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Pulmonary Drug Delivery (Standard process (Distribution: rapid (Goal…
Pulmonary Drug Delivery
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Standard process
Distribution: rapid
Limitation
most material will be swallowed and absorbed, entering systemic circulation after undergoing the first-past effect in the liver
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Absorption
Factors
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Formulation properties: desintegration, dissolution, particle size, wettability
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API: Molecular weight, charge, solubility, and lipophilicity
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The alveolocapillary permeability barrier. The dominant permeability barrier is thought to be the epithelial cell.
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Disadvantages
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Low dose delivered to lungs, some dose swallowed
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Insulin
Basics
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Insulin secretion is highly regulated process that maintains plasma glucose concentrations during fasting and post-prandial periods. Glucose stimulates insulin secretion
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Diabetes
Type II
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Although NIDDM starts off as insulin resistance, eventually patients may require insulin to control their blood sugar. eventually, these patients can lose all of their pancreatic beta-cell function and ability to produce insulin and hence become insulin dependent
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Type I
It is a hyperglycemic condition caused by inadequate production of insulin by beta cells of the pancreas.
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Insulin Analogs
Structure and PK
Rapid acting Analogues
Examples
Lispro
A lysine-proline (Lys-Pro) sequence at the end of the insulin-B chains is reversed, which creates steric hindrance and a reduced ability to self-associate
Aspart
Insulin aspart incorporates an amino-acid change that also creates charge repulsion and steric hindrance due to a local conformational change at the carboxyl terminus of the B chain
Characteristic
Absorbed more rapidly than regular insulin and reduce post-prandial glucose excursions more efficiently. Because of their short-lived action, adjustments in basal insulin levels are required to achieve improvements in overall glycaemic control
Long-acting analogues
Modification Methods
Reduce its solubility at physiological pH, or by covalent acylation
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Inhalable insulin
Afrezza Insulin
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Wrong disease for device, flaw of translational medicine (should have been recognized in pre-clinical design) = social barrier (disease stigma)
Untra-rapid insulin absorption, great advance in pulmonary drug delivery = alveolar deposition, cross endothelium (great PK, no first pass)
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Route of administration dictates the rest of ADME and barriers. Subcutaneous Lispro PK more similar to Afrezza PK than regular insulin.
In patients with type I diabetes, must use with a long-acting insulin
maintenance of blood glucose levels by glucagon and insulin. when blood glucose levels are low, the pancreas secretes glucacon, which increases endogenous blood glucose levels through glycogenolysis. After a meal, when exogenous blood glucose levels are gih insulin is released to trigger glucose uptake into insulin-dependent muscle and adipose tissues as well as to promote glycogenesis.
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