Note: Descriptions are shown in the official language in which they were submitted.
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-l- 1339080
1 BACKGROUND
1. The Field of the Invention
The present invention is related to methods and
5 compositions for use in systemically delivering potent
pharmacological agents having cardiovascular activities to
patients in a dose-to-effect manner. More particularly,
the present invention is directed to methods and
compositions for noninvasive administration of precise
10 doses of potent pharmacological agents having
cardiovascular functions (such as vasodilating, calcium
channel blocking, beta-blocking, seritonin receptor
blocking, angina blocking, anti-hypertensive, and cardiac
stimulating properties) and renal vascular functions (such
15 as increasing urine output).
2. The Prior Art
The proper functioning of a person's cardiovascular
system determines to a large extent the quality of life
20 that person will enjoy. There have been significant
advances in recent years in understanding the complex
mechanisms which control the cardiovascular system. This
has led to the development of a host of potent new drugs
available for clinical use in treating cardiovascular
25 conditions such as congestive heart failure, hypertension,
angina, ventricular and atrial fibrillation, and related
conditions, and current expectations are that additional
potent drugs will continue to become available in the
future.
For example, the physician has at his disposal a vast
array of hypotensive drugs useful for treating high blood
pressure. Blood pressure ("BP") is the product of two
hemodynamic factors, cardiac output ("CO") and total
peripheral resistance ("TPR"):
_ -2- ~339080
BP = CO x TPR
A reduction in blood pressure can occur only with a
5 reduction in either CO or TPR, or both.
It is believed that beta-blockers, such as esmolol,
nadolol, pindolol, and timolol, reduce blood pressure by
decreasing the heart rate or cardiac output. Some beta-
blockers, such as atenolol and metoprolol, are known as
10 cardioselective beta-blockers because they have a greater
affinity for the beta1 adrenoceptors that predominate in
the heart than for the beta2 receptors that predominate in
the bronchi and peripheral vasculature. The
cardioselective nature of these beta-blockers is lost if
15 too great a dose is administered.
All beta-blockers, however, if administered in excess,
may result in impaired pulmonary function, wheezing, and
asthmatic attacks. In addition, there may be serious
adverse cardiovascular effects from the use of beta-
20 blockers, such as bradycardia (abnormally slow heart rate),profound hypotension, and even precipitation of severe
congestive heart failure. Adverse central nervous system
("CNS") effects of beta-blockers include dizziness,
fatigue, mental depression, and in some cases
25 hallucinations; short-term memory impairment and vertigo
have also been observed. There may also be adverse
gastrointestinal ("GI") reactions, such as diarrhea and
nausea.
As a result, it will be appreciated that while beta-
30 blockers have a very valuable place in cardiac treatment,it is critical that the appropriate dosage be given to a
patient in order to avoid the dangers and problems caused
by overdosing or underdosing.
_ _3_ ~ 339080
1 Other hypotensive drugs, such as nitroprusside and
hydralazine, reduce blood pressure by lowering the total
peripheral resistance by direct vasodilation. These drugs
are particularly potent and are usually given in an
5 emergency or when other hypotensive treatments have failed.
Even slight overdoses of this type of hypotensive drug may
result in headache, tachycardia, nausea, and diarrhea, and
may even precipitate angina pectoris or ventricular
arrhythmia.
Still other hypotensive drugs, such a prazosin, are
alpha,-blockers which are also capable of reducing blood
pressure by lowering the total peripheral resistance as a
result of vasodilating effects. An overdose of prazosin
may result in headache, drowsiness, palpitation, nausea,
15 and even fainting.
Labetolol is a unique hypotensive drug which combines
the features of alpha-blockers with beta-blockers. Blood
pressure is reduced due to a decrease in systemic vascular
resistance, but usually without a substantial reduction or
20 increase in heart rate, cardiac output, or stroke volume.
Unfortunately, labetolol shares the toxic potentials of
both the beta and the alpha-blocking agents. In
particular, labetolol overdose may promote or exacerbate
congestive heart failure, bronchospasm, hypotension, and
25 bradycardia.
Other hypotensive drugs, such as methyldopa and
clonidine, inhibit sympathetic vasomotor centers thereby
reducing peripheral sympathetic nervous system activity,
blood pressure, and heart rate with little change in total
30 peripheral resistance. An overdose of these drugs may
result in drowsiness, headache, nausea, dry mouth, palpita-
tion and tachycardia, bradycardia, congestive heart
failure, rash, impotence, hepatic abnormalities, and muscle
cramps.
1339080
--4--
1 Some hypotensive drugs, such as captopril and enala-
pril, reduce blood pressure by suppressing the renin-angio-
tensin-aldosterone ("RAA") system. These drugs inhibit the
angiotensin-converting enzyme ("ACE") thereby resulting in
5 arterial and possibly venous dilation. Thus, blood
pressure is reduced by decreasing the total peripheral
resistance with either no change or an increase in heart
rate, stroke volume, or cardiac output.
These ACE-inhibiting drugs, if administered in excess,
10 may also result in neutropenia, an abnormally low white
blood cell count, which may further lead to systemic or
regional infections and possible death. Other adverse
effects from overdosing of ACE inhibitors include
proteinuria (an abnormally high amount of protein in the
15 urine), rash, taste impairment, excessive hypotension,
tachycardia, angina, palpitations, and even myocardial
infarction and congestive heart failure.
The physician also has at his disposal a large number
of vasodilating drugs useful for treating angina,
20 congestive heart failure, vasospasm, and in some cases
hypertension. However, each of these vasodilating drugs
also has serious side effects which present dangers when
the proper dose for the patient is not given.
For instance, calcium channel blockers (such as
25 diltiazem, nifedipine, and verapamil) dilate the coronary
and systemic arteries. This is accomplished by inhibiting
the transmembrane influx of extracellular calcium ions
across the membranes of the myocardial cells and vascular
smooth muscle cells. Calcium plays important roles in the
30 excitation-contraction coupling process of the heart and
the vascular smooth muscle cells and in the electrical
r discharge of the specialized conduction cells of the heart.
Nevertheless, despite their advantages, an overdose
of a calcium channel blocker may lead to bradycardia,
_ _5_ ~ 339 080
1 asymptomatic asystole, hypotension, congestive heart
failure, anorexia, nausea, and hallucinations.
Other vasodilating drugs include the organic nitrates,
such as isosorbide and nitroglycerin. Organic nitrates
5 relax vascular smooth muscles resulting in vasocilation.
The subsequent reduction in venous blood return to the
heart results in decreased left ventricular size and
pressure (known as "preload"). Arteriolar relaxation
reduces systemic vascular resistance and arterial pressure
10 (known as "afterload").
In addition, organic nitrates dilate the pulmonary
arteries and veins, thereby reducing right atrial,
pulmonary artery, and pulmonary capillary pressures.
Myocardial oxygen consumption and demandr~s decreased
15 because the heart simply does not need to work as hard.
Moreover, because nitroglycerin dilates the veins, it is
also an effective treatment of pulmonary edema.
They are particularly useful for relief of angina
pectoris, for prophylactic management of situations likely
20 to provoke angina attacks, and for long-term prophylactic
management of angina pectoris. Isosorbide may be
administered sublingually, lingually, buccally, nasally, or
orally. However, an overdose of isosorbide may result in
headache, dizziness, nausea, tachycardia, hypotension,
25 fainting, or other dangerous depressions of vital body
functions.
As noted above, nitroglycerin relaxes the smooth
muscles in vascular tissues, which results in lower blood
pressure. Hence, in addition to the treatment of angina,
30 nitroglycerin is an effective drug for treating high blood
pressure (i.e., "hypertension"). Moreover, the
vasodilating action of nitroglycerin reduces the myocardial
work, thereby avoiding cardiac failure during periods of
cardiac stress.
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1 Nitroglycerin is administered through a variety of
delivery systems such as injection, oral, sublingual,
buccal, or transdermal administration. The speed at which
the onset effect of nitroglycerin occurs and the length of
that effect is directly related to the method of
administration.
For instance, sublingually administered nitroglycerin
provides very fast onset resonse, usually within one to
three minutes. However, the effect of nitroglycerin
10 administered sublingually is for a very short duration,
typically no longer than thirty minutes after the
sublingual tablet or lozenge dissolves.
Finally, the physician has at his disposal a number
of cardiac drugs useful for treating ventricular
15 fibrillation, acute ventricular arrhythmias, and congestive
heart failure. Again, these drugs, while useful, can be
very dangerous when the patient's susceptibility to the
drug makes it difficult to know the proper dose.
Amrinone, for example, is an inotropic drug which
increases the force and velocity of myocardial systolic
contraction. In addition, amrinone has vasodilatory acti-
vity affecting vascular smooth muscle. In patients with
congestive heart failure, amrinone produces substantial
increases in cardiac output.
However, serious adverse effects may arise in the
event of an overdose of amrinone; these adverse effects
include: thrombocytopenia (an abnormal decrease in the
number of blood platelets), arrhythmias, hypotension,
nausea, vomiting, diarrhea, hepatotixicity marked by
30 abnormal liver function, and hypersensitivity.
Bretylium and lidocaine are well-known anti-arrhythmic
drugs. Bretylium is used in the prophylaxis and treatment
of ventricular fibrillation. However, because it commonly
causes hypotension, and may increase ventricular
'~ _7_ 1 3 ~9 080
1 irritability, bretylium is considered a second choice drug.
Lidocaine is a CNS-depressing drug which controls
ventricular arrhythmias. It also produces sedative,
analgesic, and anti-convulsant effects. Overdoses may
5 result in seizures, respiratory arrest, dizziness, nausea,
unconsciousness, or even coma.
In addition to drugs for treating cardiovascular
conditions, many new drugs for treatment of renal vascular
functions have been developed in recent years. However,
10 like most drugs affecting the cardiovascular system, the
drugs affecting the renal vascular system must be precisely
administered to avoid serious side-effects or the dangers
of overdosing and underdosing.
Dopamine is a very useful drug for increasing renal
15 blood flow and urine output. Its application is most
beneficial in a patient who has a Foley catheter in his
uninary bladder. In its clinical application, dopamine is
administered until urine output is significantly increased
or approaches a normal range.
Despite its benefits, the detriment of using too much
dopamine is reflected in increases in the heart rate, blood
pressure, cardiac output, and myocardial oxygen consump-
tion. These effects are extremely dangerous in patients
with ischemic cardiac disease. Hence, precise dosage
25 control is critical to the effective use of dopamine.
Despite the tremendous advances in the field of
pharmacology, physicians continue to administer these new
cardiovascular and renal vascular drugs using substantially
the same techniques that have been employed for many
3 ~ decades .
Thus, almost all cardiovascularly and renal vascularly
active pharmacological drugs continue to be administered
via two routes, the oral dosage form for absorption through
the stomach and/or intestines or by intramuscular or intra-
_ -8- 1 3 39 080
1 venous injection. These two drug administration modalities
are the most frequently used despite the fact that both of
these routes suffer from significant disadvantages in
particular situations.
The simplest and most prevalent administration route
is the oral dosage form. To use this method, a
pharmacological drug is incorporated into a tablet, a
capsule, or into a liquid base. The patient then ingests
the predetermined dose of the drug. Oral administration of
10 a drug is extremely convenient, and, for many drugs, it
will continue to be the method of choice. Such
administration is nonthreatening and is painless to the
patient. For most patients, it is also very simple.
Nevertheless, oral administration of a drug suffers
15 from the disadvantage that many patients, particularly
geriatric patients, frequently have difficulty swallowing
pills. Such patients often refuse to cooperate in
swallowing a liquid medication. Even more importantly,
absorption of a drug into the bloodstream after swallowing
20 a tablet varies from patient to patient and in the same
patient from time to time. The absorption of the drug is
dependent upon the movement of the drug from the stomach to
the small and large intestines and the effect of secretions
from these organs.
Even more important, there is typically a substantial
delay between the time of oral administration of a drug and
the time that the drug begins to have the desired thera-
peutic effect on the patient's cardiovascular, renal
vascular, or other systems. Generally, a drug must pass
30 from the stomach into the small and large intestines before
it will be absorbed into the patient's bloodstream;
7' unfortunately, this typically takes forty-five minutes or
longer. For many clinical situations, such a delay is
unacceptable.
- 9 1339080
1 Further, many drugs taken orally, particularly
cardiovascular-acting drugs, are metabolized almost
immediately -- they are removed from or rendered
ineffective by the patient's system before they can have
5 any therapeutic effect. This occurs because the veins from
the small and large intestines, and to a certain extent
also the stomach, drain into the liver. Thus, drugs
entering the patient's bloodstream through the intestines
immediately pass through the patient's liver before
10 distribution throughout the remainder of the patient's
body.
Unfortunately, upwards of sixty percent of a drug (and
essentially one hundred percent of certain drugs) may be
removed from the patient's bloodstream during this "first
15 pass" through the liver. The result is that the oral route
of administration is impractical for many drugs, particu-
larly many cardiovascular-acting and renal vascular-acting
drugs.
Further, additional stress is placed on the liver as
20 it removes the excess drug from the bloodstream. This is
particularly severe if the cardiovascular or renal vascular
treatment has been occurring over an extended period of
time. The liver may become overloaded with the drug's
metabolite which then must be excreted in the patient's
25 urine. As a result, there is an increased risk of hepatic
or renal disorders.
Yet a further difficulty encountered when
administering cardiac and related drugs orally is that
dosages are prepared or determined for use with an
~average~ patient. This is entirely acceptable for many
drugs, but some drugs, such as those that have a
cardiovascular, anti-hypertensive, vasodilating, anti-
anginal, or renal vascular effect, have a widely varying
effect on different patients, depending upon individual
-lO- 1 339 0 80
1 variations in susceptibility to the particular drug
utilized.
Underdosing a patient because of a low susceptibility
to the drug fails to evoke the cardiovascular or renal
S vascular response sought by the physician. Overdosing the
patient can result in too much vasodilation, hypotension,
cardiac or respiratory depression, other side effects such
as headaches, nausea, or other dangerous depression of
vital body functions.
Moreover, the slow and uncertain response time for the
onset of an observable reaction to a cardiovascular drug
when taken orally makes it even more difficult to determine
a proper dose for a particular patient; the physician may
not learn for an hour, or with some drugs for a few days,
15 whether the patient was underdosed or overdosed. By then,
extraordinary measures may be necessary to remedy the
patient's condition.
In order to avoid these serious~disadvantages inherent
in the oral administration route, physicians frequently
20 resort to the injection route for administering many drugs.
Injecting a drug (generally intravenously or intra-
muscularly) results in rapid entry of the drug into the
patient's bloodstream and onset of the desired effect. In
addition, this type of delivery avoids the removal of large
25 quantities of the drug by the patient's liver that accom-
panies oral administration. Rather, the drug becomes
rapidly distributed to various portions of the patient's
body before exposure to the liver; thus, the drug is
removed by the liver only after it has first reached the
30 cardiovascular or renal vascular systems.
Most patients have at least some aversion to receiving
r injections. In some patients, this aversion may be so
pronounced as to make the use of'injections of serious
concern to the physician. Since intense psychological
-11- 1339080
1 stress can exacerbate a patient's debilitated condition, it
sometimes becomes undesirable to use injections where the
patient is seriously ill, suffers from a debilitating
condition or injury, or where there is no immediate medical
5 assistance.
To compound the problem facing a physician, the
individual variation in susceptibility and metabolism with
respect to cardiovascular drugs, which makes it difficult
to select an appropriate dose for oral administration is
10 even more profound when utilizing the injection route.
This is because smaller doses have an increased effect due
to the rapidity in which the drug enters the bloodstream
because large portions of the drug are not immediately
metabolized by the liver.
In order to prevent overdosing a patient with potent
cardiovascular drugs, a prudent physician typically injects
a patient with a lower than average dose, and later supple-
ments the dose with additional injections as they appear
necessary. This, of course, makes necessary the use of
20 repeated injections, which in turn greatly increases the
stress on the patient. It is not uncommon for a patient to
come to fear that it is time for yet another injection
every time the patient sees a member of the hospital staff,
which is often the case for those most in need of potent
drugs.
Because of the problems associated with the oral and
injection routes of administration, physicians have sought
other delivery mechanisms for achieving the desired
cardiovascular or renal vascular action. Accordingly,
transdermal and transmucosal (including buccal, lingual and
sublingual) delivery routes have been explored. Those
approaches are more pleasant than intramuscular delivery
systems and are more reliable since they are less
susceptible to gastrointestinal variability. These
1~3go8o
-12-
l alternative medicament administration routes also result in
more stable plasma and tissue concentrations of the
medicament as it is absorbed by the body.
However, the transdermal and transmucosal delivery
5 routes do not enable precise dose-to-effect compatibility
(that is, administering a proper dose until the desire
effect is achieved and doing so in a manner that eliminates
the variabilities between patients). Moreover, these
delivery systems do not easily enable rapid adjustment of
lO plasma or tissue concentrations if clinical conditions
dictate that a higher or a lower concentration would be
more desirable in the next few minutes.
This is most easily seen with sublingual nitroglycerin
tablets used for angina. When a patient has angina, the
lS patient places a nitroglycerin tablet under his tongue (the
"sublingual" administration route). From a practical
standpoint, it is not possible to remove a sublingual
nitroglycerin tablet once it has been placed under the
tongue. The tablet is very small (typically, two to three
20 millimeters in diameter) and dissolves very quickly.
In addition, because the tablet dissolves so rapidly,
there is a lag time between the time the dose is given
(i.e., when the tablet dissolves) and when the effects are
observed. So, once it is under the tongue, the patient is
25 more or less committed to taking the entire dose of
nitroglycerin contained in the tablet, even if the angina
would have been alleviated with only one-half of the dose
in a tablet.
Consumption of the remainder of the tablet often
30 results in an overdose and a severe headache. If the first
tablet is not effective in treating angina, the patient
must then take a second or a third tablet. This is a slow
process and still may ultimately result in a relative
overdose after the final tablet.
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1 There are other practical problems with the sublingual
administration route for nitroglycerin. Sublingual
nitroglycerin tablets are intentionally very small in size
so that they may be conveniently placed and maintained
5 under the patient's tongue without evoking an undesirable
response. However, the small size of the tablet makes them
difficult for the patient to handle.
Another approach to overcoming the problems associated
with the injection and oral delivery routes has been to
incorporate the cardiovascular-acting renal vascular-acting
drug into a nasal spray. However, since intermittent,
multiple sprays of the drug are required, patients find it
difficult to deliver the appropriate dosage to alleviate
their symptoms and avoid the problems and side effects of
15 overdosing.
Moreover, the propellant in the spray can interfere
with the effectiveness and accurate delivery of the proper
dosage of the drug. Problems with the temperature
stability of the ingredients and the angle of the sprayer
20 can also affect the dose of drug actually delivered. While
these nasal sprays have avoided some of the problems of the
oral and injection routes, they have not solved many of the
problems associated with the delivery of the precise dose
necessary to relieve the symptoms of the patient while
25 accounting for the patient's individual susceptibility to
the cardiovascular-acting or renal vascular-acting drug.
For example, sprays incorporating nitroglycerin have
been developed in which the drug is sprayed on the oral
mucosa using a lingual aerosol canister (the "lingual"
30 administration route). The nitroglycerin lingual aerosol
spray delivers nitroglycerin in 0.4 mg metered doses. this
in essence is a delivery of a series of 0.4 mg boluses of
nitroglycerin, only providing an alternative method of
delivery, without any improvement whatsoever in
_ -14- 1~39080
1 titratability. The dosage options are the same as tablets,
i.e., increments of 0.4 mg doses. The dose is preferably
sprayed onto or under the tongue and then the mouth is
immediately closed. The spray canister delivers a fixed
5 dosage for each spray. As in sublingual administration,
lingual administration is relatively fast-acting, but if
relief is not attained after the initial spray, additional
sprays must be given. Again, this is a slow process which
usually results in a relative overdose after the final
lO spray. Moreover, the lingual spray suffers from the same
problems as discussed above with respect to the nasal
sprays.
Additionally, care must be taken to not shake the
aerosol canister prior to use, since shaking may generate
15 bubbles within the canister which impair the proper release
of nitroglycerin from the device. Also, the spray should
not be inhaled, and swallowing immediately after spraying
should be avoided. For many patients, particularly
geriatric patients, these administration techniques may be
20 too complex.
Physicians may also recommend buccal administration of
nitroglycerin or other cardiovascular-acting or renal
vascular-acting drugs. Buccal nitroglycerin tablets are
typically placed between the upper lip and teeth. The
25 tablet surface develops a gel-like coating that adheres to
the mucosal surface of the mouth. As long as the tablet
remains intact, nitroglycerin continues to pass from the
tablet matrix to the mucosal tissue where it is rapidly
absorbed. If the tablet is chewed and broken up, an
30 undesirable mount of nitroglycerin is released for
submucosal absorption or, if swallowed, the nitroglycerin
r would be metabolized by the liver as discussed above.
Since the nitroglycerin in a buccal tablet can enter the
body in three different areas, depending upon whether the
_ -15- 1339080
l tablet remains in place or is chewed, it is often difficult
to ensure that the proper dose is delivered.
When used properly, buccal nitroglycerin acts rapidly
after placement in the mouth--almost as fast as sublingual
5 nitroglycerin. Nitroglycerin is released into the buccal
cavity so long as the tablet remains intact. The average
tablet dissolution time is between three to five hours;
therefore, many patients, particularly geriatric patients,
will have difficulty keeping the tablet in place for so
10 long. Tablet dissolution time and the effective amount of
the medicament delivered to the patient varies from patient
to patient, and even in a given patient, because of
differences in saliva production, tongue manipulation,
inadvertant chewing (displacement of the gel "seal"), and
15 eating or drinking by the patient.
Because of the wide variation of dissolution times
from patient to patient, the same buccal nitroglycerin
tablet is likely to result in either an overdose or
underdose, depending on the patient. Although it is
20 theoretically possible to manually remove the buccal tablet
from the mouth and later replace it so as to control the
amount of nitroglycerin released to the patient, such a
procedure is not very practical.
For instance, if the tablet is manually removed from
25 the mouth by the patient, it is likely to become
contaminated by the patient's touch. Further, many
patients who need nitroglycerin medication are older; these
patients have difficulty coordinating small tablets in
their mouth and find it extremely difficult to handle the
30 small tablets with their hands.
Another alternative method of administering
cardiovascular-acting or renal vascular-acting drugs is by
applying ointment or patches to the skin which contain the
drug. For example, nitroglycerin will readily pass through
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-16-
133gO80
1 the skin (the "transdermal" administration route) and into
the patient's bloodstream. When ointment is applied to the
skin, its effect is observed within sixty minutes, with a
duration from four to eight hours. Nitroglycerin patches
5 are designed to provide continuous treatment for up to 24
hours.
The effect of nitroglycerin ointment varies from
patient to patient. The area of application of the dose as
well as the site, dosage, state of hydration of the skin
10 surface, and permeability are all variables affecting the
patient's response. In addition, nitroglycerin ointment is
impractical for many patients because of the difficulty in
application, its mess, cosmetic problems, and potential
staining.
A major advance in cutaneous administration of
nitroglycerin occurred with the development of a sustained-
release patch. These preparations contain nitroglycerin in
a reservoir or matrix and are designed to provide constant
delivery of the drug into the circulation for twenty-four
20 hours. The rate of the drug release is primarily
determined by the device itself, rather than the
characteristics of the patient's skin. However, important
questions regarding dosage requirements, efficacy, and
duration of action remain unanswered. Several recent
25 reports involving patients with either angina pectoris or
congestive heart failure have questioned the efficacy of
these products. Several mechanisms have been proposed to
account for the variability of patient response. The
development of tolerance, low nitroglycerin plasma levels
30 and tissue concentrations secondary to poor absorption of
the drug, and inability of the delivery system to deliver
drug for a full twenty-four hours are all proposed
explanations of this phenomenon.
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-17- 13 3gO80
1 Similarly, patients using nitroglycerin transdermal
patches may have reasonable plasma and tissue
concentrations of nitroglycerin, but they cannot easily or
rapidly increase or decrease those concentrations except by
5 pulling off the patches or adding additional patches. Both
of the latter processes are, at best, gross adjustments
because of the slow response in transdermal patches, which
results in relative overdose or underdose of nitroglycerin.
In addition to the problem of slow onset, recent
10 research indicates that continuous use of transdermal
patches results in the development of a tolerance to the
nitroglycerin. This suggests that continued use of
nitroglycerin transdermal patches may not be a practical
alternative for many patients.
In view of the foregoing, it will be appreciated that
it would be an important advancement in the art of admini-
stering cardiovascular, renal vascular and related drugs if
suitable methods and compositions could be provided that
were capable of rapid action, of avoiding the disadvantage
20 of immediate metabolism through the patient's liver, and of
not involving an injection.
Given the life-sustaining importance of the
cardiovascular and renal vascular systems, any drug which
affects these systems is potentially life threatening if
25 administered improperly. It would be, therefore, a further
advancement in the art of administering potent cardiovas-
cular and renal vascular drugs if suitable methods and
compositions could be provided that enabled individual
patient fine-tuning of ideal doses (providing a dose-to-
30 effect administration modality) so that doses could beadjusted not only on an individual basis but easily
increased or deceased at each time of administration.
It would also be an important advancement in the art
if methods and compositions could be provided that would
13~gO80
-18-
1 give a physician, as well as the patient (in appropriate
circumstances), control over the administration of
medication so that a desired effect is not only obtained
but also maintained during times when his cardiac status or
5 blood pressure changed.
Such methods and compositions are disclosed and
claimed herein.
BRIEF SUMMARY AND OBJECTS OF THE INVENTIO~
The present invention is directed to novel uses and
compositions for use in administering potent cardiovascular
and renal vascular related drugs capable of eliciting
appropriate cardiac, vasodilating, anti-hypertensive, anti-
anginal, renal, and related effects. The present invention
15 is capable of introducing the drug into the patient's
bloodstream almost as fast as an injection -- and much
faster than oral administration. Yet, it is nonthreatening
and painless.
These significant advantages are achieved by incorpor-
20 ating into a candy or compressed powder matrix a drugcapable of being absorbed through the mucosal tissue found
in a patient's mouth, pharynx, and esophagus. The
resultant mixture is then advantageously formed into a
lollipop, which, as discussed in greater detail
25 hereinafter, can be administered in a dose-to-effect
manner.
Even patients having difficulty swallowing a pill or
refusing to swallow a liquid, will give little resistance
to sucking on a lollipop. When dealing with resistant
30 adults, a lollipop evokes a pleasurable response in the
patient and gives the patient something nonthreatening on
which to concentrate. Further, sucking is a natural and
instinctive response which virtually all persons find
relaxing.
D
1~39080
_ ~ --19--
A cardiovascular-acting or renal vascular-acting drug
administered in this way will quickly enter the patient's
bloodstream through the veins which serve the mucosal tissues.
Appropriate monitoring of the patient's reaction to the drug
(e.g., measuring blood pressure, monitoring heart rate or
changes in the EKG, monitoring the extent of angina, observing
the degree of vasodilation, or monitoring the urine output)
will indicate when the drug has evoked a suitable response.
The lollipop may then be removed, or its rate of consumption
may be decreased.
It will be appreciated that the ever-present risk of
overdosing a patient is substantially minimized, if not almost
eliminated, through the proper practicing of the uses and
compositions within the scope of the present invention. The
rate at which the cardiovascular drug is to be absorbed by the
body can be varied by varying the rate the lollipop dissolves.
This can be achieved by modifying the composition of the
lollipop or the vigor with which the patient "sucks" on the
lollipop.
Thus, the drug dose is given over a period of time rather
than all at once, and the administration rate can be reduced
if such appears necessary. As soon as the patient's blood
pressure becomes ideal, heart rate stabilizes, urine output
increases to more normal limits, the EKG improves, or angina
disappears, he will simply stop sucking the lollipop and/or the
physician can easily remove the lollipop from the patient's
mouth.
A patient experiencing angina can self-administer small
amounts of drug "on demand" by simply licking or sucking on the
lollipop in response to his subjective experience of the
cardiovascular or renal vascular condition (for example, angina
pain, urine output, and heart rate). The patient can then
remove the lollipop
r~
V
133gO80
-20-
1 before the side effects and dangers of overdosing are
experienced.
Unlike the use of injections or oral ingestion of
cardiovascular medications where a relatively large bolus
5 dose of medication is given intermittently, use of a lolli-
pop can permit the patient to take very small doses of a
cardiac or renal drug on an almost continuous basis.
Moreover, such administration can be regulated in response
to the patient's own need for medication in light of his
10 own subjective experience of the cardiac or renal condition
and the patient's own personal susceptibility to the
particular drug utilized.
Further, the use of a lollipop to administer
cardiovascular-acting or renal vascular-acting drugs is far
15 superior to the presently used transdermal techniques. A
nitroglycerin lollipop, for example, can provide near-
immediate response, whereas transdermal nitroglycerin in
the form of ointments and patches requires up to an hour
before any therapeutic effect is realized. This large lag
20 time between the dose of nitroglycerin received via
transdermal techniques and its observable effect prohibits
the use of these methods in a true dose-to-effect manner.
In addition, the variation of skin permeability from
patient to patient makes it difficult for the physician to
25 prescribe a correct dose for each patient. Skin
permeability may vary even in the same patient from time to
time. For instance, changes in stress, skin status such as
sunburned, dry, or oily skin, and even repeated transdermal
administration in the same location all affect skin
30 permeability.
D
-20a- 1~39080
Thus, in accordance with an aspect of the present
invention, there is provided a use of a soluble matrix material
in the form of a lollipop into which a drug has been dispersed
for inducing rapidly a predetermined systemic modification of
S cardiovascular or renal vascular functions in a patient in a
dose-to-effect manner while modifying the rate of dissolution
of the drug-containing lollipop in response to the
predetermined systemic modification, whereinthe cardiovascular
or renal vascular functions of the patient are susceptible to
the drug and wherein said soluble matrix material is a
carbohydrate mass capable of releasing the drug for absorption
through mucosal tissues of the mouth, pharynx and esophagus.
There is further provided in accordance with another
aspect of the present invention a composition for use in
inducing a predetermined rapid systemic modification of
cardiovascular functions in a patient, said composition
comprising: an effective dose of a drug in substantially
powdered form capable of being absorbed through mucosal tissues
of the mouth, pharynx, and esophagus, and capable of rapidly
inducing a predetermined systemic modification of
cardiovascular functions in the patient; a soluble matrix
material, being a soluble, compressible, substantially powdered
carbohydrate material, the drug being dispersed substantially
uniformly within the matrix due to mixing the drug and
carbohydrate material at a temperature below the melting points
of the drug and the carbohydrate material so that the drug
released for absorption through mucosal tissues of the mouth,
pharynx, and esophagus as the matrix dissolves when placed in
a patient's mouth; and holder means secured to the drug-
containing matrix, said holder means being configured so as to
permit convenient insertion of the drug-containing matrix into
the mouth of a patient, and convenient removal thereof when a
desired condition is obtained.
It is, therefore, a primary object of the present
invention to provide noninvasive uses and compositions
D
- .r ' '
l339o8o
1 of rapidly reducing heart rate or blood pressure,
eliminating angina, increasing urine output, improving the
EKG, or inducing an appropriate state of cardiac function.
It is another important object of the present
5 invention to provide uses and compositions that would
allow for more physician and patient control over the
administration of cardiovascular or renal vascular drug
actions so that individual patient differences,
susceptibilities, and metabolisms can be ta~en into
10 account.
Yet another primary object of the present invention is
to provide uses and compositions for drug administration
which minimize the psychological trauma generally
associated with injections, the adverse physical and
15 psychological problems often associated with the oral
administration of potent drugs, and the limitations of the
sublingual, lingual, buccal, nasal, and transdermal
modalities of drug administrations.
It is a further object of the present invention to
20 provide for uses of drug administration that are capable
of dose-to-effect administration, thereby minimizing under-
dosing and overdosing of the patient.
Still a further object of the present invention is to
provide uses and compositions that will permit a patient
25 to control the amount of cardiac medication administered
according to individual variations in the susceptibility to
the particular medication used and in response to the
patient's subjective experience of angina, hypertension,
tachycardia, urine output, changes in EKG, etc.
These and other objects and features of the present
invention will become more fully apparent from the
following description and appended claims.
~D
133gO80
-22-
1 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As discussed above, the present invention is directed
to methods and compositions for use in the noninvasive
dose-to-effect administration of cardiovascular-acting and
5 renal vascular-acting drugs. Advantageously, the present
invention permits exceptional control over the effect of
the drug administered, despite individual susceptibility to
and metabolism of that drug.
While maintaining the convenience of oral administra-
10 tion, the present invention provides for the advantages ofthe injection route. At the same time, the present inven-
tion avoids the disadvantages identified above with respect
to these two traditional routes of administration as well
as newer lingual, sublingual, bucal, nasal, and transdermal
15 applications-
A few drugs, such as nifedipine, nitroglycerin, andisosorbide dinitrate, have been administered by absorption
through mucosal tissue because the transmucosal route is
faster than oral administration modality, and, unlike
20 injections, can be easily self-administered. While drugs
are easily given by the transmucosal route, they have not,
unfortunately, been given by a dose-to-effect method. In
dose-to-effect drug administration, the drug is
administered until a predetermined effect is obtained;
25 thereafter, the administration process is modified or
terminated.
Despite some limited use, the transmucosal route has
not been favored for routine use. Instead, where a delay
in drug action is acceptable, the oral route has been
30 preferred by most physicians, and injections have been used
where delay is not acceptable.
Transmucosal dose-to-effect delivery of a drug is
slightly slower to provide active concentrations of a drug
in a patient's system than is the use of an injection.
_ -23- 1 33~ 08~
1 Nevertheless, it has been discovered that the transmucosal
route can be adapted so that any loss in the speed of drug
uptake is more than offset by the ability to administer the
drug noninvasively (much to the appreciation of the
5 patient) and by the ability to control the dose received by
the patient.
A drug must be lipophilic in order to be absorbed
across mucosal tissue. However, this requirement is not a
serious limitation since a large number of drugs are
10 naturally lipophilic or can be provided in a lipophilic
form.
In accordance with the present invention, a suitable
drug is dispersed or compressed within a carbohydrate mass
or other suitable matrix and incorporated into a lollipop.
15 The drug-containing lollipop is then given to a patient to
suck on so that the drug will be released into the
patient's mouth as the lollipop dissolves. Being
lipophilic, a significant portion of the drug is absorbed
through the mucosal tissues of the mouth, pharynx, and
esophagus.
From the mucosal tissues, the drug rapidly enters the
patient's bloodstream. Equally important, the blood in the
veins draining from the mouth and the pharyngeal and
esophageal regions passes through a substantial portion of
25 the body (so that the drug can be absorbed) before the
blood passes through the liver (where the drug will usually
be metabolized and/or inactivated).
The use of a drug-containing lollipop to administer a
drug offers several important advantages. First, a
30 lollipop is familiar and lacks the menace of a syringe.
Being a item normally associated with pleasure, a lollipop
immediately evokes a positive psychological response. In
addition, the lollipop is easy for the patient or physician
to handle.
-24- ~339080
1 Importantly, it has been found that the use of drug-
containing lollipop can permit the physician to control the
dosage of the drug administered to the patient in order to
produce the desired anti-anginal state, blood pressure,
5 heart rate, urine output, or changes in EKG, etc., thereby
resulting in dose-to-effect drug administration. The use
of such drug-containing lollipops also permits the patient
to exert control over the dosage received of cardiac or
renal drugs in order to optimize functions of the
10 cardiovascular or renal vascular systems.
These important advantages are available because very
small amounts of the drug may be delivered to a patient
substantially continuously, and administration of the drug
may be halted at any time by simply removing the lollipop
15 from the patient's mouth. This not only allows a physician
to monitor a patient's condition so that a particular
effect is obtained and maintained, but also provides an
important safety benefit.
By contrast, once a typically bolus dose of a drug is
20 given orally, sublingually, lingually, buccally, nasally,
transdermally, or by injection, it is either impossible or
impractical to retrieve the dose. Thus, the full effects
of the administered drug will be felt by the patient.
Further, a large dose given every few hours results in wide
25 swings in plasma concentration of the drug, while the use
of a lollipop in accordance with the present invention
evens out the plasma concentration of that drug.
In practice, a physician can offer the patient a drug-
containing lollipop together with simple instructions that
30 the lollipop is to be sucked rather than chewed. Anxious
adults are particularly put at ease by this approach. The
physician can then monitor the patient's condition to
ensure the desired effect is achieved. If, for example,
the drug-containing lollipop contains nifedipine, the
~3~9080
-25-
1 physician can monitor the patient's angina or blood
pressure until a suitable modification of the blood
pressure is achieved or the angina has been relieved.
As mentioned above, it is preferred that the medicated
matrix material take the form of a lollipop. Use of a
stick or other suitable holder permits easy removal of the
lollipop when the patient has received the proper dosage of
the drug contained in the lollipop.
Provision of a suitable holder also facilitates
10 intermittent administration of the drug to maintain a
desired condition and makes it more convenient for a
patient to intermittently self-administer a cardiac
medication in response to variations in the patient's
subjective or objective evaluation of his cardiac
15 condition. Use of a suitable holder prevents contamination
of the medicated matrix material when the lollipop is
periodically removed from the mouth and later replaced.
The speed at which a sufficient amount of drug enters
the patient's bloodstream so as to produce a desired effect
20 depends on several factors. For example, a very potent
drug requires fewer drug molecules to enter the patient's
system than does a weak drug to produce a desired effect.
Accordingly, if rapid modification of cardiovascular action
(i.e., an immediate decrease in blood pressure) is desired,
25 a potent rather than a weak drug could be used.
Additionally, the degree of lipophilicity of a drug
directly affects the rate of absorption of the drug. A
highly lipophilic drug will result in the more rapid onset
of a desired response than will a more moderately
3 ~ 1 ipophi 1 ic drug -
For example, nitroprusside is a very potent drug which
* is highly lipophilic. However, nifedipine is nearly twiceas lipophilic as nitroprusside and thus is capable of
faster absorption. It will be appreciated, however, that
~ 339080
-26-
1 other pharmacokinetic properties of a drug will affect the
rate at which the effect of the drug is observed in the
patient. For example, while isosorbide is not so
lipophilic, its other pharmacokinetic properties make it
5 extremely fast-acting once it is absorbed into the
bloodstream.
The choice of matrix and the concentration of the drug
in the matrix are also important factors with respect to
the rate of drug uptake. A matrix that dissolves quickly
10 will deliver a drug into the patient's mouth for absorption
more quickly than a matrix that is slow to dissolve.
Similarly, a lollipop that contains a drug in a high
concentration will release more drug in a given period of
time than a lollipop having a low drug concentration.
It will be appreciated that varying the concentrations
of the drug in the matrix or the properties of the matrix
(particularly the rate at which the matrix dissolves) can
be advantageously used in designing specific compositions
for specific uses. A lollipop of a given concentration may
20 be used to relieve angina, while a lollipop of a stronger
concentration (which is possibly of a different color so as
to prevent confusion) can be used when it is desired to
decrease arterial blood pressure.
Another use of these properties is to prepare a multi-
25 layer lollipop where the outer layer is of a concentrationdiffering from that of the inner layer. Such a drug
delivery system has a variety of applications. By way of
example, it may be desirable to quickly get a predetermined
dose of a drug into the bloodstream to obtain a desired
30 effect and then use a different concentration to maintain
that effect.
In addition to modifying the physical characteristics
of the lollipop, the technique used by the patient to suck
the lollipop may also be used to affect the rate of the
-27- 1 3~9 080
1 absorption of the drug. If substantial portions of the
lollipop are chewed and swallowed, the normal complications
of oral administration will be encountered (i.e., slow
response and loss of drug in the stomach and liver).
If the lollipop is sucked slowly with little
production of saliva, very little drug will be swallowed,
but a reduction in the amount of saliva will also cause a
reduction in the rate at which the medicated candy portion
dissolves. It will be appreciated that the technique of
10 sucking utilized by the patient can have a significant
effect on the rate of drug uptake into the patient's
bloodstream.
Use of a lollipop, in contrast to a simple drop,
pellet, or spray, helps control proper placement of the
15 medicated matrix within the patient's mouth since the
medical professional can manipulate the matrix and
demonstrate proper placement to the patient, and the
medical professional can easily monitor placement by
observation of the angle of the protruding stick. Once a
20 suitable technique for sucking the lollipop has been
selected, the remaining factors can be adjusted
accordingly.
It will be appreciated from the foregoing that the
present invention has broad applicability to a variety of
25 cardiovascular and renal vascular agents. For example, the
present invention may be utilized in the administration of
anti-anginal and vasodilators (such as nitroglycerin and
isosorbide), calcium channel blockers (such as diltiazem,
verapamil, and nifedipine), beta-blockers (such as esmolol,
30 nadolol, pindolol, timolol, atenolol, and metoprolol),
other hypotensive agents (such as prazosin, labetolol,
f methyldopa, nitroprusside, clonidine, hydralazine,
captopril, and enalapril), cardiac drugs (such as
bretylium, lidocaine, and amrinone), and renal modification
-28- ~339080
1 drugs (such as dopamine). It will be appreciated that
other drugs may also be utilized within the scope of the
present invention. What is important is that the drug be
lipophilic, potent, and fast acting.
By incorporating a drug into a lollipop within the
scope of the present invention, the amount of the drug used
will generally differ from the amount used in more tradi-
tional injection and oral administration techniques.
Depending upon the lipophilic nature of the drug, its
10 potency, and its end use (e.q., relief of anginal pain,
lowering blood pressure, modifying cardiac functions, and
modifying urine output), the total concentration of the
drug in a typical lollipop may contain up to fifty times
the amount of the drug which may be used in an injection.
15 However, for purposes of example, Table I sets forth
presently contemplated ranges of the dosagés of certain
drugs which would typically be used.
Table I
Druq Generic Lollipop Dose Range
Amrinone 50-100 milligrams
Atenolol 50-150 milligrams
Atropine 0.4-1 milligrams
Bretylium 50-500 milligrams
Captopril 25-75 milligrams
Clonidine 0.1-0.5 milligrams
Diltiazem 30-120 milligrams
Dipyridamole 50-150 milligrams
Dopamine 350-700 micrograms
Enalapril 5-15 milligrams
Ephedrine 25-75 milligrams
Esmolol 25-250 milligrams
Hydralazine 10-75 milligrams
_ -29- 1 3 3go80
1 Isosorbide 2.5-40 milligrams
Labetolol 100-400 milligrams
Lidocaine 50-250 milligrams
Methyldopa 250-750 milligrams
Metoprolol 25-100 milligrams
Nadolol 40-160 milligrams
Nifedipine 10-40 milligrams
Nitroglycerin 0.2-1.6 milligrams
Nitroprusside 10-50 milligrams
Phenoxybenzamine 10-40 milligrams
Phentolamine 5-15 milligrams
Pindolol 5-15 milligrams
Prazosin 2-10 milligrams
Procainamide 250-500 milligrams
Timolol 10-50 milligrams
Tolazoline 25-75 milligrams
Timethaphan 10-50 milligrams
Verapamil 80-240 milligrams
When the drug is dispersed in a "candy" matrix, care
must be taken that no decomposition of the drug occurs.
Since the candy matrix must typically be heated above about
25 230~F, this can be a serious limitation to the use of
conventional candy-making processes.
Furthermore, one or more of the ingredients necessary
for the successful formulation of a hard candy base may
30 have an adverse effect, when in solution, upon the
stability of the incorporated therapeutic agent.
r
Therefore, a manufacturing technique may be employed that,
~30- 1339080
1 where necessary, will enable most therapeutic agents to be
incorporated with suitable flavors and other insipients
into a solid dosage form on an appliance or holder, for a
5 dose-to-effect modality.
To achieve this, the therapeutic agent is included in
a compressible carbohydrate matrix and stamped or directly
compressed in an appropriate mold so that the drug-contain-
ing matrix is attached to an appliance such as a holder.
The choice of a particular carbohydrate matrix is
subject to wide variation. Conventional sweeteners such as
15 sucrose may be utilized, or carbohydrates suitablé for use
with diabetic patients, such as sorbitol or mannitol, might
be employed. Other sweeteners, such as the aspartames, can
also be easily incorporated into a composition in
20 accordance with the present invention. The matrix base may
be very soft and fast dissolving, or may be hard and slower
dissolving. Various forms will have advantages in
different situations.
In one embodiment of the present invention,
nitroglycerin is incorporated into a mixture having a ratio
of compressible sugar to malto dextran in the range of from
about 1:1 to about 1:4. In addition, sweeteners and other
flavor enhancing materials are added to the mixture. The
mixture is then hydraulically compressed into a lollipop
form.
-31- 1339080
1 By increasing the hydraulic compression of the
mixture, it is possible to make the lollipop dissolve more
slowly in the mouth. In addition, the addition of a
5 hydrophobic agent will also make the lollipop ingredients
less soluble so that the lollipop dissolves more slowly in
the mouth. Further, it will be appreciated that the
patient can modify the rate of dissolution of the lollipop
(and hence, the rate of the absorption of nitroglycerin) by
modifying the vigor of the sucking action.
The nitroglycerin-containing lollipops of the present
15 invention are particularly useful in lowering blood
pressure prior to surgery. Frequently, a pateint grows
increasingly anxious as impending surgery draws closer. As
a result, a patient's blood pressure rises dramatically.
20 When the patient has an abnormally high blood pressure, it
is more difficult for the anesthesiologist to administer
safely a proper dose of anesthetic. The physician can give
the patient a nitroglycerin-containing lollipop, and within
25 a very few minutes, the patient's blood pressure is lowered
to a point where the anesthetic can be administered safely.
The nitroglycerin lollipops of the present invention
are similarly useful for treating post-operative
hypertension. The rapid absorption of the nitroglycerin
through the mucosal tissues of the mouth, pharynx, and
~ -32- ~339080
1 esophagus allows for excellent control of the patient's
blood pressure during the stressful post-operative period.
The rapid absorption of the nitroglycerin contained
5 in the lollipops of the present invention also makes
possible the treatment of hypertension during pregnancy and
particularly during labor. Another use of the lollipops of
the present invention in the treatment of hypertension is
as a supplement to the anti-hypertensive drug that a
patient may be using on a daily basis. As the patient
encounters a stressful situation, or otherwise experiences
15 an increase in blood pressure, the patient can use a
nitroglycerin lollipop to rapidly bring the blood pressure
down to within any acceptable (and even normal) level.
The nitroglycerin-containing lollipop of the present
20 invention is also particularly adaptable to the treatment
of angina. A patient can self-administer nitroglycerin
simply by licking or sucking on the nitroglycerin lollipop
until the pain in relieved. Thereafter, the lollipop may
25 be removed and subsequently reinserted (as needed) to
maintain relief from angina. Alternatively, by reducing
the rate of sucking or by using a lollipop having a lower
nitroglycerin concentration (possibly of a different color
than the original lollipop), the patient may also maintain
r relief from angina in a dose-to-effect manner over a
~~ -33- ~ ~35080
1 prolonged period of time while avoiding an overdose of
nitroglycerin.
The nitroglycerin-containing lollipops of the present
5 invention are also particularly useful in reducing the
amount of myocardial work, thereby helping to avoid cardiac
failure during periods of cardiac stress. Because of the
vasocilation action of the nitroglycerin, the present
invention is also effective in the treatment of pulmonary
edema. The lollipops can be used until the pulmonary
arterial wedge pressure and- the venous pressure in the
lS jugular veins are reduced to normal levels.
It will be appreciated from the foregoing that the
present invention has broad applicability and will be
useful in a wide variety of situations. It provides a
20 useful alternative to the traditional routes of
administration, and permits the physician extraordinary
control over the dosage of the cardiovascular-acting or
renal vascular-acting drug that is administered to a
25 patient.
Some of the more important features and advantages of
the present invention will be better appreciated and
understood by reference to a few illustrative examples:
1339080
-34-
1 EXAMPLE 1
The candy matrix or base for the drug-containing
lollipop within the scope of the present invention is
5 advantageously prepared utilizing candy preparation
formulas and techniques which are known in the prior art.
For example, a hard candy base is prepared by dissolving 50
grams of sucrose in 50 grams of water and heating the
solution to about 240~F. Next, about 40 grams of corn
syrup having a dextrose equivalent of 42 units, and a high
maltose content (30%-35% maltose) is added, and the mixture
15 is cooked at about 300~F to reduce the water content to
about three percent (3%). After recooling -the thickened
candy mass to about 240~F, a suitable oil flavoring (e.q.,
lemon, cherry, or other flavor) is added.
Concurrently, a solution containing a soluble drug is
prepared for incorporation into a candy matrix. In this
example, the drug selected is timolol. Timolol is a
potent, lipophilic beta-blocker which is useful as an anti-
25 hypertensive and for protecting a patient with post-
myocardial infraction. Its high po~ency and lipophilicity
make it an excellent drug for transmucosal administration
in accordance with the present invention. A suitable
timolol solution is prepared by dissolving 400 milligrams
r of timolol in four cubic centimeters of sterile water.
i339080
1 This timolol solution is mixed with 32 cubic centi-
meters of the hot candy mass formed as set forth above, and
the resultant mixture is gently mixed as it cools to about
5 225~F, taking care not to induce formation of air bubbles
in the candy mass.
The solution is then poured into suitable molds having
a 2.0 cubic centimeter capacity that have been
prelubricated with vegetable oil to prevent sticking. A
four inch commercially available wax-coated compressed
paper stick is next inserted into the base of each mold.
15 The mixture is then permitted to set.
The foregoing procedure results in the preparation of
20 lollipops, each containing 20 milligrams of timolol.
This dose is about two times higher than generally given
20 orally~
* * * *
The physician has at his disposal a large number of
25 vasodilating drugs useful for treating angina, congestive
heart failure, vasospasm, and in some cases hypertension.
However, each of these vasodilating drugs also has serious
side effects which present dangers when the proper dose for
the patient is not given.
The examples which follow employ the use of certain
vasodilating drugs which act as calcium channel blockers.
-
-36- 1339080
1 The calcium channel blockers (such as diltiazem,
nifedipine, and verapamil) dilate the coronary and systemic
arteries. This is accomplished by inhibiting the
5 transmembrane influx of extracellular calcium ions across
the membranes of the myocardial cells and vascular smooth
muscle cells. Calcium plays important roles in the
excitation-contraction coupling process of the heart and
the vascular smooth muscle cells and in the electrical
discharge of the specialized conduction cells of the heart.
Nevertheless, despite these advantages, an overdose of
15 a calcium channel blocker may lead to bradycardia,
asymptomatic asystole, hypotension, congestive heart
failure, anorexia, nausea, and hallucinations.
Thus, it will be appreciated that overdosing the
20 patient with any of these vasodilating drugs may result in
serious side effects to the patient which may cause the
patient great discomfort and, in some instances, may be so
serious as to cause failure of vital organs resulting in
25 death.
The following examples demonstrate methods and
compositions for safely administering such vasodilating
drugs in a dose-to-effect manner such that the undesirable
and dangerous side effects which may result from overdosing
" of these vasodilating drugs are avoided.
_37_ 1 3 39 080
1 Although the following examples only demonstrate the
methods and compositions of the present invention as they
relate to specific vasodilating drugs, it will be
5 appreciated that other drugs may also be utilized within
the scope of the present invention. What is important is
that the drug be lipophilic, potent, and fast-acting so
that the desired effects can be observed by the medical
professional (or the patient himself if the drug is self-
administered) in sufficient time to remove the lollipop
from the patient's mouth in time to prevent overdosing.
15 Indeed, any vasodilating drug having the characteristics
described above may be administered to a pati-ent according
to the present invention.
EXAMPLE 2
In this example, nifedipine is selected for incorpora-
tion into a compressed powder lollipop. Nifedipine is a
potent lipophilic drug useful for controlling blood pres-
25 sure, particularly in perioperative hypertension associated
with cardiovascular procedures, and for producing
controlled hypotension during surgical procedures. Its
-38- ~339080
l high potency and lipophilicity make it an excellent drug
for transmucosal administration in accordance with the
present invention.
A suitable matrix is prepared by combining 200
milligrams of nifedipine, 400 milligrams citric acid, 400
milligrams calcium stearate, 17.7 grams compressible sugar,
17.7 grams maltodextrin, 600 milligrams peppermint micro-
caps, 1.0 gram cherry microcaps, and 2.0 grams vanilla
microcaps. Alloquats of 2000 milligrams each are then
hydraulically compressed around a commercially available
wax-coated compressed paper holder, using a force
sufficient to provide a final~ volume of 2 cubic
centimeters. The foregoing procedure results in the
preparation of 20 lollipops, each containing 10 milligrams
20 Of nifedipine
_ _39_ ~339080
1 EXAMPLE 3
According to the procedure of this example, the dose-
to-effect administration of a nifedipine lollipop prepared
5 substantially according to the procedure of Example 2 is
illustrated. A patient's blood pressure is taken upon
entry into the operating room just before introduction of
anesthesia for removal of a gall bladder. The blood
pressure is 185/105 mm Hg (increased above a normal of
130/80 mm Hg because of anxiety). A lollipop containing 10
milligrams of nifedipine is given to the patient while the
15 anesthesiologist ad~usts other monitoring devices.
In two minutes, blood pressure is 160/95 mm Hg, and a
minute later blood pressure is 145/90 mm Hg. Thirty
seconds later, the anesthesiologist removes the lollipop
20 (when blood pressure is 132/82 mm Hg) and begins anesthetic
induction. Because blood pressure is now normal,
anesthetic induction is significantly safer than it would
have been if induction had begun only three to four minutes
25 before. In addition, the patient has received just enough
nifedipine to obtain the right blood pressure. Care must
be taken that too much of the drug is not given, which
could reduce blood pressure to dangerously low levels.
Alternatively, if too little of the drug is given, the
blood pressure will not be reduced enough.
~ _40_ 1 3 3g 080
1 EXAMPLE 4
In the procedure of this example, a patient who is
presently experiencing angina is given a drug-containing
5 lollipop, prepared substantially according to the procedure
of Example 2, in order to relieve immediately the anginal
pain. In this example, nifedipine in a lollipop dose of 10
milligrams is used. The patient experiences some relief
within 5 minutes after beginning to suck on the lollipop,
and after about 10 minutes the anginal pain is
substantially relieved. The nifedipine-containing lollipop
15 is then removed and discarded.
EXAMPLE 5
A drug-containing lollipop in accordance with the
20 present invention is prepared substantially according to
the procedure of Example 1, except that the drug nifedipine
in a lollipop dose of 10 milligrams is substituted for the
timolol. The nifedipine-containing lollipop is used in the
25 procedure set forth in Example 3 ~or treating a patient
with hypertension. As the patient sucks on the candy
matrix lollipop, the patient's blood pressure is rapidly
lowered to the desired value at substantially the same
rates as the compressed powder, nifedipine-containing
lollipop of Example 3.
-41- ~339080
1 EXAMPLE 6
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
5 the procedure of Example 1, except that the drug nifedipine
in a lollipop dose of lO milligrams is substituted for the
timolol. The nifedipine-containing, candy matrix lollipop
is used in the procedure set forth in Example 4 for rapid
relief from angina. The patient experiences relief within
approximately the same time parameters as the compressed
powder, nifedipine-containing lollipop of Example 4.
lS EXAMPLE 7
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug diltiazem
20 in a lollipop dose of 30 milligrams is substituted for the
nifedipine. The diltiazem-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
25 the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 8
A drug-containing lollipop in accordance with the
r present invention is prepared substantially according to
the procedure of Example 2, except that the drug diltiazem
l~9q8~
_ -42-
1 in a lollipop dose of 50 milligrams is substituted for the
nifedipine. The diltiazem-containing lollipop is used in
the procedure set forth in Example 4, for rapid relief from
5 angina. The patient experiences some relief within 4
minutes, and after about 7 minutes the anginal pain is
substantially relieved.
EXAMPLE 9
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
15 the procedure of Example 2, except that the drug verapamil
in a lollipop dose of 80 milligrams is substituted for the
nifedipine. The verapamil-containing lollipop is used in
the procedure set forth in Example 3, for treating a
20 patient with hypertension. As the patient sucks on the
lollipop, the patient's blood pressure is rapidly lowered
to a predetermined value.
-43- 1 3 3g 080
1 EXAMPLE 10
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
5 the procedure of Example 2, except that the drug verapamil
in a lollipop dose of 120 milligrams is substituted for the
nifedipine. The verapamil-containing lollipop is used in
the procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
5 minutes, and after about 8 minutes the anginal pain is
substantially relieved.
EXAMPLE 11
In the procedure of this example, a patient who is
presently experiencing supraventricular tachyarrhythmias is
20 given a drug-containing lollipop in accordance with the
present invention. The lollipop is prepared substantially
according to the procedure of Example 2, except that the
drug verapamil in a lollipop dose of 200 milligrams is
25 substituted for nifedipine. Rapid conversion to normal
sinus rhythm is observed, and the heart rate goes from
about 200 beats per minute to about 80 beats per minute in
about 3 minutes. The verapamil-containing lollipop is then
removed and discarded.
* * * *
13~9080
The following examples describe the preparation and
use of a drug-containing lollipop wherein the drug
5 dispersed within the lollipop is a beta-blocker. Some
beta-blockers, such as esmolol, nadolol, pindolol, and
timolol, reduce blood pressure by decreasing the heart rate
or cardiac output. Other beta-blockers, such as atenolol
and metoprolol, are known as cardioselective beta-blockers
because they have a greater affinity for the beta,
adrenoceptors that predominate in the heart than for the
15 beta2 receptors that predominate in the bronchi and
peripheral vasculature. The cardioselective nature of
these beta-blockers is lost if too great a dose is
administered. The dose-to-effect modality of
20 administration of these beta-blockers described in the
following examples enables the physician, other medical
professional, or even the patient, in some cases, to
administer a proper dose of these beta-blockers.
All beta-blockers, however, if administered in excess
may result in impaired pulmonary function, wheezing, and
asthmatic attacks. In addition, serious adverse
cardiovascular effects such as ~bradycardia, profound
hypotension, and even precipitation of severe congestive
heart failure may result from the excess use of beta-
blockers. Adverse central nervous system effects of
_45_ 1339080
1 overdose of beta-blockers include dizziness, fatigue,
mental depression, and in some cases hallucinations; short-
term memory impairment and vertigo have also been observed.
5 There may also be adverse gastrointestinal reactions, such
as diarrhea and nausea.
The following examples demonstrate that beta-blockers
can be safely administered in a dose-to-effect manner
thereby avoiding the harmful and undesirable side effects
of overdosing and underdosing. Safe administration of
beta-blockers is accomplished by the dose-to-effect
15 modality of administration described in the following
examples wherein a precise dose of beta-blockers is
administered to the patient.
Although the following examples only demonstrate the
20 methods and compositions of the present invention as they
relate to specific drugs having a beta-blocking effect in
the patient, it will be appreciated that other drugs may
also be utilized within the scope of the present invention.
25 What is important is that the drug be lipophilic, potent,
and fast-acting so that the desired beta-blocking effects
can be observed by the medical professional (or the patient
himself if the drug is self-administered) in sufficient
time to remove the lollipop from the patient's mouth in
time to prevent overdosing. Indeed, any beta-blocker
having the characteristics described above may be
'- -46- 1~39080
l administered to a patient according to the present
inventlon .
EXAMPLE 12
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug esmolol in
a lollipop dose of 5 milligrams is substituted for the
nifedipine. The esmolol-containing lollipop is used in the
procedure set forth in Example 3 for treating a patient
15 with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 13
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug esmolol in
25 a lollipop dose of 6 milligrams is substituted for the
nifedipine. The esmolol-containing lollipop is used in the
procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within 3
minutes, and after about 5 minutes the anginal pain is
substantially relieved.
1~39080
1 EXAMPLE 14
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
5 the procedure of Example 2, except that the drug nadolol in
a lollipop dose of 40 milligrams is substituted for the
nifedipine. The nadolol-containing lollipop is used in the
procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 15
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
20 the procedure of Example 2, except that the drug nadolol in
a lollipop dose of 80 milligrams is substituted for the
nifedipine. The nadolol-containing lollipop is used in the
procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
5 minutes, and after about 8 minutes the anginal pain is
substantially relieved.
EXAMPLE 16
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
~ -48- ~3~9080
1 the procedure of Example 2, except that the drug
propranolol in a lollipop dose of 10 milligrams is
substituted for the nifedipine. The propranolol-containing
5 lollipop is used in the procedure set forth in Example 3
for treating a patient with hypertension. As the patient
sucks on the lollipop, the patient's blood pressure is
rapidly lowered to a predetermined value.
EXAMPLE 17
A drug-containing lollipop in accordance with the
15 present invention is prepared substantially according to
the procedure of Example 2, except that the drug
propranolol in a lollipop dose of 10 milligrams is
substituted for the nifedipine. The propranolol-containing
20 lollipop is used in the procedure set forth in Example 4
for rapid relief from angina. The patient experiences some
relief within 2 minutes, and after about 8 minutes the
anginal pain is substantially relieved.
EXAMPLE 18
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug pindolol
in a lollipop dose of 5 milligrams is substituted for the
nifedipine. The pindolol-containing lollipop is used in
_49_ 1339080
1 the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
5 predetermined value.
EXAMPLE 19
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug pindolol
in a lollipop dose of 6 milligrams is substituted for the
15 nifedipine. The pindolol-containing lollipop is used in
the procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
3 minutes, and after about 5 minutes the anginal pain is
20 substantially relieved.
EXAMPLE 20
A drug-containing lollipop in accordance with the
25 present invention is prepared substantially according to
the procedure of Example 1. In this example, timolol in a
lollipop dose of 10 milligrams is used. The timolol-
containing, candy matrix lollipop is used in the procedure
30set forth in Example 5 for treating a patient with hyper-
tension. As the patient sucks on the lollipop, the
l339o8o ~
-50-
1 patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 21
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 1. In this example, timolol in a
lollipop dose of 15 milligrams is used. The timolol-
containing, candy matrix lollipop is used in the procedure
set forth in Example 6 for rapid relief from angina. The
15 patient experiences some relief within 3 minutes, and after
about 5 minutes the anginal pain is substantially relieved.
EXAMPLE 22
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug timolol in
25 a lollipop dose of 20 milligrams is substituted for the
nifedipine. The timolol-containing lollipop is used in the
procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
l339o8o
-51-
1 EXAMPLE 23
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
S the procedure of Example 2, except that the drug timolol in
a lollipop dose of 25 milligrams is substituted for the
nifedipine. The timolol-containing lollipop is used in the
procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
3 minutes, and after about 4 minutes the anginal pain is
substantially relieved.
EXAMPLE 24
A drug-containing lollipop i~ accordance with the
present invention is prepared substantially according to
20 the procedure of Example 2, except that the drug atenolol
in a lollipop dose of 50 milligrams is substituted for the
nifedipine. The atenolol-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
25 with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
1339080
_ -52-
1 EXAMPLE 25
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
5 the procedure of Example 2, except that the drug atenolol
in a lollipop dose of 80 milligrams is substituted for the
nifedipine. The atenolol-containing lollipop is used in
the procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
1 minute, and after about 3 minutes the anginal pain
is substantially relieved.
EXAMPLE 26
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
20 the procedure of Example 1, except that the drug metoprolol
in a lollipop dose of 25 milligrams is substituted for the
timolol. The metoprolol-containing lollipop is used in the
procedure set forth in Example 3 for treating a patient
25 with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 27
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
- 1339080
-53-
1 the procedure of Example 2, except that the drug metoprolol
in a lollipop dose of 40 milligrams is substituted for the
nifedipine. The metoprolol-containing lollipop is used in
5 the procedure set forth in Example 4 for rapid relief from
angina. The patient experiences some relief within
3 minutes, and after about 4.5 minutes the anginal pain is
substantially relieved.
* * * *
Vasodilating drugs which may be administered according
to the methods and compositions of the present invention
include the organic nitrates, such as isosorbide and
nitroglycerin.
Organic nitrates relax vascular smooth muscles. They
are particularly useful for relief of angina pectoris, for
prophylactic management of situations likely to provoke
angina attacks, and for long-term prophylactic management
25 of angina pectoris. However, an overdose of isosorbide may
result in headache, dizziness, nausea, tachycardia,
hypotension, fainting, or other dangerous depressions of
vital body functions.
Thus, it will be appreciated that overdosing the
patient with any of these vasodilating drugs may result in
serious side effects to the patient which may cause the
1339080
1 patient great discomfort and, in some instances, may be so
serious as to cause dangerous depression of vital organs.
The following examples demonstrate methods and
5 compositions for safely administering such vasodilating
drugs in a dose-to-effect manner such that overdosing is
avoided thereby avoiding the undesirable and dangerous side
effects which may result from overdosing of these
vasodilating drugs.
Although the following examples only demonstrate the
methods and compositions of the present invention as they
15 relate to specific vasodilating drugs, it will be
appreciated that other drugs may also be utilized within
the scope of the present invention. What is important is
that the drug be lipophilic, potent, and fast-acting so
20 that the desired effects can be observed by the medical
professional (or the patient himself if the drug is self-
administered) in sufficient time to remove the lollipop
from the patient's mouth in time to prevent overdosing.
25 Indeed, any vasodilating drug having the characteristics
described above may be administered to a patient according
to the present invention.
EXAMPLE 28
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
1339080
-55-
1 the procedure of Example 2, except that the drug isosorbide
in a lollipop dose of 2.5 milligrams is substituted for the
nifedipine. The isosorbide-containing lollipop is used in
5 the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 29
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
15 the procedure of Example 2, except that the drug isosorbide
in a lollipop dose of 20 milligrams is substituted for the
nifedipine. The isosorbide-containing lollipop is used in
the procedure set forth in Example 4 for rapid relief from
20 angina. The patient experiences some relief within 1.5
minutes, and after about 3 minutes the anginal pain is
substantially relieved.
EXAMPLE 30
In the procedure of this example, a patient is given
an isosorbide-containing lollipop as treatment for
congestive heart failure. In this example, the isosorbide-
containing lollipop was prepared substantially according to
the procedure of Example 2, except that the drug isosorbide
in a lollipop dose of 25 milligrams is substituted for
- -56- 1 339 080
1 nifedipine. Shortly after initiating the administration of
the isosorbide-containing lollipop, the patient's breathing
rate decreases, and the patient no longer experiences a
5 shortness of breath. The patient's exercise tolerances
increase, and the heart rate of the patient decreases. In
addition, there is "ST wave" improvement in EKG. As the
blood pressure decreases, the "ST segment" of the EKG
approaches normal.
EXAMPLE 31
A compressed powder lollipop containing nitroglycerin
within the scope of the present invention was made
according to the following procedures: A suitable matrix
was prepared by combining 16 milligrams of nitroglycerin,
20 400 milligrams citric adic, 400 milligrams calcium
stearate, 17.7 grams compressible sugar, 17.7 grams
maltodextrin, 600 milligrams peppermint microcaps, 1.2
grams cherry microcaps, and 2.0 grams vanilla microcaps.
Alloquats of about 2 grams each were then
hydraulically compressed around a commercially available
wax-coated compressed paper holder using a force sufficient
to provide a final volume of about 2 cubic centimeters.
This procedure resulted in the preparation of 20 lollipops,
r each containing about 0.8 milligrams of nitroglycerin.
-57- ~339080
Example 32
According to the method of this example, a
nitroglycerin-containing compressed powder lollipop made
5 according to the procedure of Example 31 was administered
in a dose-to-effect manner in order to reduce a patient's
blood pressure immediately prior to a surgical procedure.
Upon entry into the operating room prior to
anesthesia induction for removal of a gall baldder, the
patient's blood pressure was found to be 185/105 mm Hg
(increased above an upper normal range of 130/80 mm Hg
lS because of anxiety).
The nitroglycerin lollipop of Example 31 was given to
the patient, while the anesthesiologist was adjusting other
monitoring devices. In two minutes, the patient's blood
20 pressure had dropped to 160/95 mm Hg, and a minute later,
the blood pressure was 145/90 mm Hg. Thirty seconds
thereafter, the anesthesiologist removed the lollipop (when
blood pressure is 132/82 mm Hg) and began anesthesia
25 induction.
Because the patient's blood pressure was then within
normal ranges, anesthetic induction was significantly safer
than it would have been if induction had begun only three
to four minutes earlier. In addition, the patient received
the proper amount of nitroglycerin to bring the blood
pressure to the desired level without the danger of
133908~
-58-
1 receiving too much, which would have reduced the blood
pressure to a dangerously low level, and without the danger
of receiving too little, which would have not reduced the
5 blood pressure enough.
Example 33
According to the method of this example, a
nitroglycerin-containing compressed powder lollipop made
according to the procedure of Example 31 was administered
to an adult patient in order to immediately reduce the
15 patient's blood pressure.
Before administration, the patient's blood pressure
was 175/120 mm Hg. After three minutes of sucking on the
lollipop, the patient's blood pressure had decreased to
135/90 mm Hg. The nitroglycerin-containing lollipop was
then removed and discarded.
Example 34
According to the method of this example, an adult
patient is given a nitroglycerin-containing lollipop in
order to rapidly reduce the patient's blood pressure
similar to the procedure of Example 33. However, in this
example, the nitroglycerin dose in the lollipop is 1.2
milligrams.
~ _59_ 1 3 39 0 80
1 The patient is permitted to suck on the lollipop
until a sufficient dose of the nitroglycerin is received by
the patient so that the patient's blood pressure is
5 decreased to the desired level. The nitroglycerin-
containing lollipop is then removed and discarded.
Example 35
According to the method of this example, an adult
patient is given a nitroglycerin-containing lollipop in
order to rapidly reduce the patient's blood pressure
15 similar to the procedure of Example 34. However, in this
example, the nitroglycerin dose in the lollipop is 0.4
milligrams.
The patient is permitted to suck on the lollipop
20 until a sufficient dose of the nitrogycerin is received by
the patient so that the patient's blood pressure is
decreased to the desired level. The patient then continues
to suck the nitroglycerin-containing lollipop at a much
25 reduced rate and even removes the lollipop periodically in
order to maintain blood pressure within normal ranges.
Example 36
According to the method of this example, an adult
patient who is presently experiencing anginal pain is given
a nitrogycerin-containing lollipop in order to rapidly
_ -60- 1339080
1 relieve the anginal pain. In this example, a
nitroglycerin-containing lollipop manufactured according to
the procedures of Example 31 is given to the patient.
Within one minute, the patient experiences some
relief from angina, after two minutes, the anginal pain is
relieved. The nitroglycerin-containing lollipop is then
removed and discarded.
Example 37
According to the method of this example, an adult
patient is given a nitroglycerin-containing lollipop in
order to rapidly relieve anginal pain similar to the
procedure of Example 36. However, in this example, the
nitroglycerin dose in the lollipop of 1.2 milligrams is
used.
The patient is permitted to take a sufficient dose of
the nitroglycerin so that the anginal pain is relieved.
The nitroglycerin-containing lollipop is then removed and
25 discarded.
Example 38
According to the method of this example, an adult
patient is given a nitroglycerin-containing lollipop in
order to rapidly relieve anginal pain similar to the
procedure of Example 36. However, in this example, the
-61- 1339080
1 nitroglycerin dose in the lollipop of 0.4 milligrams is
used.
The patient is permitted to take a sufficient dose of
5 the nitroglycerin so that the anginal pain is relieved.
After the anginal pain is relieved and the lollipop is
removed and discarded, a second lollipop is of a different
color than the first lollipop and is used to maintain a
desired anti-anginal condition.
Example 39
According to the method of this example, a patient
who is experiencing pulmonary edema is given a
nitroglycerin-containing lollipop in order to rapidly
relieve the effects of the pulmonary edema. In this
20 example, a nitroglycerin-containing lollipop manufactured
according to the procedures of Example 31 is given to the
patient.
Within a few minutes, the patient's head and neck is
25 noticeably less swollen and the patient's breathing rate
begins to slow down. Continued administration of the
nitroglycerin lollipop slows down the heart, and the
patient becomes less anxious. Once the pulmonary edema
episode passes, which can be determined by monitoring the
reduction in the pulmonary arterial wedge pressure and the
_ -62- 1339080
1 venous pressure of the jugular vein, the lollipop is then
removed and discarded.
* * * *
The following examples describe the preparation and
use of a drug-containing lollipop wherein the drug
dispersed within the lollipop is a hypotensive drug which
reduces blood pressure by lowering the total peripheral
resistance by direct vasodilation. Hypotensive drugs of
15 this nature, such as nitroprusside and hydralazine, are
particularly potent and are usually given in an emergency
or when other hypotensive treatments have failed. Slight
overdoses of this type of hypotensive drug may result in
20 headache, tachycardia, nausea, and diarrhea, and may even
precipitate angina pectoris or ventricular arrhythmia.
Still other hypotensive drugs, such as prazosin, are
alpha1-blockers which are also capable of reducing blood
25 pressure by lowering the total peripheral resistance as a
result of vasodilating effects. An overdose of prazosin
may result in headache, drowsiness, palpitation, nausea,
and even fainting.
Labetolol is a unique hypotensive drug which combines
the features of alpha-blockers with beta-blockers. Blood
pressure is reduced due to a decrease in systemic vascular
_ -63- 1 339 080
1 resistance, but usually without a substantial reduction or
increase in heart rate, cardiac output, or stroke volume.
~ Unfortunately, labetolol shares the toxic potentials of
5 both the beta and the alpha-blocking agents. In
particular, labetolol overdose may promote or exacerbate
congestive heart failure, bronchospasm, hypotension, and
bradycardia.
Other hypotensive drugs, such as methyldopa and
clonidine, inhibit sympathetic vasomotor centers thereby
reducing peripheral central nervous system activity, blood
15 pressure, and heart rate with little change in total
peripheral resistance. An overdose of these drugs may
result in drowsiness, headache, nausea, dry mouth,
palpitation and tachycardia, bradycardia, congestive heart
20 failure, rash, impotence, hepatic abnormalities, and muscle
cramps.
Thus, it will be appreciated that overdosing the
patient with any of these hypotensive drugs may result in
25 serious side effects to the patient which may cause the
patient great discomfort and, in some instances, may be so
serious as to cause failure of vital organs resulting in
death.
The following examples demonstrate methods and
compositions for safely administering such hypotensive
drugs in a dose-to-effect manner such that the undesirable
_ -64- 1339080
1 and dangerous side effects which may result from overdosing
of these hypotensive drugs are avoided.
Although the following examples only demonstrate the
5 methods and compositions of the present invention as they
relate to specific hypotensive drugs, it will be
appreciated that other drugs may also be utilized within
the scope of the present invention. What is important is
that the drug be lipophilic, potent, and fast-acting so
that the desired effects can be observed by the medical
professional (or the patient himself if the drug is self-
administered) in sufficient time to remove the lollipopfrom the patient's mouth in time to prevent overdosing.
Indeed, any hypotensive drug having the characteristics
described above may be administered to a patient according
to the present invention.
EXAMPLE 40
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug clonidine
in a lollipop dose of 0.1 milligrams is substituted for the
nifedipine. The clonidine-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
_ -65- 1 339080
1 the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 41
In the procedure of this example, a patient is given
a clonidine-containing lollipop as treatment for hyperten-
sion. In this example, the clonidine-containing lollipop
was prepared substantially according to the procedure of
Example 2, except that the drug clonidine in a lollipop
dose of 0.2 milligrams is substituted for nifedipine.
15 Substantially the same effects as those set forth in
Example 40 are observed.
EXAMPLE 42
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug
hydralizine in a lollipop dose of lO milligrams is
25 substituted for the nifedipine. The hydralizine-containing
lollipop is used in the procedure set forth in Example 3
for treating a patient with hypertension. As the patient
sucks on the lollipop, the patient's blood pressure is
rapidly lowered to a predetermined value.
1339080
-66-
1 ExAMpLE 43
In the procedure of this example, a patient is given
a hydralizine-containing lollipop as treatment for
5 hypertension. In this example, the hydralizine-containing
lollipop was prepared substantially according to the
procedure of Example 2, except that the drug hydralizine in
a lollipop dose of 20 milligrams is substituted for
nifedipine. Substantially the same effects as those set
forth in Example 40 are observed.
EXAMPLE 44
In the procedure of this example, a patient is given
a nitroprusside-containing lollipop as treatment for hyper-
tension. In this example, the nitroprusside-containing
20 lollipop was prepared substantially according to the
procedure of Example 2, except that the drug nitroprusside
in a lollipop dose of 10 milligrams is substituted for
nifedipine. The patient's blood pressure decreases by
25 about 20 mm Hg after one minute, and by lOmm Hg more, at
which time the lollipop is removed.
EXAMPLE 45
A drug-containing lollipop in accordance with the
7; present invention is prepared substantially according to
the procedure of Example 2, except that the drug methyldopa
~ -67- 1339080
1 in a lollipop dose of 250 milligrams is substituted for~ the
nifedipine. The methyldopa-containlng lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 46
In the procedure of this example, a patient is given
a methyldopa-containing lollipop as treatment for hyperten-
sion. In this example, the methyldopa-containing lollipop
was prepared substantially according to the procedure of
Example 2, except that the drug methyldopa in a lollipop
dose of 400 milligrams is substituted for nifedipine.
Substantially the same effects as those set forth in
Example 40 are observed.
-68- 1 339 080
1 EXAMPLE 47
In the procedure of this example, a patient is given
a methyldopa-conntaining lollipop as treatment for
5 hypertension. In this example, the methyldopa-containing
lollipop was prepared substantially according to the
procedure of Example 1, except that the drug methyldopa in
a lollipop dose of 400 milligrams is substituted for
timolol. As the patient sucks on the candy matrix
lollipop, substantially the same effects as those set forth
in Example 40 are observed.
EXAMPLE 48
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
20 the procedure of Example 2, except that the drug prazosin
in a lollipop dose of 3 milligrams is substituted for the
nifedipine. The prazosin-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
25 with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 49
In the procedure of this example, a patient is given
a prazosin-containing lollipop as treatment for hyperten-
_ -69- ~339080
1 sion. In this example, the prazosin-containing lollipop
was prepared substantially according to the procedure of
Example 2, except that the drug prazosin in a lollipop dose
of 4 milligrams is substituted for nifedipine. The
patient's blood pressure decreases by about 20 mm Hg after
one minute, and by 10 mm Hg more, at which time the
lollipop is removed.
EXAMPLE 50
In the procedure of this example, a patient is given
a prazosin-containing lollipop as treatmént for
hypertension. In this example, the prazosin-containing
lollipop was prepared substantially according to the
procedure of Example 1, except that the drug prazosin in a
lollipop dose of 4 milligrams is substituted for timolol.
As the patient sucks on the candy matrix lollipop,
substantially the same effects as those set forth in
Example 40 are observed.
-70_ 1 3 39 080
1 EXAMPLE 51
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
5 the procedure of Example 2, except that the drug labetolol
in a lollipop dose of 100 milligrams is substituted for the
nifedipine. The labetolol-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 52
In the procedure of this example, a patient is given
a labetolol-containing lollipop as treatment for hyperten-
20 sion. In this example, the labetolol-containing lollipop
was prepared substantially according to the procedure of
Example 2, except that the drug labetolol in a lollipop
dose of 200 milligrams is substituted for nifedipine.
25 Substantially the same effects as those set forth in
Example 40 are observed.
* * * *
rThe following examples describe the preparation and
use of a drug-containing lollipop wherein the drug
13~9080
_ -71-
1 dispersed within the lollipop is a hypotensive drug which
reduces blood pressure by suppressing the renin-angio-
tensin-aldosterone system. These drugs inhibit the
5 angiotensin-converting enzyme thereby resulting in arterial
and possibly venous dilation. Thus, blood pressure is
reduced by decreasing the total peripheral resistance with
no change or an increase in heart rate, stroke volume, or
cardiac output.
These ACE-inhibiting drugs, if administered in excess,
may also result in neutro-penia, an abnormally low white
15 blood cell count, which may further lead to systemic or
regional infections and possible death. Other adverse
effects from overdosing of ACE inhibitors include
proteinuria, rash, taste impairment, excessive hypotension,
20 tachycardia, angina, palpitations, and even myocardial
infarction and congestive heart failure.
Thus, it will be appreciated that overdosing the
patient with any of these hypotensive drugs may result in
serious side effects to the patient which may cause the
patient great discomfort and, in some instances, may be so
serious as to cause loss of vital organs resulting in
death.
The following examples demonstrate methods and
compositions for safely administering such hypotensive
drugs in a dose-to-effect manner such that overdosing is
_ -72- 1 3 39 080
1 avoided thereby avoiding the undesirable and dangerous side
effects which may result from overdosing.
Although the following examples only demonstrate the
5 methods and compositions of the present invention as they
relate to specific hypotensive drugs, it will be
appreciated that other drugs may also be utilized within
the scope of the present invention. What is important is
that the drug be lipophilic, potent, and fast-acting so
that the desired effects can be observed by the medical
professional (or the patient himself if the drug is self-
15 administered) in sufficient time to remove the lollipopfrom the patient's mouth in time to prevent overdosing.
Indeed, any hypotensive drug having the characteristics
described above may be administered to a patient according
20 to the present invention.
EXAMPLE 53
A drug-containing lollipop in accordance with the
25 present invention is prepared substantially according to
the procedure of Example 2, except that the drug captopril
in a lollipop dose of 25 milligrams is substituted for the
nifedipine. The captopril-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
- -73- 1 339 080
1 the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 54
In the procedure of this example, a patient is given
a captopril-containing lollipop as treatment for hyperten-
sion. In this example, the captopril-containing lollipop
was prepared substantially according to the procedure of
Example 2, except that the drug captopril in a lollipop
dose of 70 milligrams is substituted for nifedipine.
Substantially the same effects as those set forth in
Example 40 are observed.
EXAMPLE 55
A drug-containing lollipop in accordance with the
present invention is prepared substantially according to
the procedure of Example 2, except that the drug enalapril
in a lollipop dose of 5 milligrams is substituted for the
nifedipine. The enalapril-containing lollipop is used in
the procedure set forth in Example 3 for treating a patient
with hypertension. As the patient sucks on the lollipop,
the patient's blood pressure is rapidly lowered to a
predetermined value.
EXAMPLE 56
1339080
1 In the procedure of this example, a patient is given
an enalapril-containing lollipop as treatment for hyperten-
sion. In this example, the enalapril-containing lollipop
5 was prepared substantially according to the procedure of
Example 2, except that the drug enalapril in a lollipop
dose of lO milligrams is substituted for nifedipine.
Substantially the same effects as those set forth in
Example 40 are observed.
* * * *
The physician also has at his disposal~ a number of
cardiac drugs useful for treating ventricular fibrillation,
acute ventricular arrhythmias, and congestive heart
20 failure. Again, these drugs, while useful, can be very
dangerous when the patient's susceptability to the drug
makes it difficult to know the proper dose.
Amrinone, for example, is an inotropic drug which
25 increases the force and velocity of myocardial systolic
contraction. In addition, amrinone has vasodilatory
activity affecting vascular smooth muscle. In patients
with congestive heart failure, amrinone produces
substantial increases in cardiac output.
However, serious adverse effects may arise in the
event of an overdose of amrinone; these adverse effects
~ -75- 1 339080
1 include: thrombocytopenia, arrhythmias, hypotension,
nausea, vomiting, diarrhea, hepatotixicity marked by
abnormal liver function, and hypersensitivity.
Thus, it will be appreciated that overdosing the
patient with these cardiac drugs may result in serious side
effects to the patient which may cause the patient great
discomfort.
The following example demonstrates methods and
compositions for safely administering such cardiac drugs in
a dose-to-effect manner such that overdosing is avoided
15 thereby avoiding the undesirable and dangerous sidé effects
which may result from overdosing of these cardiac drugs.
Although the following example only demonstrates the
methods and compositions of the present invention as it
20 relates to amrinone, it will be appreciated that other
drugs may also be utilized within the scope of the present
invention. What is important is that the drug be
lipophilic, potent, and fast-acting so that the desired
25 effects can be observed by the medical professional (or the
patient himself if the drug is self-administered) in
sufficient time to remove the lollipop from the patient's
mouth in time to prevent overdosing. Indeed, any cardiac
drug having the characteristics described above may be
administered to a patient according to the present
invention.
_ -76- 1339080
EXAMPLE 57
A drug-containing lollipop in accordance with the
5 present invention is prepared substantially according to
the procedure of Example 2, except that the drug amrinone
in a lollipop dose of 50 milligrams is substituted for the
timolol. The amrinone-containing lollipop is used in the
procedure set forth in Example 30 for treating a patient
with congestive heart failure. As the patient sucks on the
lollipop, substantially the same effects as those set forth
15 with respect to Example 41 are observed.
Anti-arrhythmic drugs, such as bretylium and
lidocaine, may also be safely administered to a patient
20 according to the methods and compositions of the present
invention as is demonstrated in the following examples.
Bretylium and lidocaine are well-known anti-arrhythmic
drugs. Bretylium is used in the prophylaxis and treatment
25 of ventricular fibrillation. However, because it commonly
causes hypotension, and may increase ventricular irrita-
bility, bretylium must be used with care. Lidocaine is a
CNS-depressing drug which controls ventricular arrhythmias.
It also produces sedative, analgesic, and anti-convulsant
,.
_ -77~ 1339080
1 effects. Overdoses may result in seizures, respiratory
arrest, dizziness, nausea, unconsciousness, or even coma.
Thus, it will be appreciated that overdosing the
5 patient with any anti-arrhythmic drugs may result in
undesirable side effects to the patient which may cause the
patient great discomfort.
The following examples demonstrate methods and
compositions for safely administering such anti-arrhythmic
drugs in a dose-to-effect manner such that overdosing is
avoided thereby avoiding the undesirable and dangerous side
effects which may result from overdosing of thése anti-
arrihythmic drugs.
Although the following examples only demonstrate the
methods and compositions of the present invention as they
relate to specific anti-arrhythmlc drugs, it will be
appreciated that other drugs may also be utilized within
the scope of the present invention. What is important is
that the drug be lipophilic, potent, and fast-acting so
that the desired effects can be observed by the medical
professional (or the patient himself if the drug is self-
administered) in sufficient time to remove the lollipop
from the patient's mouth in time to prevent overdosing.
Indeed, any anti-arrhythmic drug having the characteristics
~ -78- 1 339080
1 described above may be administered to a patient according
to the present invention.
EXAMPLE 58
In the procedure of this example, a patient exper-
iencing ventricular fibrillation is given a bretylium-
containing lollipop. In this example, the lollipop is
10prepared substantially according ~to the procedure of
Example 2 except that the drug bretylium in a lollipop dose
of 60 milligrams is substituted for nifedipine. Rapid
15 conversion to normal sinus rhythm is observed. The
bretylium-containing lollipop is removed and~discarded.
EXAMPLE 59
In the procedure of this example, a patient experi-
encing acute ventricular arrhythmias is given a lidocaine-
containing lollipop. In this example, the lollipop is
prepared substantially according to the procedure of
25 Example 2 except that the drug lidocaine in a lollipop dose
of 10 milligrams is substituted for nifedipine. Rapid
conversion to normal sinus rhythm is observed. The
lidocaine-containing lollipop is removed and discarded.
7~
~79~ 1339080
1 EXAMPLES 60-64
In the procedures of these examples, drug-containing
lollipops in accordance with the present invention are
5 prepared according to the procedures of Example 1, except
that the following drugs are dispersed in the "candy"
matrix in the indicated doses and are substituted for the
timolol.
Table II
Example ~y~ Dose
Diltiazem 30 milligrams
61 Pindolol ~5 milligrams
62 Metoprolol 25 milligrams
63 Prazosin 3 milligrams
64 Methyldopa 250 milligrams
EXAMPLES 65-67
In the procedures of these examples, drug-containing
lollipops in accordance with the present invention are
prepared according to the procedures of Example 1, except
that the following drugs are dispersed in the "candy"
matrix in the indicated doses and are substituted for the
timolol.
..
1339080
1 Table III
Example Druq Dose
Diltiazem50 milligrams
66 Pindolol6 milligrams
67 Metoprolol40 milligrams
These drug-containing lollipops are used in the proce-
10 dure set forth in Example 4 in order to relieve immediate
anginal pain. As the patient sucks on the candy matrix
lollipop, the patient's experiences relief from anginal
pain at substantially the same rates as the respective com-
15 pressed-powder, drug-containing lollipops of Examples 8,
21, and 27.
* * * *
In addition to drugs for treating cardiovascular
conditions, many new drugs for treatment of renal vascular
25 functions have been developed in recent years. Like most
drugs affecting the cardiovascular system, the drugs
affecting the renal vascular system must be precisely
administered to avoid serious side effects or the dangers
30 of overdosing and underdosing.
One of the most useful drugs employed today for
increasing renal blood flow and urine output is dopamine.
In its clinical application, dopamine is administered until
_ -81- 1339080
1 urine output is significantly increased or approaches a
normal stage. Despite its benefits, the detriment of using
too much dopamine is reflected in increases in the heart
rate, blood pressure, cardiac output, and myocardial oxygen
consumption. These effects are extremely dangerous in
patients with ischemic cardiac disease. Hence, precise
dosage control is critical to the effective use of
dopamine.
Thus, it will be appreciated that overdosing the
patient with any of these renal vascular-acting drugs may
result in serious side effects to the patient which may
cause the patient great discomfort and, in some instances,
may be so serious as to cause failure of vital organs
resulting in death.
The following examples demonstrate methods and
compositions for safely administering such renal vascular-
acting drugs in a dose-to-effect manner such that
overdosing is avoided thereby avoiding the undesirable and
dangerous side effects which may result from overdosing.
Although the following examples only demonstrate the
methods and compositions of the present invention as they
relate to dopamine, it will be appreciated that other drugs
may also be utilized within the scope of the present
invention. What is important is that the drug be
lipophilic, potent, and fast-acting so that the desired
-82- 1339080
1 effects can be observed by the medical professional (or the
patient himself if the drug is self-administered) in
sufficient time to remove the lollipop from the patient's
5 mouth in time to prevent overdosing. Indeed, any renal
vascular-acting drug having the characteristics described
above may be administered to a patient according to the
present invention.
EXAMPLE 68
In the procedure of this example, a patient who is
15 presently experiencing oliguria is given a dopamine-
containing lollipop in order to immediately increase the
patient's urine output. The lollipop of this example is
made according to the procedures of Example 2, except that
20 dopamine in a lollipop dose of 350 milligrams is used
instead of nifedipine.
After the patient is permitted to suck on the lollipop
for only a matter of a few minutes, the urine output is
25 increased with no change in the heart rate of blood
pressure.
EXAMPLE 69
In the procedure of this example, a patient who is
presently experiencing insufficient urine output is given
a dopamine-containing lollipop according to the procedures
1339080
-83-
of Example 68, except that the dopamine is in a lollipop
dose of 700 milligrams.
After the patient is permitted to suck on the lollipop
for only a few minutes, the urine output is increased with
no change in the heart rate or blood pressure.
From the foregoing, it will be appreciated that the
present invention allows great flexibility and permits
physician control on a case-by-case basis with respect to
the dose given to a particular patient and the rate at
15 which that dose is given.
The use of a drug-containing lollipop for administra-
tion of cardiovascular-acting and renal vascular-acting
agents provides for much faster onset than oral
20 administration and also avoids unacceptable loss of drug on
a first pass through the liver before systemic
distribution. Further, the use of a lollipop in accordance
with the present invention provides for a relatively level
25 drug plasma concentration, which is preferable when dealing
with cardiovascular and renal vascular related drugs.
Further, a physician can easily monitor a patient's
condition to ensure the patient receives a dose adequate to
evoke a desired cardiovascular state. If necessary, the
physician can instruct the patient to alter the aggressive-
_ -84- i 339 080
ness with which he sucks the lollipop, or the physician can
take the lollipop from the patient.
A patient can also self-administer suitable anti-
anginal medication using a lollipop in accordance with the
present invention. Thus, a patient can place a drug-
containing lollipop passively in his mouth for continuous
low level administration of a drug, or the patient can take
a lick of the lollipop from time to time as it may be
needed to reduce his own subjective experience of the
symptoms of the cardiovascular or renal vascular condition.
Although the methods and compositions of thé present
invention have been described with reference to specific
examples, it is to be understood that the methods and
compositions of the present invention may be practiced in
20 other forms without parting from its spirit or essential
characteristics. The described methods and compositions
are considered in all respects only as illustrative, and
not restrictive. The scope of the invention is, therefore,
indicated by the appended claims rather than by the
foregoing description. All changes which come within the
meaning and range of equivalency of the claims are to be
embraced within their scope.
