Note: Descriptions are shown in the official language in which they were submitted.
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A RAPIDLY-DISSOLVING ORALLY ADMINISTRABLE
WAFER FORMULATION
FIELD OF INVENTION
[0001 ] The present invention relates to a wafer formulation, and in
particular, it relates to
a rapidly dissolving formulation suitable for oral administration.
BACKGROUND OF THE INVENTION
[0002] Medical efforts to treat pain, known as "pain management", address a
large market,
as clinical pain is a worldwide problem with serious health and economic
consequences.
For example, in the United States, medical economists estimate that the
effects of pain
result in approximately $100 billion (USD) in costs annually, including an
estimated $515
million (USD) in lost work days. According to the National Institute of
Health,
approximately 40 million Americans are unable to find relief from their pain.
This
includes approximately one million cancer patients that suffer from severe
pain at any
given time, and an estimated 10% of the more than 200,000 AIDS patients that
suffer
severe pain.
[0003] Drugs are a key element in the treatment of pain. The worldwide market
for pain
was about $40.7 billion in 2004. The pain management market has grown
immensely in
recent years and is expected to continue to grow significantly. The pain
management
market has grown by more than 34% per year during the past five years. This is
likely due
to a number of factors, such as, a rapidly aging population, patient demand
for rapid
effective pain relief, increasing recognition of the therapeutic and economic
benefits of
rapid and effective pain management by physicians, healthcare providers and
payers, and
longer survival times for patients with painful chronic conditions, such as
cancer and
AIDS.
[0004] Many different kinds of pain exist including acute, chronic, persistent
and
breakthrough pain. As well, there exist different approaches to treat pain.
Opioids are
typically prescribed to manage moderate-to-severe acute or chronic
breakthrough pain due
to the fact that fast-acting, short-lived opioids can provide rapid delivery.
The most
common acute use of opioids is for post-surgical pain. Opioid drugs used to
treat acute
pain include intravenous fentanyl, hydrocodone and oral oxycodone, which
provide rapid
CA 02624110 2008-03-27
pain relief Intravenous therapy, however, is expensive and is suitable for
hospitalized
patients only.
[0005] The route of administration of any medication is an important
consideration.
Although many patients prefer oral administration of medications, oral
medication is not
always "fast-acting" , a property which is clearly desirable in the treatment
of acute
breakthrough pain, for example. Also, orally administrable medications are
generally
provided in the form of solid shaped articles such as tablets, pills, caplets
and capsules that
retain their shape under moderate pressure. Some patients, particularly
pediatric and
geriatric patients, have difficulty administering an oral medication due to
inability to
swallow, nausea or other gastrointestinal problems. Breakthrough pain
medications can be
taken in other ways, including by injection, under the tongue (sublingual),
rectally, or
transmucosally absorbed in the mouth but not swallowed; however, these forms
of
administration are often not as "fast-acting" as would be desired.
[0006] Liquid, syrups or suspensions are an alternative to solid dosage forms
and are often
preferred for pediatric and geriatric patients who have problems swallowing
tablets.
However, these dosage forms can be difficult to measure accurately and
administer easily.
Liquid formulations often deteriorate rapidly upon exposure to heat or other
atmospheric
conditions and consequently have a relatively short shelf life. Furthermore,
liquid
formulations require a relatively large volume and are bulky to store.
[0007] The bitter after-taste of many drugs which are orally administered,
such as tablets,
capsules or suspensions, often contributes to patient non-compliance in taking
medicine.
Apart from the taste of a chewable nutritional supplement, the 'mouth-feel' of
the
supplement must also be taken into account. 'Mouth-feel' is a concept that
encompasses
non-taste-related aspects of the sensation experienced by a person while
chewing or
swallowing a nutritional supplement. Aspects of mouth-feel include, for
example, the
hardness and brittleness of a composition, whether the composition is chewy,
gritty, oily,
creamy, watery, sticky, easily dissolved, astringent, effervescent, and the
like, and the size,
shape, and form (tablet, powder, gel, etc.) of the composition.
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[0008] In view of the foregoing, there remains a need to develop a formulation
for the oral
delivery of a pharmaceutical agent that overcomes at least one of the
disadvantages of
prior formulations.
SUMMARY OF THE INVENTION
[0009] The present invention provides a novel orally administrable and rapidly
dissolving
wafer. The wafer is advantageously stable but readily dissolves on oral
administration.
Accordingly, the wafer is suitable for the oral administration of a compound
such as a
pharmaceutical agent to permit rapid release and onset of activity of the
compound
incorporated within the wafer.
[0010] Thus, in one aspect of the present invention, there is provided an
orally
administrable wafer comprising at least one physiologically acceptable film
forming agent
and an aqueous solvent, wherein said wafer is characterized by a dissolution
rate of at least
about 2 mg/s in an aqueous environment.
[0011] In another aspect of the invention, an orally administrable wafer is
provided,
comprising at least one physiologically acceptable film forming agent, wherein
said wafer
is formed by exposing an aqueous mixture of the film forming agent to a
plurality of
heating and cooling cycles.
[0012] In another aspect of the present invention, there is provided an orally
administrable
wafer comprising an aqueous mixture of a pharmaceutical agent and at least one
physiologically acceptable film forming agent, wherein the wafer is formed by
exposing
the mixture to a plurality of heating and cooling cycles.
[0013] In another aspect of the present invention, there is provided an orally
administrable
wafer comprising a pharmaceutical agent and at least one physiologically
acceptable film
forming agent, wherein the pharmaceutical agent is present in a pre-defined
quantity.
[0014] In another aspect, there is provided a method of preparing an orally
administrable
wafer. The method comprises the steps of:
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1) mixing at least one physiologically acceptable film forming agent with an
aqueous solution to form a gel;
and
2) exposing the gel to cycles of heating and cooling to transform the gel
mixture
into a wafer.
[0015] In a further aspect of the present invention, there is provided a
method of
administering a pharmaceutical agent to a mammal comprising the step of orally
administering to the mammal a wafer comprising the pharmaceutical agent,
wherein said
wafer comprises at least one physiologically acceptable film forming agent and
the
pharmaceutical agent and is characterized by a dissolution rate of at least
about 2 mg/s in
an aqueous environment.
[0016] These and other aspects of the invention will become apparent in the
detailed
description and drawings in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 graphically compares blood levels of fentanyl when administered to a
mammal
by injection and orally in a wafer in accordance with an aspect of the
invention.
DETAILED DESCRIPTION
[0017] An orally administrable wafer is provided comprising at least one
physiologically
acceptable film forming agent. The wafer is formed by exposing an aqueous
mixture of
the film forming agent to a plurality of heating and cooling cycles to result
in a wafer
product having a very rapid rate of dissolution in an aqueous environment.
[0018] An orally administrable wafer according to the present invention may be
made
using one or more physiologically acceptable film forming agents. The term
"physiologically acceptable" is used herein to refer to film-forming agents
that are
acceptable for consumption by a mammal and that exhibit minimal or no adverse
side
effects on consumption. Suitable film-forming agents for use to make the wafer
include,
for example, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,
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hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,
polyvinyl
alcohol, sodium alginate, polyethylene glycol, polyacrylic acid, glycolide,
polylactide,
methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose
starch,
hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan,
levan, elsinan and
mixtures thereof A preferred film forming agent is pullulan, in amounts
ranging from
about 0.01 to about 99 wt %, preferably from about 30 to about 80 wt %, more
preferably
from about 45 to about 70 wt % of the film and even more preferably from about
60 to
about 65 wt % of the film. Another preferred film forming agent is a mixture
of pullulan,
PEG and poly vinyl alcohol and carrageenan, each in amounts ranging from about
0.01 to
about 95 wt % of the film.
[0019] Secondary film forming agents may be added to the formulation to
optimize wafer
characteristics such as tensile strength, stability, flexibility and
brittleness including agents
such xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, collagen,
gelatin,
zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures
thereof. The
amount of secondary film forming agent will vary depending on the primary film
forming
agent used as well as the desired properties of the wafer.
[0020] The one or more selected film-forming agents are dissolved in an
aqueous solution
to form a gel. The aqueous solution may simply be water, or a water-based
solution such
as mixtures of water and ethyl alcohol. One of skill in the art will be
familiar with the
amounts of aqueous solution to add to a film-forming agent to form a gel.
Generally, a gel
is formed by mixing a 4:1 ratio of film forming agent to aqueous solution. One
of skill in
the art will appreciate that this may vary with the selected film forming
agent and aqueous
solution.
[0021] To form the wafer, a novel method is employed comprising exposing the
gel to a
plurality of heating and cooling cycles. Thus, the gel is exposed to a period
of heating in
which the gel is rapidly heated to a temperature of up to about 90 C, for
example a
temperature of between about 60 - 80 C, for a period of time of not more than
about 20s,
for example 5 - 15 s, and preferably 8 - 12 s. Following the heating period,
the gel is
exposed to a cooling or non-heating period for a period of time of not more
than about 20s,
for example 5 - 15 s, and preferably 8 - 12 s. This cycle is repeated a number
of times to
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yield a wafer in accordance with the present invention, for example, the gel
is exposed to
at least 3 cycles of heating and cooling in which the total time is between
about 30s-3
minutes, preferably about 1-2 minutes. Preferably, the method of making the
wafer
comprises at least about 6 heating and cooling cycles.
[0022] The present method, thus, provides a means of rapidly preparing a
dissolvable
wafer product, e.g. a preparation time of minutes, as opposed to the
conventional batch
extrusion method of preparing films which can take hours to yield a product.
[0023] Although the method of heating the gel during the heating period is not
to be
restricted, the application of microwaves is particularly suitable since
microwaves are
suitable to achieve rapid high temperature heating of the gel. The application
of
microwaves may be by a mono-mode or multi-mode structure. Typically the
wavelength of
the microwave radiation is chosen so as to excite the solvent molecules,
especially water,
and expedite their evaporation. A standard microwave oven, designed to use
1,100 W AC
and producing 700 W of microwave power, emitting microwaves at a frequency of
2.45
GHz and a wavelength of 12.24 cm, is suitable to heat the gel during the
heating period of
the present method.
[0024] The result of the multiple heating and cooling cycles on the gel is a
wafer having
unique morphological characteristics that confer on it a very high rate of
dissolution that
exceeds the dissolution rate of other film-like formulations. The wafer is
thus
characterized by a dissolution rate of at least about 2 mg/s, for example 3-5
mg/s. The
rapid dissolution rate of the wafer results in very rapid absorption of the
components
thereof, through the buccal mucosa, rendering the wafer particularly suitable
as a means to
orally deliver a pharmaceutical agent. Thus, the wafer exhibits maximum or
peak
absorption of a component therein within about 5-10 minutes (Tm.), for
example, within
about 5-7 minutes which is at least comparable or less than the absorption
time for a
component administered intravenously.
[0025] In addition, the maximum plasma concentration (Cmax) of a component
administered to a patient via the wafer is increased in comparison to the Cmax
of the
component when administered intravenously. Notably, the Cmax attained on
administration of a component via a wafer according to the invention is at
least about 25%
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greater, preferably at least about 30-40% greater and more preferably, at
least about 50%
greater than the Cm,, attained on administration of the component to a patient
intravenously.
[0026] The present method advantageously yields a wafer product that is
extremely thin,
exhibiting a thickness of no more than about 0.Imm, for example, 0.05mm or
less. This
property of the wafer contributes to its rapid dissolution, and ease of
administration.
[0027] In another aspect, thus, of the invention, an orally administrable
wafer formulation
comprising a pharmaceutical agent and at least one physiologically acceptable
film
forming agent is provided.
[0028] As used herein, the term "pharmaceutical agent" is meant to refer to
any compound
useful to treat or reduce the symptoms of a medical condition. Examples of
pharmaceutical agents include, but are not limited to:
a. antimicrobial agents, such as triclosan, cetyl pyridium chloride, domiphen
bromide, quaternary ammonium salts, zinc compounds, sanguinarine,
fluorides, alexidine, octonidine, EDTA, and the like;
b. non-steroidal anti-inflammatory drugs, such as aspirin, acetaminophen,
ibuprofen, ketoprofen, diflunisal, fenoprofen calcium, naproxen, tolmetin
sodium, indomethacin, and the like;
c. anti-tussives, such as benzonatate, caramiphen edisylate, menthol,
dextromethorphan hydrobromide, chlophedianol hydrochloride, and the
like;
d. decongestants, such as pseudoephedrine hydrochloride, phenylepherine,
phenylpropanolamine, pseudoephedrine sulfate, and the like;
e. anti-histamines, such as brompheniramine maleate, chlorpheniramine
maleate, carbinoxamine maleate, clemastine fumarate,
dexchlorpheniramine maleate, diphenhydramine hydrochloride,
diphenylpyraline hydrochloride, azatadine meleate, diphenhydramine
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citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine
maleate, tripelennamine citrate, triprolidine hydrochloride, acrivastine,
loratadine, brompheniramine, dexbrompheniramine, and the like;
f. expectorants, such as guaifenesin, ipecac, potassium iodide, terpin;
g. anti-diarrheals, such a loperamide, and the like;
h. H2-antagonists, such as famotidine, ranitidine, and the like;
i. proton pump inhibitors, such as omeprazole, lansoprazole;
j. general nonselective CNS depressants, such as aliphatic alcohols,
barbiturates and the like;
k. general nonselective CNS stimulants such as caffeine, nicotine, strychnine,
picrotoxin, pentylenetetrazol and the like;
1. drugs that selectively modify CNS function such as phenyhydantoin,
phenobarbital, primidone, carbamazepine, ethosuximide, methsuximide,
phensuximide, trimethadione, diazepam, benzodiazepines, phenacemide,
pheneturide, acetazolamide, sulthiame, bromide, and the like;
m. antiparkinsonism drugs such as levodopa, amantadine and the like;
n. opioid analgesics such as alfentanil, allylprodine, alphaprodine,
anileridine,
benzylmorphine, bezitramide, buprenoorphine, butorphanol, clonitazene,
codeine, cyclazocine, desomorphine, dextromoramide, dezocine,
diampromide, dihydrocodeine, dihydromorphine, dimenoxadol,
dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,
eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,
etonitazine, fentanyl, heroin, hydrocodone, hydromorphone,
hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,
levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,
methadone, metopon, morphine, myrophine, nalbuphine, narceine,
nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,
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norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts thereof, mixtures of any
of the foregoing, mixed mu-agonists/antagonists, mu-antagonist
combinations, and the like. The opioid analgesic may be in the form of the
free base, or in the form of a pharmaceutically acceptable salt, or in the
form of a pharmaceutically acceptable complex;
o. analgesic-antipyretics such as salycilates, phenylbutazone, indomethacin,
phenacetin and the like;
p. psychopharmacological drugs such as chlorpromazine, methotrimeprazine,
haloperidol, clozapine, reserpine, imipramine, tranylcypromine, phenelzine,
lithium and the like;
q. hypnotics, sedatives, antiepileptics, awakening agents;
r. vitamins and minerals;
s. amino acids and peptides;
t. compound like sildenafil citrate (Viagra etc);
u. proteins, hormones and peptides e.g., insulin, erythropoietin, etc.; and
v. antidiabetic drugs, e.g., metformin, glyburide and insulin secretart agent,
insulin stimulators, fat metabolizers, carbohydrates metabolizers, insulin,
cholesterol lowering agents like statins, etc.
[0029] Thus, a wafer formulation according to the invention comprising a
pharmaceutical
agent is an effective tool in the treatment of many diseases.
[0030] To incorporate a pharmaceutical agent into a wafer according to the
invention, the
pharmaceutical agent is dissolved in an aqueous solution and added to a gel
formed by an
aqueous mixture of a selected film-forming agent as previously described. The
wafer-
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forming heating and cooling cycles are then applied to the admixture of the
pharmaceutical
agent and gel as described.
[0031] A method of administering a pharmaceutical agent to a mammal is also
provided.
The term "mammal" is used herein to encompass both human and non-human mammals
such as domestic animals, livestock and wild animals. The method comprises the
step of
orally administering to the mammal a wafer in accordance with the invention
comprising
the pharmaceutical agent as described. The wafer dissolves in the aqueous
environment of
the oral cavity at a rate of at least about 2 mg/s, for example 3-5 mg/s, and
on dissolution,
the pharmaceutical agent is rapidly and effectively absorbed into the
bloodstream to
provide a plasma concentration that is at least comparable to the plasma
concentration of
the pharmaceutical agent that would be achieved by the intravenous injection
thereof, and
preferably the wafer provides an increased plasma concentration of the
pharmaceutical
agent.
[0032] Delivery of a pharmaceutical agent via an orally administrable wafer in
accordance
with the invention advantageously provides a mechanism for rapid access to the
activity of
the pharmaceutical agent in comparison with currently available orally
administrable
formulations. The wafer exhibits a very rapid rate of dissolution in an
aqueous
environment and, thus, provides expedited delivery of a pharmaceutical agent
which
translates into accelerated access to the activity of the pharmaceutical
agent.
[0033] In addition, the present wafer formulation provides a rapidly
dissolving oral dosage
form comprising a defined quantity or dose of pharmaceutical agent not
previously
attainable. While prior batch extrusion methods for making film-like products
cannot be
used to generate dosage forms comprising a defined quantity of pharmaceutical
agent, the
heating/cooling cycling method of making the present wafer provides this
capability.
Generally, although the present method may be applied to produce a batch wafer
product,
the gel (film-forming agent in aqueous solution) may also be exposed to the
heating/cooling cycles in plates having wells, for example, wherein each well
contains a
measured defined amount of pharmaceutical agent.
[0034] As will be appreciated by one of skill in the art, the present wafer
formulation may
comprise additional components. Such components may include one or more
additives
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and/or excipients to optimize its use for oral administration. Examples of
suitable
additives include antimicrobial agents, plasticizing agents, flavoring agents,
sulfur
precipitating agents, saliva stimulating agents, cooling agents, surfactants,
stabilizing
agents, emulsifying agents, thickening agents, binding agents, coloring
agents, sweeteners,
fragrances, and the like. These additives/excipients are generally dissolved
in an aqueous
solution to form a solution of appropriate concentration with respect to the
additive and
then admixed with the film-forming gel prior to wafer formation.
[0035] The wafer formulation may include an anti-microbial agent such as one
or more
essential oils that confer antimicrobial properties. Preferably, the amount of
a selected
essential oil for use in the formulation is sufficient to provide
antimicrobial efficacy.
Generally, an oil such as thymol, methyl salicylate and eucalyptol may be
present in an
amount of about 0.01 to about 4 wt % of the formulation, preferably about 0.50
to about
3.0 wt % and even more preferably from about 0.70 to about 2.0 wt % of the
formulation.
Menthol may be added in an amount ranging from about 0.01 to about 15 wt % of
the
formulation, preferably about 2.0 to about 10 wt % and even more preferably
from about 3
to about 9 wt % of the formulation. The appropriate amount of a selected oil
in the
formulation can readily be determined by one of skill in the art. The amount
of a selected
oil in the formulation may exceed the foregoing amounts; however, the total
oil content is
such that it does not change the physical characteristics of the wafer
formulation.
[0036] Saliva stimulating agents may be added to the wafer formulation
according to the
present invention. Saliva stimulating agents include food acids such as
citric, lactic, malic,
succinic, ascorbic, adipic, fumaric and tartaric acids. Preferred food acids
are citric, malic
and ascorbic acids. The amount of saliva stimulating agents suitable for
inclusion in the
present formulation may range from about 0.01 to about 12 wt %, preferably
about 1 wt %
to about 10 wt %.
[0037] Plasticizing agents may be included in the formulation to attain
desired wafer
flexibility and mold-releasing properties. Suitable plasticizing agents
include, for
example, triacetin, monoacetin and diacetin. Plasticizing agent may be added
to the
formulation in an amount ranging from about 0 to about 20 wt %, preferably
about 0 to
about 2 wt % of the formulation.
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[0038] Cooling agents may be added to the formulation to increase boiling
point of the gel
and thereby prevent bubble formation. An example of a cooling agent that may
be added
to the formulation is monomenthyl succinate, in an amount ranging from about
0.001 to
about 2.0 wt %, preferably about 0.2 to about 0.4 wt % of the formulation. A
monomenthyl succinate-containing cooling agent is available from Mane, Inc.
Other
suitable cooling agents include WS3, WS23, Ultracool II and the like.
[0039] Another additive that may be included within the formulation is a
surfactant.
Mono- and di-glycerides of fatty acids and polyoxyethylene sorbitol esters,
such as, Atmos
300 and Polysorbate 80, are examples of suitable surfactants for inclusion.
The surfactant
may be added in amounts ranging from about 0.5 to about 15 wt %, preferably
about 1 to
about 5 wt % of the formulation. Other suitable surfactants include pluronic
acid, sodium
lauryl sulfate, and the like.
[0040] Stabilizing agents such as xanthan gum, locust bean gum, guar gum and
carrageenan, in amounts ranging from about 0 to about 10 wt %, preferably
about 0.1 to
about 2 wt % of the formulation, may be included in the formulation.
[0041] Emulsifying agents such as triethanolamine stearate, quaternary
ammonium
compounds, acacia, gelatin, lecithin, bentonite, veegum, and the like, may be
included in
the formulation in amounts ranging from about 0 to about 5 wt %, and
preferably about
0.01 to about 0.7 wt % of the formulation.
[0042] Thickening agents such as methylcellulose, carboxyl methylcellulose,
and the like,
may be added to the formulation in amounts ranging from about 0 to about 20 wt
%, and
preferably about 0.01 to about 5 wt %.
[0043] Binding agents such as starch, may be included in the formulation in
amounts
ranging from about 0 to about 10 wt %, preferably about 0.01 to about 2 wt %
of the film.
[0044] To render the formulation more desirable for oral administration,
natural and/or
artificial sweeteners may be included in the formulation. Suitable sweeteners
include, e.g.:
a. water-soluble sweetening agents such as monosaccharides, disaccharides
and polysaccharides such as xylose, ribose, glucose (dextrose), mannose,
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galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a
mixture of fructose and glucose derived from sucrose), partially hydrolyzed
starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and
glycyrrhizin;
b. water-soluble artificial sweeteners such as the soluble saccharin salts,
i.e.,
sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium
or calcium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2, 2-
dioxide, the potassium salt of 3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-
one-2,2-dioxide (acesulfame-K), the free acid form of saccharin, and the
like;
c. dipeptide based sweeteners, such as L-aspartic acid derived sweeteners,
such as L-aspartyl-L-phenylalanine methyl ester (aspartame) and materials
described in U.S. Pat. No. 3,492,131, L-alpha-aspartyl-N-(2,2,4,4-
tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-
aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenyl-glycine, L-
aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(1-cyclohexyen)-
alanine, and the like;
d. water-soluble sweeteners derived from naturally occurring water-soluble
sweeteners, such as a chlorinated derivative of ordinary sugar (sucrose),
known, for example, under the product description of sucralose; and
e. protein based sweeteners such as thaumatoccous danielli (Thaumatin I and
11).
[0045] In general, an effective amount of auxiliary sweetener is utilized to
provide the
level of sweetness desired for a particular composition, and this amount will
vary with the
sweetener selected. Generally, an amount of sweetener in the range of 0.01% to
about 10%
by weight of the formulation is appropriate, and will vary with the ability of
the sweetener
to sweeten and the desired level of sweetness. Of course, sweeteners need not
be added to
the formulation to render it orally administrable. In addition, the inclusion
of sweeteners is
independent from the inclusion of flavors in the formulation.
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[0046] The flavorings that may be used in the formulation include both natural
and
artificial flavors. These flavorings may be chosen from synthetic flavor oils
and flavoring
aromatics and/or oils, oleo resins and extracts derived from plants, leaves,
flowers, fruits
and so forth, and combinations thereof. Representative flavor oils include:
spearmint oil,
cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil,
oil of nutmeg, oil
of sage, and oil of bitter almonds. Also useful are artificial, natural or
synthetic fruit
flavors such as vanilla, chocolate, coffee, cocoa and citrus oil, including
lemon, orange,
grape, lime and grapefruit and fruit essences including apple, pear, peach,
strawberry,
raspberry, cherry, plum, pineapple, apricot and so forth. These flavorings may
be used
individually or in admixture. Commonly used flavors include mints such as
peppermint,
artificial vanilla, cinnamon derivatives, and various fruit flavors, whether
employed
individually or in admixture. Aldehydes and esters may be used to flavour as
well.
Examples include cinnamyl acetate, cinnamaldehyde, citral, diethylacetal,
dihydrocarvyl
acetate, eugenyl formate, p-methylanisole. Generally, any flavoring or food
additive, such
as those described in Chemicals Used in Food Processing, publication 1274 by
the
National Academy of Sciences, pages 63-258, may be used. Further examples of
aldehyde
flavorings include, but are not limited to, acetaldehyde (apple); benzaldehyde
(cherry,
almond); cinnamic aldehyde (cinnamon); citral, i.e., alpha citral (lemon,
lime); neral, i.e.
beta citral (lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla,
cream);
heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream);
alpha-amyl
cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter, cheese);
valeraldehyde
(butter, cheese); citronellal (modifies, many types); aldehyde C-8 (citrus
fruits); aldehyde
C-9 (citrus fruits); aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde
(berry fruits);
hexenal, i.e. trans-2 (berry fruits); tolyl aldehyde (cherry, almond);
veratraldehyde
(vanilla); 2,6-dimethyl-5-heptenal, i.e. melonal (melon); 2-6-dimethyloctanal
(green fruit);
and 2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof; and the
like.
[0047] The amount of flavoring employed is normally a matter of preference
subject to
such factors as flavor type, individual flavor, and strength desired. Thus,
the amount may
be varied in order to obtain the result desired in the final product. In
general, amounts of
about 0.1 to about 30 wt % may be used.
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CA 02624110 2010-01-26
[0048] The formulation may also contain coloring agents or colorants. The
coloring agents
are used in amounts effective to produce the desired color. The coloring
agents useful in
the present invention include pigments such as titanium dioxide, which may be
incorporated in amounts of up to about 5 wt %, and preferably less than about
I wt %.
Colorants can also include natural food colors and dyes suitable for food,
drug and
cosmetic applications. These colorants are known as FD&C dyes and lakes. The
materials
acceptable for use are preferably water-soluble, and include FD&C Blue No. 2,
which is
the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known as
Green No. 3
comprises a triphenylmethane dye and is the monosodium salt of 4-[4-N-ethyl-p-
sulfobenzylam ino) diphenyl-methylene]-[I-N-ethyl-N-p-sulfonium benzyl)-2,5-
cyclo-
hexadienimine]. A full recitation of all FD&C and D&C dyes and their
corresponding
chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical
Technology, Volume 5, Pages 857-884.
[0049] The present invention advantageously provides an oral formulation that
is rapidly
dissolving on administration to provide rapid release of the pharmaceutical
agent within
the mouth and stomach. This renders the formulation particularly suitable to
deliver pain
medications such as medications used to treat acute breakthrough pain. In
addition, the
formulation may readily incorporate flavouring and sweetening agents to mask
the taste of
unpleasant pharmaceutical agents such as analgesic agents. Another advantage
is provided
in the efficiency of the method of making the present wafer formulation which
involves a
cost-effective technique of applying cycles of heating/cooling.
[0050] The above disclosure generally describes the present invention. It is
believed that
one of ordinary skill in the art may, using the preceding description, make
and use the
compositions and practice the methods of the present invention. A more
complete
understanding can be obtained by reference to the following specific examples.
These
examples are described solely to illustrate preferred embodiments of the
present invention
and are not intended to limit the scope of the invention. Changes in form and
substitution
of equivalents are contemplated as circumstances may suggest or render
expedient. Other
generic configurations will be apparent to one skilled in the art.
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CA 02624110 2008-03-27
EXAMPLES
[0051] Although specific terms have been used in these examples, such terms
are intended
in a descriptive sense and not for purposes of limitation. Methods of
molecular biology,
biochemistry and chemistry referred to but not explicitly described in the
disclosure and
these examples are reported in the scientific literature and are well known to
those skilled
in the art.
Example 1. Preparation Method I
[0052] The following method was used to prepare a wafer. Examples of
appropriate
ingredient amounts are listed in Example 3.
a. The film-forming ingredients (e.g., xanthan gum, locust bean gum,
carrageenan and pullulan) are mixed and hydrated in hot purified water to
form a gel and stored in a refrigerator overnight at a temperature of
approximately 4 C. to form preparation A;
b. The coloring agent(s) (selected food dye) and sweetener (sorbitol) are
added
to and dissolved in purified water to form preparation B;
c. Preparation B is added to preparation A and mixed well to form preparation
C;
d. The flavoring agent and the oils (e.g. thymol, methyl salicylate,
eucalyptol
and menthol) are mixed to form preparation D;
e. The polysorbate 80 and Atmos 300 are added to preparation D and mixed
well to form preparation E;
f. Preparation E is added to preparation C and mixed well to form preparation
F; and
g. Fentanyl (100 micrograms) dissolved in water was added to the final
mixture F and mixed well.
-16-
CA 02624110 2008-03-27
[0053] Preparation G is poured on a mold and cast to form a film of a desired
thickness.
The molds containing the film forming solutions were put on a conveyor belt
and then
passed through a special microwave chamber. Five microwave chambers were
utilized for
the quick film formation. Each microwave chamber had dimensions of about
14"x11"x 9"
and were programmed to heat the solution for 10 seconds. The conveyor belt
speed was
adjusted to move the molds slowly enough to complete the 10 seconds heating
and drying
cycle. Specifically the belt speed was adjusted to move the molds about 1 foot
per 7
seconds (approximately 8 feet travel time) to provide sufficient time for the
microwaves to
complete one heating cycle. The microwaves were stationed about 18" away from
each
other. The whole chamber containing the microwave was designed to maintain the
temperature of 37 C with constant positive air flow. The wafers thus made
were stored at
room temperature. The whole cycle of making wafers of 1.5" long, 0.5 inch wide
and 0.1
mm thick was about 90 seconds in total. The wafers were packaged and stored at
room
temperature.
Example 2. Preparation Method II
[0054] An alternative method for making a wafer as described herein includes
the
following steps. Examples of appropriate ingredient amounts are listed in
Example 3.
[0055]
a. dissolve copper gluconate, acesulfame K, aspartame, glycerin, sorbitol and
dye in purified water to form an aqueous mixture;
b. mix pullulan, xanthan gum, locust bean gum and carrageenan together in
powder form to form a powder mixture;
c. add the powder mixture from step B to the aqueous mixture from step A to
form a hydrated polymer gel;
d. stir the hydrated polymer from step C at slow speed (about 50-100 RPM)
overnight at room temperature;
-17-
CA 02624110 2008-03-27
e. mix and dissolve cooling agent, thymol, in menthol flavor oil;
f. add methyl salicylate, eucalyptol, Polysorbate 80 and Atmos 300 to the oil
mixture from step E;
g. add the oil mixture from step F to the hydrated polymer gel from step D and
mix until uniform;
h. add fentanyl (100 micrograms) to the mixture from step G (or the
pharmaceutical agent of the choice) and mix well to form homogenous
mixture;
i. cast the uniform mixture from step H on a suitable backing; and
j. expose the cast mixture to heating/cooling cycles as described in Example 1
using microwaves to form a wafer.
Example 3. Examples of film formulations
Examples of film formulations according to the present invention are set out
in the
following table.
Example. I Example 2
Ingredients wt (mg) wt (mg)
Xanthan Gum, Food Grade 0.1000 0.10
Locust Bean Gum, Clarified 0.1150 0.10
Polyvinyl Pyrrolidone 0.1000 0.25
Carrageenan 1.0000 0.85
PEG (mole wt 3000) 1.0000 0.85
Avicel 0.2500 0.35
Pullulan 51.500 45.5
Thymol NF 0.4000 0.500
Menthol NF 0.5500 0.75
Eucalyptol 0.3500 0.25
Methyl Salicylate USP 0.5000 0.45
Mint flavor 8.5000 10.00
Citric Acid 0.7500
Copper gluconate 1.1150 0.15
Purified water, USP/EP 23.584 31.94
Sodium lauryl sulfate 0.5000 0.500
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CA 02624110 2008-03-27
Aspartame 6.500 5.00
Cooling agent 0.0750 0.05
Sorbitol (crystalline) 1.0000 1.000
Glycerin 1.0000 .075
Polysorbate 80 NF/EP 0.5500 0.025
Atmos 300 0.5500 0.55
FD&C Green #3 0.0090 0.075
D&C Yellow #10 0.0020 0.0100
Total 100%
Example 4 - Characteristics of Wafer Formulation
[0056] A dissolution experiment was conducted to compare dissolution rate of a
wafer
prepared according to Example 1 with commercially available films prepared
using the
conventional extrusion process.
Fentanyl wafer
Film Weight (average of 5 films) = 107 mg +/- 3 mg.
Thickness = 15 micrometer
[0057] The wafer was put in a clear 20 ml glass vial with I ml of cold water
and vial was
gently shaked (20 strokes/min) on rotating shaker. Dissolution time from solid
to gel to
complete solubilization was measured using a stop watch. The following
observations
were recorded at 5 second intervals:
Time (sec) Gel time Complete Solubilization
0 solid film
thick gel approx 20% soluble
sticky gel approx 40-45% soluble
Still some gel approx 70%+ soluble
little gel left approx 90% soluble
no gel complete soluble
-19-
CA 02624110 2008-03-27
[0058] The experiment was repeated 5 times using 5 different wafer samples
under
identical conditions. The average complete dissolution time was calculated to
be about 27
sec.
Listerine Film (made by Wrigleys)
[0059] The same procedure was conducted on samples of Listerine film,
manufactured by
extrusion, to determine dissolution and gelling time of this film
Avg film sample wt = 115 mg +l- 5 mg
Thickness = 20 micrometer
Time (sec) Gel time Complete Solubilization
0 solid film
Solid Approx 10% soluble
Solid Approx 15-20% soluble
Solid Approx 30%+ soluble
Thick gel Approx 45% soluble
Thick gel Approx 45% soluble
Thick gel Approx 50% soluble
Thick gel Approx 65% soluble
Thick gel approx 80% soluble
Thick some gel Approx 90% soluble
75sec no gel complete soluble
The average dissolution time of 5 different Listerine film samples was
determined to be
approximately 70 sec.
Fruit Roll
[0060] The same procedure was conducted on samples of Listerine film,
manufactured by
extrusion, to determine dissolution and gelling time of this film.
-20-
CA 02624110 2008-03-27
Average film wt 330 mg +1- 15 mg (same size as the listerine film)
Thickness = almost 4X the thickness of the listerine and fentanyl wafer (0.1
cm 100 m)
0 solid film
thick gel approx 1% soluble
sticky gel approx 1% soluble
gel approx 2%+ soluble
gel approx 3% soluble
gel approx 5% soluble
gel approx 10% soluble
gel approx 15% soluble
gel approx 20% soluble
some gel approx 25% soluble
75 sec some gel approx 30% soluble
100 sec some gel approx 45% soluble
130 sec some gel approx 50% soluble
150 sec some gel approx 50% soluble
180 sec some gel approx 60% soluble
240 sec some gel approx 70% soluble
300 sec some gel approx 80% soluble
360 sec some gel approx 90% soluble
500 sec some gel approx 95% soluble
700 completely soluble (water became viscous)
The average dissolution time of 5 samples of the Fruit Roll-Up film was about
725-750
seconds.
Conclusion
[0061] A wafer made using the heating/cooling cycling method described herein
exhibits a
much quicker dissolution rate in comparison to comparable films made using the
conventional extrusion methodology.
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CA 02624110 2008-03-27
Example 4. Dog Clinical Data
To evaluate the safety and efficacy of an oral Fentanyl-containing wafer
prepared using the
ingredients described in Example 1 above, the wafer was delivered to 16
healthy dogs as
described below. This study was conducted at the University of Guelph (Ontario
Veterinary College)as an open label, randomized, crossover, and dose ranging
comparative
study of i.m. injection of 200 microgram Fentanyl vs three different doses
(200, 400 and
800 micrograms) of oral Fentanyl wafer. The wafers used were 1.5-2 cm in
diameter
(circular shape) and approximately 0.05 mm thick
[0062] The inclusion criteria were as follows:
Healthy dogs, no sign of any major illness
Normal findings during the screen visit
Male Female
Age 2-8 years
Weight < 30 kgs
[0063] Dogs having any oral cavity disorder (for example, lesions, blisters,
etc) were
excluded from the study.
Screening Procedure Prior to Dosing:
[0064] Prior to the study, each dog underwent a general physical examination
to establish
general health status, including an electrocardiogram (six lead). Only those
dogs with
normal findings were considered healthy and permitted to enter the study.
Fentanyl Administration: Dogs were randomly assigned to treatment (study)
groups; oral
vs. intramuscular injection. All dogs were numbered in order to achieve proper
randomization and to ensure that each dog received each treatment at different
times.
Each group was studied on separate days; the doses were scheduled at least 48-
72 hrs apart
to allow a complete wash out period. Treatment groups were as follows:
-22-
CA 02624110 2008-03-27
Treatment Group 1 (4 dogs) = Oral fentanyl (wafer containing 200 mg fentanyl)
Treatment Group 2 (4 dogs) = Oral fentanyl (wafer containing 400 mg fentanyl)
Treatment Group 3 (4 dogs) = Oral fentanyl (wafer containing 800 mg fentanyl)
Treatment Group 4 (4 dogs) = Intramuscular fentanyl injection (200 mg
fentanyl)
All dogs received all four treatments on a separate occasion as per the
randomization
schedule
An intravenous catheter (Insyte-W) was placed in a cephalic vein and a resting
blood
sample was drawn.
[0065] Drug levels were measured at time 0 (prior to drug administration), and
at 10, 20,
30, 40, 50, 60, 75, 90, 120, 180, and 240 minutes following drug
administration. Fentanyl
blood concentrations (serum) were measured using the standardized ELISA
method.
Fentanyl ELISA Kits were purchased from either Bio-Quant Inc., San Diego,
California, or
from Neogen Corp, Lexington, KY.
Assessment of Safety Precautions during the Study Period:
All safety measures were observed strictly during the study period. In case of
respiratory
depression, and abnormal vital signs, the study for that particular animal was
terminated
immediately. Pulse oxymetry was measured prior to and during the study at
specified time
points, and arterial blood pressure were also monitored via Doppler. The ECG
was
monitored throughout the study period at 0, 1, 3, 5 and 8 hrs
Results:
[0066] The quantitative data analysis showed that administration of the
fentanyl wafer was
at least comparable to the i.m. administration of fentanyl as shown in Fig. 1.
[0067] The Cmax and Tmax for the absorption of fentanyl on administration of
the 800
mcg wafer was determined to be approximately 6.93 ng in 5.6 min. The Cmax and
Tmax
for the absorption of fentanyl on administration of the 400 mcg wafer was
determined to
be approximately 4.83 ng in 5.7 min, and the Cmax and Tmax for the absorption
of
-23-
CA 02624110 2008-03-27
fentanyl on administration of the 200 mcg wafer was determined to be
approximately 0.93
ng in 5.6 min. In contrast, the Cmax and Tmax for the absorption of fentanyl
on
administration of 200 mcg of fentanyl by i.m. injection was approximately 0.63
ng in 13.8
min.
[0068] There were no serious adverse events observed during the entire trial.
All animals
tolerated the oral wafer well. The heart rates, respiratory rates and blood
pressure of each
animal remained normal during the entire study period for all dosages. In
addition, there
were no signs that administration of the fentanyl wafer resulted in buccal
mucosa damage,
peeling of the mouth skin or burning/redness during the study.
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