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Delivery of Biologics (Protein Therapeutics (Insulin (Regulate Blood…
Delivery of Biologics
Protein Therapeutics
Insulin
Regulate Blood Glucose
Isophane Insulin
Slower onset of action & longer duration
Insulin Inhalation
Faster onset of action
Factor IX
Coagulation (L => S) Factor
Enfuvirtide
36 AA-peptide that inhibits HIV entry into host cells
Protein Delivery Challenges
Large Size
Difficult to develop NP formulations
Stability
Result in aggregation, deamidation, oxidation, isomerization, denaturation
Sensitive to pH, ionic strength, temp
Viscosity
High for small doses
CNS Targets
Amyloid-beta
Beta-Secretase
Alpha-Synuclein
Mechanism of Action in Cancer
Direct tumour cell killing
Vascular & Stromal Cell Ablation
Immune-Mediated Tumor Cell Killing
Delivery Methods
Exosomes
Carry Proteins & RNA Molecules
Messenger to communicate with neighbouring cells
Considerations
Pros
Controlled release
Sufficient Loading
Delivery by subcutaneous injections
Cons
Not suitable for IV injections
Burst release can occur
Local Toxicity
Delivery Systems
Drug Depot
Pros
Can deliver multiple drugs
Low Burst Release
Avoids suspension
Cons
Large Gauge Needle for injection
Incisions into skin
NP
Pros
Target Delivery
Enhance Stability
Improve PD & PK
Cons
Difficult to load large proteins
Immunotoxicity
Non-Specific Uptake in RES organs
Drug Delivery Pumps
Pros
Long Delivery Duration
Controlled Delivery Rate
Cons
Infection
Invasive Implanted Devices
Pulmonary (Inhaler)
Pros
High Bioavailability
User-friendly
Rapid Systemic Uptake
Cons
Difficult Formulation
Local Toxicity & Immunogenicity
Oral
Pros
User-Friendly
High Patient Compliance
Cons
Low Bioavaillability
Variable Absorption
Absorption Rate Interference
Enzymatic Degradation in stomach & liver
Biopharma Delivery Approach
Hydrophilic Polymer Conjugate
PEG
HA
Starch
Sialic Acid
Pros
Variety of chemistries
Successful Commercial Products
Ease of Evaluation at discovery stage
Reduce immunogenicity of proteins
Cons
Create new molecular entity
Potential immunogenicity of polymer
Action duration increases
Genetic Constructs & Fusion
Albumin
Fc Fusion
PolyAA Fusion Protein
Pros
Proteins with improved half-life can be developed & formulated
Conventional Protein Therapeutic
Successful Commercial Products
Fusion can reduce immunogenicity risk
Cons
Creates new molecular entity
Fusion Construct can elicit antibody response
Poor Solution Stability & Aggregation
Recombinant DNA Technology
Protein Drugs
Insulin
Diabetes Mellitus
Interferon-alpha2a
Hepatitis C
Factor VIII
Hemophilia A
Factor IX
Hemophilia B
Beta-Glucocerebrosidase
Gaucher's Disease
Erythropoietin
Anaemia
Interferon-beta
Multiple Sclerosis
Monoclonal Anitbodies
Cancer