Biomedical Engineering Reference
In-Depth Information
hypoglycemic effect [203]. Pfizer in collaboration with Inhale Therapeutic Systems
(NASDAQ: INHL) announced a Phase II clinical trial for its pulmonary insulin prod-
uct EXUBERA in March 1996. Insulin-loaded PLGA nanospheres having weight
mean diameters of 400 nm found 75% of insulin were successfully delivered into the
alveolar fraction in a cascade impactor inhaled at 28.3 l/min [204]. The further study
showed that after administration of 3.9 IU/kg insulin with PLGA nanospheres into the
trachea of a fasted guinea pig for 20 min, the blood glucose level was reduced signifi-
cantly and hypoglycemia was prolonged over 48 h, compared to 6 h with the nebulized
aqueous solution of insulin. The enhancement of insulin bioactivity by the pulmonary
route using a combination of absorption promoters like sodium caprylate, sorbitan
trioleate, oleic acid sodium salt, sodium tauroglycocholate, bacitracin, bestatin, and
chymostatin in anesthetized rat concluded that absorption promoters in combination
have significant potential for increasing the pulmonary bioactivity of insulin [205]. An
open label, random, crossover study found that the relative bioavailability of inhaled
insulin (xubera) with injectable insulin (lispro) in healthy volunteers for 10h had
faster onset of action and longer duration of action than subcutaneous lispro [206].
In January 2006, human insulin inhalation powder (Exubera; Pfizer) was approved
by the US FDA for the treatment of adult patients with diabetes mellitus. Exubera
consists of blisters that contain recombinant human insulin formulated as a dry pow-
der with excipients that help stabilize the insulin during the spray-drying production
process and allow room-temperature storage [207]. Blisters of Exubera, which con-
tain either 1 or 3 mg of insulin to facilitate dosing flexibility, are administered by the
patient using the Exubera inhaler [208]. Although several inhaled insulin devices are
in various stages of development, the Exubera (Pfizer, New York, NY) formulation
and delivery system is the first inhaled insulin to be approved for use in the USA
and Europe. Clinical studies on diabetic patients [209] have shown that Exubera con-
sistently improves glycemic control, in combination with longer-acting subcutaneous
insulin regimens, in patients with type 1 or type 2 diabetes, or is used to supplement
or replace oral antidiabetic therapy in patients with type 2 diabetes.
9.6.2.2 Luteinizing Hormone-Releasing Hormone Analogs
Luteinizing hormone-releasing hormone (LH-RH) is the bloodborne messenger
between the hypothalamus and the anterior pituitary, which controls reproductive
function. This hormone is synthesized and stored in the hypothalamus in neurons
and is released in periodic bursts into the hypophyseal portal circulation. These com-
pounds are large in molecular size and also are generally ionized at physiological pH
because of their multiple sites for ionization at physiological pH, and therefore suffer
a variety of membrane transport liabilities like pore filtration, aggregation, and com-
plexation phenomena when they are administered orally. Studies were conducted with
leuprolide in purebred, tracheostomized, male and female beagle dogs, using an instil-
lation method to deliver the drug to various regions within the lung [210]. All blood
samples were central and plasma drug levels were determined by a modified radio-
immunoassay procedure that uses an antibody that recognizes the tripeptide antigenic
determinant [211]. Five groups of four to six dogs each were administered leuprolide
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