Advanced Drug Delivery Systems: Mechanisms, Technologies, and Challenges
Advanced Drug Delivery Systems
The major obstacles for efficient transport to the site of action are enzymatic degradation and biological membranes.
Antioxidant substances (AS) are added to medicaments because the oxidation process is supposed to act first on the AS, then on the active ingredient.
The role of the drug delivery system is to allow the effective, safe, and reliable application of the drug to the patient.
Mechanisms of Drug Release Control
- Diffusion-controlled release
- Dissolution-controlled release
- Osmosis-controlled release
- Mechanical-controlled release
- Bioresponsive-controlled release
Commercial Reasons for Developing Advanced Drug Delivery Systems
- Convenience and compliance
- Efficiency
- Protecting franchises
- Adding value to generics
- Market expansion
- Creating new markets
Hurdles for New Drug Delivery Technologies
- Large-scale production and reproducibility
- Safety concerns
- Cost-benefit ratio
Factors Influencing Physical Protein Stability
Temperature, pH, solvation, surfactants (e.g., SDS), surface-associated mechanism, processing (shear, dehydration/lyophilization)
Parenteral Delivery Systems
- Depot systems (needle-free injection systems, microparticles, implants, liposomes, polymeric gels, protein crystallization, precipitation)
- Chemical modifications (PEGylation, acylation, AS substitution, protein fusion, glycoengineering)
Formulation & Fill Process
- Freeze/thaw bulk drug substance (cold denaturation, L&E from container)
- Formulation (dilution/concentration addition) (shear during mixing, excipient impurities initiating degradation actions)
- Filtration and/or UF/DF (protein loss due to absorption/shear during filtration)
- Drug product (DP) filling vials/syringes (shear/foaming, contamination)
- Lyophilization – if needed (freezing/drying stress, pH, residual moisture level)
- Inspection (light & shear, micro-bubbles)
- Labeling & packaging (temperature/light)
- DP storage (interactions with container or silicone oil)
- Transport (shock & drop, pressure, vibration)
- Delivery device (shear, interactions with silicone oil/protein-device)
Needle-Free Injection Systems (NFI)
Reasons: pain, needle phobia, accidental needlesticks, limited self-administration
Principle: Compressed gas or spring creates high-pressure jets of drug solution, delivering the drug through an orifice at high velocity in the subcutaneous or intramuscular region.
Microparticles
Slow-release dosage (controlled release); allows once-monthly administration; enhancement of stability; drug targeting (conjugates).
Production:
- Macromolecular drug solution
- Polymer solution homogenized
- Water-in-oil emulsion
- Solvent evaporation
- Phase separation
- Spray drying (emulsion through pump with hot air stream, microcapsules become powder because liquid is evaporated through temperature)
Possible Chemical Modifications for Proteins
PEGylation, protein fusion, glycoengineering, AS substitution, and acylation.
PEGylation
One or more units of chemically activated polyethylene glycol react with a biomolecule, creating a putative new molecular entity processing physicochemical and physiological characteristics (distinct from its predecessor molecules).
Reason: Transforming existing biopharmaceuticals into clinically more efficacious therapeutics (molecular size-increasing effect, shielding effect, stabilization effect).
Glycoengineering
Used to link saccharides to proteins, influencing stability, solubility, in vivo activity, serum half-life, and immunogenicity.
In insulin analogues, different amino acids are added or substituted at certain positions along the A & B chains. These changes, while altering insulin action times, don’t hinder the molecules’ ability to control blood glucose levels in the body.
Carrier Systems
Liposomes, micelles, nanoparticles, microspheres, lipoproteins.
A homing device is a target-specific recognition moiety (galactose-receptor, antibody).
Problems & Limitations in Development of a Targeted Delivery System
Enormous amount of R&D investment, effort, and time required; market entrance can therefore be delayed; the product will most likely be relatively expensive; advanced drug delivery systems (ADTS) must therefore offer real therapeutic advantages to justify their use.
- Active targeting: homing device attached to carrier system with specific recognition site for target; home device mostly covalently bound to carrier but also non-covalent attachment is possible; particulate & soluble carriers.
- Passive targeting: carrier without homing device; natural distribution is used for the targeting; mainly particulate carrier systems.
Importance of the Enhanced Permeability & Retention (EPR) Effect in Cancer Therapy
Hyper-permeable tumor vasculature allows preferential extravasation of the circulating macromolecular drug carriers due to the enhanced permeability & retention (EPR) effect. Drug carriers act as circulating drug reservoirs.
Particulate carriers have to be modified to be able to use them for intracellular targeting, especially carriers for mitochondria & nucleus targeting. Surface modification with PEG for prolonged presence in circulation. Modification by covalent attachment of peptides or other ligands.
Solubility of polymeric carriers enables them to be taken up into target cells by pinocytosis. A major advantage over particulate carriers is their greater ability to extravasate.
Possibilities for Drug Binding
Via direct linkage; binding via spacer; covalently bound.
Principle of Prodrug Concept
A biologically inactive agent converted in vivo through enzymatic or chemical reactions to a therapeutically active drug. Requires the natural existence of tissue-specific mechanisms for prodrug uptake and/or transformation that enables high tissue targeting.
Radioimmunotherapy
Uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. The principal methods are: conventional directly-radiolabeled antibody; 3-step pretargeted radioimmunotherapy (comprising injection of streptavidin-antibody conjugate, followed by clearing agent & then radiolabeled biotin); 2-step bispecific, trivalent antibody (bsAb) pretargeted RIT (“affinity enhancement system”).
Immunotoxin
A human-made protein consisting of a targeting portion linked to a toxin. When the protein binds to a cell, it’s taken in through endocytosis, and the toxin kills the cell. They consist of:
- Monoclonal antibody (mAb) (vehicle, recognition of specific antigens that are overexpressed on the surface of the tumor cells)
- Warhead (strong cytotoxic drug with high potency)
- Linker (connects the mAb with the warhead(s) to form an inactive prodrug)
Categories of Pulmonary Products
Preparations to be converted into vapor, liquid preparations for nebulization, pressurized metered-dose preparations for inhalation, non-pressurized metered-dose preparations for inhalation, inhalation powders.
pMDI vs. DPI
Metered-dose inhalers (MDI) require the user to coordinate pressing down the canister and inhaling the medication, while dry powder inhalers (DPI) do not. The inspiratory flow rate is a drawback of DPI (30-120 L/min); MDI is better for children because the rate required is approximately 30 L/min. With DPI, be careful not to disperse medication via exhalation into the device prior to using. MDI may be misused, leading to overdose or subdose. DPI is more susceptible to contamination.
Pulmonary Drug Delivery
Serves to be the best alternative to non-invasive administration for systemic delivery of therapeutic agents (mainly proteins & peptides) because the lungs could provide a large absorptive surface area, an extremely thin absorptive mucosal membrane, and good blood supply.
Desired particles are between 1 and 5 μm.
Inactive Ingredients Used in pMDI & DPI
Lactose, mannitol, sucrose, and sorbitol.
Four Principle Formulation Strategies for DPIs
Drug (carrier-free); drug-additive; drug-carrier; and drug-carrier-additive.
Drug Carriers
(50-100 μm) used in DPIs for aiding the fluidization of fine particles and allowing more precise filling.
Quality Control Tests for Preparations for Inhalation
Assay, impurities & degradants, aerodynamic particle size distribution, excipients, moisture content, etc.
First Pulmonary Insulin Product Failed Because
False marketing strategy, device too big & complex, often not paid by health insurance, no obvious advantages to subcutaneous insulin, and safety concerns.
Risk Factors in Pulmonary Drug Delivery
Possibility of nasal irritation and that the histological toxicity of absorption enhancers isn’t clearly established.
Possibilities for Nasal Delivery of Macromolecules
Single-dose DPI (powder, disposable option available, challenges: strict requirements, production costs should be low, not suitable for children) and nebulizer (aqueous solution/dispersion or powder for reconstitution, disposable option available but pressurized air system required, challenges: formulation stability or clean disinfected water required, long administration time, large residual time, still not optimal for children).
Bioencapsulation
The envelopment of tissues or biologically active substances in semipermeable membranes to protect the enclosed biological structures from potential hazardous processes.
Microencapsulation Technologies
Solvent evaporation, spray drying/coating, interfacial polymerization, dripping methods, thermal/ionotropic gelation (polymer should be non-toxic, biocompatible, polymerization under mild conditions, low shear stress, appropriate temperature, pH, salts & sterile).
Cells used are autologous cells (from the patient), allogenic cells (from another donor), or xenogenic cells (from other species). Also, stem cells or myoblasts can be used.
Requirements for Successful Encapsulation
Biocompatible polymer (mechanically & chemically stable semi-permeable matrix); uniformly sized micro-capsules & appropriate use of immune-compatible polycations (stabilize capsules).
Alginate
The most frequently used biomaterial for cell encapsulation because of its capacity to form excellent gels in very mild conditions, great biocompatibility shown in vivo, allows complete processing of capsules under physiological conditions, and its matrices show good mechanical properties & high porosity.
Considerations for Industrial Bioencapsulation Processes
Chemistry/purity of polymer; biodegradable matrix; modification of matrix properties; permeability/strength of capsules; stability of capsules; capsules swell/contract; scale of process; reduction of formulation steps; costs; validations.
How Does Alginate Form Gel Networks?
Alginate chains are modified with RGD adhesion motifs and matrix metalloproteinases (MMP)-sensitive peptides to subsequently form gels in the presence of calcium. Cells encapsulated within the hydrogel attach the RGD motifs via integrin’s and secrete MMPs to degrade the matrix (F), thereby eliminating the physical constraints and acquiring a more spread phenotype to better interact with the surrounding matrix and cells (G).
Modification of capsules to control their release (drug delivery in optimal amount, in the right period of time): by pressure or shear stress, by melting the wall, by dissolving it under particular conditions, by enzyme attack, by chemical reaction, by hydrolysis, or slow disintegration.
Potential Application Field for Therapeutic Cell Encapsulation
Clinical application.