Note: Descriptions are shown in the official language in which they were submitted.
- 133919Q
B~CKGROUND
1. The Field of the Invention
The present invention relates to compositions and
methods of manufacture of compressed po~der matrixes for
medicaments used in the transmucosal delivery of the
medicaments. More part-icularly, the present invent-;on ;s
directed to compositions, and methods and apparatus for
producing such compositions, for non-invasive
administration of precise amounts of medicaments through
the mucosal tissues of the mouth, pharynx, and esophagus.
2- The Background of the Invention
lS Recently, numerous advancements have taken. place in
the field of pharmacology with respect to the
administration of drugs to treat various conditions.
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Despite the tremendous advancements in the field, however,
drugs continue to be administered using substantially the
same techniques that have been used for many decades. The
vast majority of pharmaceutical agents continue to be
administered either orally or by injection. Nevertheless,
it is frequently found in the art that neither of these
administration routes are effective in all cases, and both
administration routes suffer from several disadvantages.
Oral administration is probably the most prevalent
method of administering pharmacological medicaments. The
medicament is generally incorporated into a tablet,
capsule, or a liquid base, and then swallowed. The oral
administration modality is often preferred because of its
convenience. In addition, oral administration is generally
nonthreatening, painless, and simple to accomplish for most
patients.
Nevertheless, oral administration of drugs suffers
from several disadvantages. One disadvantage is that
pediatric and geriatric patients frequently have difficulty
swallowing pills, and such patients often refuse to
cooperate in swallowing a liquid medication. In addition,
for many medicaments, the act of swallowing the medicament
increases gastric volume and the likelihood of nausea and
vomiting; this is a particularly dangerous condition for
patients prior to anesthesia.
A further problem with oral administration is that the
rate of absorption of the drug into the bloodstream after
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swallowing varies from patient to patient. The absorption
of the drug is dependent upon the movement of the drug from
the stomach to the small and large intestines and the
effects of secretions from these organs. Anxiety and
stress can dramatically reduce these movements and
secretions, prevent or reduce the final effects of the
drug, and delay onset of the drug's effects.
Most significant is the fact that there is normally a
substantial delay between the time of oral administration
and the time that the therapeutic effect of the drug
begins. As mentioned above, the drug must pass through the
gastrointestinal system in order to enter the bloodstream;
this typically takes forty-five minutes or longer. As
mentioned above, anxiety and stress often increase this
delay.
For many applications, such as premedication before
surgery or where immediate relief from pain or a serious
medical condition or immediate effectiveness of the drug is
required, this delay is unacceptable. In modern outpatient
units and operating rooms where rapid turnover of patients
is essential for cost containment, extensive delays in the
action of a drug are simply unacceptable.
An additional disadvantage of oral administration is
that many drugs, particularly drugs with central nervous
system ~"CNS") or cardiovascular action, are almost
immediately metabolized. The veins from the stomach and
the small and large intestines pass directly through the
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liver. Thus, drugs entering the bloodstream must first
pass through the liver before distribution into the general
blood circulation. More than sixty percent of most drugs
(and essentially one hundred percent of certain drugs) are
removed from the patient's bloodstream during this "first
pass" through the liver. The result is that oral
administration is impractical for many drugs, particularly
most central nervous system and cardiovascular-acting drugs
that are used in critical care situations, as a
premedication prior to surgery, or for the induction of
anesthesia.
Further, additional stress is placed on the liver as
it removes the excess drug from the bloodstream. This is
particularly severe if the 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 urine. As a result, there is an increased risk
of hepatic or renal disorders.
Another difficulty encountered in administering drugs
orally is that dosages are prepared or determined for use
with an "average" patient. Most drugs have widely varying
effects on different patients. These effects depend upon
patient habits, subtle genetic differences between
patients, blood volumes, age, and numerous other known and
unknown factors. Introducing a bolus of drug orally does
not provide the ability to control the precise dose needed
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to obtain the desired effect, rather the dose is estimated
in order to produce an average effect in an average
patient. The result may be underdosing or overdosing a
particular patient.
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, especially the heart
and lungs. This can cause prolonged respiratory depression
(necessitating mechanical ventilation after surgery),
cardiac depression, and cardiac arrest.
In order to avoid some of the disadvantages of oral
administration, injection is frequently used. Injecting a
drug (generally intravenously or intramuscularly), 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. The
drug instead becomes rapidly distributed to various
portions of the patient's body before exposure to the
liver.
Most patients, particularly children and geriatric
adults, have an aversion to injections. In some patients,
this aversion may be so pronounced as to make the use of
injections a serious concern. Since intense psychological
stress can exacerbate a patient's debilitated condition,
it sometimes becomes undesirable to use injections where
the patient is seriously ill or suffers from a debilitating
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condition or injury.
In addition, individual variations in susceptibility
in the metabolism of various drugs (particularly drugs with
central nervous system activity) are even more profound
when utilizing the injection route. In order to prevent
overdosing, it is the practice to inject a patient with a
lower than average dose and then supplement the dose with
additional injections as necessary. This "titration" makes
necessary the use of repeated injections, which in turn
greatly increases stress on the patient. Again, a precise
dose cannot be administered to produce a precise effect
because the patient's response varies widely depending on
the specific characteristics of the specific patient.
One common approach to preparing a patient for surgery
is to orally administer a sedative or anxiolytic. Although
quick onset of sedation or anxiolysis has not always been
a critical factor, it is more so now. Changing practices,
including the increased use of outpatient units for day
surgery and the pressures for cost containment in modern
medicine, dictate rapid onset of action and the use of an
absolutely ideal dose in order to avoid increased costs of
caring for patients with delayed recovery secondary to
slightly overdosing with anesthesia. Oral administration
of premedication drugs with central nervous system activity
(which cause a rapid onset of sedation and anxiolysis
without producing excessive sedation) is difficult to
accomplish.
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Some investigators have suggested that it may be
possible to administer medication through the buccal mucosa
of the cheek pouch or by sublingual administration. See,
United States Patent No. 4,671,953, issued June 9,
1987 in the name of the inventors hereof, and entitled
METHODS AND CO~POSITIONS FOR NONINVASIVE A~I~INISTRATION OF
SEDATIVES, ANALGESICS, AND ANESTHETICS." Such
administration through the mucosal tissues of the mouth,
pharynx, and esophagus of therapeutic drugs possesses a
distinct usefulness. Administration of drugs by this route
does not expose the drug to the gastric and intestinal
digestive juices. In addition, the drugs largely bypass
the liver on the first pass through the body, thereby
avoiding additional metabolism and/or inactivation of the
drug.
- Generally the drugs which are administered by any of
the methods described above have an unpleasant taste. As
a result, in order to allow for buccal or sublingual
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administration through the oral mucosal tissues, it is also
necessary to incorporate the drug into some type of
pleasant tasting mass, such as a "candy" matrix.
In the manufacture of medicated candy products by
existing methods, the therapeutic agent is added to a
molten candy mass. The resultant mixture is then
thoroughly mixed to ensure proper distribution of the drug
within the molten candy mass. The mixture is then poured
while still molten and allowed to solidify into a semi-
solid mass. Alternatively, the hot candy mass may bepoured into molds, the size and shape of which may be
determined as desired.
For effective application of the drug, the final candy
product must contain the drug uniformly distributed
throughout in order to ensure uniform levels of medication.
Alternatively, for some applications, varying
concentrations within known and controlled ranges may be
desired to vary the rate of drug administration.
Difficulties are encountered in attempting to blend solid
drugs in a uniform or otherwise carefully controlled
manner. Many drugs are insoluble, or only partially
soluble, in one or more of the ingredients of the hard
candy base. Thus, the resultant product is often found to
be lacking in uniform distribution of the drug.
In addition, it is often found that when the
temperature of the candy mass is increased in order to
enable a more uniform distribution (generally to a
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g
temperature above approximately 230~C), considerable
decomposition of the drug takes place. While the extent of
decomposition may vary, high temperatures are generally
undesirable in the handling and processing of medications.
Thus, the process of formation of the candy product may
itself degrade and/or inactivate the therapeutic agent.
Furthermore, many presently available medicated candy
lozenges tend to crumble when placed in the mouth. As a
result, uniform release of the drug into the mucosal
tissues does not take place. Rather, the crumbled lozenge
is mostly chewed, and swallowed, and the drug enters the
bloodstream through the stomach and intestines as described
above. Thus, it will be appreciated that candy lozenges
have very definite limitations for use in the
administration of a drug through the oral mucosal tissues.
As a result, lozenges have not been used to administer
potent, fast-acting drugs, such as drugs that affect the
central nervous system, the cardiovascular system, or the
renal vascular system.
While the administration of certain drugs through the
oral mucosal tissues has shown promise, development of a
fully acceptable method for producing a medication in a
desirable form and administering the medication has been
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elusive. It has not been possible to develop an acceptable
candy product for use with most drugs without heating the
product to the point where degradation will be expected.
It should also be noted that pH conditions within the
mouth tend to adversely affect the administration of
certain drugs by the mucosal administration route. It has
been found in the art that administration of drugs through
the mucosal tissues occurs best when the drug is in the
non-ionized form. Variations in pH affect drastically the
percentage of the drug which is non-ionized at a particular
point in time. As a result, the pH conditions within the
mouth limit the effectiveness of certain drugs administered
buccally or sublingually in that those conditions cause the
drug to exist in the ionized form which is largely
unavailable for transfer across the mucosal tissues.
In view of the foregoing, it would be an important
advancement in the art of administering potent, fast-acting
drugs, if suitable methods and compositions provided a
precise dosage to a precise effect in every patient. It
would be a related advancement in the art to provide such
methods and compositions which avoided the disadvantages of
overdosing, underdosing, and the immediate metabolism
encountered in the "first pass effect," yet did not involve
injection by needle into the patient.
It would be a further significant advancement in the
art to provide methods and compositions for incorporating
drugs (including insoluble drugs) into a soluble matrix
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without heating the mixture to the point that degradation
occurs. It would be a related advancement in the art to
provide such a method which provided the capability of
uniformly incorporating insoluble drugs into the soluble
matrix. It would be another advancement to provide methods
of controlling pH during mucosal delivery of a drug such
that the drugs exist primarily in the non-ionized form.
Such compositions and methods of manufacture are
disclosed and claimed herein.
BRIEF SUMMARY AND OBJECTS OF THE INVENTION
The present invention relates to compositions and
methods of manufacture for producing a medicament
composition for use in administering potent, fast-acting
drugs transmucosally. Furthermore, the present invention
relates to such compositions and methods which are useful
in administering drugs in a dose-to-effect manner such that
sufficient drug is administered to produce precisely the
desired effect. The invention also relates to a
manufacturing technique that enables a therapeutic agent to
be incorporated into a flavored confectionary base and to
compress or otherwise attach the solid confectionary
mixture onto an appliance or holder. In use, the present
invention provides for the administration of drugs through
the mucosal tissue of the mouth, pharynx, and esophagus,
thereby avoiding the problems of both injection and oral
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administration.
Employing the present invention, the drug may be
introduced into the patient's bloodstream almost as fast as
through injection, and much faster than using the oral
administration route, while avoiding the negative aspects
of both methods.
The present invention achieves these advantages by
incorporating the drug into a soluble candy matrix. The
soluble candy-drug mixture, in the form of a compressed
powder lollipop, can be used to administer drugs in a dose-
to-effect manner, or until the precise desired effect is
achieved. The lollipop can then be removed from the
patient's mouth.
The methods of the present invention also provide for
a compressed powder composition which overcomes many of the
limitations previously encountered in forming a medicated
lozenge. The present invention teaches the combination of
dry powdered ingredients by geometric dilution. That is,
the two smallest ingredients by weight are first thoroughly
mixed, then the next smallest ingredient or ingredients by
weight equal to the weight of the previous ingredients is
added and is thoroughly mixed with the existing mixture.
1 }39 1 qO
This procedure is repeated until all of the components,
including the desired therapeutic agents, are fully
combined.
After mixing, the mixture is then compressed under
high pressure to form an integral candy product. Specific
confectionary components are combined in order for the
mixture to form an integral solid mass. These components
may include, for example, compressible confectioner's sugar
and maltodextrin.
This procedure overcomes many of the problems of the
prior art. According to the present invention, insoluble
drugs can be added to the matrix without the necessity of
attempting to dissolve the drug. In addition, the high
temperatures, which are generally required to form a molten
candy matrix and which will cause degradation of the drug,
are avoided using the present invention. Therefore, even
drugs with melting points below approximately 130~C to
140~C or those drugs which can experience decomposition
below their melting points, can be incorporated into a
soluble matrix.
A further advantage of the present invention is that
flavoring problems are overcome. Flexibility in adding
flavors is provided in that solubility of the components is
not required in order to incorporate any particular flavor
1 34391 qU
into the matrix. Thus, flavorings, drugs, and other
components (which may be insoluble in liquid form) are
easily mixed when they exist as a dry powder.
Buffers and other types of pH and pKa control can also
be added simultaneously in order to provide for maximum
drug efficiency. It will be appreciated that drugs in the
non-ionized form are more readily transported across the
mucosal membrane. Therefore, if pH (and corresponding pKa)
conditions can be adjusted to maximize the percentage of
non-ionized drug available, the effectiveness of the drug
is maximized.
Various lollipop configurations are also possible
employing the present invention. For example, layers of
drug may be interspersed between layers of candy. Since
the present invention teaches the use of solid powders, any
desired type of mold can be used for the compression
formation of the lollipop.
It may also be desirable to incorporate a stick into
the candy matrix as the matrix is being compressed.
Alternatively, the stick may be glued to the candy matrix
by a confectioner's glue once the lollipop is formed. The
stick provides for easy removal of the lollipop from the
mouth of the patient once the desired effect has been
achieved. This is a substantial improvement over existing
methods of administering drugs through the mucosal tissues
of the mouth.
The present invention also provides the advantage of
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controlling the dissolution rate of the composition once it
is administered to a patient. This can be accomplished in
two ways. First, the dissolution rate may be modified
chemically by including a hydrophobic agent (such as
calcium stearate) to slow dissolution or lactose to enhance
dissolution. Dissolution may also be controlled by the
extent to which the mixture is mechanically compacted.
A drug administered through the oral mucosal tissues
from such a compressed powder matrix within the scope of
the present invention will quickly enter the patient's
bloodstream through the veins which serve these tissues.
Appropriate monitoring of the patient's reaction to the
drugs which has an observable or monitorable effect (such
as a drug effecting the central nervous, cardiovascular, or
renal vascular systems) will indicate when the drug has
evoked a suitable response. The lollipop may then be
removed, or its rate of consumption may be modified in
order to maintain the desired effect.
It will be appreciated that the ever present risk of
overdosing a patient is substantially minimized through the
use of the present invention. The rate at which the drug
is to be absorbed by the body can be varied by varying the
rate the lollipop dissolves. This can be accomplished by
varying the rigor with which the patient sucks on the
lollipop. It can also be accomplished by varying the
extent to which the lollipop is compressed during formation
or by adding certain agents which reduce the solubility of
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the compressed powder matrix.
According to the present invention, the drug dose is
given over a period of time rather than all at once, and the
administration rate can be adjusted if it appears to be
necessary. Once a sufficient drug response has been achieved,
the patient can simply stop sucking on the lollipop or the
physician can easily remove the lollipop from the patient's
mouth.
An advantage of the present invention is the provision
of methods of manufacture and compositions for the non-invasive
administration of a drug to a patient for rapidly inducing a
desired central nervous system effect.
Another advantage is the provision of methods of
manufacture for forming a drug-containing compressed powder
matrix, which methods are for avoiding degradation of the drug,
overcoming problems related to insolubility of the various
components in the candy matrix, and providing a product which is
not likely to crumble in the patient's mouth.
Another advantage is the provision of compositions for
precise control of the dosage and effect of the drug to be
ad
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BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a perspective view of a mold for forming
the candy-drug matrix along with an associated ram.
Figure 2 is a perspective view of one embodiment of a
lollipop within the scope of the present invention.
Figure 3 is an exploded plan view of the embodiment of
the lollipop shown in Figure 2.
Figure 4 is a perspective view of an alternative
embodiment of the lollipop of the present invention.
Figure 5 is a cutaway plan view of an alternative
embodiment of the lollipop of the present invention
illustrating one method of attachment of the stick to the
candy matrix.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
1. General Discussion
The present invention is related to methods of
20 manufacture and compositions which facilitate the
transmucosal delivery of a medication. Simply stated, the
present invention relates to a lollipop, or similar type of
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composition, which contains a therapeutic drug. The drug
is delivered to the patient through the mucosal tissues of
the mouth, pharynx, and esophagus as the patient sucks on
the drug-containing lollipop.
This particular method of delivery overcomes several
of the limitations encountered in the delivery of drugs
either orally or by injection. One of the primary
advantages of the present invention is the ability to
introduce drugs to a patient in a "dose-to-effect" manner.
The drug is given to the patient until the precisely
desired effect is obtained; this is in distinction to prior
art methods where a predetermined quantity of the drug is
introduced to the patient. Once the desired effect is
obtained, the patient or the medical professional simply
removes the lollipop from the patient's mouth.
The present invention discloses a method of producing
a lollipop containing one or more therapeutic agents. The
present invention overcomes many of the problems
encountered generally in incorporating drugs into a
confection. For example, the present invention teaches the
mixing of solid powders at room temperature, as opposed to
liquid components at elevated temperatures. The
degradation of drugs, which often occurs at the elevated
temperatures needed to produce a molten candy mass, is
thereby avoided. This facilitates use of drugs having
melting points in the 130~C-140~C range and below, or those
drugs which can experience decomposition below their
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melting points.
In addition, because solid powders are combined
together, constituents which may be chemically incompatible
when in a heated solution or suspension can be mixed. In
forming medicated confections by known methods, severe
problems are encountered in that the medication,
flavorings, and other components may be insoluble when
placed in the same liquid environment. In addition,
problems of chemical incompatibility between ingredients is
eliminated in the present invention.
Once the desired constituents are thoroughly mixed,
they are compressed into a solid mass under high pressure.
Typically, compressive forces in the range from
approximately 2,000 Newtons to approximately 5,000 Newtons
are preferred. As a result, the compressed powdered matrix
is held together by physical means rather than by chemical
means. The extent of the compressive forces can be
modified to vary the rate that the lollipop will dissolve
in a patient's mouth. The greater the compressive forces
that form the mixture, the slower the dissolution of the
compressed powder matrix in the mouth.
The rate of the dissolution of the lollipop can also
be controlled chemically. For example, the rate of
dissolution can be reduced adding hydrophobic agents such
as calcium stearate. Alternatively, dissolution can be
increased by adding hydrophilic agents, such as lactose.
According to the present invention, the compressed
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powder matrix is attached to a holder, such as a stick to
form a lollipop. Attaching the compressed powder matrix to
a holder facilitates the administering of precise dosages.
Once a particular effect is induced, the lollipop can be
withdrawn using the holder as described above. In
addition, a compressed solid mass containing a drug having
complex disagreeable flavor characteristics require
multiple ingredients to be added in order to provide a
significant bulk to overcome the disagreeable flavor
characteristics; hence, a mechanical support system such as
a holder is necessary.
The attachment of the confection to a holder may be
made by compressing the stick into the powder matrix as the
lollipop is being formed. Alternatively, the stick may be
glued to the candy matrix by confectioner's glue or some
other appropriate adhesive once the matrix is formed. In
the alternative, as will be discussed below, a lollipop may
be assembled immediately prior to use by sliding disks of
drug and candy onto an appropriately configured holder.
It will be appreciated that compression or attachment
of the drug-containing confection onto a holder can
facilitate the transmucosal absorption of a variety of
therapeutic agents. Attachment to a holder also
facilitates verifiable transfer of the medication to the
patient. The holder provides a convenient point of
reference concerning quantities of drug administered at any
particular point in time; it is easy to determine how much
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of the lollipop has been dissolved in the patient's mouth.
Localization of effects by agents such as local
anesthetic agents, antiplaque agents, local antipruitic
agents, local antisecretory agents, and local antifungal
agents can also be accomplished according to the present
invention. Immediate systemic effects from central nervous
system-acting drugs (such as sedation, anxiolysis,
analgesia, amnesia, and anesthesia), cardiovascular-acting
agents (such as antihypertensives and and antianginal
drugs), renal vascular-acting agents, and numerous other
therapeutic agents can also be accomplished by employing
the present invention.
Placing a drug dosage onto a holder also facilitates
the temporary removal of medication for inspection or the
reduction of the effect when necessary. Unlike
administration of drugs orally or even sublingually, the
present composition can easily be removed to assess the
effect induced at any particular time. When a pill or
lozenge is used, removal from the patient's mouth at an
intermediate stage to assess effect is generally
impractical, if not impossible.
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Compressed powder matrixes attached to a holder can
also avoid aspiration of the confection. One major problem
with existing lozenges and the like is their tendency to
crumble. Once the lozenge crumbles, controlled
transmucosal delivery is impossible. In addition, there is
some possibility that the patient will choke on the pieces
of lozenge.
The present invention provides the capability of
providing a good tasting medication. With many drugs, it
has previously been impossible to provide a good tasting
medicine because of the extreme bitterness or other
unpleasant taste of many drugs. Using the present
invention, favorable taste characteristics can be
accomplished by adding various flavors, sweeteners, and the
like to form an ideal mix of products. Since the
components are combined as solids, problems associated with
combining flavoring components insoluble in a molten candy
mass are avoided.
It is also important to note that it has been found
that it is possible, according to the present invention, to
use the free acid form of certain drugs and to buffer those
drugs such that extremes in pH, and resulting bad taste,
are avoided.
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2. Methods of Manufacture
In order to prepare a desirable drug-confection
mixture for formation into a lollipop, it is generally
necessary to combine several general types of components.
These components include the types of components used to
prepare typical confections, the desired drug, and other
chemically active ingredients such as buffers and the like.
The types of components involved generally fall into the
following categories:
(1) flavorings,
(2) sweeteners,
(3) flavor enhancers,
(4) releasing agents,
(5) buffers, and
(6) one or more therapeutic agents.
As mentioned above, it is preferred that these
components each be provided in a powder, in order to
facilitate the mixing and compression steps. This provides
for convenient combination of the ingredients, even if they
happen to be insoluble or otherwise chemically
incompatible. All the incipients or inactive ingredients
should be on the GRAS list ("generally regarded as safe").
A wide range of flavors are available for preparing
good tasting and desirable medications within the scope of
the present invention. These are required in order to mask
the unpleasant taste of the drug. Flavorings may be
combined, as desired, to produce a particular flavor mix
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which is compatible with a particular medication. Some of
the confectioner's flavorings which have been used in the
context of the present invention include artificial
vanilla, vanilla cream, mint, cherry, spearmint, grape,
coconut, chocolate, menthol, licorice, lemon, and
butterscotch.
Each of these flavorings is obtainable in a
concentrated powder form. Other flavorings known in the
confectionary arts may also be acceptable because of the
ease of combining the ingredients of the present invention.
Any number of flavorings may be combined in any desired
ratio in order to produce the specific desired taste
characteristics required for any particular application.
For example, flavor combinations may be varied in order to
be compatible with the flavor characteristics of any
specific drug.
In order to produce a desirable color for the end
product, artificial colorings may also be added to the
composition. The flavorings described above are generally
a white powder, as are the other major components.
Therefore, additional coloring is necessary if a colored
end product is desired. Coloring may also be important as
a code to indicate the type and concentration of drug
contained within a particular lollipop. Any type of color
known to be "generally regarded as safe~ ("GRAS"), and thus
generally used in the confectionary trade, may be used to
provide coloring to the product.
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In order to provide a good tasting medication, it is
necessary to add sweeteners to the composition. Sweeteners
which are presently preferred include aspartame
(NutraSweet~) and compressible confectioner's sugar. Other
sweeteners, such as fructose, may also be acceptable for
use within the scope of the present invention. Again, it
is desired that a sweetener or combination of sweeteners
be obtained which is compatible with the drug and the other
components such that a good tasting confection is produced.
Maltodextrin may also be added to provide a better
tasting composition. Maltodextrin is generally employed in
order to dissipate unpleasant flavors (such as the bitter
taste of most drugs) within the composition. In addition,
maltodextrin is a highly compressible powder which
facilitates the formation of the final lollipop product.
For some applications, it may be desirable to add a
flavor enhancer to the composition in order to achieve a
good tasting product. Flavor enhancers provide a more
pleasant sensation in the patient's mouth during
consumption of the lollipop. Flavor enhancers within the
scope of the present invention include materials such as
ribotide (a nucleotide) and monosodium glutamate ("msg").
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In certain medications, it may also be desirable to
add a lubricating agent in order to release the lollipop
from the mold. Such agents may also provide a certain
amount of waterproofing. As mentioned above, the rate of
dissolution of the lollipop within the patient's mouth may
be controlled chemically, as well as physically, through
the extent of compression of the composition. These
lubricating or releasing agents may include substances such
as compritol 888, calcium stearate, and sodium stearate.
These agents may enhance dissolution or they may inhibit
dissolution as necessary.
As will be discussed in more detail below, it may also
be desirable to buffer the composition. Buffers provide
the ability to place the medication in the mouth in a
favorable pH environment for passage across the mucosal
tissues of the mouth, pharynx, and esophagus. Buffers
incorporated within the composition can be used to affect
a pH change in the salival environment of the mouth in
order to favor the existence of a non-ionized form of the
active ingredient or drug which more readily moves through
the mucosal tissues.
In addition, appropriate pH adjustment can aid in
producing a more palatable product with drugs which are
either severely acidic (and thus sour) or severely basic
1 33q 1 90
(and thus bitter). As a result, a buffer system such as
citric acid/sodium citrate has been found to be desirable
for addition into the soluble compressed powder matrix.
It will be appreciated that miscellaneous other agents
S such as lactose, to provide filling and bulk, may also be
desirable. Other filling and bulking agents of the type
known in the art may also be used.
Added to the confectionary matrix described above will
be the appropriate therapeutic agent or drug. As will be
discussed in more detail below, various types of drugs are
easily incorporated into this type of matrix. These
include agents which affect the central nervous system, the
cardiovascular system, or the renal vascular system.
A typical lollipop within the scope of the present
invention may include the following ingredients in order to
make 20 dosage forms of 2000 milligrams (2 grams) each:
Ingredient % grams
citric acid 1% 0.2
ribotide 2% 0.4
compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
1 339 1 9r~J
-28-
vanilla cream microcaps 5% l.o
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
23% 4.6 grams
generic active agent X% (about 0.05%)
maltodextrin 100% - (23% + active agent%)
10 x 2 3
compressible sugar 100% - (23% + active agent %)
Appropriate changes in flavoring ingredients can be made in
this formula to mask or optimize flavor perception in order
to achieve ultimate acceptance of the dosage formed by the
desired patient group, be it adult, juvenile, pediatric, or
neonate.
Each of the components is mixed with the other
components in dry form to produce the compositions of the
present invention. It is presently preferred to use the
method of geometric dilution in mixing the various
components. Using this method, the two smallest
ingredients by weight (as a proportion of the final
product) are first mixed together thoroughly.
When complete mixing has been obtained between
those two components, the next smallest ingredient or
ingredients by weight equal to the weight of the previous
ingredients is added and mixed thoroughly with the existing
mixture. This procedure is repeated until all of the
1 339 1 90
-29-
components are added to the mix and mixed thoroughly with
all other components.
Geometric dilution provides for complete and
thorough mixing of all of the components. Using the method
described above, there is little chance for incomplete
mixing and uneven distribution of components throughout the
mix. It will be recognized that this is an advancement
over the art in that existing methods may result in
incomplete mixing because of the insolubility of the
products.
Once complete mixing is accomplished, the mixture
is compressed under relatively high forces to provide a
coherent dosage. Compressive forces in the range of from
approximately 2,000 Newtons to approximately 5,000 Newtons
are presently preferred, however, any force which is
sufficient to compress the ingredients into a coherent,
integrated mass could be used.
When employing the present invention, there is no
need to heat the mixture to a molten mass as has been the
practice in the past in forming drug-containing
confections. As a result, heat degradation of the drug
component is avoided while good mixing and a uniform
product are provided.
The confectionary mass may be attached to a holder
such as a stick or other similar type of holder. The
holder may be glued to the confection by confectioner's
glue. Alternatively, the holder may be compressed into the
l33qlqo
-30-
lollipop by the compressive forces described above.
The figures illustrate several methods of forming
the mass of confection, as well as methods of attaching the
holder. Figure 1 discloses a mold block 10. The interior
of mold block 10 includes a cavity 12 formed in any desired
shape so that the ingredients described above can be
compressed sufficiently to form an appropriately shaped
dosage. Mold block 10 may comprise two separate halves 14
and 16. Each half of the mold block 10 can be removed in
order to remove the confection once it is sufficiently
compressed.
Also illustrated in Figure 1 is ram 18. Ram 18 is
configured so that it fits into the cavity 12 and
compresses the confection into the base of cavity 12. Ram
18 may have a hole disposed through its interior in order
to accommodate stick 20. Thus, stick 20 can be placed into
the mass of confection prior to compression. Ram 18 will
then compress the confection tightly around stick 20.
Following compression of the confection, the stick is
securely bound in place.
Figure 2 discloses an additional embodiment of the
confection of the present invention. The confection
illustrated in Figure 2 has alternating layers of
confectionary mass 22 and a drug mass 24. Each alternating
segment is disk-shaped with the width of the disk being
varied according to particular needs. Disks 22 and 24
easily slide over stick 26 and seat against button 28.
1 33q 1 Y~)
-31-
Thus, the method of assembly of the confection can be
adapted to produce various dosages to fit varying
circumstances. Indeed, the patient himself may be capable
of assembling an appropriate confection and varying the
content of the medicament to correspond to his specific
needs at any particular time.
Figure 3 illustrates the method of assembling the
embodiment of the invention as illustrated in Figure 2. In
Figure 3, the drug disks 24 and confection disk 22 are
spaced apart along stick 26. As can be appreciated from
Figure 3, disks 22 and 24 will slide onto stick 26 and will
seat against button 28. The number of disks and the
composition of these disks can be easily varied to meet
particular patient needs.
Stick 26 may take various shapes. For example, it
may be desirable for stick 26 to be oval or triangular in
cross section. This would prevent disks 24 and 26 from
turning on the stick. In addition, an additional sleeve
(not shown) may be positioned over the exposed portion of
the stick with a catch that engages stick 26 so that disks
24 and 26 are locked in place.
Figure 4 illustrates a further embodiment of a
composition within the scope of the present invention. In
Figure 4, the drug and confection are divided laterally
along the cylindrical mass of the confection. Thus, pie-
shaped segments of drug 32 and confection 34 are pressed
together around stick 30. As illustrated in Figure 4, drug
1 33q 1 qO
-32-
segments 32 and confection segments 34 may alternate around
a periphery of the confectionary mass. Alternatively, the
spacing of the segments may be varied to provide other
appropriate levels of drug dosage.
Figure 5 illustrates an alternate method of
attachment between the confectionary mass 36 and the stick
38. Stick 38 illustrated in Figure 5 is constructed with
a plurality of protrusions 40. Protrusions 40 extend
toward the exposed portion of the handle such that they
prevent the confection from sliding off the handle. Thus,
when the confectionary mass 36 is compressed around stick
38, the mass is securely bound to the stick.
It can be seen, therefore, that the present
invention provides a great deal of flexibility in the
construction of an appropriate drug-containing confection.
The quantity of drug contained in any confection can be
varied within wide ranges. In addition, various methods of
attachment of the confection to the stick are available in
order to provide a wide range of flexibility.
1339lqo
-33-
3. Control of pH and pKa
It is well known that most drugs are weak acids or
weak bases and are present in solution in both the non-
ionized and ionized forms. It has been found that the non-
ionized portion of the drug is usually lipid soluble andcan readily diffuse across the cell membrane. The ionized
portion, conversely, is lipid insoluble and is often unable
to penetrate the lipid membrane of the cell. Furthermore,
the ionized drug is often unable to cross the cell membrane
pores because of its positive or negative charge. As a
result, drugs in the ionized form are generally inefficient
in producing a drug effect on the central nervous,
cardiovascular, and renal vascular systems.
Whether a drug exists in the ionized or non-ionized
form is largely dependent upon its pKa, and correspondingly
on the pH of the solution. The present invention provides
the unique ability to control the pH of the solution and
thus the pKa of the drug.
Ingredients of the lollipop or other dosage form
can be designed to impart sufficient change in the pH of
the saliva within the mouth such that the concentration of
the non-ionized drug is increased. When the percentage of
non-ionized drug is increased, transmucosal absorption of
the drug is correspondingly increased. Therefore, by
influencing the salival pH environment, it is possible to
greatly improve the extent and rapidity of actual drug
absorption, and therefore, the initial onset of the effect
133'~190
of the drug. Adding pH buffering systems (such as citric
acid/sodium citrate) into the lollipop dosage can greatly
facilitate delivery of the drug in the non-ionized (lipid
soluble) form.
It is often desirable for the pKa to range from
approximately 5 to approximately 8 in order to maximize
drug delivery. pKa is the dissociation constant, which is
generally defined as the pH at which a given acid or base
is 50% ionized and 50% non-ionized. pKa can be calculated
from pH, if the concentrations of the charged and uncharged
species are known, using the well-known Henderson-
Hasselbach equation if concentrations of the changed and
unchanged species are known. The Henderson-Hasselbach
equation is as follows:
~5
pKa = pH + log I A- I
where A-/HA is the ratio of the ionized drug form ("A-") to
the non-ionized drug form ("HA").
The effect on the pKa of varying pH, and thus on
the non-ionized drug available, is extremely dramatic. For
example, methohexital, a potent central nervous system-
acting drug, has a pKa of 7.9. If at the same time the
1 3 3 ~ 0
-35-
general pH of the saliva is about 7.5, these values can
then be placed in the Henderson-Hasselbach equation as
follows:
7.9 = 7.5 + log (X) (log of the ratio
of ionized to non-ionized)
where X is the ratio of the ionized to the non-ionized drug
form. Solving this calculation indicates that under
typical conditions in the mouth, 60% of the methohexital
available would exist in the non-ionized form. As was
mentioned above, the non-ionized drug form is the primary
form that is transported across the lipid cell membrane.
In the event that the salival pH is buffered down
to approximately 6.7, the pKa changes dramatically. This
results in a corresponding dramatic change in the amount of
drug available. Under these conditions, 94% of the drug
available exists in the non-ionized form.
Comparing the pKa produced under the two sets of pH
conditions described above, it can be seen that dramatic
changes occur. Changing the pH from 7.5 to 6.7 produces
more than a 50% improvement in the concentration of non-
ionized drug available for delivery across the lipid
membrane. This results directly in a dramatic improvement
133ql~0
-36-
in drug delivery across the cell membranes in the mouth and
a corresponding increase in the effectiveness of the drug
administered.
Changes in pH such as those discussed above can be
accomplished by incorporating particular buffer systems
within the confection composition. One presently preferred
buffer system is a citric acid/sodium citrate system;
however, other conventional buffers (such as phosphate) may
also be used. By using such a buffer, dramatically better
results may be achieved such that buccal drug absorption is
a fully feasible and optimal delivery method.
It will be appreciated that an additional advantage
of the change of the pH may be that the taste
characteristics of the drug can be improved. Drugs which
are very high in pH typically are very bitter in taste. As
the pH drops, the taste becomes less bitter, then salty,
and may eventually become sour. Flavorings can more
adequately improve the taste characteristics of drugs in
the lower pH ranges. As a result, in addition to improving
the drug delivery, buffering pH may also improve the taste
characteristics of the composition.
4. Suitable Therapeutic Aqents
In order for the present invention to operate
effectively, it is necessary that the therapeutic agent
incorporated within the candy matrix be generally
lipophilic or, in the alternative, be capable of being
1 33q 1 9G
placed in lipophilic form by suitable adjustments in the
environmental pH or other chemical modification. Thus, it
is presently preferred that the drug have a pKa in the
range of from approximately 6 to approximately 8.
It will be appreciated that the present invention
may be used with drugs having a variety of melting points.
Even low melting point drugs may be used in the present
invention, whereas such drugs were difficult to incorporate
into a candy matrix using known methods because of problems
such as degradation of the drug. For example,
methohexital, one of the presently preferred drugs for use
in connection with the present invention, has a melting
point of approximately 96~C. In order to incorporate
methohexital into a hard candy by conventional techniques,
the drug would have to be melted and there would be a risk
of extensive decomposition of the active agent.
The present invention has applicability to a
variety of drugs affecting the central nervous system. For
example, the present invention may easily be utilized in
the administration of buterophenones (such as droperidol
and haloperidol); benzodiazepines (such as valium,
midazolam, triazolam, oxazolam, and lorazepam); gABA
stimulators (such as etomidate); barbiturates (such as
pentathol, methohexital, thiamazol, pentobarbital, and
hexabarbital); di-isopropylphenols drugs (such as
diprivan); and other central nervous system-acting drugs
such as levodopa. It will be appreciated that other drugs
1 33~ 1 9~
-38-
may also be utilized within the scope of the present
invention either singly or in combination. It is
important, however, that the drug be generally lipophilic,
potent, and have the other general characteristics
described herein.
Table 1 lists some of the CNS-acting drugs which
are suitable for incorporation into the lollipop of the
present invention, as well as some of the characteristics
of those drugs.
Drugs having effects on the cardiovascular and
renal vascular systems may also be incorporated into the
compressed powder lollipop of the present invention. A few
examples of such drugs are identified in Table 2.
In addition to the foregoing, there are many other
drugs which can be incorporated into the compressed powder
matrix of the present invention. Exemplary of such drugs
are those identified in Table 3.
Table 3
Antiemetic
Drug Generic Dose Range
Benzquinamide 25-100 milligrams
Meclizine 25-100 milligrams
Metoclopramide 5-20 milligrams
Prochlorperazine 5-25 milligrams
Trimethobenzamide 100-2500 milligrams
Antifungal
1 3391 9a
-39-
Drug Generic Dose Range
Clotrimazole 10-20 milligrams
Nystatin 100,000-500,000 units
Antiparkinson
Druq Generic Dose Range
Carbidopa with levodopa 10-50
milligrams
Levodopa 100-750 milligrams
Antisecretory
Druq Generic Dose Ranqe
Sucralfate 1-2 grams
Bronchodilator
Drug Generic 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
1 3 3 q ~ a [)
-40-
Oxtriphylline 50-400 milligrams
Terbutaline 2.5-10 milligrams
Theophylline 50-400 milligrams
Miqraine
Druq Generic Dose Ranqe
Ergotamine 2-4 milligrams
Methysergide 2-4 milligrams
Propranolol 80-160 milligrams
Suloctidil 200-300 milligrams
Oxytocic
Drug Generic Dose Range
Ergonovine 0.2-0.6 milligrams
Oxytocin 5-20 units
Antidiuretic
Drug Generic Dose Range
Desmopressin 10-50 micrograms
acetate
Lypressin 7-14 micrograms
Vaspressin 2.5-60 units
Hypoglycemic
Drug Generic Dose Range
Insulin 5-20 units
1 339 1 90
-41-
When incorporating a drug into a lollipop or candy
matrix within the scope of the present invention, the
amount of drug used will generally differ from the amount
used in more traditional injection and oral administration
techniques. Depending upon the lipophilic nature of the
drug, its potency, and its end use, the total concentration
of the drug in the typical lollipop may contain up to 50
times the amount of drug which would typically be used in
an injection. For purposes of example, Tables 1, 2, and 3
set forth presently contemplated ranges of the dosages of
certain drugs which could be typically used.
A wide variety of drugs may be used within the
scope of the present invention. The present invention
allows drugs to be incorporated within the candy matrix
which would otherwise be insoluble, unpleasant tasting, or
have other undesirable characteristics. This capability is
provided by the compression formation of the candy dosage.
As was mentioned above, methohexital is one
presently preferred drug for use in the lollipop of the
present invention. Tests were run in which methohexital
lollipops were given to six volunteers. The lollipops each
contained 500 milligrams of methohexital. Each patient
experienced the sedative effects of the drug in a matter of
minutes after beginning to suck on the lollipop. These
tests indicated that the lollipop of the present invention
is effective in administering methohexital in a dose-to-
1 3391 ~0
-42-
effect manner.
Using the methohexital lollipop described above, it
was possible to produce either mild or heavy sedation or
induce anesthesia. By removing the lollipop when the ideal
degree of sedation was achieved, it was possible to
gradually increase sedation to the desired level.
In addition, the results show that the use of oral
transmucosal methohexital significantly decreases the drug
dosage required to produce optimal sedation. The dosage
was reduced from between 25 and 30 mg/kg when methohexital
is administered rectally to between 6 and 8 mg/kg
methohexital is given by way of the lollipop.
In summary, it will be appreciated that a wide
variety of drugs can be used within the scope of the
present invention. At the same time, several benefits are
provided. Efficient delivery of the drug is facilitated
while at the same time drug degradation is avoided. The
drug can also be administered in a dose to effect manner so
that the drug effect produced is precisely controlled.
5. Examples of the Present Invention
The following examples are given to illustrate
various embodiments which have been made or may be made in
accordance with the present invention. These examples are
given by way of example only, and it is to be understood
that the following examples are not comprehensive or
exhaustive of the many types of embodiments of the present
1 33q 1 qo
-43-
invention which can be prepared in accordance with the
present invention.
Example 1
In this example, methohexital was incorporated into
a compressed dosage form. Methohexital is a known potent
lipophilic drug useful as an anxiolytic, sedative and for
anesthetizing a patient. Its high potency and
lipophilicity makes it an excellent drug for transmucosal
administration in accordance with the present invention.
A suitable mixture was prepared by combining the
following ingredients as follows:
Ingredient % grams
citric acid 1% 0.2
ribotide 2% 0.4
compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
compressible sugar 20% 4.0
methohexital sodium 25~ 5.0
maltodextrin 32% 6.4
100% 20
The ingredients were combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 2 grams each
1 33q 1 qO
-44-
were 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 procedure resulted in the preparation of
10 oral transmucosal dosage forms, each containing 0.5
grams of methohexital.
Example 2
In this example, triazolam was incorporated into a
compressed dosage form. Triazolam is a known potent
lipophilic drug useful as an anxiolytic, amnestic, and for
sedating a patient. Its high potency and lipophilicity
makes it an excellent drug for transmucosal administration
in accordance with the present invention.
A suitable mixture was prepared by combining the
following ingredients as follows:
Ingredient % grams
triazolam 0.05% 0.01
citric acid 1% 0.2
Ribotide 2% 0.4
Compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps 5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
compressible sugar 25.65% 5.13
maltodextrin 50.3% 10.26
100% 20.0
1 33~ 1 ~O
The ingredients were combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 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 2 cubic
centimeters. The procedure resulted in the preparation of
10 oral transmucosal dosage forms, each containing 1.0
milligrams of triazolam.
Example 3
In this example, oxazepam was incorporated into a
compressed dosage form. Oxazepam is a known potent
lipophilic drug useful as an anxiolytic, an amnestic, and
for sedating a patient. Its high potency and lipophilicity
makes it an excellent drug for transmucosal administration
in accordance with the present invention.
A suitable mixture was prepared by combining the
following ingredients as follows:
Ingredient % grams
citric acid 1% 0.2
oxazepam 1.5% 0.3
ribotide 2% 0.4
compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps 5% 1.0
wild cherry microcaps 3% 0.6
1 339 1 90
-46-
peppermint microcaps 3% 0.6
compressible sugar 25.17%5.03
maltodextrin 50.33%10.07
100% 20
The ingredients were combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 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 2 cubic
centimeters. The procedure resulted in the preparation of
oral transmucosal dosage forms, each containing 30
milligrams of oxazepam.
Example 4
In this example, lorazepam is incorporated into a
compressed dosage form. Lorazepam is a known potent
lipophilic drug useful as an anxiolytic, an amnestic, and
for sedating a patient. Its high potency and lipophilicity
makes it an excellent drug for transmucosal administration
in accordance with the present invention.
A suitable mixture is prepared by combining the
following ingredients as follows:
Ingredient % grams
Lorazepam 0.2%0.04
citric acid 1% 0.2
Ribotide 2% 0.4
1 33ql ~0
-47-
Compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
compressible sugar 25.6% 5.12
maltodextrin 51.2% 10.24
100% 20
The ingredients are combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 2 grams 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 procedure results in the preparation of
10 oral transmucosal dosage forms, each containing 4.0
milligrams of lorazepam.
1 339 1 qO
-48-
Example 5
In this example, etomidate was incorporated into a
compressed dosage form. Etomidate is a known potent
lipophilic drug useful as an anxiolytic, sedative and for
anesthetizing a patient. Its high potency and
lipophilicity makes it an excellent drug for transmucosal
administration in accordance with the present invention.
A suitable mixture was prepared by combining the
following ingredients as follows:
Ingredient % grams
etomidate 1% 0.2
citric acid 1% 0.2
ribotide 2% 0.4
compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps 5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
compressible sugar 25.3% 5.06
maltodextrin 50.7 10.14
100% 20
The ingredients were combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 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 2 cubic
centimeters. The procedure resulted in the preparation of
1339190
-49-
10 oral transmucosal dosage forms, each containing 20
milligrams of etomidate.
Example 6
In this example, thiamylal was incorporated into a
compressed dosage form. Thiamylal is a known potent
lipophilic drug useful as an anxiolytic, sedative and for
anesthetizing a patient. Its high potency and
lipophilicity makes it an excellent drug for transmucosal
administration in accordance with the present invention.
A suitable mixture was prepared by combining the
following ingredients as follows:
Ingredient % grams
citric acid 1% 0.2
ribotide 2% 0.4
compritol 888 2% 0.4
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
thiamylal sodium 25% 5.0
maltodextrin 32% 6.4
compressible sugar 20% 4.0
100% 20
1 33q 1 ~0
-50-
The ingredients were combined in a mixer in such a fashion
as to ensure a uniform distribution of all ingredients
within the mixture. Aliquots of 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 2 cubic
centimeters. The procedure resulted in the preparation of
10 oral transmucosal dosage forms, each containing 0.5
grams of thiamylal.
Example 7
The same procedure described with reference to
Example 1 is used but levadopa is used in place of
methohexital. Levadopa is used as necessary to treat
Parkinson's Disease.
Example 8
In this example, isosorbide dinitrate was
incorporated into a compressed dosage form. In order to
make 20 dosage forms of 2000 milligrams (2 grams), each
containing 20 milligrams of isosorbide dinitrate (for a
total formula weight of 20 grams), the following
ingredients were combined:
Ingredient % grams
isosorbide dinitrate 1% 0.2
citric acid 1% 0.2
ribotide 2% 0.4
compritol 888 2% 0.4
1 33~ 1 ~0
aspartame 2% 0.4
vanilla microcaps 5% 1.0
vanilla cream microcaps5% 1.0
wild cherry microcaps 3% 0.6
peppermint microcaps 3% 0.6
compressible sugar 25.3% 5.06
maltodextrin 50.7% 10.14
100% 20
The ingredients were combined in a mixer in such a
fashion as to ensure a uniform distribution of all
ingredients within the mixture. Aliquots of 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 2 cubic
centimeters. The foregoing procedure resulted in the
preparation of 20 oral transmucosal dosage forms, each
containing 10 milligrams of isosorbide dinitrate.
Example 9
In this example, the same procedure as that
described in Example 8 is followed except captopril is
substituted for isosorbide dinitrate.
Example 10
In this example, the same procedure as that
described in Example 8 is followed except nifedipine was
substituted for isosorbide dinitrate.
~33q~0
-52-
Example 11
In this example, the same procedure as that
described in Example 8 is followed except clonidine is
substituted for isosorbide dinitrate.
Example 12
In this example, the same procedure as that
described in Example 8 is followed except esmolol is
substituted for isosorbide dinitrate.
Example 13
In this example, nitroglycerin was selected for
incorporation into a compressed dosage form. Nitroglycerin
is a potent lipophilic drug useful to control angina and
blood pressure in perioperative hypertension, especially
when associated with cardiovascular procedures and to
produce controlled hypertension during surgical procedures.
The high potency and lipophilicity of the
nitroglycerin make it an excellent drug for transmucosal
administration in accordance with the present invention.
A suitable mixture is prepared by combining 16 milligrams
of nitroglycerin; 400 milligrams citric acid; 400
milligrams calcium stearate; 17.7 grams compressible sugar;
17.7 grams of maltodextrin; 600 milligrams peppermint
microcaps; 1.2 grams cherry microcaps and 2 grams vanilla
microcaps. Aliquots of 2000 milligrams each are then
hydraulically compressed around a commercially available
1 3391 ~
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 0.8 milligrams
of nitroglycerin.
Example 14
To make 10 dosage forms of 2000 milligrams (2
grams), each containing 10 mg of nifedipine (for a total
formula weight of 20 grams) the following ingredients were
combined:
Ingredient % grams
Ribotide 1% 0.2
lS Compritol 888 5% 1.0
vanilla microcaps 5% 1.0
vanilla cream microcaps 5% 1.0
Nifedipine 19.0%3.8
Compressible sugar 21.7%4.34
Dextromaltrin 43.3%8.66
100%20 grams
Appropriate changes in flavoring ingredients can be
made in this formula to mask or optimize flavor perception
in order to achieve ultimate acceptance of the dosage form
by the desired patient group, be it adult, juvenile,
pediatric, or neonate.
Example 15
1 33ql qn
-54-
In this example, ergotamine is selected for
incorporation into a compressed dosage form. Ergotamine is
a potent lipophilic drug useful for relieving the pain
associated with migraines. Its 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 40
milligrams of ergotamine; 5.22 grams compressible sugar;
10.44 grams maltodextrin; 400 milligrams of Aspartame; 200
milligrams natural mint; 600 milligrams cherry; 1.0 gram
artificial vanilla; 1.0 artifical vanilla cream; 300
milligrams ribotide; and 800 milligrams Compritol 888.
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 10
lollipops, each containing 4 milligrams of ergotamine.
Example 16
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of pain
associated with oral candiasis is made according to the
procedure of Example 15, except that the ingredients are
combined in the following amounts.
Ingredient ~ grams
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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 cream5.0% 1.0
Compressed sugar 25.83% 5.17
Maltodextrin 51.67% 10.33
The foregoing procedure results in the preparation
of 10 lollipops, each containing 20 milligrams of
clotrimazole.
Example 17
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of pain
associated with symptoms of esophagitis is made according
to the procedure of Example 15, except that the ingredients
are combined in the following amounts.
Inqredient % grams
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
1 33q 1 qO
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The foreoing procedure results in the preparation
of 10 lollipops, each containing 1 gram of aluminum sucrose
sulfate.
S Example 18
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of pain
associated with respiratory distress is made according to
the procedure of Example lS, except that the ingredients
are combined in the following amounts.
Ingredient % grams
Natural mint 1.0% 0.2
Ribotide l.S% 0.3
lS Aspartame 2.0% 0.4
Wild cherry 3.0% 0.6
Compritol 888 4.0% 0.8
Artificial vanilla S.0% 1.0
Artificial vanilla creamS.0% 1.0
Oxtriphylline 10.0% 2.0
Compressed sugar 22.83% 4.S7
Maltodextrin 45.67% 9.13
1 3391 qn
The foregoing procedure results in the preparation
of 10 lollipops, each containing 200 milligrams of
oxtriphylline.
Example 19
A drug-containing lollipop within the scope of the
present invention to be used in the treatment associated
with patients experiencing nausea and vomiting is made
according to the procedure of Example 15, 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
The foregoing procedure results in the preparation
of 10 lollipops, each containing 50 milligrams of
meclizine.
Example 20
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
1 33q 1 ~n
-58-
procedure of Example 15, except that the ingredients are
combined in the following amounts.
Ingredient % qrams
Desmopressin 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 cream5.0% 1.0
Compressed sugar 26.17% 5.234
Maltodextrin 52.33% 10.47
The foregoing procedure results in the preparation
of 10 lollipops, each containing 20 micrograms of
desmopressin.
Example 21
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
symptoms of Parkinson's Disease is made according to the
procedure of Example 15, except that the ingredients are
combined in the following amounts.
Ingredient % qrams
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
1 33q 1 qn
-59-
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 22
A drug-containing lollipop within the scope of the
present invention to be used to induce labor or reduce
postpartum hemorrhage is made according to the procedure of
Example 15, except that the ingredients are combined in the
following amounts.
Ingredient % grams
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.
1 339 1 9~)
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Example 23
A drug-containing lollipop within the scope of the
present invention to be used in the treatment of the
symptoms of diabetes is made according to the procedure of
Example 15, except that the ingredients are combined in the
following amounts.
Ingredient % grams
Insulin 0.05% 0.01
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 26.15% 5.23
Maltodextrin 52.3% 10.46
The foregoing procedure results in the preparation
of 10 lollipops, each containing the equivalent of 30 units
of insulin.
1 3391 qn
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6. Summary
In summary, it can be seen that the present
invention accomplishes the objects set forth above. The
present invention provides compositions and methods of
manufacture for administering a drug in a precise dose in
order to obtain a rapid effect. In addition, the present
invention provides methods for forming a drug containing
candy matrix having the following attributes:
(1) drugs having relatively low melting
points can be used without degrading the drug;
(2) disagreeable flavor characteristics can
be masked;
(3) insoluble ingredients can be used;
(4) chemically incompatible ingredients can
be used;
(5) buffers can be added to optimize the
ratio of ionized and nonionized drug form;
(6) chemical agents to modify the dissolution
characteristics of the drug can be added;
(7) dissolution characteristics can be
modified mechanically by changing the compressive forces
used to form the lollipop;
(8) stratification of active ingredients can
be accomplished; and
(9) the dosage can be modified by utilizing
an assembly of dosage units onto a holder.
The present invention, therefore, provides the
l 33~ l ~n
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ability to provide precise control over the dosage and
effect of the drug. This is obtained by transmucosal
administration by sucking on a lollipop containing the
drug. As a result, the precise dosage and effect can be
obtained.
The present invention may be embodied in other
specific forms without departing from its spirit or
essential characteristics. The described embodiments are
to be 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.
