleared via respiration from the lungs (Exercise #2: PLGA degradation mechanism). PLGA copolymers To improve the in vivo circulation and biocompatibility of PLGA NPs, block copolymers of PLGA and polyethylene glycol (PEG) (PLGA–PEG) were developed Due to the hydrophilicity of PEG, PEG chains can orient themselves toward the surface of NPs and lead to increase hydration PEGylated NPs of neutral surface charges are used in vivo to prolong circulation, minimize bioadhesion and immunological response as a result of sterically inhibiting both electrostatic and hydrophobic interactions of plasma components with NPs. The solubility of PEG allows for various targeting ligands to be conjugated to the distal end, leading to targeted NPs. PLGA copolymers Triblock polyester of PLGA–PEG–PLGA copolymers (ABA) are conjugated via ester linkages and can form highly viscous gels at physiological temperatures, leading to temperature responsive degradable polymers PLGA–PEG–PLGA copolymers  Polycaprolactones (PCL) Polycaprolactones is a commonly utilized degradable aliphatic polyester in drug delivery applications PCL  is made from the ROP of ε-caprolactone  has very low Tg (−60°C), making it a semi-rigid material at room temperature  is used in tissue engineering as scaffold matrix due to its lack of solubility and slow degradation rates (2–3 years) Modification of PCL with other polymers (block polymer synthesis or blending with PLGA and PLA) have led to improvements in its degradation and reactivity Poly(amides) Poly(amino acids) are most frequently utilized to deliver low-MW drugs Poly(amino acids) are relatively nontoxic, and typically cleaved by enzymes as they are stable to hydrolysis The degradation rates of poly(amino acids) are dependent on the hydrophilicity of the amino acids that make up the polymer Most poly(amino acids) are made up of a single type of amino acid, the most widely used are poly(γ-glutamic acid) and poly(L-lysine) Poly(amides) Polymeric NPs composed of poly(γ-glutamic acid) have been developed for the delivery of chemotherapeutics and therapeutic proteins Poly(L-lysine)-based polymers have been used in gene delivery, where the highly positively charged amino groups can interact with negatively charged siRNA or DNA chains Poly(γ-glutamic acid) Poly(L-lysine) Pluronic Also known by the trade name Poloxamers Nonionic triblock copolymers composed of the hydrophilic polyethylene oxide (PEO) and the hydrophobic poly(propylene oxide) (PPO) blocks (PEO–PPO–PEO) Due to their amphiphilic characteristics, Pluronic exhibits surfactant properties having the ability to self-assemble into micelles above their critical micelle concentration (CMC) in aqueous solutions The FDA has approved several members of this class of polymers for pharmaceutical applications Naturally occurring biodegradable polymers Used in drug delivery applications due to their abundance in nature and biocompatibility Include protein-based polymers (collagen, albumin, gelatin), and polysaccharides (agarose, alginate, carrageenan, hyaluronic acid (HA), dextran, chitosan, and cyclodextrins) Widely used in tissue engineering, bioscaffold designs, and NP fabrication for drug delivery Although highly biodegradable in nature, limitations of natural polymers are their batch-to-batch variability and broad MW distributions, making them less attractive than synthetic polymers that are more reproducible and versatile Chitosan Biodegradable polysaccharides that have shown potential in drug delivery applications Derived from the chitin found naturally in crustacean exoskeleton Deacetylation of chitin produces randomly repeating units of D-glucosamine and N-acetylglucosamine, with the degree of deacetylation being related to chitosan’s crystallinity and degradation rates Chitosan is highly insoluble in water (due to its crystalline nature) and must be solubilized in dilute acid solutions prior to use It is broken down by lysozyme Chitosan polymers with low degrees of acetylation can remain in vivo for several months Chitosan Chitosan’s degradation can be accelerated by disrupting the significant network of hydrogen bonding, through the inclusion of bulky side groups Major applications of chitosan involve  wound dressing and healing due to its anti-inflammatory and antibacterial properties  gene delivery due to its highly positive charge  oral and pulmonary drug delivery due to its mucoadhesive properties Chitosan has been fabricated into numerous NPs for drug delivery applications  Hyaluronic acid (HA) A naturally occurring linear polysaccharide polymer composed of D-glucuronic acid and N-acetyl-D-glucosamine disaccharide HA has been utilized in surgical, tissue engineering, and drug delivery applications due to its biodegradable, biocompatible, nontoxic, and nonimmunogenic properties HA has been used to develop numerous conjugates of HA to drugs, peptides, and proteins, and hydrogel depot drug delivery systems Bioconjugation of HA to therapeutics improves drug solubility, pharmacokinetics, and clearance The pKa of HA carboxyl groups is between 3 and 4, rendering the polymer anionically charged at neutral pH Hyaluronic acid (HA) HA is highly hydrophilic, it absorbs water and can expand up to 1000 times its solid volume, making it an attractive material for hydrogel-based drug delivery HA has intrinsic targeting ability for the delivery of anticancer drugs; it can selectively interact with the CD44 receptor (hyaluronan receptors for endocytosis, HARE) Alginate Alginates (ALG) is a naturally occurring anionic polysaccharides derived from brown algae cell walls and several bacteria strains refers to alginic acid and its salts are linear biopolymers consisting of 1,4-linked 𝛽-D-mannuronic acid (M) and 1,4 𝛼-L-guluronic acid (G) residues arranged in homogenous (poly-G, poly- M) or heterogenous (MG) block-like patterns are commercially available in various grades of molecular weight, composition, and distribution pattern of M-block and G-block, the factors responsible for their physicochemical properties such as viscosity, sol/gel transition, and water-uptake ability can be used to form stimuli-responsive hydrogels possess mucoadhesive properties resulting from the presence of free carboxyl groups allowing the polymer to interact with mucin by hydrogen and electrostatic bonding Alginate Environmental pH has a strong impact on alginate solubility and consequently on their mucoadhesive character as only ionized carboxyl groups are capable of interacting with mucosal tissue. Sodium alginate is one of the most widely investigated in the pharmaceutical and biomedical field Bovine serum albumin (BSA) Bovine serum albumin (BSA) is highly water soluble and binds drugs and inorganic substances noncovalently The structure of BSA is homologous to the three-dimensional structure of human serum albumin (HSA) The main difference lies in the number of tryptophans (Trps). BSA has two Trps, while HSA has only one BSA particles have controlled properties for drug delivery BSA containing charged amino acids, albumin NPs could favor the electrostatic adsorption of negatively or positively charged molecules inside or on the surface, and the presence of hydrophobic cavities may facilitate the incorporation of water- insoluble drugs Evolution of controlled-release polymers Controlled release of drugs from polymeric drug delivery systems is typically achieved by regulating:  rates of polymer biodegradation  drug diffusion out of the polymer matrix Controlled drug delivery field can be chronicled in evolving the following phases  macroscopic controlled drug delivery devices  microscopic degradable polymer depot drug delivery systems  nanoscopic era of NP-based controlled drug release Macroscale polymeric drug delivery systems Developed to achieve spatiotemporal control of drug delivery from a local drug depot device Allowed for a range of payloads (small molecule drugs, proteins, and bioactive agents) to be delivered in a controlled manner at the site of treatment Drugs are generally released via one or all of three mechanisms: (1) diffusion-controlled release, (2) drug- carrier affinity, or (3) degradation of the matrix material. Earlier drug delivery devices were mostly made of non- degradable polymers, including polyurethanes, silicone rubber, and poly(ethylene-co-vinyl acetate) (PEVA) Drug transport in the nondegradable systems was primarily driven by diffusion Macroscale polymeric drug delivery systems E.g. Norplant I was approved by the FDA in 1990 An upper-arm-implanted contraceptive formed of six silicone tube capsules, each 2.4 mm × 34 mm long and containing 36 mg of the progestin levonorgestrel The hormone is released at 3.8 pg/cm length/day and the implant is effective for 5 years after implantation Norplant II (Improved version) was approved by the FDA in1996. This implant uses polysiloxanes consisting of a backbone of inorganic Si–O–Si units One limitation of these DDS is that since silicone capsules are nondegradable, thus they must be removed after drug release is complete Macroscale polymeric drug delivery systems Ocusert is an ocular implant composed of PEVA which delivered pilocarpine at zero-order kinetics over a one-week period PEVA shows a slow release over a long period of time and good biocompatibility The diffusivity of the polymer matrix is dependent on the crystallinity of the polymer, where increasing the crystallinity reduces the diffusivity Ocusert can be placed in the lower eyelid, leading to an improvement over daily eye drop administration of pilocarpine and resulted in fewer side effects Macroscale polymeric drug delivery systems Progestesert is an intrauterine device for the release of progesterone It is a T-shaped intrauterine (IUD) macroscale drug delivery device composed of PEVA, capable of delivering 65 pg/day of progesterone for 1 year Transderm Scop was the first skin-patch that also used PEVA as the rate–controlling membrane to deliver 1 mg of scopolamine over 3 days for the treatment of motion sickness Progestesert Transderm Scop Macroscale polymeric drug delivery systems OROS (osmotic controlled-release oral delivery system) It is a pulsatile-release oral capsule that has a permeable outer shell with small laser-drilled holes, which allows water to enter via osmotic pressure during its trafficking through the GI tract, pushing the drug through the opening with controlled zero-order The rate–controlling membrane consists of cellulose acetate, which maintains a constant rate of water diffusion into the capsule while an equal volume of the drug liquid or suspension is forced out A small amount of low-MW PEG may also be used to initiate water diffusion Macroscale polymeric drug delivery systems Geomatrix is a controlled delivery system made of hydroxylpropyl methylcellulose (HPMC) HPMC is a highly swellable hydrophilic polymer used to modulate drug release The combination of polymer layers with different swelling, gelling, and erosion rates results in a controlled rate of drug release Microscale Polymeric Drug Delivery Systems PLGA microparticles were developed to control the release of luteinizing hormone-releasing hormone (LHRH) for up to 1 month to treat prostate cancer The plasma half-life of LHRH is 2.9 h; however, as the polymer slowly degrades, therapeutic levels of this antitumor peptide can be maintained for up to 3 months First degradable microparticle drug delivery system approved for human use and is still available today Lupron Depot (LHRH) Microscale Polymeric Drug Delivery Systems A long acting PLGA microsphere is Risperdal Consta contains risperidone in intramuscular formulation, with improved efficacy in the treatment of patients with schizophrenia ReGel are thermally responsive, degradable, controlled-release polymeric drug depot delivery systems developed using diblock and triblock copolymers of PLGA–PEG  Drug release can be controlled from hours to months  Blending of other polymers can further control drug release The in vivo degradation of PLGA facilitated sustained release with tunable dosing without the need for surgical procedures Risperidone microparticles Nanoscale Polymeric Drug Delivery Systems Nanoparticles (NP)-based drug delivery lead to investment in nanomedicine research Modifying the surface of NPs using the inert hydrophilic polymer PEG (PEGylation) facilitated the widespread use of nanoscale DDS in vivo and led to the preclinical NP development Antibodies, antibody fragments, peptides, aptamers (Apts), sugars, and small molecules have also been used to create targeted NPs Specific targeting of polymeric NPs allows for their differential spatial localization within the body, minimizing the drug payload’s off-target adverse effects Due to the large micrometer sizes, these particles are cleared from circulation rapidly, significantly hindering their use. Therefore, in order to facilitate longer circulation times in vivo, nanospheres with PEGylated surfaces were developed Nanoscale Polymeric Drug Delivery Systems NP targeting includes “passive” and “active” targeting Passive targeting refers to the preferential accumulation of NPs (bearing no affinity ligands) at active sites and is directly related to the biophysicochemical properties of the NP (size, shape, charge, flexibility) Active targeting describes the surface modification of NP to incorporate affinity ligands such as sugar molecules with specificity to disease cells and tissues  Nanoscale Polymeric Drug Delivery Systems Passive targeting is enabled by the enhanced permeability and retention (EPR) effect theory observed that colloidal macromolecular drug conjugates accumulated in tumors due to “leaky” vasculature Passive targeting of NPs to tumors has been widely exploited in oncology applications Polymeric micelles NPs Polymeric micelles are formed when amphiphilic block copolymers self-assemble in aqueous media into micelles These micelles range in size from 10–100 nm and are characterized by a core-shell architecture and a fairly narrow size distribution Compared to surfactant micelles, polymeric micelles have significantly lower CMC (~10-6 M) Lower CMC greater stability lower sensitivity to dissociation when diluted in the systemic circulation Advantages of polymeric micelles NPs Ability to solubilize a wide variety of hydrophobic drugs in the core Prolonged circulation times  Presence of the hydrophilic head groups forms a hydrated “stealth” layer which prevents recognition by the immune system  Their size is sufficiently large to prevent renal excretion Passive targeting through the EPR effect  Their size is typically < 200 nm, allowing passive accumulation at tumor and inflamed tissues Ability to modify surface groups with targeting agents, where the terminal distal ends of the PEG polymers can be conjugated to targeting ligands, creating targeted NPs  Polymeric micelles NPs Pluronic polymeric micelle NPs of a doxorubicin (DOX)- entrapping hydrophobic core and a hydrophilic tail.  Undergoing phase II studies in patients with metastatic cancer of the esophagus  It was shown to be efficacious in bypassing p-glycoprotein- mediated drug resistance  Patients were treated with a single dose (75 mg/m2 DOX) given as an intravenous infusion every 3 weeks  Preclinical studies demonstrated superior antitumor efficacy when compared to free DOX Fabrication techniques of polymeric NPs Numerous methods have been developed for the encapsulation of therapeutics into polymeric NPs The choice of the method depends on the polymer and drug properties and NP size and loading requirements Either bottom-up or top-down techniques have been employed. (Exercise #3) Bottom-up methods include emulsion, interfacial polymerization, and precipitation polymerization Top-down include nanoprecipitation (solvent displacement), emulsification/solvent evaporation, and salting-out methods (preparation of NPs via the self-assembly of block copolymers) Mechanisms of drug release from polymeric systems 1. Diffusion through water-filled pores  Describes the random movement of drug molecules driven by a concentration gradient  In degradable polymeric systems, water is immediately absorbed by polymeric NPs, forming water-filled pores over time  The size of the pores becomes larger and more numerous, eventually facilitating drug release 2. Diffusion through the polymer matrix  Drug molecules simply diffuse out of the polymer matrix  Predominant mechanism in nondegradable drug delivery systems  The rate of release remains constant and not affected by concentration gradients but by properties of the polymeric membrane (e.g. permeability and thickness) Mechanisms of drug release from polymeric systems 3. Erosion a) Surface erosion  When polymers degrade starting at the matrix surface, slowly reducing the size of the matrix, from the exterior toward the interior  Occurs when the rate of erosion is greater than the rate of water penetration in the bulk polymer b) Bulk erosion  When water penetrates the bulk of the polymer, which results in homogeneous degradation of the entire matrix  Occurs when the rate at which water permeates into the bulk is greater than the rate of surface erosion Drug release mechanisms from polymeric NPs (A) diffusion through water filled pores (B) diffusion through the polymer matrix (C) osmotic pumping (D) erosion  Drug release profiles The preferred zero-order release profile is not representative of drug release from polymeric NPs The most common drug release profile from polymeric drug delivery systems is a triphasic profile:  Phase I: burst release due to the rapid release of surface-bound drug molecules  Phase II: slow release as the drug molecules in the NP core slowly diffuse out  Phase III: faster release phase as erosion begins Dominant factors in drug release  Concentration gradients  Shape of the drug delivery device  Rate of polymer degradation  Whether the payload is hydrophobic or hydrophilic, hydrophobic drugs produce a zero-order release rate, whereas hydrophilic drugs display a triphasic pattern