Application to Controlled Release of Drugs by Osmotic Pumps Read the paper by Verma et al. 2002 J. Controlled Release 1. Novel Drug Delivery Systems (NDDS) have low development costs and time to market, perhaps $20 – 50 million and 3-4 years 2. A new chemical entity takes about $500 million - $ 1 billion and 10-12 years 3. NDDS can give an existing drug new life giving it better market value, competitiveness, and patent life Controlled release drugs have many benefits 1. targeted drug delivery to a particular site 2. better control within the therapeutic range 3. reduced dosing frequency 4. better patient compliance/easier to use 5. better for chronic conditions 6. potential for reduced side effects

Design options for CR dosage forms 1. matrix system – drug embedded in a polymeric material 2. reservoir system – drug core surrounded or coated by a rate controlling membrane; however oral delivery affected by pH, food, state of the GI tract 3. osmotic pump systems – use osmotic pressure to deliver the drug at a controlled rate; independent of pH and physiological state

 = RT  C

Founded in 1968 by Dr Alejandro Zaffaroni; the company's name is a portmanteau of his name. ALZA pioneered the field of drug delivery systems, bringing over 20 prescription pharmaceutical products to market, and employing about 10,000 people during 20 years. In 2001, ALZA was acquired by Johnson & Johnson via a stock-for-stock transaction worth US$10.5 billion

Delivery orifice issues too small, then need large P inside device leading to deformation and damage and possible non-zero order release kinetics Too big, the drug can just diffuse out on its own Shows linear relationship between release rate and osmotic pressure difference

Read the paper by Wright et al 2001 J. Controlled Release on an Osmotic implant for the treatment of prostate cancer For palliative (relieve symptoms w/o curing) treatment of advanced prostate cancer by lowering the levels of testosterone, for advanced cases where radiation or surgery will not be effective Based on the use of gonadotropin releasing hormone (GnRH) analogs as an alternative to orchiectomy (removal of testicles) 3. GnRH analogs stimulate the pituitary-testicular axis temporarily increasing testosterone levels in the body, however this causes a down-regulation of pituitary GnRH receptors resulting in a decrease in luteinizing hormone (LH) secretion, which then leads to the suppression of testosterone levels in the body to below castration levels 4. They used the GnRH analog called leuprolide or Lupron (also used to treat endometriosis in women by stopping menstruation by knocking down estrogen levels to postmenopausal levels) (PDR on Lupron)

1. Implant consists of a Ti alloy cylinder 4 mm in diameter and 45 mm length 2. Holds about 150 microL of the drug formulation 3. Subassemblies include the reservoir, membrane, osmotic tablets of NaCl, piston, diffusion moderator, silicone lubricant 4. Entire assembly is gamma-irradiated to sterilize 5. Drug is dissolved in DMSO as a solvent Lots of interesting studies reported in this paper basically showing the device development process.

Drug stability study in DMSO

In vitro release rate studies of the device

Canine and Phase I/II Human Clinical Trials

Designing an Osmotic Pump