drug administration

• General goal of drug delivery

  Maximize the fraction of a drug dose delivered to target tissues and cells directly responsible for therapeutic effects and limit exposure of other tissues to the drug
• Over 90% of protein and peptide drugs in the US are designed for parenteral administration
• Parenteral administration


  • Provides rapid and predictable access to the circulation and tissues
  • Therapeutic proteins are rapidly cleared from the system, resulting in very short durations of action
  • Therapeutic proteins may exhibit limited distribution outside of endothelial cells lining blood vessels
• Rapid clearance of therapeutic proteins from the system


  May be advantageous for thrombolytic agents like tissue plasminogen activator, which requires rapid clearance when the clot is resolved
• Most biopharmaceuticals designed for chronic therapies require sustained presence of drugs in target tissues and cells that are some distance away from blood capillaries and outside of blood vessels
• Only a small fraction of drug is distributed to the sites of action
• Parenteral administration


  Solution or suspension for injection (intravenous, subcutaneous, intramuscular, intraperitoneal, intravitreal, or intrathecal)
• Parenteral administration


  • Provides more predictable therapeutic profile than oral administration
  • Incurs additional costs due to requirement of trained health care professionals
  • High degree of sterility and purity standards required
  • Rapid elimination of proteins contributes to high cost
• Oral administration


  Preferred and most widely used route for small molecule drugs due to ease of formulation, patient convenience and compliance, and usually good absorption in the intestine
• Orally administered therapeutic proteins are exposed to high levels of proteases in the stomach and intestine that can readily inactivate the drug
• It only takes about 10 minutes for a therapeutic protein to degrade when taken orally
• Strategy to minimize protease-catalyzed protein degradation

  Modifying the l-amino acid to the d-amino-acid isomer at strategic peptide sequences
• Modification of glucagon-like peptide 1

  • Converting native l-ala2-glucagon-like peptide 1 to d-ala2-glucagonlike peptide-1 results in a peptide resistant to breakdown by dipeptidylpeptidase IV
• Only a small fraction of protein surviving proteolytic cleavage is absorbed into the blood, and that small fraction is further subject to metabolism as it passes through the liver
• Buccal administration


  Drugs designed to dissolve under the tongue or in the cheek pouch but not to be swallowed
• Buccal administration


  • Convenient and promotes compliance
  • Mucosa in the oral cavity exhibits lower protease activity than intestinal mucosa
  • Membrane barrier is permeable to peptides with about 5 to 10 amino-acid residues
  • Permeation enhancers may be needed to promote absorption of larger peptides and proteins
• Rectal and vaginal administration

  • Attractive because of the cavities' large mucosal surface area and richly vascularized nature
  • Only about one-third of the drug absorbed into rectal veins is shunted to the liver, the remaining two-thirds avoids first-pass metabolism
• Bioavailability of aspirin suppositories is 54% to 64% for individuals with retention times of less than 5 hours but greater than 80% for individuals with retention times of 10 or more hours
• Protease activity may be high in the rectal cavity, which is a concern for peptide and protein pharmaceuticals
• Ocular administration


  Typically less than 3% of topically applied drugs in ocular dosage forms permeate the corneal epithelium and reach the aqueous humor
• Only a very small fraction (<0.1%) of leucine enkephalin and a protease-resistant derivative made their way into aqueous humor as intact peptides
• Nasal administration


  • Therapeutic proteins must cross mucosal epithelial cells coated with degradative enzymes
  • Adequate protein absorption will probably require an absorption enhancer
• Intranasal delivery of small peptides

  • 75% bioavailability for somatostatin (6 aa), 10% for desmopressin (9 aa), and 100% for metkephamid (5aa)
  • Less than 1% bioavailability for peptides greater than 20 amino-acid length such as glucagon (29aa) and calcitonin (32aa)
• Pulmonary administration


  • The deep lung consists of alveolar epithelium that is more permeable to peptides and proteins
  • 10% to 15% bioavailability for insulin (51 aa) and growth hormone (192aa) when instilled into the deep lung
  • Avoids first-pass liver metabolism
• Aerosolized therapeutics for pulmonary delivery


  • Aerosolized DNase (dornase) for local effects in the deep lung of cystic fibrosis patients
• Transdermal delivery of proteins and peptides

  • Absorption across the skin for molecules larger than 1000 daltons has proved to be difficult, even with the addition of permeation enhancers
  • High interindividual variation in drug absorption across the skin
  • The amount of drug that can be delivered is limited by the size of the dosage form
• Recent developments in ion-current or iontophoresis may overcome the limitations of transdermal delivery of proteins and peptides
• Parenteral administration of protein therapeutics

  • Often require frequent administration that sometimes incurs alternating periods of drug insufficiency and high drug concentrations
  • Dose range is relatively small and often described in activity units rather than mass
  • Half-life tends to be short
  • Eliminated from the body by renal and hepatic mechanisms, as well as nonspecific phagocytic uptake by scavenger cells
• Controlled and sustained release strategies

  Aim to maintain plasma drug levels within the therapeutic concentration range for longer periods, minimizing periods of excessive or ineffective drug concentrations and reducing the frequency of administration
• Benefits of controlled delivery of biopharmaceuticals

  • Improved patient compliance, fewer injections, and potentially fewer adverse effects
• Biodegradable drug carriers


  Composed of biopolymers or lipid membrane vesicles (liposomes) to formulate protein drugs in colloidal or suspension dosage forms and release the protein in a controlled and sustained manner
• Requirements for a biopolymer-based drug carrier designed for protein delivery

  • Biocompatible and degradation products must be nontoxic
  • Incorporate the protein in a sufficiently gentle manner to retain bioactive conformation
  • Able to incorporate the protein in pharmaceutical scale
• Biopolymers


  • Polylactide co fabricated with glycolide (PLG) is one of the most well studied and has been demonstrated to be both biocompatible and biodegradable
• PLG polymers are hydrolyzed in vivo and revert to the monomeric forms of glycolic and lactic acids, which are intermediates in the citric acid metabolic pathway
• Controlled delivery of biopharmaceuticals

  • Improved patient compliance
  • Fewer injections
  • Potentially fewer adverse effects
• Controlled release


  Achieved using infusion devices in hospital and clinical settings
• Advances in miniaturization of infusion devices is beginning to provide portability
• Infusion devices are not ideal for most applications due to their cost and complex training requirements
• Biodegradable drug carriers


  • Composed of biopolymers or lipid membrane vesicles (liposomes)
  • Can release incorporated protein in a controlled and sustained manner
• Requirements for a biopolymer-based drug carrier designed for protein delivery

  • Biocompatible and degraded products must be nontoxic
  • Incorporate the protein in a sufficiently gentle manner to retain bioactive conformation
  • Able to incorporate the protein in pharmaceutical scale