Advances
in Therapy®
Volume 22 No. 6
November/December 2005
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Drug Delivery Systems
Improve Pharmaceutical
Profile and Facilitate
Medication Adherence
Albert I. Wertheimer, MBA, PhD
Director
Thomas M. Santella, BS
Research Coordinator
Center for Pharmaceutical Health Services Research
Temple University
Albert J. Finestone, MD
Professor of Medicine
Director of the Center on Aging
Temple University School of Medicine
Richard A. Levy, PhD
President
Levy Consulting
ABSTRACT
Innovations in dosage forms and dose delivery systems across a wide range of
medications offer substantial clinical advantages, including reduced dosing frequency and improved patient adherence; minimized fluctuation of drug concentrations and maintenance of blood levels within a desired range; localized drug
delivery; and the potential for reduced adverse effects and increased safety. The
advent of new large-molecule drugs for previously untreatable or only partially
treatable diseases is stimulating the development of suitable delivery systems for
these agents. Although advanced formulations may be more expensive than conventional dosage forms, they often have a more favorable pharmacologic profile
and can be cost-effective. Inclusion of these dosage forms on drug formulary lists
may help patients remain on therapy and reduce the economic and social burden
of care.
Keywords:
dosage forms; drug delivery; adherence;
cost-effectiveness; medication technology
2005 Health Communications Inc
Transmission and reproduction of this material in whole
or part without prior written approval are prohibited.
©
0894
Address reprint requests to
Albert I. Wertheimer, MBA, PhD
Director
Center for Pharmaceutical Health
Services Research
Temple University
3307 North Broad Street
Philadelphia, PA 19140
559
OVERVIEW OF DRUG DELIVERY SYSTEMS
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Since the dawn of modern medicine, researchers have continually searched for new
and improved ways to administer medicinal products. An early result of this quest
was the invention of the syringe during the Civil War years in the United States, which
made possible intravenous morphine injections for quick relief of pain. Over the past
50 years, drug delivery technology has been considerably enhanced. The 1950s brought
the first microencapsulated drug particles, and in the 1960s, polymers came into use
for delivery of drug products into the body. By the 1980s, transdermal delivery
became a reality, and transepithelial delivery systems were introduced in the 1990s.
The current decade has seen the advent of liposomal systems for the delivery of peptides and other large-molecule drugs and biologicals.
Novel drug delivery methods offer substantial clinical advantages, including
reduced dosing frequency and improved patient compliance; minimized fluctuation
of drug concentrations and maintenance of blood levels within a desired range;
localized drug delivery; and the potential for reduced adverse effects.1
Although tablets, capsules, ointments, aerosols, injectables, and liquids remain
the primary modes of drug delivery, they have been increasingly enhanced by and
embedded within technology that allows them to work at a desired rate of delivery,
thereby sustaining drug concentration within an optimal therapeutic range, maximizing the efficacy/dose relationship, minimizing dosing frequency, and promoting
patient adherence.2
The principal drawback of traditional dosage forms is that delivery is uncontrolled, which can lead to a number of undesired results. For many drugs, rapid
release causes fast absorption, and although this is often necessary or intended, it
may also increase adverse effects or lead to more frequent dosing. By controlling the
rate at which the drug is released, advanced dosage systems can reduce the number
of necessary doses, making a drug more convenient, which tends to enhance adherence and effectiveness.
Transdermal delivery is one approach to achieving controlled release of medication.
In avoiding hepatic first-pass metabolism, transdermal patches allow drug delivery
over longer periods. They also provide more efficient delivery of drugs with limited
oral bioavailability. Patch formulations are now available for a wide variety of agents,
including birth control and smoking cessation medications, as well as fentanyl, clonidine, nitroglycerin, lidocaine, oxybutynin, and testosterone. In many cases, transdermal delivery is preferable to oral administration because it lessens the adverse effects
that these drugs sometimes cause.
ADVANCES IN ORAL FORMULATIONS
Although conventional oral formulations are still the most widely administered
dosage forms, they are enhanced today by many different controlled-release technologies, including delayed-onset and extended/sustained-release formulations.
The many advantages of these new formulations are illustrated by the following
examples.
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Chronic Pain
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For patients with continuous pain who respond well to opioids, long-acting sustained-release formulations offer many important advantages over their short-halflife counterparts, including the following3:
• Because serum levels remain steady, mini-withdrawals or rebound reactions do
not occur, as they sometimes do with long-term use of short-acting opioids.
• Sleep patterns are more normal; with careful titration, the intermittent sedation
that occurs with high-peaking, short-acting agents can be avoided.
• The use of fewer daily pills and resultant reduced fluctuations in serum levels
may help patients to shift their focus away from somatic concerns. Patients who
have used sustained-release opioids report greater satisfaction with outcomes
and an improved quality of life.
• Sustained-release dosage forms provide less reinforcement of inappropriate use.
Because they are more difficult to convert into injectable forms, they have a lower
potential for diversion. The vast majority of prescription opioid abuse or drug
diversion involves short-acting agents. Sustained-release preparations are also
associated with relatively fewer medical emergencies related to prescription opioid
abuse.4
Cardiovascular Disease
Patients with hypertension have benefited significantly from delayed-onset
formulations of the calcium channel antagonist verapamil. Drug release is delayed
so that when the drug is taken with food at night, its concentration in the bloodstream parallels the circadian increase in blood pressure that occurs overnight and
into the morning (Fig 1).
Other drugs for cardiovascular disease, such as nifedipine, have been formulated
with controlled-release technology to “extend efficacy, optimize blood pressure control, and reduce [adverse] effects.”1 When a steady stream of a drug is slowly
released over an extended period, only a limited quantity is found in the bloodstream at any given point, thereby lessening the chance of an adverse effect caused
by high blood concentrations. This formulation effectively lowers blood pressure
without the accompanying supervasodilation and adverse effects that are associated with immediate-release nifedipine.5-7
Attention Deficit Disorder
Twelve-hour formulations of methylphenidate often increase efficacy while reducing the frequency of dosing. In addition, because children can take these formulations
before they go to school,8 there is no requirement for storage of medication at school
or supervised administration by the school nurse, and the child’s school day is not
disrupted. Long-acting preparations may be particularly helpful to adolescents
because their day is much longer than that of a young child in terms of school and
after-school activities.
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Fig 1. Advanced dosage form provides high level of drug when chance
of cardiovascular incident is greatest.
Conventional
dosage form
Delayed onset
sustained-release
dosage form
Blood Level of Drug
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Greatest chance
of heart attack,
stroke, or angina
Dose
taken
9:00
3:00
6:00
9:00
12:00
PM
AM
AM
AM
PM
Adapted from Prisant LM. Chronobiol Hypertens Med Crossfire. 1999;1:1-16.
Some clinicians believe that long-acting preparations are optimal for achieving
the important therapeutic goals of stability and predictability of attention, mood,
and behavior.9 Consistency in brain function is a key therapeutic action of these
drugs. Long-acting agents are more likely to produce a normalized attention span
and a stable and predictable inner core that a person can bring to interactions with
the environment. A stable mood and the ability to pay attention over time help
patients to anticipate that each day will be like the next. The fluctuating effects of
short-acting agents can worsen a chronically disruptive inner state.
In addition, because a major problem for these patients is an inability to remember and plan, they often do not recognize when they need to take another pill and
can be unaware of the medication’s decreasing effectiveness as it wears off. Longacting preparations can help to minimize this problem.
Dyslipidemia
Niacin, which is used in the treatment of patients with dyslipidemia and is effective in reducing coronary events, is a complete cholesterol medication in that it lowers low-density lipoprotein cholesterol (LDL-C) and triglycerides while raising
high-density lipoprotein cholesterol. Long-acting niacin causes less flushing and is
more effective than its immediate-release cousin. One study found that immediaterelease niacin lowered LDL-C by 14% to 22%, and the sustained-release form reduced
LDL-C levels by 22% to 50%.10
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Urge Incontinence
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Urge incontinence (UI) and overactive bladder are conditions faced by millions of
adults, particularly the elderly. The primary drug used to treat these conditions is
oxybutynin, an anticholinergic agent. However, typical adverse effects of such
agents, including dry mouth, constipation, blurred vision, confusion, drowsiness,
and cognitive impairment (especially in the elderly), occur in more than 50% of
patients, frequently leading to early termination of therapy.
Since its introduction in 1975, oxybutynin has undergone significant advancements,
resulting in extended-release and transdermal formulations. A once-daily, extendedrelease (ER) version provides a smooth concentration profile over its 24-hour dosage
interval. One study concludes, “Given its overall efficacy/tolerability profile and
dosage flexibility, oxybutynin ER provides an excellent treatment option in the firstline pharmacotherapy of overactive bladder.”11 A transdermal formulation of oxybutynin has demonstrated improvement rates of 80% to 90% and has reduced
incontinence episodes by 19 per week.12 It has done this while reducing unwanted
anticholinergic effects. Delivery across the skin bypasses initial drug metabolism in
the liver and gastrointestinal tract; adverse effects are reduced because they arise
mostly from the drug’s metabolites.
INNOVATIONS IN INHALED MEDICATIONS
In 2000, the US Food and Drug Administration (FDA) approved Pulmicort
Respules® (AstraZeneca Pharmaceuticals LP, Wilmington, Del), an asthma medication
for young children. Although the active ingredient in this medication, budesonide,
had been used worldwide for more than 15 years in various antiasthma formulations,
Pulmicort Respules offered a novel delivery mechanism. Before this innovation,
corticosteroid therapy traditionally was administered via an asthma inhaler that was
difficult for young children to use correctly. Pulmicort Respules uses a jet nebulizer to
convert the medication into a fine mist, which children can inhale through a face mask
or mouthpiece.
Another asthma medication with an advanced delivery system is Advair Diskus®
(GlaxoSmithKline, Research Triangle Park, NC), which effectively treats both airway
constriction and inflammation. Unlike traditional aerosol inhalers, Advair contains
a novel Diskus device with which patients use their own breath to inhale premeasured doses of medication. Patients open the device, click a lever to prepare the dose,
inhale, and close the device. No hand/breath coordination or spacers are needed.
IMPROVEMENTS IN OTHER DELIVERY SYSTEMS
Depot injections, transmucosal delivery, microemulsions, and liposome and polymer technologies contribute to the arsenal of advanced delivery options. Improved
efficacy and increased bioavailability have resulted from a microemulsion formulation of cyclosporine for the treatment of patients with psoriasis.13
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Depot injections, in the form of long-acting intramuscular preparations, have
proved particularly useful for treating patients with schizophrenia, in whom they
have been shown to improve adherence.14 Depot injections and implants that last
several months to a year have been developed for the delivery of large-molecule
peptides and other compounds. These formulations are currently used for cancerrelated indications, for which sustained blood levels are required if optimal efficacy
is to be achieved. Drugs used include somatostatin analogues for pituitary adenoma
and luteinizing hormone–releasing hormone for prostate cancer.
Liposome and polymer delivery systems are now being used to significantly extend
the duration of drug release and to target release at specific sites in the body.
Incorporating drugs into liposomal particles offers the advantages of longer circulation times in the blood, protection of the drug within the lipid particle, and selective
delivery into tissues where the drug is needed. Small liposomes coated with polyethylene glycol (PEG) can localize in tumors because the blood vessels are disorganized
or “leaky.” The PEGylated formulation of the cancer drug doxorubicin has been associated with less cardiac toxicity than has the conventional form of doxorubicin.15
PEGylated doxorubicin has been approved for the treatment of patients with Kaposi’s
sarcoma and acquired immunodeficiency syndrome (AIDS).
PEGylated lysosomes are also being used for the delivery of protein drugs to
achieve greater bioavailability, sustained duration, reduced toxicity, and enhanced
efficacy. Two approved PEGylated formulations of interferon-alfa products are now
part of the standard of treatment for hepatitis C.16 These are administered weekly (as
opposed to thrice-weekly dosing for non-PEGylated interferon formulations) and
maintain more constant levels of interferon in the blood. Another FDA-approved
PEGylated drug is pegfilgrastim, the second-generation filgrastim product that is
used to elevate white blood cell count after chemotherapy. Pegfilgrastim has a relatively long biological half-life and enhanced bioavailability, enabling a dosing frequency of only once per chemotherapy cycle.16
Another example of targeted drug delivery with the use of biopolymers is the
Gliadel® Wafer (Guilford Pharmaceuticals, Baltimore, Md), a dime-sized polymer
wafer that dissolves slowly when placed in the brain following surgical removal of
a brain tumor; it gradually releases the cancer chemotherapeutic drug carmustine.
Up to 8 wafers that are implanted in the cavity formerly occupied by the tumor
slowly deliver the drug directly to the tumor site, thereby delaying tumor recurrence.
Gliadel has been approved to treat patients with glioblastoma multiforme, a common brain cancer that progresses rapidly and is often fatal within 1 year. Gliadel
improves the survival rate of patients with such tumors.17
The Gliadel Wafer eliminates the traditional problem of getting drugs across the
blood–brain barrier by delivering high concentrations of drug directly onto the affected site. Because delivery is localized, the debilitating adverse effects of conventional
chemotherapy are reduced. The wafer dissolves evenly, similar to a bar of soap, ensuring the release of a steady flow of drug without sudden release of chunks of the drug,
which may cause an overdose. The wafer dissolves within 2 or 3 weeks, but through
a change in its chemistry, the polymer can be made to last from 1 day to 6 years for
other medical applications.18
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Other formulation innovations include melting and chewable tablets, as well as
capsules whose contents are sprinkled on food. These formulations can be quite
helpful to patients who have difficulty swallowing conventional tablets, especially
children and elderly persons.19 Finally, new packaging and labeling technologies,
including blister packaging, dosage schedule packaging, Braille labels, and big-print
and individualized information sheet printouts, provide additional assistance in
the management of dosage regimens (Table).
Medicine Delivery Technology Examples
Technology
Advancement
Delayed-onset
Sustained-release
Transdermal patch
Treatment Target
or Class
Cardiovascular disease
Attention deficit disorder/
hypertension
Birth control
Melting tablets
Depot injections
Chewable tablets
Fixed-dose combinations
Migraine
Anti-inflammatory,
schizophrenia
Geriatric, pediatric
Diabetes
Advantage
Less frequent dosing
Eliminates need to take
drug during school
Prevents dependence
on memory
Avoids need to locate
water source (immediate
administration)
Long-term therapy,
fewer doctor visits
Easier to swallow
Simplified therapy
enhances adherence,
can save money
COMBINATION PRODUCTS
Combining multiple drugs that have the same overall functional effects can
enable reduced dosage of each agent, thereby resulting in diminished overall
adverse effects. In addition, combining both agents in the same pill simplifies the
drug regimen, which may improve adherence. Advantages of combination products
include the following:
• A diuretic and β-blocker combination is often used in the treatment of patients
with hypertension; the diuretic corrects the salt and water retention that sometimes accompanies β-blocker therapy.20
• The fixed combination of dorzolamide–timolol, which is used topically in the eye
for the treatment of patients with glaucoma, is more effective than is separate
administration of each agent.21
• Adherence with 2-drug medication regimens is much better when patients take
fixed-dose combination products versus 2 separate pills (examples in the management of diabetes and hypertension are described later).
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ADVANCED DOSAGE FORMS FACILITATE
MEDICATION ADHERENCE
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A great source of waste in health care is patient nonadherence with medications.
Excessive health and economic costs are associated with resultant hospitalizations, office
visits, disease progression, complications, and premature disability and death.22-29
In the United States, death from coronary heart disease attributed solely to nonadherence with long-term medications (antihypertensive, cholesterol-lowering, and hypoglycemic) results in a huge annual economic burden in medical costs and lost life-years,
estimated at $138.5 billion.30
Overall, 50% to 70% of patients do not properly take their prescribed medication.
The rate of nonadherence is even higher in patients with chronic illnesses.23 The likelihood of nonadherence increases with the complexity of the regimen and is of particular concern with elderly patients, who often take multiple medications.31
Improved drug formulations and dosage form designs reduce many of the barriers
to taking medication properly, including complex dosage regimens, undesirable
adverse effects or physical characteristics (eg, size of tablet, aftertaste, gastrointestinal
distress), and the stigma or shame experienced when one is observed taking medicines.
Advanced delivery systems have in many cases improved adherence by facilitating administration or reducing the number of doses required. Once-daily, onceweekly, and even once-monthly formulations have helped patients take their
medications correctly, ultimately improving patient adherence and treatment effectiveness simultaneously (Fig 2).32 Improved adherence associated with new formulations of drugs used in the treatment of patients with human immunodeficiency
virus (HIV)/AIDS, osteoporosis, diabetes, hypertension, the need for contraception,
and UI are described below.
Human Immunodeficiency Virus/Acquired
Immunodeficiency Syndrome
Adherence to antiretroviral therapy is crucial for maintaining effective outcomes
in the treatment of patients with HIV/AIDS. Adherence with a once-daily formulation is much better than adherence with a twice-daily formulation of the same
agent.33,34 Numerous once-daily formulations are now available among the range of
treatment options and drugs for HIV/AIDS. These include the nucleoside/nucleotide
analogs Epivir® (3TC; GlaxoSmithKline, Research Triangle Park, NC) and sustainedrelease Zerit® (d4T; Bristol-Myers Squibb, Princeton, NJ), nonnucleoside reverse transcriptase inhibitors such as Sustiva® (efavirenz; Bristol-Myers Squibb) and
Viramune® (nevirapine; Boehringer Ingelheim, Ridgefield, Conn), and protease
inhibitors such as Agenerase® (amprenavir; GlaxoSmithKline) and Kaletra® (lopinavir/
ritonavir; Abbott Laboratories, North Chicago, Ill).35 Twice-daily to once-daily
switches are advantageous; a representative study concludes, “Subjects switching
from twice-daily therapy to once-daily therapy demonstrate a reduced decline in
adherence over 24 weeks.”34
Osteoporosis
Because it is an asymptomatic chronic condition, treatment for osteoporosis is typically hampered by nonadherence. Several studies show that half of women with post-
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Fig 2. Dosing frequency and adherence. Meta-analysis of 8 studies involving
11,485 patients with hypertension.
Once Daily (n=1830)
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92
P<.03
Twice Daily (n=4405)
87
P<.001
P<.07
83
>Thrice Daily (n=5250)
0
20
40
60
80
100
Mean Adherence, %
Adapted from Iskedjian M et al. Clin Ther. 2002;24:302-316.
menopausal osteoporosis who are being treated with bisphosphonate therapy do not
stay on their medications.36-38 Medication persistence is better with weekly versus
daily bisphosphonates, but it remains suboptimal; these studies found that 80% of
patients taking once-daily formulations versus 60% of those taking once-weekly medications discontinue treatment before the end of the first year. A new once-monthly
bisphosphonate treatment for osteoporosis is now available that should further reduce
the adherence burden.
Diabetes
The use of combination products can substantially simplify the dosage regimen in
the treatment of patients with diabetes, for whom multiple drugs are frequently
required. For example, a patient who requires metformin, rosiglitazone, and a sulfonylurea might take a total of 8 pills per day if maximum doses of each medication
are prescribed. The total number of pills could be halved if available metformin–
rosiglitazone and metformin–glyburide combination products are given to the same
patient. In this instance, half the metformin dose would be found in the rosiglitazone
combination, and half in the sulfonylurea combination.39 Among patients with diabetes previously taking metformin or glyburide who then required addition of the
alternate agent, those receiving a combination pill that contained both agents demonstrated better adherence than those receiving 2 separate pills (Fig 3).40
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Fig 3. Adherence is greater in patients with diabetes switched to fixed-dose
combination versus 2 pills.
80
77*
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70
Adherence Rate, %
60
54
50
40
30
20
10
0
Gly/Met Fixed Dose
(n=105)
Gly+ Met†
(n=1815)
P<.001 vs glyburide + metformin.
Patients receiving glyburide or metformin monotherapy who had the alternate agent added.
*
†
Adherence=days supplemented/total days.
Previously treated patients defined as patients who had received an antidiabetic agent for at least 6 months.
From Melikian C et al. Clin Ther. 2002;24:460-467.
Hypertension
The principal goal of antihypertension treatment is to maintain blood pressure
control without causing significant adverse effects. Although scores of antihypertensive therapies are available, adherence is often poor. Over the past 2 decades,
however, advances in drug delivery technology have helped to improve adherence
with antihypertension treatments. Transdermal clonidine has proved particularly
beneficial in this regard. One study found that prescribed clonidine patches were
worn during 99% of treatment time intervals, compared with a 64% adherence rate
for patients taking oral captopril.41 A similar study found that “the clonidine patch
was worn as directed during 96% of 668 patient-weeks of therapy,” while “adherence with the oral enalapril regimen was highly variable.”42
Combination products are beneficial in helping patients with hypertension adhere
to medication regimens. In one study, it was found that a lisinopril/hydrochlorothiazide combination pill resulted in a 19% improvement in adherence over its separate counterparts (Fig 4).43
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Fig 4. The combination of 2 hypertensive agents in 1 pill enhances adherence.
100
Adherence, %
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90
Lisinopril/diuretic
combination pill
(n=1644)
80
69%
70
19%*
Lisinopril + diuretic
(n=624)
60
58%
50
0
1
2
3
4
5
6
7
8
9
10
11
12
Months
P<.05 vs fixed-dose combination.
*
HCTZ=hydrochlorothiazide.
Adapted from Dezii CM. Manag Care. 2000;9(9 suppl):S2-S6.
Contraceptive Therapy
Although an estimated 12 million women in the United States use oral contraceptives (OCs), nonadherence can have tremendous consequences in that pills must be
taken precisely as directed to avoid pregnancy. Lapses in OC therapy result in more
than 3.6 million unintended pregnancies each year.44
Adherence difficulties with OCs have been well documented. In one study, 19% of
OC users reported missing 1 or more pills per cycle. A similar study found that 47%
of OC users missed 1 or more pills, and 22% missed 2 or more pills, per cycle. A study
using electronic monitoring of the time and date of pill removal from the bottle container found that 30% to 51% of women skipped 3 or more dosing days per cycle.44
To combat this problem, a transdermal contraceptive patch was developed that
improves adherence by about 10%.45 Other innovative contraceptive therapies based
on advanced drug delivery methods include a transdermal patch that contains
ethinyl and norelgestromin, a combination product that delivers both progesterone
and etonogestrel and is inserted once a month, and an intrauterine system that
is effective for 5 years.46 All of these innovative contraceptives have helped reduce
the burden of adherence.
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Urge Incontinence
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The fraction of patients who continue to take medication over time was found to
be better with the extended-release formulation of oxybutynin than with conventional oxybutynin (Fig 5).47,48 A study of the Medi-Cal Program found that, when
compared with conventional oxybutynin, extended-release oxybutynin was associated with a 125% increase in the rate of prescription renewal.49
Fig 5. Persistence with immediate-release and extended-release oxybutynin
formulations for overactive bladder.
Percentage Taking Therapy
100
Oxybutynin IR
Oxybutynin ER
10
1
1
2
3
4
5
6
7
8
9
10
11
12
Month
IR=immediate release; ER=extended release.
Adapted from Chui MA et al. Value Health. 2004;7:366; and Noe L et al. Manag Care Interface. 2004;17:54-60.
DOSAGE FORMS AND COST SAVINGS
Although they often carry higher price tags than their predecessors, new dosage
forms have the potential to reduce the overall cost of treatment through reduced use
of healthcare services.
Cost Savings in Long-Term Care Facilities
The amount of time required for drug administration contributes to the total cost
of drug therapy for nursing home residents. Administration of medications involves
giving the right dose of the right drug to the right patient at the right time; this must
be done by a person who is licensed to perform this task—usually a nurse. Direct
care time with the patient and indirect time in preparing the dose are both involved.
This time commitment can prevent a nurse from performing other direct patient care
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responsibilities. The labor costs associated with more frequent administration of
immediate-release products may exceed the acquisition and labor costs of the sustained-release products.
Zlotnick and colleagues modeled the labor costs associated with the administration of immediate- versus sustained-release dosage forms of a drug for Parkinson’s
disease and 2 drugs for cardiovascular disease to patients in a long-term care facility. In all 3 cases, the sustained-released products, which required less frequent dosing, saved labor time over the immediate-release brand and generic equivalent
products, despite their higher acquisition costs.50
Cost Savings With Combination Products
In a study of prices of combination products of agents for diabetes and cardiovascular disease, most combination agents were found to cost the same or less than their
component drugs cost individually. This was true for both brand name products and
their generic equivalents. In some cases, the combination medication was considerably less expensive than the individual components purchased separately. The use of
2 combination pills for diabetes (metformin–glyburide and metformin–rosiglitazone)
in patients who require 8 single pills a day could save more than $50 per month.40
Two-drug combination products can offer cost savings to patients with prescription
insurance because they eliminate 1 copayment. In the best case, the combination product may cost the same in copayments as either of the 2 individual drugs alone. In the
worst case, if the insurance plan places combination medications on a higher copayment “tier” (ie, charges a higher copayment for combination medications), then
the copayment cost of the combination product may be closer to the cumulative cost
of both individual products.39
Cost Savings With Transdermal Antihypertensive Therapy
Savings in overall medical costs have been demonstrated with respect to transdermal clonidine (Fig 6).6 In a study of a cohort of 1135 patients, 261 received transdermal
clonidine and the remaining 874 received oral clonidine. Initial acquisition costs for
oral clonidine were lower than those for the transdermal alternative; however, after
12 months, the total medical costs for the oral group were $865.76 compared with
$483.30 for the transdermal group. This cost savings of $382.46 per transdermal
patient “reflected less use of hospital, physician, and laboratory services.”51
Cost Savings With Long-Acting Antipsychotics
Effective treatment of patients with schizophrenia is often compromised by patient
nonadherence followed by relapse that leads to hospitalization, which is the largest
expenditure for this disease. Long-acting dosage forms of antipsychotic medications
have been reported to improve adherence, delay relapse, and lower overall treatment
costs. In an economic modeling study, the relapse rate of patients who were taking
long-acting risperidone was compared with relapse rates of patients who were taking haloperidol depot, oral risperidone, and oral olanzapine. It was found that the
rates of relapse leading to hospitalization after 1 year of treatment were 66% for
haloperidol depot, 41% for oral risperidone, 41% for oral olanzapine, and 26% for
long-acting risperidone (relapse percentages for patients not requiring hospitalization
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were 60%, 37%, 37%, and 24%, respectively).52 Improved adherence and reduced rates
of relapse with long-acting risperidone over oral risperidone translated to an annual
cost savings of $161 per patient; a corresponding savings of $8224 was calculated
when long-acting risperidone was compared with haloperidol depot—a cheaper but
less effective agent that results in almost 3 times as many relapses.52 Other studies on
long-acting dosage forms have also reported improved adherence, reduced relapse
rates, and overall cost savings.53-56 Cost savings with long-acting formulations are
likely to be greater for psychiatric patients at high risk of nonadherence or with more
severe disease.55,56
Fig 6. Cost savings with clonidine patch for hypertension.
Oral formulation
Skin patch
Yearly Cost per Patient, US$
1000
800
600
400
200
0
Drugs
Office Visits
Lab
Hospital
Total
Adapted from Sclar A et al. Pharmacoeconomics. 1992;2:267-269.
Cost Savings With Extended-Release Drugs for Urge Incontinence
New formulations of UI drugs can potentially reduce the overall costs of UI.
Although these therapies are generally more costly compared with immediate-release
oxybutynin, their improved profiles may result in overall cost savings. For example,
a cost-effectiveness model that compared immediate-release oxybutynin with both
extended-release oxybutynin and extended-release tolterodine found the extendedrelease formulations to be cost-effective in the management of UI.57
THE FUTURE OF DRUG DELIVERY
The flowering of modern medicine in the late 19th century brought with it the modern pharmaceutical industry and the eventual development of the numerous drugs
that are available today. Over time, many of these drugs have been improved upon
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through their incorporation into more sophisticated formulations and dosage forms.
Even smarter dosage forms are on the horizon, including new biofeedback systems
that sense conditions in the body and release the drug only when it is needed. New
modes of delivery, such as implanted microchips and microspheres, that will enable
the improved use of proteins have the potential to revolutionize drug delivery.58
Although invasive methods of drug delivery (injections and infusions) are undesirable, they have served as the primary mode for administering proteins and peptides. The advent of new large-molecule drugs for previously untreatable or only
partially treatable diseases has stimulated the development of suitable delivery systems. Noninvasive pulmonary delivery is routinely used for lung disease; however,
advances in technologies used to manufacture drug powders for inhalation now
offer the potential application of pulmonary delivery for many systemic diseases.
The pulmonary route provides many advantages over oral, intranasal, and transdermal alternatives. For instance, proteins and peptides are destroyed by the gastrointestinal system, and most large molecules do not pass easily through the skin
or mucous membranes. Pulmonary delivery to the deep lung has additional biological advantages as well: “The alveolar epithelium that lines the lungs naturally
absorbs proteins and peptides without enhancers... and offers an enormous surface
area for absorption at low local drug concentration. Further, deep lung delivery can
yield rapid onset of action, which may be important in some applications, for example, meal-time insulin and other endocrine hormones where biological effects are
much more strongly tied to the rate of increase of their concentration in blood as
opposed to their average level.”16
Inhaled formulations of large-molecule therapies have shown considerable
promise. Pulmonary insulin, now in late stages of clinical testing, may provide
glycemic control equal to that of insulin injections and better than that provided by
combinations of oral diabetic agents.59-63 Patients with diabetes have affirmed their
desire for such an alternative to repeated painful injections.64
Additional agents that are currently being investigated for pulmonary delivery
include growth hormone (for growth hormone deficiencies), antitrypsin (for emphysema and cystic fibrosis), interferons (for multiple sclerosis and hepatitis B and C), and
parathyroid hormone (PTH) and other peptides (for osteoporosis). Inhalation delivery
methods may eventually be applied to gene therapy as well as to vaccines.
CONCLUSIONS
New dosage forms and formulations can represent meaningful advances in pharmacotherapeutics, providing both clinical and economic value. “Patient access to
innovative pharmaceutical formulations affords physicians an opportunity to tailor
therapeutic regimens to enhance the probability of compliance, and thereby
improve patient outcomes.”65 The advantages of advanced dosage forms should be
considered in decisions regarding inclusion of drug products in formularies or their
assignment to copayment tiers. Because many of these formulations can improve
treatment outcomes in diseases of the elderly, who are often sensitive to adverse
effects and must adhere to complex treatment regimens, they should receive particular consideration for placement on drug lists associated with the Medicare Part D
drug benefit.
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573
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