Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1 BACKGROUND
1. The Field of the Invention
The present invention is related to methods and
5 compositions for use in delivering pharmacological agents
to a patient. More particularly, the present invention is
directed to methods and compositions for the noninvasive
administration of precisely the proper dose of potent
pharmacological agents having antimigraine, oxytocic,
10 antiemetic, hypoglycemic, anti-Parkinsonian, antidiuretic,
antifungal, antisecretory, or bronchodilator properties.
2. The Prior Art.
In recent years, a host of potent new drugs have
15 become available for clinical use in treating migraine
headaches, nausea, vomiting, asthma, respiratory distress,
polyuria, Parkinson's disease, systemic or oral fungal
infections, esophagitis or heartburn, symptoms of diabetes,
post partum and post abortion hemorrhage, and for inducing
20 labor at term, stimulating uterine contraction during
labor, or inducing abortion. Current expectations are that
additional potent drugs will continue to become available
in the future.
In addition to treating specific diseases and
25 conditions, physicians can prescribe drugs that will permit
the physician to regulate many body functions and
processes. Yet, despite the tremendous advances in the
field of pharmacology, physicians continue to administer
these new drugs using substantially the same techniques
30 that have been employed for many decades.
Thus, almost all pharmacological agents continue to be
administered via two routes, by oral administration for
absorption through the stomach or intestines or by
intramuscular or intravenous injection, despite the fact
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1 that both of these routes suffer from significant
disadvantages under typical situations.
The simplest and most prevalent administration route
is oral administration. To use this method, a
5 pharmacological agent is incorporated into a tablet, a
capsule, or into a liquid base; the patient then ingests an
appropriate dose. Oral administration of a drug is
extremely convenient, and for many drugs, it will continue
to be the method of choice. Such administration is
10 nonthreatening and is painless to the patient. For most
patients, it is also very simple.
Nevertheless, oral administration of a drug suffers
from the disadvantage that pediatric and geriatric patients
frequently have difficulty swallowing pills, and such
15 patients often refuse to cooperate in swallowing a liquid
medication. Even more importantly, absorption of a drug
into the bloodstream after swallowing 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
20 movement from the stomach to the small and large intestines
and the effects of secretions from these organs.
Moreover, there is often a substantial delay between
the time of oral administration of a drug until it begins
to have the desired therapeutic effect on the patient's
25 system. Generally, a drug must pass from the stomach into
the small and large intestines before it will be absorbed
into the patient's bloodstream; unfortunately, this
typically takes forty-five minutes or longer. For some
applications, such a delay is unacceptable.
Further, many drugs taken orally are metabolized
almost immediately -- they are removed from or rendered
ineffective by the patient's system before they can have
any therapeutic effect. This occurs because the veins from
the stomach and the small and large intestines drain into
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1 the liver. Thus, drugs entering the patient's bloodstream
through the stomach and the intestines immediately pass
through the patient's liver before 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
pass through the liver. Therefore, when utilizing oral
administration, much larger doses of the drug than would
10 otherwise be necessary must be administered to the patient
to compensate for the large percentage of the drug removed
during the first pass through the liver and obtain the
desired effect in the patient.
Adverse reactions from the large doses necessary to
15 elicit a systemic or local effect despite metabolism by the
liver include nausea, vomiting, involuntary movement,
gastrointestinal bleeding, duodenal ulcers, and epigastric
abdominal distress. Other dose-related side effects may
adversely affect renal and hepatic functions, especially in
20 the geriatric patient. Some drugs, if present in the liver
in excess, may also be hepatoxic.
The result is that the oral route of administration is
inefficient for many drugs, particularly many antimigraine,
antiemetic, hypoglycemic, brochodilator, oxytocic, anti-
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1 Parkinsonian, antidiuretic, antifungal, or antisecretory
acting drugs.
In some instances, a dose approximately one hundred
times the actual effective dose must be administered to the
5 patient in order to retain a sufficient dose of the drug in
the blood after the first pass through the liver. Thus,
oral administration results in a highly inefficient use of
the drug. Further, in addition to the other adverse
effects resulting from large amounts of the drug being
10 removed by the liver, oral administration is also
disadvantageous because of the cost in providing such a
large dose of the drug.
A yet further difficulty encountered when
administering drugs orally is that dosages are prepared or
15 determined for use with an "average" patient. This is
entirely acceptable for many drugs, but some drugs have a
widely varying effect on different patients, even when
weight and size differences between patients are
considered. The effects of these drugs can vary depending
20 upon the patient's habits, subtle genetic differences
between patients, the patient's blood volume, the patient's
age, and numerous other known and unknown individual
variations in susceptibility to the particular drug
utilized.
Underdosing a patient because of a low susceptibility
to the drug fails to evoke the response sought by the
physician. Overdosing the patient can result in dangerous
depression of vital body functions. Moreover, the slow and
uncertain response time for the onset of an observable
30 reaction to a 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, whether the patient was under-
dosed or overdosed.
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1 In order to avoid these serious disadvantages inherent
in the oral administration modality, physicians frequently
resort to the injection modality for administering many
drugs. Injecting a drug (generally intravenously or intra-
5 muscularly) results in rapid entry of the drug into the
patient's bloodstream; in addition, this type of delivery
avoids the removal of large quantities of the drug by the
patient's liver that accompanies oral administration.
Rather, the drug becomes rapidly distributed to various
10 portions of the patient's body before exposure to the
liver; thus, the drug is removed by the liver at a
substantially slower rate.
Most patients have at least some aversion to receiving
injections. In some patients, particularly children and
15 certain "high strung" adults, this aversion may be so
pronounced as to make the use of injections of serious
concern to the physician. Since intense psychological
stress and anxiolysis can exàcerbate a patient's
debilitated condition, it sometimes becomes undesirable to
20 use injections where the patient is seriously ill or
suffers from a debilitating condition or injury.
To compound the problem facing a physician, the
individual variation in susceptibility and metabolism with
respect to various drugs, which makes it difficult to
25 select an appropriate dose for oral administration, is even
more profound when utilizing the injection modality of
administration. This is because smaller doses have an
increased effect due to the rapidity with which the drug
enters the bloodstream and because large doses of the drug,
30 when injected, are not immediately metabolized by the
liver.
In order to prevent overdosing a patient with potent
drugs, a prudent physician typically injects a patient with
a lower than average dose, and later supplements the dose
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with additional injections as they appear necessary. This
"titration" makes necessary the use of 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.
In view of the foregoing, it will be appreciated that it
would be an important advancement in the art of administering
drugs if suitable methods and compositions could be provided
for administering drugs in order to provide for rapid onset of
the desired action and precise dosage delivery in each patient
so as to avoid the dangers of overdosage and underdosage.
It will also be appreciated that it would be an important
advancement in the art of administering drugs if suitable
methods and compositions could be provided that avoid immediate
metabolism of the drug through the patient's liver and yet not
involve injection of the drug.
It would be an additional important advancement if methods
and compositions could be provided that would permit a
physician and/or a patient to easily control the amount of the
drug the patient receives according to the patient's own
subjective need for medication.
Such methods and compositions are disclosed and claimed
herein.
BRIEF SUMMARY AND OBJECTS OF THE INVENTION
In accordance with an aspect of the present invention,
there is provided a use of a soluble matrix material in the
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form of a lollipop into which insulin has been dispersed for
treating a patient suffering from hypoglycemia in a
dose-to-effect manner while modifying the rate of dissolution
of the lollipop in response to reduction of said suffering,
wherein the patient's hypoglycemia is susceptible to treatment
with insulin and wherein said soluble matrix material being a
carbohydrate mass capable of releasing the insulin for
absorption through mucosal tissues of the mouth, pharynx and
esophagus.
In accordance with another aspect of the invention, there
is provided a composition for use in treating in a dose-to-
effect manner a patient experiencing pain associated with a
migraine. The composition comprises 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 relieving the pain associated with a
migraine; 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 is released in a dose-
to-effect manner 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
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~ 1339075
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while accounting for the patient's susceptibility to the drug
and the patient's individual subjective experience of the pain
associated with the migraine. The present invention is capable
of introducing the drug into the patient's bloodstream almost
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13~9075
_ --7
1 injection -- and much faster than by oral administration.
Yet, the delivery modality is nonthreatening, painless, and
minimizes the dangers of overdosing and underdosing.
These significant advantages are achieved by incorpor-
5 ating into a candy matrix a drug or combination of drugscapable 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
10 hereinafter, can be administered in a dose-to-effect manner
to achieve a systemic effect on the patient.
Even patients that have difficulty swallowing a pill
or tablet or refuse to swallow a pill, tablet, and/or a
liquid, will give little resistance to sucking on a
15 lollipop. Particularly when dealing with children, a
lollipop evokes a pleasurable response in the patient and
gives the patient something nonthreatening on which to
concentrate.
An antimigraine, antiemetic, hypoglycemic,
20 bronchodilator, oxytocic, anti-Parkinsonian, antidiuretic,
antifungal, or antisecretory acting drug administered by
way of a lollipop will quickly enter the patient's
bloodstream through the veins which serve the mucosal
tissues in the mouth and pharynx, thereby serving to
25 further lessen any remaining tension and fear. Appropriate
monitoring of the patient's reaction (e.g., pain, asthma,
hemorrhage, urine output, etc.) to these potent drugs will
indicate when the drug has evoked a suitable response. The
lollipop may then be removed, or its rate of consumption
30 may be decreased.
It will be appreciated that the ever-present risk of
overdosing a patient is substantially minimized, if not
almost eliminated, by the dose-to-effect administration
method of the present invention. The rate at which the
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drug is to be absorbed by the body can be varied by varying the
rate the lollipop dissolves.
Accordingly, the drug dose is given over a period of time
rather than all at once (as in a pill or other bolus
injection), and the administration rate can be reduced if such
appears necessary. If a patient begins showing signs of any
overdose, he will simply stop sucking the lollipop and/or the
physician can easily remove the lollipop from the patient's
mouth.
Unlike the use of injections or oral ingestion of
medication where a relatively large bolus dose of medication
is given intermittently, use of a lollipop can permit the
patient to take very small doses of a 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 own subjective experience and his own personal
susceptibility to the particular drug utilized. The result is
that lower amounts of drugs can be used to achieve a more even
medication of the patient.
An advantage of the present invention is the provision of
noninvasive uses and compositions capable of rapidly inducing
an antimigraine, or hypoglycemic effect through the dose-to-
effect administration of appropriate drugs without the dangers
of overdose or underdosage.
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Another advantage is the provision of uses and
compositions that allow for more physician control over the
administration of these potent drugs so that individual patient
differences in susceptibility and metabolism can be take into
account.
Yet another advantage is the provision of uses and
compositions for drug administration to minimize the
psychological trauma qenerally
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9 133907~
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1 associated with injections and the adverse physical and
psychological problems often associated with the oral
administration of potent drugs.
Yet another advantage is the provision of methods and
5 compositions to permit a patient to control the amount of
medication administered according to the individual
variations in the susceptibility to the particular
medication used and in response to the patient's
subjective experience of pain or other biological
10 indicator-
DETAILED DESCRIPTION OF THE INVENTION
As discussed above, the present invention is directedto methods and compositions for use in the noninvasive
administration of antimigraine, antiemetic, hypoglycemic,
bronchodilator, oxytocic, anti-Parkinsonian, antidiuretic,
20 antifungal, or antisecretory agents. Advantageously, the
present invention permits exceptional control over the
effect of the drug administered, despite individual
susceptibility to and metabolism of that drug by the
patient.
While maintaining the convenience of oral administra-
tion, the present invention provides for many of the
advantages of the injection modality of drug administra-
tion. At the same time, the present invention avoids the
disadvantages identified above with respect to these two
30 traditional routes of administration. The present
invention achieves these results by utilizing yet a third
administration route -- absorption through the mucosal
tissues in the mouth and around the pharynx and esophagus.
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1 A very few drugs, such as nitroglycerin, have his-
torically been administered by absorption through ~ucous
tissue because the transmucosal route is faster tha~ oral
administration, and unlike injections can be easily self-
5 administered. While such drugs are easily given ~y 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; thereafter, the
10 administration process is modified or terminate~ By
contrast, the prior art has consistently utilized the
procedure of administering a bolus of the drug.
Despite some limited use, the transmucosal route has
not been favored for routine use. Instead, where ~ delay
15 in drug action is acceptable, the oral route has been
preferred by most physicians, and injections have been used
where delay is not acceptable.
Transmucosal dose-to-effect delivery of a drug is
somewhat slower to provide active concentrations of a drug
20 in a patient's system than is the use of an intravenous
injection. 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
25 of the patient) and by the ability to control the dose
received by the patient vis-a-vis the effect of the drug.
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 natu-
30 rally lipophilic or can be provided in a lipophilic form.
In accordance with the present invention, a suitable
v drug is dispersed within a carbohydrate mass, a compressed
powder form, or other suitable matrix in the form of a
lollipop.
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The drug-containing lollipop is then given to- a
10 patient to suck on so that the drug will be released into
the patient's mouth as the carbohydrate mass or compressed
powder matrix dissolves. ~ Being lipophilic, a significant
portion of the drug is absorbed into and/or through the
mucosal tissues of the mouth, pharyngeal, and esophageal
15 areas. The drug rapidly enters the patient's bloodstream,
and importantly, the blood in the veins draining from the
mouth and the pharyngeal and esophageal areas passes
through the central nervous system and then through a
substantial portion of the body (so that the drug can be
20 absorbed) before the blood passes through the liver (where
most of the drug is inactivated). In case of a localize
effect, the drug quickly contacts the affected area in
order to provide effective relieve as soon as possible,
while minimizing the amount of the drug administered to the
25 patient.
The use of a carbohydrate or compressed powder
matrix (i.e., "candy") to administer a drug offers some
important advantages, particularly when dealing with pedia-
tric patients. First, a candy lollipop is familiar and
30 lacks the menace of a syringe and needle. Being a
substance normally associated with pleasure, the drug-
containing candy lollipop immediately evokes a positive
psychological response.
... . . ..
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1 Importantly, it has been found that the use of drug-
containing candy in the form of a lollipop can permit the
physician to control the dosage of the drug administered to
the patient in order to relieve a migraine headache,
5 asthma, nausea, vomiting, or bronchospasm, or to induce
childbirth, increase urine output, relieve the effects of
Parkinson's disease, or treat systemic or oral fungal
infections, polyuria or gastric and duodenal ulcers,
thereby resulting in dose-to-effect drug administration.
10 Use of such drug-containing lollipops also permits the
patient in certain circumstances to exert control over the
dosage received of certain medication in order to diminish
feelings of discomfort or pain.
These important advantages are available because very
15 small amounts of a potent drug may be delivered to a
patient substantially continuously, and administration of
the drug may be halted at any time by simply removing the
candy from the patient's mouth. This not only allows a
physician to monitor a patient's condition so that a
20 particular effect is obtained and maintained, but also
provides the important safety benefit of reducing the risk
of overdose.
It is much less likely that a patient receiving
medication in accordance with the dose-to-effect method of
25 the present invention will become overdosed since the dose
builds relatively slowly until a desired effect is
achieved. Further, if a patient becomes slightly overdosed,
it is likely that the patient will stop sucking the drug-
containing lollipop and/or the physician or other medical
30 personnel will observe the situation and remove the
lollipop before the patient becomes seriously overdosed.
In contrast, once a typically large dose of a drug is
given orally, by injection, or even sublingually or
nasally, there is no retrieving it; thus, the full effects
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1 Of the administered drug will be felt. Further, a large
dose given every few hours results in wide swings in plasma
concentration of the drug, while the use of a lollipop in
accordance with the present invention evens out the plasma
5 concentration of that drug.
In practice, a physician can offer the patient a piece
of medicated candy on a holder, together with simple
instructions that the candy is to be sucked rather than
chewed. Children will particularly be put at ease by this
10 approach but so will anxious adults. The physician can
then monitor the patient's condition to ensure the desired
effect is achieved. If, for example, the drug-containing
candy contains oxytocin, the physician can monitor the
patient's uterine contractions during labor until a
15 suitable effect is achieved.
As mentioned above, it is preferred that the medicated
candy take the form of a lollipop. Use of a stick or other
suitable holder permits easy removal of the candy when a
physician deems that a patient has received a proper dosage
20 of the drug contained therein. Provision of a suitable
holder also facilitates intermittent administration of a
drug to maintain a desired condition and makes it more
convenient for a patient to intermittently self-administer
the drug in response to variations in the patient's subjec-
25 tive perception of physiologic condition.
The speed at which a sufficient amount of drug enters
the patient's bloodstream so as to produce a desired effect
depends on several factors. For example, a very potent
drug requires fewer drug molecules to enter the patient's
30 system than does a weak drug to produce a desired effect.
Accordingly, if rapid onset of bronchodilation is desired,
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
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1 highly lipophilic drug will result in the more rapid onset
of a desired patient response than will a more moderately
lipophilic drug. For example, ergotrate is a very potent
drug which is highly lipophilic. However, ergonovine is
5 nearly twice as lipophilic as ergotrate and thus is capable
of faster absorption. It will be appreciated, however,
that 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 oxytocin is not so lipophilic,
10 its other pharmacokinetic properties make it extremely fast
acting once it is absorbed into the bloodstream.
The choices 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
15 quickly will deliver drug into the patient's mouth for
absorption more quickly than a matrix that is slow to
dissolve. Similarly, a candy that contains a drug in a
high concentration will release more drug in a given period
of time than a candy 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 containing meclizine of a
25 given concentration may be used to relieve nausea, while a
lollipop having a stronger concentration (and preferably a
different color so as to prevent confusion) may be used
when it is desired to relieve vomiting or emesis.
Another use of these properties is to prepare a multi-
~0 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
~ -15- 1339075
1 effect and then use a different concentration to maintain
that effect.
The choice of a particular carbohydrate or compressed
powder matrix is subject to wide variation. Conventional
5 sweeteners such as sucrose or corn syrup may be utilized,
or carbohydrates suitable for use with diabetic patients,
such as sorbitol or mannitol might be employed. Other
sweeteners, such as aspartame, can also be easily
incorporated into a composition in accordance with the
10 present invention. The candy base may be very soft and
fast-dissolving, or may be hard and slower-dissolving.
Various forms will have advantages in different situations.
It will be appreciated that all suitable drugs within
the scope of the present invention~may be prepared in the
15 compressed powder form whereas only those drugs with
relatively high melting points may be prepared in the more
traditional hard candy form. It has been found that both
forms operate in substantially the same way. Typical
examples illustrating the method of preparing a hard candy
20 matrix and a compressed powder candy matrix are given
herein below.
EXAMPLE 1
The candy matrix or base for the drug-containing
25 lollipop within the scope of the present invention is
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
30 ~olution 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
is cooked at about 300~F to reduce the water content to
about three percent (3%). After recooling the thickened
-16- 1 3 3g 0 75
l candy mass to about 240~F, a suitable oil flavoring (e.q.,
lemon or cherry) is added.
Concurrently, a solution containing a soluable drug is
prepared for incorporation into a candy matrix. In this
S example, the drug selected is clotrimazole. Clotrimazole
is a potent antifungal agent useful in treating oral
candidiasis or monoliasis. Its high potency and
lipophilicity make it an excellent drug for transmucosal
administration in accordance with the present invention.
A suitable clotrimazole solution is prepared by
dissolving 200 milligrams of clotrimazole in lO cubic
centimeters of sterile ethanol. This clotrimazole solution
is mixed with 32 cubic centimeters of the hot candy mass
formed as set forth above, and the resultant mixture is
15 gently mixed as it cools to about 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
20 four inch commercially available wax-coated compressed
paper stick is next inserted into the base of each mold.
The mixture is then permitted to set.
The foregoing procedure results in the preparation of
lollipops, each containing 10 milligrams of
25 clotrimazole.
EXAMPLE 2
In this example, ergotamine is selected for incorpora-
tion into a compressed dosage form. Ergotamine is a potent
30 lipophilic drug useful for relieving the pain associated
with migraines. It high potency and lipophilicity make it
an excellent drug for transmucosal administration in
accordance with the present invention.
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1 A suitable matrix is prepared by combining 40 milli-
grams of ergotamine; 5.22 grams compressible sugar; 10.44
grams maltodextran; 300 milligrams ribotide, 400 milligrams
aspartame, 800 milligrams compritol 888, 1.0 grams
5 artificial vanilla cream, 200 milligrams natural mint; 600
milligrams cherry, and 1.0 grams artificial vanilla.
Alloquats of 2000 milligrams each are then hydraulically
compressed around a commercially available wax-coated
compressed paper holder, using a force sufficient to
10 provide a final volume of 2 cubic centimeters. The fore-
going procedure results in the preparation of 10 lollipops,
each containing 4 milligrams of ergotamine.
In addition to modifying the physical characteristics
of the lollipop, the technique used by the patient to
15 suck the lollipop may also be used to affect the rate of
the absorption of the drug. If substantial portions of
dissolved candy and drug are swallowed, the normal
complications of oral administration will be encountered
(i.e., slow response and loss of drug in the stomach and
20 liver).
If the candy 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
25 dissolves. It will be appreciated that the technique of
sucking utilized 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 or
pellet, helps control proper placement of the candy within
30 the patient's mouth since the physician, nurse, or even the
patient can manipulate the candy. Accordingly, the medical
professional can easily monitor placement by observation of
the angle of the protruding stick. Once a suitable tech-
~ -18- 1 339 o 7~
1 nique 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
5 antimigraine, antiemetic, hypoglycemic, bronchodilator,
oxytocic, anti-Parkinsonian, antidiuretic, antifungal, or
antisecretory agents. For example, the present invention
may be utilized in the administration of antimigraine
agents such as ergotamine, methysergide, propranolol, or
10 suloctidil; bronchodilators such as albuterol,
aminophylline, beclomethasone, dyphylline, epinephrine,
flunisolide, isoetharine, isoproterenol HCl,
metaproterenol, oxtriphylline, terbutaline, and
theophylline; oxytocic agents such as ergonovine and
15 oxytocin; anti-Parkinsonian agents such as carbidopa and
levodopa; antidiuretics such as desmopressin acetate,
lypressin, and vaspressin; antifungal agents such as
clotrimazole and nystatin; antisecretory agents such as
sucralfate; antiemetic agents such as benzquinamide,
20 meclizine, metoclopramide, prochlorperazine, and
trimethobenzamide; and hypoglycemic agents such as insulin.
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
25 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.
In 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 water
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1 solubility, its potency, and its end use, the total concen-
tration of the drug in a typical lollipop may contain from
one to fifty times the amount of the drug which may be used
in an in~ection.
However, for purposes of example, Table I sets forth
presently contemplated ranges of the dosages of certain
drugs which would typically be used.
Table I
Antiemetic
Drug Generic Lollipop Dose Range
Benzquinamide 25-100 milligrams
Meclizine 25-100 milligrams
Metoclopramide 5-20 milligrams
Prochlorperazine 5-25 milligrams
Trimethobenzamide 100-2500 milligrams
Antifunqal
Druq Generic Lollipop Dose Ranqe
Clotrimazole 10-20 milligrams
Nystatin 100,000-500,000 units
Anti-Parkinsonian
Drug Generic Lollipop Dose Range
Carbidopa with levodopa 10-50
milligrams
Levodopa 100-750 milligrams
-20- 13390 7~
Antisecretory
Drug Generic Lollipop Dose Range
Sucralfate 1-2 grams
Bronchodilator
Druq Generic Loll~ipop Dose Range
Albuterol 0.8-1.6 milligrams
Aminophylline 100-500 milligrams
Beclomethasone 20-50 micrograms
Dyphylline 100-400 milligrams
Epinephrine 200-500 micrograms
Flunisolide 25-50 micrograms
Isoetharine 170-680 micrograms
Isoproterenol HCl 60-260 micrograms
Metaproterenol 0.65-10 milligrams
Oxtriphylline 50-400 milligrams
Terbutaline 2.5-10 milligrams
Theophylline 50-400 milligrams
Antimigraine
Druq Generic Lollipop Dose Range
Ergotamine 2-4 milligrams
Methysergide 2-4 milligrams
Propranolol 80-160 milligrams
Suloctidil 200-300 milligrams
oxytOcic
Drug Generic Lollipop Dose Range
Ergonovine 0.2-0.6 milligrams
Oxytocin 5-20 units
_ -21- 1339~7~
Antidiuretic
Drug Generic Lollipop Dose Range
Desmopressin 10-50 micrograms
acetate
Lypressin 7-14 micrograms
Vaspressin 2.5-60 units
Hypoglycemic
Drug Generic Lollipop Dose Range
Insulin 5-20 units
It will be appreciated from the foregoing that the
15 present invention has broad applicability and will be
useful in a wide variety of situations. It provides a
useful alternative to the traditional oral and injection
routes of administration, and permits the physician
extraordinary control over the dosage of a potent
20 antimigraine, antiemetic, bronchodilator, oxytocic, anti-
Parkinsonian, antidiuretic, hypoglycemic, antifungal, or
antisecretory drug that is administered to a patient.
Some of the more important features and advantages of
the present invention as applied to the above drug classes
25 will be better appreciated and understood by reference to
the specific discussion below:
A. Antifungal Agents
Patients with compromised immunological function,
30 extended antibiotic therapy, or a severely debilitating
condition may experience systemic or oral fungal infec-
tions. Antifungal agents act by direct or intimate contact
with the fungal cell wall and therefore the activity or
effectiveness is directly proportional to the length of
~ -22- 1 339 o 7~
1 time of contact. The current topical methodology for oral
candidiasis (fungal infection) uses either a rinsing
solution or a troche (lozenge). Neither preparations
possess the necessary palatability to provoke effective
5 patient compliance. Consequently, they fail to eliminate
the oral fungal infection which unnecessarily extends the
patient's discomfort, pain, and period of therapy.
Furthermore, anoral fungal infection may ultimately result
in a life-threatening systemic fungal infection.
Alternatively, a lollipop containing an acceptably
flavored antifungal preparation such clotrimazole or
nystatin can be kept in the mouth for an extended period of
time before complete dissolution occurs. Patients that
require such oral antifungal therapy can be instructed to
lS use a drug-containing lollipop three times a day (versus
the current five to six times a day) and usually, until all
observed or perceived traces of the infection have
disappeared. In the event of a reappearance of the oral
fungal infection, therapy can be resumed.
There is a need for sustained or extended contact of
the antifungal agent, such as clotrimazole, with the fungal
organisms in order to bind with the phospholipids in the
fungal cell membrane and thereby alter the cell membrane
permeability, with subsequent loss of potassium and other
25 cellular constituents.
Dissolution of a palatable oral preparation over 30
minutes should inhibit most species of candida for up to 3
hours. The long term effective concentration of clotri-
mazole in saliva appears to be related to the slow release
30 of the drug from the oral mucosa to which the drug is
apparently bound.
Thus, a clotrimazole-containing lollipop is an ideal
mode of delivery, especially since patient compliance is
based on patient acceptance and patient compliance can be
_ -23- 133907~
1 directly translated into drug effectiveness. In current
practice, the admonition "use till the symptoms are
resolved" is questionable, as the candidiasis or monoliasis
may not be cured until the underlying cause is resolved.
5 This exposes the patient to a potentially life-threatening
systemic fungal infection.
The clotrimazole-containing lollipop provides quick
and effective treatment of an oral fungal infection.
Elimination of the fungus is significantly fast than under
10 present treatment methods. Therefore, the patient is not
subjected to more medication than is actually necessary to
treat the infection. Thus, dose-to-effect drug admini-
stration is achieved; the patient receives just enough
medication to eliminary the fungus and not any more than is
15 needed.
Examples of compositions and methods of using
lollipops containing anti-fungal agents are given herein
below.
EXAMPLE 3
A drug-containing lollipop within the scope of the
present invention to be used in the~treatment of oral can-
didiasis is made according to the procedure of Example 2,
except that the ingredients are combined in the following
25 amounts:
-
-24- 1 3 3go 75
1 Ingredient % grams
Clotrimazole 1.0% 0.2
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream 5.0% 1.0
Compressed sugar 25.83% 5.17
Maltodextrin 51.67% 10.33
10 The foregoing procedure results in the preparation of 10
lollipops, each containing 20 milligrams of clotrimazole.
EXAMPLE 4
In the procedure of this example, a patient who is
presently experiencing oral candidiasis is given a
clotrimazole-containing lollipop in order to rapidly
relieve the oral candidiasis. In this example,
20 clotrimazole in a lollipop dose of 20 milligrams is used.
As the patient sucks on the lollipop, regression of the
plaque within the oral cavity is observed.
Although the above discussion focused on the
antifungal agent clotrimazole, it will be appreciated that
other antifungal drugs may also be utilized within the
scope of the present invention. What is important is that
30 the antifungal drug be lipophilic, potent, and fast-acting
so that the desired effects can be observed by the medical
professional or by the patient himself, if the drug is to
be self-administered, in sufficient time to remove the
~ -25- ~ 33g o 7~
1 lollipop from the patient's mouth in time to prevent
overdosing.
5 B. Antisecretory Aqents
Reflux of small amounts of gastric juice into the
lower part of the esophagus is a common event. Its
frequency is increased by overindulgence. Whether or not
~ reflux occurs and whether it produces symptoms are
determined by three factors: (1) the competency of the
lower esophageal sphincter, the primary barrier to reflux;
(2) the irritant nature of the refluxed material; and (3)
the sensitivity of the esophageal mucosa to the refluxed
material. In the past, the symptoms of reflux were
attributed to inflammation of the esophagus, l.e.,
20 esophagitis. Today, it is clear that esophagitis is a
complication of severe reflux of acidic gastric juice
rather than being the cause of the symptoms associated with
reflux. It appears that the competency of the lower
25 esophageal sphincter correlates well with the presence or
absence of reflux.
Heartburn, the typical symptom of reflux, is charac-
terized by a burning epigastric or retrosternal pain which
30 spreads upward. Typically, heartburn appears after meals,
especially large meals, and is aggravated by bending over,
133907~
-26-
1 lying down, or straining. It is relieved by standing up or
drinking something, usually antacids.
In the treatment of esophagitis, the medication from
5 a swallowed tablet is expected to be refluxed up into the
esophagus and absorbed onto the eroded tissue. However,
aluminum sucrose sulfate (a minimally absorbed sulfated
disaccharide known as "sucralfate") is essentially
insoluble in water, and very little, if any, is refluxed
into the esophagus. Aluminum sucrose sulfate suspensions
are also used, but because the downward transit time is
very short, perhaps three seconds, they are barely more
effective than refluxed aluminum sucrose sulfate.
Furthermore, in the final phase of swallowing, the
esophagus is swept clean by a peristaltic wave proceeding
20 from the pharynx to the lower esophageal sphincter.
Consequently, neither mode of administration is effective
in delivering aluminum sucrose sulfate to the eroded tissue
areas.
Antisecretory agents such as aluminum sucrose sulfate
are used in the treatment of gastric and duodenal ulcers.
Although not as lipophilic as some of the other drugs
discussed herein, sucralfate exhibits a distinct and unique
30 preferrential absorbent action to the protein molecules in
damaged esophogeal, gastric, and duodenal mucosal wall
tissues. It forms an adherent and protective chemical
_ -27- 1339075
1 complex with proteins at the site of ulceration which
protects the ulcer from pepsin, acid, and bile. Sucralfate
also exhibits an ability to absorb bile acids.
The same regimen ta one-gram tablet swallowed four
times a day) is commonly used to treat esophagitis,
injection schlerosis, and gastroesophageal reflux.
A drug-containing lollipop in accordance with the
present invention may effectively treat gastric and
duodenal ulcers, as well as esophagitis, injections
schlerosis, and gastroesophageal reflux. This modality
provides for the gradual dissolution of the agent (aluminum
sucrose sulfate), mixed with, and aided by, the viscosity
of the saliva, allowing it to slowly but constantly trickle
down the esophagus, and thereby allowing for the adhesion
20 to the eroded tissue. The effectiveness of the therapy can
be symptomatically assessed and controlled by the patient
thereby providing dose-to-effect modality.
Examples of compositions and methods of using
25 lollipops containing antisecretory agents are given herein
below.
EXAMPLE 5
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
symptoms of esophagitis is made according to the procedure
1339075
-28-
l of Example 2, except that the ingredients are combined in
the following amounts:
Ingredient % qrams
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream5.0% 1.0
Compressed sugar 9.5% 1.9
Maltodextrin 19.0% 3.8
Al. sucrose sulfate 50.0% 10.0
The foregoing procedure results in the preparation of 10
15 lollipops, each containing 1 gram of aluminum sucrose
sulfate.
EXAMPLE 6
In the procedure of this example, a patient who is
presently experiencing the symptoms of esophagitis is given
an aluminum sucrose sulfate-containing lollipop in order to
rapidly relieve the symptoms of esophagitis. In this
example, aluminum sucrose sulfate in a lollipop dose of 1.0
gram is used. As the patient sucks on the lollipop, the
pain associated with esophagitis or heartburn is rapidly
30 relieved.
Although the above discussion focused on the anti-
secretory agent aluminum sucrose sulfate as a treatment for
esophagitis or heartburn, it will be appreciated that other
_ -29- 133907~
1 antisecretory drugs may also be utilized within the scope
of the present invention. What is important is that the
antisecretory agent be lipophilic, potent, and fast-acting
5 so that the desired effects can be observed by the medical
professional or by the patient himself, if the drug is to
be self-administered, in sufficient time to remove the
lollipop from the patient's mouth in time to prevent
overdosing.
C. Bronchodilator Aqents
Respiratory smooth muscle relaxants are used to
produce relief of bronchospasm and increase respiratory
flow rates and vital capacity. Theophylline is a typical
bronchodilator commonly used for the symptomatic treatment
20 ~f asthma and reversible bronchospasm that may occur in
association with chronic bronchitis or emphysema.
Following oral administration of theophylline capsules
or uncoated tablets, peak serum concentrations are usually
25 reached in one to two hours. Peak serum theophylline
concentrations are usually obtained after about one hour
when theophylline oral solutions or microcrystalline
tablets are administered. Absorption of theophyllines may
30 be delayed, but generally not reduced, by the presence of
food in the gastrointestinal tract. When administered
intramuscularly, theophylline is usually absorbed slowly
13390~
-30-
l and incompletely. In addition, rectal suppositories are
slowly and erratically absorbed.
In maintenance-dose theophylline schedules, serum
5 concentrations among patients vary at least six-fold and
serum half-lives exhibit wide interpatient variation
because of differences in the rate of metabolism. (The
elimination half-life is the time required for the plasma
drug concentration to decrease by one-half.) Serum half-
life ranges from about 3 to 12.8 (average 7-9 hours) in
otherwise healthy, nonsmoking asthmatic adults, from about
1.5 to 9.5 hours in children, and from about 15 to 58 hours
in premature infants.
When compared with that of otherwise healthy
nonsmoking asthmatic adults, the serum half-life of
20 theophylline may be increased and total body clearance
decreased in patients with congestive heart failure,
chronic obstructive pulmonary disease, cor pulmonale, or
liver disease, and in geriatric patients. In cigarette
25 and/or marijuana smokers, theophylline serum half-life
averages 4-5 hours and total body clearance is increased
compared with nonsmokers.
Therefore, due to the wide variation in patient
metabolism of theophylline to administer to proper dose
required by each patient. Too much theophylline may result
in nausea, vomiting, headache, nervousness, seizures, sinus
- -31- 13 3gO 7S
tachycardia, hypotension, circulatory failure or
ventricular arrhythmias. If insufficient theophylline is
administered, the respiratory distress continues, which can
be as serious as receiving an overdose.
Hence, a theophylline-containing lollipop administered
in a dose-to-effect manner would be capable of providing
rapid relief of asthma or bronchospasm associated with
respiratory distress. The precise dosage necessary to
achieve a precise effect in each individual patient could
be provided thereby substantially reducing the risk of
severe consequences associated with an underdose or
overdose. Thus, the wide variation in -the rate of
metabolism from patient to patient would be accounted for
by the dose-to-effect modality.
Examples of compositions and methods of using
lollipops containing bronchodilator agents are given herein
below.
EXAMPLE 7
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of
respiratory distress is made accordlng to the procedure of
Example 2, except that the ingredients are combined in the
following amounts:
~ -32- ~ 33g 0 7~
Inq,redient % qrams
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 - 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream5.0% 1.0
Oxtriphylline 10.0% 2.0
Compressed sugar 22.83% 4.57
Maltodextrin 45.67% 9.13
The foregoing procedure results in the preparation of 10
lollipops, each containing 200 milligrams of oxtriphylline.
EXAMPLE 8
In the procedure of this example, a patient who is
presently experiencing the respiratory distress is given an
oxtriphylline-containing lollipop in order to rapidly
relieve the respiratory distress. In this example, oxtri-
phylline in a lollipop dose of 200 milligrams is~used. As
the patient sucks on the lollipop, the symptoms of respira-
tory distress are rapidly relieved and the patient returnsto more normal respiratory function.
EXAMPLE 9
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of
respiratory distress is made according to the procedure of
Example 1, except that an oxtriphylline solution, in which
~33907S
_ -33-
4 grams of oxtriphylline is dissolved in 10 cubic
centimeters of water, is substituted for the clotrimazole
solution. This procedure results in the preparation of 20
lollipops, each containing 200 milligrams of oxtriphylline.
Although the above discussion focused on the bron-
chodilators theophylline and oxtryphilline, it will be
appreciated that other bronchodilators may also be utilizedwithin the scope of the present invention. What is impor-
tant is that the bronchodilator be lipophilic, potent, and
fast-acting so that the desired effects can be observed by
the medical professional or by the patient himself, if the
drug is to be self-administered, in sufficient time to
remove the lollipop from the patient's mouth in time to
prevent overdosing.
D. Antimiqraine Agents
Migraines refer to sudden periodic attacks of
throbbing headaches which begin in childhood, adolescence,
or early adult life and continue to reoccur with
diminishing frequency during advancing years. A migraine
may last from about five minutes to fifteen minutes,
_ _34_ 1 3390 75
followed by hemicranial headache, nausea, and vomiting, all
of which last for hours or as long as a day or two.
The drug ergotamine provides symptomatic relief from
the pain of a migraine. Ergotamine is usually administered
orally or sublingually, 2 milligrams taken as soon as the
headache starts, with subsequent doses of 2 milligrams at
intervals of 30 minutes thereafter, if necessary, until a
total of 6 milligrams has been taken. No more than 10
milligrams should be ingested per week. Since overdosage
is the chief cause of untoward effects from ergotamine, the
smallest amount effective for relief of the headache should
be employed.
The speed and thoroughness of the relief from pain are
directly proportional to the promptness with which medica-
tion is started after the onset of an attack. If the drug
is given early, the dose may be decreased considerably.
But if the headache has reached its peak, large quantities
of ergotamine are needed. Not only is a longer time than
required for effective action needed, but also undesirable
side effects from this medication are more pronounced.
An ergotamine-containing lollipop administered in a
dose-to-effect manner provides the precise dosage necessary
_ _35_ 1339075
1 to obtain rapid symptomatic relief from migraine pain while
at the same time minimizing potential side effects.
Examples of compositions and methods of using
5 lollipops containing antimigraine agents are given herein
below.
EXAMPLE 10
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of a migraine
is made according to the procedure of Example 2, except
that the ingredients are combined in the following amounts:
Ingredient % qrams
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Propranolol 4.0% 0.8
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream5.0% 1.0
Compressed sugar 25.33% 5.07
Maltodextrin 50.67% 10.13
The foregoing procedure results in the preparation of 10
lollipops, each containing 80 milligrams of propranolol.
EXAMPLE 11
In the procedure of this example, a patient who is
presently experiencing the pain associated with a migraine
- -36- 1 33go 7~
1 is given an ergatomine-containing lollipop in order to
rapidly relieve the pain associated with the migraine. In
this example, ergotamine in a lollipop dose of 4 milligrams
5 is used. As the patient sucks on the lollipop, the pain
associated with the migraine is rapidly relieved.
Although the above discussion focused on the anti-
migraine agents ergotamine and propranolol, it will be
appreciated that other antimigraine agents may also be
utilized within the scope of the present invention. What
is important is that the antimigraine agent be lipophilic,
potent, and fast-acting so that the desired effects can be
observed by the medical professional or by the patient
himself, if the drug is to be self-administered, in
sufficient time to remove the lollipop from the patient's
20 mouth in time to prevent overdosing.
E. Antiemetic Agents
Nausea and vomiting may occur independently of each
25 other, but generally they are so closely related that they
can be considered together. Nausea denotes the feeling of
the imminent desire to vomit, while vomiting refers to the
forceful oral expulsion of gastric contents. Nausea often
30 precedes or accompanies vomiting and is usually associated
with diminished functional activity of the stomach and
alterations of the motility of the duodenum and small
_ _37- 133907~
1 intestine. Increased perspiration, salivation, and the
occasional association of hypotension and bradycardia often
accompanies severe nausea.
S The stomach plays a relatively passive role in the
vomiting process, the major ejection force being provided
by the abdominal musculature. Repeated emesis (vomiting)
may have deleterious effects in a number of ways. The
process of vomiting itself may lead to traumatic rupture or
tearing of the region of the cardioesophageal junction,
resulting in massive hematemesis (the vomiting of blood).
Prolonged vomiting may also lead to dehydration and
the loss of gastric secretions, particularly hydrochloric
acid, and metabolic alkalosis and th~e potentially dangerous
loss of potassium. In states of central nervous system
20 depression, such as coma, the gastric contents may actually
be aspirated into the lungs, with a resulting aspiration
pneumonitis.
The act of vomiting is under the control of two func-
25 tionally distinct medullary (central nervous system)
centers: the vomiting center and the chemoreceptor zone.
The vomiting center controls and integrates the actual act
of emesis, receiving stimuli from the intestinal tract, the
labyrinthine apparatus in the ear, the chemoreceptor zone
and other parts of the body. The~ chemoreceptor trigger
zone is also located in the medulla. Activation of this
~ -38- 1 339 0 7~
1 zone initiates impulses to the medullary vomiting center
which then initiates the act of emesis. The chemoreceptor
trigger zone can be activated by many stimuli, including
5 drugs such as morphine, codeine, cardiac glycocides
(digoxin) and ergot alkaloids (ergotamine) and a great many
antineoplastic agents. Nausea and vomiting are common
manifestations of organic and functional disorders.
Table II provides examples of many disorders which may
be accompanied by nausea and vomiting.
Table II
1. acute abdominal emergencies (i.e., acute appendicitis,
cholecystitis)
2. chronic indigestion
20 3 acute infectious diseases accompanied with fever,
especlally ln young chlldren
4. disorders of the nervous system,~especially the central
nervous system
5. heart diseases such as acute myocardial infarction,
especially of the posterior wall of the heart
6. metabolic and endocrine disorders, including diabetic
acidosis
7. drugs and chemicals
8. emotional stress may lead to psychogenic vomiting
As described above, nausea and subsequent vomiting is
not only an undesirable sensation, it can be severely debi-
litating and even life threatening in some cases. There
_ _39_ 1~3907~
are currently only three modalities used to deliver the
drugs to ameliorate nausea and vomiting. These are oral
(tablets or liquids), intramuscular or intravenous
injection, and rectal.
For rapid onset of antiemetic action, the
intramuscular or intravenous route is preferred. But it is
only rarely available outside of medical facilities, and
even then, being an injection, it is the least appealing.
The rectal route can be effective, but it is unpredictable
at best, due to the variability and placement of the
15 suppository and subsequent rapid liver metabolism. The
oral route is the easiest, but as is usually the case, the
antiemetic agent in tablet or solution is expectorated with
the emesis before dissolution or absorption can take place.
A lollipop into which a suitable antiemetic agent has
been dispersed when administered in a dose-to-effect manner
provides a delivery method superior to current methods.
Transmucosal administration provides for absorption of the
antiemetic agent almost as fast as by the intravenous
route. Having a handle, an antiemetic-containing lollipop
may be quickly removed from the mouth in the case of
unanticipated emesis. Further, transmucosal administration
bypasses immediate hepatic metabolism which occurs with
oral administration. More importantly, the antiemetic
agent cannot be expectorated during transmucosal
13390~
-40-
administration, which usually occurs after oral ingestion
of an antiemetic agent. Finally, a drug-containing
lollipop administered in a dose-to-effect manner is a
highly acceptable mode of delivery.
Examples of compositions and methods of using
lollipops containing antiemetic agents are given herein
below.
EXAMPLE 12
A drug-containing lollipop within the scope of the
15 present invention to be used in the treatment of nausea and
vomiting is made according to the procedure of Example 2,
except that the ingredients are combined in the following
amounts:
Ingredient % grams
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Meclizine 2.5% 0.5
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream5.0% 1.0
Compressed sugar 25.33% 5.07
Maltodextrin 50.67% 10.13
3 The foregoing procedure results in the preparation of 10
lollipops, each containing 50 milligrams of meclizine.
_ -41- 133907~
EXAMPLE 13
In the procedure of this example, a patient who is
presently experiencing nausea and vomiting is given a
meclizine-containing lollipop in order to rapidly relieve
the nausea and vomiting. In this example, meclizine in a
lollipop dose of 50 milligrams is used. As the patient
sucks on the lollipop, the distress associated with nausea
and vomiting is eliminated.
Although the above discussion focused on the
antiemetic agent meclizine, it will be appreciated that
15 other antiemetic agents may also be utilized within the
scope of the present invention. What is important is that
the antiemetic agent be lipophilic, potent, and fast-acting
so that the desired effects can be observed by the medical
20 professional or by the patient himself, if the drug is to
be self-administered, in sufficient time to remove the
lollipop from the patient's mouth in time to prevent
overdosing.
F. Antidiuretic Agents
Diabetes insipidus is a chronic symptom complex
characterized by the passage of large quantities of pale,
dilute urine with secondary excessive thirst. It results
from a defect in a chain of events by which vasopressin is
released from the neurohypophysis (the posterior part of
-42- 133907~
the pituitary gland) and acts on the cells of the renal
tubules. Diabetes insipidus was a rare disease, but with
the advent of hypophysectomy in recent years for the treat-
ment of far-advanced breast cancer and other serious dis-
orders, the disease is becoming much more prevalent in the
general hospital population.
The chief symptoms of diabetes insipidus are exces-
sive production of urine (polyuria) and excessive thirst.
The loss of large quantities of pale, dilute urine, occa-
sionally as much as 15-29 liters per day, results in
15 dehydration and consequently, such related symptoms as dry
skin, constipation, and an intense, almost insatiable
thirst. Water deprivation to the limit of tolerance does
not prevent polyuria. No consistent physical or chemical
20 changes are noted other than those of dehydration and low
urine specific gravity. However, there may be symptoms
referable to the localized disease process causing the
syndrome.
The role of trauma in the production of diabetes
insipidus deserve special comment, since the polyuria that
sometimes follows head injury is frequently transient, in
contrast with the chronicity of most other forms of the
disease. A similar syndrome may develop subsequent to
cerebrovascular accidents or intracranial surgery and in
association with other forms of cerebral disease. When the
~43~ 1335075
full-blown syndrome develops under these conditions,
serious dehydration may occur before the diagnosis is
suspected.
Treatment of diabetes insipidus may be divided into
two phases: (1) correction of the underlying intracranial
difficulty, if present; and (2) replacement therapy with
vasopressin, which usually must be continued throughout
life. Current treatment consists of intranasal admini-
stration of desmopressin acetate or lypressin.
Desmopressin acetate or lypressin solution should be
15 administered intranasally with care to insure that the drug
is deposited high in the nasal cavity and yet-does not pass
either down the throat or too high into the sinuses.
Although intranasal administration of the drug is preferred
20 for chronic therapy, parenteral administration of the drug
may be necessary when other factors make nasal administra-
tion ineffective or inappropriate. Such factors may
include poor intranasal absorption, nasal congestion and
blockage, nasal discharge, atrophy of nasal mucosa, and
severe atrophic rhinitis. In addition, parenteral
administration is also necessary when the patient has an
impaired level of consciousness, during recovery from
surgery, or when nasal packing is present.
7 The lowest effective intranasal or parenteral dosage
sho,uld always be given. Adverse effects of this nasal
_44_ 1 3 3~ 0 75
delivery system include rhinorrhea, nasal congestion,
irritation with a burning sensation, and pruritus of the
nasal passages, nasal ulceration, headache, and dizziness.
A lollipop into which a suitable antidiuretic has
been dispersed administered in a dose-to-effect manner
provides an ideal method for treating polyuria. In
particular, an antidiuretic-containing lollipop
administered in a dose-to-effect manner rapidly introduces
the antidiuretic into the bloodstream yet avoids the
inconvenience and adverse consequences associated with
15 nasal delivery.
Dose-to-effect administration permits the patient to
receive just enough of the antidiuretic to decrease the
patient's urine output while avoiding an overdose with its
20 serious side effects.
Examples of compositions and methods of using
lollipops containing antidiuretic agents are given herein
below.
EXAMPLE 14
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
symptoms associated with polyuria is made according to the
7 procedure of Example 2, except that the ingredients are
combined in the following amounts:
~_ _45_ 1339075
Ingredient % grams
Desmopressin o.ool 0.0002
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream 5.0% 1.0
Compressed sugar 26.17% 5.234
Maltodextrin 52.33% 10.47
10 The foregoing procedure results in the preparation of 10
lollipops, each containing 20 micrograms of desmopressin.
EXAMPLE 15
In the procedure of this example, a patient who is
presently experiencing the symptoms of polyurea is given a
desmopressin-containing lollipop in order to rapidly
relieve the symptoms of polyuria. In this example,
desmopressin in a lollipop dose of 20 micrograms is used.
As the patient sucks on the lollipop, a rapid decrease in
urine output is observed.
Although the above discussion focused on the
antidiuretics desmopressin and lypressin, it will be
appreciated that other antidiuretic drugs may also be
utilized within the scope of the present invention. What
is important is that the antidiuretic drug be lipophilic,
potent, and fast-acting so that the desired effects can be
observed by the medical professional or by the patient
himself, if the drug is to be self-administered, in
~339073
-46-
sufficient time to remove the lollipop from the patient's
mouth in time to prevent overdosing.
G. Anti-Parkinsonian Agents
The therapeutic management of Parkinson's disease is
a complex problem in which drug therapy plays a major role.
In Parkinson's disease, the lenticular nuclei and globus
pallidus have a reduced content of dopamine, serotonin, and
norepinepherine. The quantity of L-dopa (levodopa) in the
striatum and substantia nigra is also decreased, lending
15 support to the idea that Parkinson's disease is a disorder
of a particular neuronal (central nervous system) system.
In its fully developed form, Parkinson's disease
cannot be mistaken for any other. The victim exhibits
20 stooped posture, stiffness and slowness of movement, a
fixed facial expression, and rhythmic tremor of the limbs
which subsides on active willed movement or complete
relaxation.
Also typical are more or less general hypokinesia
(slow reflexes) and stiffness of the musculature. Even
where tremor is inapparent, the disease may still be
3 indicated by a staring and immobile facial expression, a
monotonous voice, a general slowness and decrease of all
motor activity, and a curious lack of the little
-47- 1 339~ 75
spontaneous movements of postural change that are
characteristic of the normal individual.
When tremor is minimal, patients often are able to
alleviate it by resting their hands on a table or on the
arms of a chair or by keeping them in their pockets. The
tremor is generally most pronounced in the hands but may
involve also the legs, lips, tongue, and neck muscles, and
is easily seen in the eyelids when they are lightly closed.
There is no total paralysis, although general
enfeeblement of voluntary movement is characteristic of the
15 fully developed disorder. Together with the stooped
attitude, there is the typical gait, whereby the patient,
prevented by the abnormality of postural tone from making
the appropriate reflex adjustments required for effective
20 walking, progresses with the quick, shuffling steps at an
excellerating pace as if to catch up with the center of
gravity. Intellectual deterioration is not a consistent
feature of Parkinsonism, but it must be conceded that in
the very advanced stages of the condition, dementia may be
encountered.
Although there is no treatment that is known to halt
or reverse the neuronal degeneration that presumably
underlies Parkinson's disease, current methods do attempt
to bring about a considerable degree of relief from
symptoms in many patients.
~_ -48- 1 339 0 75
At the present, levodopa is unquestionably the most
effective method available. Although rapidly absorbed from
the gastrointestinal tract, less than one percent of
absorbed levodopa penetrates into the central nervous
system (the site of action) where it is converted to
dopamine (which does not cross the blood-brain barrier).
It is then metabolized such that 85% of the dose is
excreted as dopamine metabolites in the urine within 24
hours. The plasma half-life of levodopa is approximately
one hour.
The adverse reactions are usually dose-related and
included: nausea, vomiting, involuntary movement, gastro-
intestinal bleeding, duodenal ulcers, epigastric abdominal
distress, and mild to severe central nervous system
20 disturbances. The dosage requirement of levodopa can be
reduced with simultaneous adminis~tration of carbidopa.
Levodopa, with or without carbidopa, completely or
partially relieves akinesia, rigidity, and tremor in about
80% of patients treated.
Akinesia paradoxica, a sudden hypnotic freezing in
which the patient frequently falls because he becomes
30 akinetic just as he starts to walk, may be relieved by
reducing the dosage of levodopa. Although the cause of
r these episodes has not been precisely determined, it
appears that they may result from a combination of
_ _49_ 133907~
progression of the disease and excessive levodopa dosage.
The "on-off" phenomenon is a sudden loss of effective-
ness of levodopa with an abrupt onset of akinesia ("off"
effect) which may last from one minute to an hour, followed
by an equally sudden return to effectiveness ("on" effect);
this may occur many times daily. At present, this can
occasionally be minimized by increasing the number of doses
per day.
A levodopa-containing lollipop administered in a dose-
to-effect manner reduces the total dose of levodopa
15 required and minimizes related side effects. In addition,
a lower but effective dose of levodopa can protect against
potentially compromised renal and hepatic functions,
particularly in the geriatric patient. Furthermore, the
20 patient can be instructed to optimally utilize the dose-to-
effect modality in order to avoid the "on-off" effect, or
use the dose-to-effect modality during the "on-off"
experiences.
Examples illustrating compositions and methods of
using lollipops containing levodopa and carbidopa are given
herein below.
EXAMPLE 16
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
~ -50- 13390 75
symptoms of Parkinson's disease is made according to the
procedure of Example 2, except that the ingredients are
combined in the following amounts:
Ingredient % grams
Natural mint 1.0% 0.2
Carbidopa 1.25% 0.25
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream 5.0% 1.0
Levodopa 12.5% 2.5
Compressed sugar 21.58% 4.32
Maltodextrin 43.17% 8.63
The foregoing procedure results in the preparation of 10
lollipops, each containing 25 milligrams of carbidopa and
250 milligrams of levodopa.
EXAMPLE 17
In the procedure of this example, a patient who is
presently inflicted with Parkinson's disease is given a
25 levodopa/carbidopa-containing lollipop in order to rapidly
relieve the symptoms of Parkinson's disease. In this
example, levodopa in a lollipop dose of 250 milligrams and
carbidopa in a lollipop dose of 25 milligrams is used. As
30 the patient sucks on the lollipop, the symptoms associated
with Parkinson's disease are rapidly reduced.
-51- 1~3907~
Although the above discussion focused on the anti-
Parkinsonian drugs levodopa and carbidopa, it will be
appreciated that other anti-Parkinsonian drugs may also be
utilized within the scope of the present invention. What
is important is that the anti-Parkinsonian drug be
lipophilic, potent, and fast-acting so that the desired
effects can be observed by the medical professional or by
the patient himself, if the drug is to be self-
administered, in sufficient time to remove the lollipop
from the patient's mouth in time to prevent overdosing.
H. oxYtocic Aqents
The dramatic effect of ergot (a drug obtained from a
species of rye fungus) ingested during pregnancy has been
20 recognized for over two thousand years, and it was first
used by physicians as an oxytocic agents almost four
hundred years ago. All the natural alkaloids of ergot
markedly increase the motor activity of the uterus. The
character of the changes elicited is related to the dose
administered. After small doses, contractions are
increased in force or frequency, or both, but are followed
by a normal degree of relaxation. After larger doses,
contractions become forceful and prolonged and resting
tonus is increased. Very high doses can cause sustained
contracture.
-52- 133907~
The sensitivity of the uterus to ergot alkaloids
varies, especially with the degree of maturity and the
stage of gestation, but even an immature uterus is
stimulated. The gravid uterus, however, is very sensitive.
Even small doses of ergot alkaloids can be given at term or
immediately post partum to obtain a marked uterine
response. The mechanism of activation is one of direct
stimulation.
All natural ergot alkaloids have qualitatively the
same effect on the uterus, but they exhibit important
15 differences in potency. Ergonovine is the most active of
all. Among the amino acid alkaloids, ergotamine is by far
the most potent. However, when ergotamine is used
clinically, there is an appreciable latent period between
20 its intravenous administration and the onset of uterine
activity. This is not true for ergonovine, which manifests
its activity almost immediately. Furthermore, ergonovine
is active after oral administration, whereas ergotamine is
not. Finally, ergonovine is much less toxic than
ergotamine.
Oxytocin is an octapeptide hormone secreted by the
30 neurons of the supraoptic and paraventricular nuclei of the
hypothalamus and is stored in the posterior pituitary
(neurohypophysis) in mammals. Oxytocin indirectly stimu-
_ _53_ ~3~307~
lates contraction of uterine smooth muscle by increasingthe sodium permeability of uterine myofibrils.
Uterine response to oxytocin increases with the dura-
tion of pregnancy and is greater in patients who are in
labor than in those not in labor. Only very large doses
elicit contractions in early pregnancy. Contractions
produced in the term uterus by oxytocin are similar to
those occurring during spontaneous labor. In the term
uterus, oxytocin increases the amplitude and frequency of
uterine contractions which in turn tends to decrease
15 cervical activity producing dilation and effacemeht of the
cervix and also tends to transiently impede-uterine blood
flow. In addition oxytocin contracts myoepithelial cells
surrounding the alveoli of the breasts, forcing milk from
20 the alveoli into the larger ducts and thus facilitating
milk ejection. Oxytocin is destroyed by chymotrypsin in
the gastrointestinal tract.
Uterine response occurs almost immediately and
subsides within one hour following intravenous administra-
tion of oxytocin. Following intramuscular injection of the
drug, uterine response occurs within three to five minutes
30 and persists for two to three hours. Following intranasal
application of oxytocin, contractions of the myoepithelial
tissue surrounding the alveoli of the breasts begin within
a few minutes and continue for twenty minutes. Intravenous
_ _54- 1339 0 73
oxytocin produces the same effect as intranasal oxytocin,
but with a dose one hundred times less. Intranasal
oxytocin may also be of some value in cases of post partum
breast engorgement. Oxytocin has a plasma half-life of
about three to five minutes, since most of the drug is
rapidly destroyed in the liver and kidneys. Only small
amounts of oxytocin are excreted in the urine unchanged.
Incorporating an oxytocic drug into a lollipop for
transmucosal dose-to-effect administration can be used to
produce controlled contractions of the uterus for the
15 induction of labor. The drug-containing lollipop could
also augment contractions if labor is prolonged during the
first and second stages of labor, or it may be used to
shorten the third stage of labor immediately following
20 delivery of the infant.
Importantly, the drug-containing lollipop administered
in a dose-to-effect manner would provide just enough
oxytocic agent at critical stages of labor to facilitate
proper childbirth. Too much oxytocic agent could be
dangerous to both mother and child.
Examples of compositions and methods of using
lollipops containing oxytocic agents are given herein
below.
EXAMPLE 18
_ _55- 1339~7~
A drug-containing lollipop within the scope of the
present invention to be used in order to induce labor or
reduce postpartum hemorrhage is made according to the
procedure of Example 2, except that the ingredients are
combined in the following amounts:
Ingredient % qrams
Oxytocin 0.001% 0.0002
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% 1.0
Artificial vanilla cream 5.0% 1.0
Compressed sugar 26.17% 5.234
Maltodextrin 52.33% 10.466
The foregoing procedure results in the preparation of 10
lollipops, each containing 20 micrograms of oxytocin.
EXAMPLE 19
In the procedure of this example, a patient is given
an oxytocin-containing lollipop in order to induce labor or
induce postpartum hemorrhage. In this example, oxytocin in
a lollipop dose of 20 micrograms is used. As the patient
sucks on the lollipop, labor is induced or pospartum
hemorrhaging is stopped.
Although the above discussion focused on the oxytocic
agents ergonovine and oxytocin, it will be appreciated that
other oxytocic drugs may also be utilized within the scope
_ -56- 1339075
of the present invention. What is important is that the
oxytocic drug be lipophilic, potent, and fast-acting so
that the desired effects can be observed by the medical
professional or by the patient himself, if the drug is to
be self-administered, in sufficient time to remove the
lollipop from the patient's mouth in time to prevent
overdosing.
G. Hypoglycemic Agents
Insulin is a hormone produced by the beta cells of the
15 pancreatic Islets of Langerhans. The diabetic syndrome is
characterized by an absolute or relative lack of
circulating insulin. It develops as a consequence of in
imbalance between insulin production and release on the one
20 hand, and hormonal or tissue factors modifying the insulin
requirement on the other hand. Insulin is absolutely
lacking in those forms of secondary diabetes in which
destruction or removal of the pancreas has taken place.
Similarly, overt growth-onset diabetes is characterized by
insulin deficiency. Regardless of the type of diabetes, by
definition the cardinal sign is hyperglycemia, frequently
associated with glycosuria (glucose in the urine).
Exogenous insulin elicits all the pharmacological
responses usually produced by endogenous insulin. Insulin
stimulates carbohydrate metabolism in skeletal and cardiac
-
-57~ 133907~
muscle and adipose tissue by facilitating transport of
glucose into these cells. In the liver, insulin
facilitates phosphorylation of glucose to glucose-D6-
phosphate which is converted to glycogen or further
metabolized.
Insulin also has a direct effect on fat and protein
metabolism. The hormone stimulates lipogenesis and
inhibits lipolysis and releases the free fatty acids from
disposed cells. Insulin also stimulates protein synthesis.
In addition, insulin promotes an intracellular shift of
15 potassium and magnesium, thereby temporarily décreasing
elevated blood concentrations of these ions.
Administration of suitable doses of insulin to
patients with insulin-dependent (type 1) diabetes mellitus
20 temporarily restores their ability to metabolize
carbohydrates, fats, and proteins, to store glucose in the
liver, and to convert glycogen to fat. When insulin is
given in suitable doses at regular intervals to a patient
with diabetes mellitus, blood glucose is maintained at a
reasonable concentration, the urine remains relatively free
of glucose and ketone bodies and diabetic acidosis and coma
30 are prevented.
Because of its protein nature, insulin is destroyed
in the gastrointestinal tract and must be administered
parenterally. Following subcutaneous or intramuscular
1333075
-58-
administration, insulin is absorbed directly into the
blood. The rate of absorption depends on many factors,
including the route of administration, site of injection,
volume and concentration of the injection, and the type of
insul in .
Hyperinsulinism, resulting in hypoglycemia, may occur
in patients with brittle diabetes or in patients who have
received an overdose of insulin, a decreased or delayed
food intake, or an excess amount of exercise in relation to
the insulin dose. Mild hypoglycemia may be relieved by
15 oral administration of carbohydrates such as orange juice.
Insulin is usually administered by subcutaneous injection
and is preferred to intramuscular administration because it
provides more prolonged absorption and is less painful.
An insulin-containing lollipop within the scope of the
present invention would be capable of rapid action and
would provide a precise dosage necessary to lower the blood
glucose level in every patient. Importantly, the insulin
could be delivered painlessly without the need of multiple
daily injections.
Furthermore, if administered after a meal, the insulin
30 level could reach a peak level within approximately fifteen
minutes and then slowly diminish over the next hour, anala-
gous to the normal physiological response to rising blood
sugar levels following a meal.
_59_ ~ 1~39~75
With the recent advent of noninvasive continuous
monitoring of blood glucose level, the precise insulin dose
necessary to normalize the patient's blood glucose level
may be given. Thus, the serious risk of hypoglycemia or
hyperglycemia can be avoided.
Examples of compositions and methods of using
lollipops containing hypoglycemic agents are given herein
below.
EXAMPLE 20 o
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
symptoms associated with diabetes is made according to the
procedure of Example 2, except that the ingredients are
20 combined in the following amounts:
Ingredient % grams
Insulin 0.05% O.O1
Natural mint 1.0% 0.2
Ribotide 1.5% 0.3
Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla 5.0% l.O
Artificial vanilla cream . 5.0% l.O
Compressed sugar 26.15% 5.23
Maltodextrin 52.3% 10.46
The foregoing procedure results in the preparation of lO
lollipops, each containing the equivalent of 30 units of
insulin.
-60- 1 3 390 7
EXAMPLE 21
In the procedure of this example, a patient who is
presently experiencing the symptoms of diabetes is given an
insulin-containing lollipop in order to rapidly relieve the
achieve a more normal blood glucose level. In this
example, insulin in a lollipop dose of 1 milligram, equal
to about 30 units, is used. As the patient sucks on the
lollipop, the patient's blood sugar level normalizes.
Although the above discussion focused on the hypogly-
15 cemic agent insulin, it will be appreciated that otherhypoglycemic drugs may also be utilized within the scope of
the present invention. What is important is that the
hypoglycemic drug be lipophilic, potent, and fast-acting so
20 that the desired effects can be observed by the medical
professional or by the patient himself, if the drug is to
be self-administered, in sufficient time to remove the
lollipop from the patient's mouth in time to prevent
overdosing.
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
which that dose is given.
-61-
133907~
The use of a drug-containing lollipop for admini-
stration of antimigraine, antiemetic, bronchodilator,
oxytocic, anti-Parkinsonian, antidiuretic, hypoglycemic,
antifungal, or antisecretory agents is much faster acting
than oral administration, and also avoids unacceptable loss
of the 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 drug plasma concentration, which is
preferable when dealing with potent drugs.
Further, a physician can easily monitor a patient's
condition to ensure the patient receives a dose adequate to
evoke a desired physiological state. If necessary, the
physician can instruct the patient to alter the aggressive-
20 ness with which he sucks the lollipop, or he can take the
lollipop from the patient.
A patient can also self-administer suitable anti-
migraine, antiemetic, hypoglycemic, bronchodilator, anti-
Parkinsonian, antidiuretic, antifungal, or antisecretory
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 can take a lick of the
lollipop from time to time as it may be needed to reduce
-62- 1339~7~
his own subjective experience of pain or physical
discomfort.
Although the method and compositions of the present
invention have been described with reference to specific
examples, it is to be understood that the method and
compositions of the present invention may be practiced in
other forms without parting from its spirit or essential
characteristics. Described methods and compositions are
considered in all respects only as illustrative, and not
restrictive. The scope of the invention is, therefore,
15 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.