[U.S. Food and Drug
Administration]

This article was published in FDA Consumer magazine several years ago. It is no longer being maintained and may contain information that is out of date. You may find more current information on this topic in more recent issues of FDA Consumer or elsewhere on the FDA Website, by checking the site index or home page, or by searching the site.

Patches, Pumps and Timed Release:
New Ways to Deliver Drugs
by Marian Segal

    If, 25 years ago, someone tried to sell you an adhesive patch, telling    
you to stick it behind your ear and it would keep you from getting sick on    
the high seas, you could make a safe bet that you were being sold up the      
river by a modern-day snake oil salesman.
    Today, however, a similar patch can be legitimately prescribed by your    
doctor. Technological advances over the last 20 to 30 years have enabled      
scientists to develop new forms of delivering drugs to our bodies, including  
a transdermal patch containing the drug scopolamine to prevent motion         
sickness.
    Drug dosage forms are keeping pace with the high-tech times. Indeed, the  
ubiquitous tablet of 1990 may one day become obsolete, going the way of the   
spirits, powders and tinctures of a century ago.
    What might replace the tablet? How about pills that are pumps and         
implanted drug-filled devices with or without tiny computers to regulate the  
time and amount of drug dispensed? These and other unconventional dosage      
forms already exist, heralding advances in drug delivery that promise even    
safer and more effective treatments.
    One of the most active areas of research and development in drug          
delivery involves "controlled-release" products. Rather than develop new      
drug entities at great cost, some drug therapies already on the market can    
be improved simply by controlling the rate at which they enter the            
bloodstream.
    "Virtually all the delivery systems marketed are initially in what we     
would call 'immediate-release preparations'--things that disintegrate and     
dissolve in 5 or 10 minutes," says FDA visiting scientist Gordon Amidon,      
Ph.D. "For some drugs, dissolution may take longer because of drug or dosage  
form properties, but the controlled release is not designed in."

Timing Is Everything
    "Drugs that are released rapidly produce a relatively rapid and high      
concentration in the body, followed by a sharp decline--a peak and valley     
effect," says Amidon. "We know that at too low a blood level the drug is not  
effective, at optimum level it's effective, and at too high a level           
undesirable effects are produced. The objective is to try to maintain the     
range in between."
    Controlled-release systems deliver a drug at a slower rate for a longer   
period. The dosage form contains more drug than a conventional tablet or      
injection, for example, but delivers the medication far more slowly--over a   
period of hours, days, or even years, rather than seconds or minutes.
    Depending on the mechanism, the delivery system may simply release the    
drug at a variable, but slower, rate, or release it at a constant rate over   
the period of release. Sometimes, by decreasing the variability of blood      
levels, it may reduce side effects.

The Ways to Delay
    Milo Gibaldi, Ph.D., dean of the University of Washington's School of     
Pharmacy in Seattle, writes in Biopharmaceutics and Clinical                  
Pharmacokinetics: "The early history of the prolonged-release oral dosage     
form is probably best forgotten. Products were developed empirically, often   
with little rationale, and ... problems were common. Today, the situation     
has improved; many of the available products are well-designed drug delivery  
systems and have a defined therapeutic goal. In some cases, the               
prolonged-release dosage form is the most important and most frequently used  
form of the drug."
    Prolonged-release preparations usually require less frequent dosing.      
Being able to take a pill once a day instead of four times or more, for       
example, can help improve patient compliance. That is, it's often easier and  
less bothersome for patients to remember to take fewer doses of medications.
    There are a number of ways of controlling the rate of delivery of oral    
medicines. One system uses the principle of osmosis to release the drug. The  
drug and an osmotic agent are surrounded by a semipermeable membrane pierced  
by one or more small, laser-drilled holes. As water from the digestive tract  
is drawn through the membrane, the osmotic layer expands, pushing the drug    
through the holes.
    In other systems, the drug simply diffuses through a polymer coating of   
the pill. The drug may be contained in a reservoir surrounded by a polymer    
film, or it may be uniformly distributed through the polymeric material.
    "Most of the polymers used in human pharmaceuticals are derivatives of    
natural products such as gelatin and cellulose, or the synthetic polymer      
silicone," says Amidon. "When designing a drug delivery system, you select    
the polymer best suited for that particular system based on the properties    
of the specific polymer."
    An erosion-controlled release system uses a polymer that is relatively    
water-soluble with the drug incorporated in it. As the polymer dissolves, it  
releases the drug. The formulation of Contac's "tiny time pill" capsules is   
based on an erosion system. It consists of coated and uncoated granules that  
erode at various rates, thus releasing the drug at varying rates and          
providing relief for an extended period.

Skin Patches
    Some drugs that have the right properties to penetrate the skin and are   
potent enough to be effective at low doses can be delivered transdermally     
(through the skin). The first transdermal patch was approved by FDA in 1979.  
It contained the drug scopolamine, used to treat motion sickness.
    Scopolamine can cause dry mouth, drowsiness, blurred vision and other     
eye problems, and sometimes more serious side effects, including dizziness    
and confusion, hallucinations, difficulty urinating, and rashes. Delivered    
through the skin at a slow rate in small amounts over three days, however,    
the drug can protect against motion sickness with fewer or less severe side   
effects.
    One patch design consists of four layers of thin, flexible membranes: an  
impermeable backing, a drug reservoir, a rate-controlling membrane, and an    
adhesive. When the patch is applied, the drug begins flowing through the      
skin into the bloodstream at a rate regulated by the membrane,                
pre-programmed to keep the drug at levels that provide effectiveness with     
acceptable adverse effects.
    Another transdermal preparation is a nitroglycerin patch for patients     
with angina pectoris (chest pain). Unlike nitroglycerin tablets placed under  
the tongue at the onset of an attack to relieve pain, the patch is applied    
once a day (usually to the chest) to help prevent angina attacks. As with     
scopolamine, a goal of delivering a steady concentration of nitroglycerin     
was to provide the lowest effective blood level of the drug while minimizing  
adverse effects, such as headaches in the case of nitroglycerin.
    With the nitroglycerin patch, however, it was discovered that             
maintaining constant blood levels is not advantageous. Studies showed that    
when patches are worn continuously, drug tolerance develops within 24 hours   
and the medication is no longer effective. Revised labeling recently          
approved by FDA recommends a dosing schedule alternating a daily patch-on     
period of 12 to 14 hours a day with a patch-off period of 10 to 12 hours.
    Another extended-release preparation that did not prove as successful as  
originally expected is Ocusert, a reservoir system in a wafer-like disk,      
designed to treat glaucoma. Glaucoma is characterized by increased pressure   
in the eye that can cause blindness. At the time Ocusert was developed, the   
standard treatment for glaucoma was application four times a day of eye       
drops containing the pressure-lowering drug pilocarpine. The drops often      
caused side effects, however, and patients sometimes did not take them as     
prescribed. Ocusert, on the other hand, placed in the lower eyelid, where it  
floats in the tear film, delivers low-dose pilocarpine continuously for one   
week.
    Although it was seen as having the potential to solve patient compliance  
problems, Ocusert was never widely used, in part because older patients were  
reluctant to place the object in their eyes. Also, Ocusert costs the patient  
approximately five times more than the pilocarpine drops. A new drug,         
timolol, has since been developed, which, although not a controlled-release   
preparation, requires only two applications of drops a day instead of the     
four needed with pilocarpine.

Implants and Intrauterine Devices
    Devices implanted under the skin are also being developed to deliver      
drugs at a controlled rate. FDA approved one such device for contraception    
in December 1990. The Norplant system is implanted under the skin and         
protects against pregnancy for five years, unless removed sooner. It          
consists of six flexible silicone tubes filled with a five-year supply of     
the hormone levonorgestrel. It is implanted in the upper arm, and small       
amounts of the hormone continuously seep through the permeable tubes into     
the bloodstream, providing contraception. (For more on this device, see       
"Norplant: Birth Control at Arm's Reach" in the May 1991 FDA Consumer.)
    Similarly, an intrauterine device called Progestasert releases the        
hormone progesterone directly into the uterus for one year to prevent         
pregnancy. An advantage of these controlled-release contraceptives over       
contraceptive pills is convenience; their effectiveness does not depend on    
remembering to take a daily pill.

The Mechanical Pump
    Although the advantages of a steady rate of drug release are evident,     
some drugs are more effective given in intervals. Infusion pumps can be       
programmed to deliver drugs at very precise dosages and delivery rates.       
These pumps may have a feedback device that controls drug delivery according  
to need.
    "I think we're going to see more complex dosing patterns that are going   
to be more difficult to regulate orally," says Amidon. "With further          
development of electronics and miniaturization of pumps and sensors, we'll    
be able to monitor various vital signs, and that will lead to feedback        
systems." Such a feedback system could monitor blood glucose levels and       
deliver insulin when needed.
    Amidon explains that the size of the pump depends on the amount of drug   
and the intended length of treatment. Some pumps are portable, some           
wearable. For miniaturized, implantable pumps, methods will have to be        
devised to refill the device externally, perhaps once a month or once a       
year, through a catheter.
    "I would say that 50 years from now we're going to have implantable       
pumps with multiple drugs that we can externally program once a month and,    
rather than going to the doctor for checkups, we will plug ourselves into a   
telephone monitoring device," Amidon predicts. "To solve problems like drug   
tolerance, we're going to have to develop drug delivery programs that are     
not constant, but programmed with time or circadian doses. We're going to     
see more complicated therapy in order to be able to reduce the amount of      
drug exposure and increase its efficacy."
    If Amidon's vision is to become reality, several technological            
roadblocks will have to be solved first. Donald Marlowe, director of FDA's    
division of mechanics and material science, points out just one, as an        
example. Before feedback technology can be applied in humans, problems with   
the pump's sensor mechanism must be overcome, Marlowe says. "For example,"    
he explains, "contact with body proteins causes reduced sensitivity of the    
sensors, compromising [feedback] reliability."
    One implanted pump, approved by FDA in 1982, allows chronic infusion of   
the liver cancer drug FUDR directly into the artery leading to that organ,    
thereby delivering a high concentration of the drug to the target organ.
    William Ensminger, M.D., Ph.D., Professor of Internal Medicine and        
Pharmacy at the University of Michigan Medical School in Ann Arbor, says      
that people live and function with implanted pumps quite well. One of his     
patients had a pump for eight years, which was refilled every couple of       
weeks. "We've had other people who have had them in for four years and a few  
people who have had them taken out when the liver tumor was eradicated."
    Last July, FDA approved a concentrated form of morphine specially         
developed for microinfusion pumps that can be implanted under the skin of     
the abdomen or worn outside the body. Given this way, the drug can provide    
more constant relief to people in severe pain, such as terminal cancer        
patients. Programmed with dosing information before it is filled with the     
concentrated morphine, the pump constantly delivers fractional doses of the   
drug. The dose can be changed by beaming information through skin and         
tissues to the implanted pump.
    Concentrated morphine can have severe side effects, such as seizures and  
respiratory depression if the starting dose is misjudged. Therefore,          
patients must be monitored in a fully equipped and staffed facility for at    
least 24 hours after the initial "test" dose. Patients may then go home and   
return periodically--sometimes as seldom as once a month--for a physician to  
refill the reservoir in the pump.
    It's clear that we're witnessing an evolution--or revolution--in drug     
delivery, with many innovations in administering drugs to improve safety and  
effectiveness. The process continues, using techniques as varied as advanced  
electronics and genetic engineering. n

Marian Segal is a member of FDA's public affairs staff.


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