Targeted and Modified Release

Kevin B. Ita, PhD

Targeted Delivery Systems: Understand the mechanisms and benefits of targeted drug delivery systems.
Modified-Release Systems: Explore the different types of modified-release systems and their applications.
Extended-Release Systems: Understand what constitutes extended-release systems and their significance.
Delayed-Release Systems: Learn about delayed-release systems and their mechanisms.
Repeat-Action Systems: Familiarize with the concept of repeat-action systems in drug delivery.

Definition: Targeted drug delivery systems are designed to deliver drugs to specific target or receptor sites in the body to maximize therapeutic activity. They prevent degradation or inactivation during transit and protect the body from adverse reactions due to inappropriate drug disposition.
Design Considerations:
- Requires a comprehensive understanding of the drug involved, the disease being treated, and the specific target location in the body.
- Effective targeting enhances therapeutic efficacy, minimizes side effects, and potentially reduces the dosage required.
Examples of Targeted Systems:
- Monoclonal Antibodies (mAb): These are antibodies that can be engineered to target specific receptors or antigens on cells. They have significant potential in cancer therapy.
Control Mechanisms:
- Parameters such as plasma clearance kinetics, tissue distribution, metabolism, and cellular interactions can be managed through site-specific delivery systems.
Targeting Techniques:
- Drugs can be targeted to specific sites by attaching them to particulate or macromolecular systems linked with monoclonal antibodies or cell-specific ligands (e.g., asialofetuin, glycoproteins, immunoglobulins).

Definition: Monoclonal antibodies (mAb or moAb) are identical antibodies produced by a single clone of B lymphocytes, resulting in uniformity and specificity for their target.
- Produced by replicating a single parent immune cell, thus all antibodies from these clones are genetically identical.
Applications:
- Since the 1980s, mAbs have been anticipated to have transformative efficacy in tumor therapy
- By conjugating tracers and toxins with mAbs, one can target specific tissues or cells effectively.
Functionality:
- Can detect or purify specific substances; when developed as medications, these products typically have generic names ending in -mab.
Immune Response:
- Upon introduction of an antigen, a specific immune response is initiated, inducing the proliferation of B lymphocytes that produce antibodies matching the specific epitopes of the antigen.
Hybridoma Technology:
- A significant advancement enabling the production of large quantities of identical monospecific antibodies by fusing B lymphocytes (activated by an antigen) with immortal myeloma cells.
Applications in Targeted Therapy:
- Monoclonal antibodies like Rituxan (rituximab) target specific receptor proteins on cancer cells, enhancing the immune response to cancer.

Examples of Targeted Therapies:
- Gleevec (imatinib) - A small-molecule inhibitor designed to block the activity of the Bcr-Abl protein in chronic myeloid leukemia cells, keeping ATP away to halt cancer progression.
- Herceptin (trastuzumab) - Targets HER2 receptors, suppressing activity to prevent tumor proliferation.
- Rituxan (rituximab) - Targets CD20 on B cells in non-Hodgkin lymphoma.
- Avastin (bevacizumab) - Inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF).

Modified Release Definition:
- Refers to dosage forms that provide drug release based on specific timing, course, or location to achieve therapeutic benefits not offered by immediate-release forms.
Types of Modified Release Systems:
- Extended-Release: Reduces dosing frequency compared to conventional forms, ensuring consistent drug levels over a prolonged period.
- Delayed-Release: Designed to release the drug after a specified delay from the time of administration.
- Repeat-Action Systems: Feature an initial immediate release followed by delayed doses.

Theo-Dur:
- A sustained-release formulation that maintains serum theophylline concentrations above 1μg/ml for 24 hours.
Quinidex Extentabs:
- Contain 300 mg of quinidine sulfate with a sustained-release mechanism for antiarrhythmic action.
Prilosec:
- Delayed-release capsules for omeprazole, protecting the drug from acid until it reaches the intestines for absorption.

Criteria for Drug Selection:
- Drugs should have moderate rates of absorption and elimination; drugs that are too fast or slow may not be suitable for extended release.
- Uniform absorption from the gastrointestinal tract is essential along with good aqueous solubility.
- Doses that are too large may not be practical for extended-release formulations.
Safety Concerns:
- The therapeutic index measures a drug’s safety (median toxic dose / median effective dose). A larger therapeutic index indicates a safer drug.
- Narrow therapeutic indices are poor candidates for extended release due to risks of dose dumping and inaccurate dosing.
Clinical Considerations:
- Patients stabilized on modified-release products should not be switched to immediate-release forms without ensuring compatibility with their blood levels.

Development Techniques:
- Technologies such as microencapsulation and hybridoma evaluated for targeted delivery can also apply here.
- Complex formation techniques where drugs react with specific agents leading to slow solubility can be utilized for creating extended-release properties.