U.S. patent application number 15/821751 was filed with the patent office on 2018-04-05 for compositions and methods for administration to subjects with dysphagia.
The applicant listed for this patent is Cape Spear Pharmaceuticals, Ltd.. Invention is credited to Jonathan Barker, David Barnes, Stephen Haggerty.
Application Number | 20180092856 15/821751 |
Document ID | / |
Family ID | 51538208 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180092856 |
Kind Code |
A1 |
Barnes; David ; et
al. |
April 5, 2018 |
COMPOSITIONS AND METHODS FOR ADMINISTRATION TO SUBJECTS WITH
DYSPHAGIA
Abstract
Provided are novel methods and compositions for administration
of pharmaceuticals to subjects with dysphagia. Pharmaceuticals are
associated with beads and administered with food, beverage or
cosmetic to provide ease of administration to subjects with
dysphagia. Environmental indicators are associated with beads for
Quality Assurance.
Inventors: |
Barnes; David; (Ottawa,
CA) ; Barker; Jonathan; (Ottawa, CA) ;
Haggerty; Stephen; (Paradise, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cape Spear Pharmaceuticals, Ltd. |
Ottawa |
|
CA |
|
|
Family ID: |
51538208 |
Appl. No.: |
15/821751 |
Filed: |
November 22, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14421940 |
Feb 16, 2015 |
9849093 |
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PCT/IB14/01041 |
Mar 14, 2014 |
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15821751 |
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61788038 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/34 20130101;
A23L 33/10 20160801; A61K 31/4425 20130101; A61K 9/5047 20130101;
A61K 9/5073 20130101; A61K 9/5063 20130101; A61K 31/138 20130101;
G01N 31/221 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A61K 31/4425 20060101 A61K031/4425; A61K 31/138
20060101 A61K031/138; A61K 31/34 20060101 A61K031/34 |
Claims
1-118. (canceled)
119. A composition comprising an active pharmaceutical ingredient
formed into one or more beads and a colored layer and an outer
layer, wherein the one or more beads comprise a first surface,
wherein the colored layer is positioned on the outside of the first
surface, wherein the colored layer comprises a second surface that
is exposed when an outer layer or layers positioned outside the
first and second surfaces is degraded by environmental
conditions.
120. The composition of claim 119, wherein the outer layer is a
polymeric chemical.
121. The composition of claim 120, wherein the polymeric chemical
degrades due to solubilization, exposing the colored layer
underneath.
122. The composition of claim 121, wherein the solubilization
occurs after a duration when the composition is mixed with food or
beverage, exposing the colored layer underneath.
123. The composition of claim 119, wherein the one or more beads
are between 50 and 200 .mu.m in diameter.
124. The composition of claim 123, wherein the one or more beads
are between 50 and 100 .mu.m in diameter.
125. The composition of claim 119, wherein the one or more beads
have an average diameter of between 50 and 1000 .mu.m in
diameter.
126. The composition of claim 125, wherein the one or more beads
have an average diameter of between 50 and 300 .mu.m in
diameter.
127. The composition of claim 119, wherein the active
pharmaceutical ingredient is selected from the group consisting of
nifedipine, metoprolol succinate, isosorbide mononitrate,
furosemide, hydrochlorothiazide, diltiazem, verapamil, digoxin,
enalapril, lisinopril, ramipril, amlodipine, theophylline, ferrous
fumarate and gluconate, atorvastatin, rosuvastatin, levothyroxine,
metformin, potassium chloride, trazodone, carbidopa/levodopa,
gabapentin, carbamazepine, bupropion, olanzapine, chlorpromazine,
valproic acid, clarithromycin, azithromycin, ciprofloxacin,
amoxicillin, naproxen sodium, prednisone, acetaminophen, ibuprofen
and ranitidine.
128. The composition of claim 120, wherein polymeric chemical
degrades above a certain temperature, exposing the colored layer
underneath.
129. The composition of claim 128, wherein the polymeric chemical
degrades at or below 10.degree. C.
130. The composition of claim 128, wherein the polymeric chemical
degrades at or below 0.degree. C.
131. The composition of claim 120, wherein polymeric chemical
degrades below a certain temperature, exposing the colored layer
underneath.
132. The composition of claim 131, wherein the polymeric chemical
degrades at or above 30.degree. C.
133. The composition of claim 131, wherein the polymeric chemical
degrades at or above 50.degree. C.
134. The composition of claim 120, wherein the polymeric chemical
degrades when exposed to low pH, exposing the colored layer
underneath.
135. The composition of claim 134, wherein the low pH is below
about 8.0.
136. The composition of claim 134, wherein the low pH is below
about 6.5.
137. The composition of claim 120, wherein the polymeric chemical
degrades when exposed to high pH, exposing the colored layer
underneath.
138. The composition of claim 137, wherein the high pH is above
about 6.0.
139. The composition of claim 137, wherein the high pH is above
about 7.5.
140. The composition of claim 119, wherein the composition is
formulated to alleviate difficulty swallowing in a subject in need
thereof.
141. The composition of claim 119, wherein the subject in need
thereof suffers from dysphagia.
142. The composition of claim 119, wherein the composition is
formulated to be safe and efficacious when administered to the
subject in food, beverage or cosmetic.
143. The composition of claim 119, wherein the mouthfeel of the
food, beverage or cosmetic is not substantially changed from food,
beverage or cosmetic not comprising the composition in the subject
in need thereof.
144. The composition of claim 119, wherein the taste of the food,
beverage or cosmetic is not substantially changed from food,
beverage or cosmetic not comprising the composition to the subject
in need thereof.
145. The composition of claim 119, wherein the smell of the food,
beverage or cosmetic is not substantially changed from food,
beverage or cosmetic not comprising the composition to the subject
in need thereof.
146. A method of making a dosage form comprising adding the
composition of claim 119 to a food, beverage or cosmetic.
147. A method of administering an active pharmaceutical ingredient
to a subject with difficulty swallowing comprising administering
the composition of claim 119 in food, beverage or cosmetic.
Description
RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/421,940, filed on Feb. 16, 2015, which is a
35 U.S.C. 371 of PCT/IB2014/001041, filed Mar. 14, 2014, which
claims priority from U.S. Provisional Patent Application No.
61/788,038, filed on Mar. 15, 2013. The entire contents of these
applications are incorporated by reference, herein, in their
entirety.
BACKGROUND OF THE INVENTION
[0002] Drug administration in people with swallowing difficulties
(dysphagia), particularly the elderly, is challenging. For example,
residents in extended care facilities take an average of nine
medications daily, ranging from vitamins to support an
anti-osteoporosis regimen, through to cardio-vascular medications
of varying types--blood pressure, cholesterol lowering, diabetes
medications and so on. Typical drug administration is three or even
four times a day. Thirty-five percent of patients in these
facilities have difficulty swallowing.
[0003] Solid oral dosage forms (e.g. pills or tablets etc.) come in
a variety of size, shapes, textures and coatings and are generally
unpleasant and time consuming to administer, even for people who
can manage to swallow them, due to size, stickiness, taste,
aftertaste or frequency of administration. In people who have
dysphagia, swallowing solid oral dosage forms may be very painful,
if not impossible (e.g. stroke patients).
[0004] A standard method of drug administering solid oral
medications such as tablets and pills is to grind them using a
crushing device (manual or motorized) and mix them with whatever
food the patient will tolerate. This process disrupts the
fundamental behavior of the medicine. For the patient, it can
result in toxicity if the drug is absorbed quicker than usual or if
the blood concentration becomes too high (dose dumping). The drug
effects (desirable clinical effects) may wear off quicker than
usual, leaving the patient `unmedicated` until the next dose. It
also results in unpleasant experiences for patients due to bad
taste or unpleasant texture making administration even more
challenging for staff. Crushing pills can result in dosing
inaccuracy as powdered drug can be left behind in the crushing
device or lost during transfer to the food. The process of crushing
can aerosolize the drug and it can be inhaled by staff or patients,
a clear safety issue. Crushing pills by staff can result in
repetitive strain or other workplace injury, a significant
logistical and economic problem for facilities. In addition, among
many other problems, grinding and mixing medications results in
exposure of the active pharmaceutical ingredient (API) to an
environment it was not designed or approved for, in terms of
acidity, temperature, liquid exposure, dissolution outside of the
patient's own body, and other factors. Compounding this problem,
long acting formulations of some drugs have been developed to
reduce the frequency of administration to once daily from 2-4 times
daily; these long acting pills that cannot be ground up because to
do so would release a potentially dangerous bolus of medications to
the patient. Yet this is consistently the primary method by which
drugs are administered to these challenging patients.
[0005] There is a need in the art for pharmaceutical compositions
that are easily taken by subjects with difficulty swallowing and
methods of making and administering these compounds.
SUMMARY
[0006] The disclosure provides a composition comprising an active
pharmaceutical ingredient, a bead and an indicator. In one
embodiment, the composition is formulated to alleviate difficulty
swallowing in a subject in need thereof. The subject in need
thereof can be suffering from dysphagia. In certain embodiments,
the composition is formulated to be safe and efficacious when
administered to the subject in food, beverage or cosmetic. In other
embodiments the compositions are designed for compatibility with
and stability in foodstuffs. The mouthfeel, taste, smell and/or
texture of the food, beverage or cosmetic is generally not
substantially changed from food, beverage or cosmetic not
comprising the composition in the subject in need thereof.
[0007] In some embodiments, the indicator provides information
regarding pH, the presence of temperature changes and the
occurrence of freeze-thaw. According to some aspects of this
embodiment, the indicator provides information regarding lowering
of pH below about 8.0, 7.5, 7.0 or 6.5 or 6.0 or 5.5 or 5.0 or 4.5
or 4.0 In other aspects of this embodiment, the indicator provides
information regarding raising of pH above 4.0 or 4.5 or 5.0 or 5.5
or 6.5 or 6.5 or 7.5 or 8.0.
[0008] In other embodiments, composition of the beads that contain
active pharmaceutical ingredient allows for visual identification
by color of the beads when mixed with food or other administration
matrices or crushed solid oral drug products. The composition of
the beads that contain active pharmaceutical ingredient can also
show when bead integrity is compromised due to solubilization.
[0009] In another embodiment, the indicator provides information
regarding a temperature change wherein the temperature drops below
10 or 5.degree. C. In yet another embodiment, the indicator
provides information regarding a temperature change wherein the
temperature rises above 30 or 50.degree. C.
[0010] In certain embodiments, the indicator changes color in order
to provide information. The color change can be from white or gray
to red, green, blue, orange, yellow or violet. In other more
specific embodiments, the indicator is selected from the group
consisting of: a dark blue and light blue indicator once sold under
the trademark REFLEX BLUE.TM., Black Pantone 7C 2x, Red 192,
Process Magenta, Orange 165, Green 349, green C, Purple 2735,
Yellow 100U, gentian violet, leucomalachite green, thymol blue,
methyl yellow, bromophenol blue, congo red, methyl orange, screened
methyl orange, bromocresol green, methyl red, azolitmin,
bromocresol purple, bromothymol blue, phenol red, a eurhodin dye
once sold under the trademark NEUTRAL RED.TM., naphtholphthalein,
cresol red, phenolphthalein, thymolphthalein and alizarene yellow
R.
[0011] In other embodiments the indicator may be comprised of a
colored layer that is exposed when an outer layer or layers is
changed by the environmental conditions. In one embodiment the bead
is coated with a polymeric chemical that degrades above a certain
temperature, exposing a colored indicator layer underneath. In
another embodiment, the bead is coated with a polymeric chemical
that fractures at or below 0 degrees Celsius revealing a colored
indicator layer underneath. In another embodiment the bead is
coated with a polymeric chemical that will degrade when exposed to
low pH, revealing a colored indicator layer underneath. In another
embodiment the bead is coated with a polymeric chemical that will
degrade when exposed to high pH, revealing a colored indicator
layer underneath. In another embodiment, the beads are between 50
and 200, 50 and 100, 50 and 1000 and 50 and 300 .mu.m in
diameter.
[0012] In other embodiments, the composition comprises two groups
of beads, wherein the first group of beads comprises the active
pharmaceutical ingredient and the second group comprises the
indicator. The beads of the first group can be between 50 and 200,
50 and 100, 50 and 1000 and 50 and 300 .mu.m in diameter. The beads
of the second group can be between 50 and 1000, 50 and 750, 50 and
750 and 50 and 200 .mu.m in diameter.
[0013] In another embodiment the indicator beads population may be
comprised of one population of beads that indicate all
environmental parameters described, being pH, freeze/thaw, and high
temperature. In other embodiments the indicator beads population
may be comprised or two or three or more bead sub-populations each
of which indicates one single environmental parameter. In one
embodiment the population of indicator beads would be comprised of
three distinct populations of indicator beads, one of which would
indicate temperature excursion, the second of which would indicate
pH excursion, the third of which would indicate freeze/thaw.
[0014] In one embodiment the indicator bead population is packaged
separately from the medicinal beads population. In another
embodiment indicator beads for each environmental parameter are
packaged separately.
[0015] In another embodiment, the active pharmaceutical ingredient
is selected from the group consisting of Nifedipine, Metoprolol
succinate, isosorbide mononitrate, furosemide, hydrochlorothiazide,
diltiazem, verapamil, digoxin, enalapril, lisinopril, ramipril,
amlodipine, theophylline, ferrous fumarate and gluconate,
atorvastatin, rosuvastatin, levothyroxine, metformin, potassium
chloride, trazodone, carbidopa/levodopa, gabapentin, carbamazepine,
bupropion, olanzapine, chlorpromazine, valproic acid,
clarithromycin, azithromycin, ciprofloxacin, amoxicillin, naproxen
sodium, prednisone, acetaminophen, ibuprofen and ranitidine.
[0016] The disclosure also provides a method of making a dosage
form comprising adding the composition to a food, beverage or
cosmetic.
[0017] The disclosure also provides a kit including an active
pharmaceutical ingredient and a first group of beads and an
indicator and a second group of beads, wherein the active
pharmaceutical ingredient and the first group of beads are provided
in a first container and the indicator and the second group of
beads are provided in a second container.
[0018] The disclosure also provides a kit wherein indicator beads
for each individual environmental parameter are provided in
individual containers. In another embodiment combinations of two or
more indicators are provided in a container. In another embodiment,
in additional individual containers wherein individual containers
can contain: a single population of beads, wherein each bead
contains a plurality of indicators, a single population of beads
wherein each bead contains one individual indicator, a single
population of beads wherein each bead contains combinations of two
or more indicators, a mixed population of beads, wherein the
container contains a mix of two or more beads and wherein each bead
contains one individual indicator.
[0019] In one embodiment, the beads of the first group are between
50 and 200, 50 and 100, .mu.m in diameter or have an average
diameter between 50 and 200, 50 and 100. In another embodiment, the
beads of the second group are between or have an average diameter
between 50 and 1000, 50 and 750, 50 and 500 and 50 and 200 .mu.m in
diameter.
[0020] In another embodiment, the active pharmaceutical ingredient
is selected from the group consisting of Nifedipine, Metoprolol
succinate, isosorbide mononitrate, furosemide, hydrochlorothiazide,
diltiazem, verapamil, digoxin, enalapril, lisinopril, ramipril,
amlodipine, theophylline, ferrous fumarate and gluconate,
atorvastatin, rosuvastatin, levothyroxine, metformin, potassium
chloride, trazodone, carbidopa/levodopa, gabapentin, carbamazepine,
bupropion, olanzapine, chlorpromazine, valproic acid,
clarithromycin, azithromycin, ciprofloxacin, amoxicillin, naproxen
sodium, prednisone, acetaminophen, ibuprofen and ranitidine.
[0021] In other embodiments, the indicator provides information
regarding pH, the presence of temperature changes and the
occurrence of freeze-thaw. According to some aspects of this
embodiment, the indicator provides information regarding lowering
of pH below about 8.0, 7.5, 7.0, 6.5, 6.0, 5.5 or 5.0. According to
other aspects of this embodiment, the indicator provides
information regarding raising of pH above about 5.0, 5.5, 6.0, 6.5,
7.0 7.5 or 8.0.
[0022] In another embodiment, the indicator provides information
regarding a temperature change wherein the temperature drops below
10 or 5.degree. C. In yet another embodiment, the indicator
provides information regarding a temperature change wherein the
temperature rises above 30 or 50.degree. C.
[0023] In certain embodiments, the indicator changes color in order
to provide information. The color change can be from white or gray
to red, green, blue, orange, yellow or violet. In other more
specific embodiments, the indicator is selected from the group
consisting of: a dark blue and light blue indicator once sold under
the trademark REFLEX BLUE.TM., Black Pantone 7C 2x, Red 192,
Process Magenta, Orange 165, Green 349, green C, Purple 2735,
Yellow 100U, gentian violet, leucomalachite green, thymol blue,
methyl yellow, bromophenol blue, congo red, methyl orange, screened
methyl orange, bromocresol green, methyl red, azolitmin,
bromocresol purple, bromothymol blue, phenol red, a eurhodin dye
once sold under the trademark NEUTRAL RED.TM., naphtholphthalein,
cresol red, phenolphthalein, thymolphthalein and alizarene yellow
R.
[0024] In some embodiments the indicator may be comprised of a
colored layer that is exposed when an outer layer or layers is
changed by the environmental conditions. In one embodiment the bead
is coated with a polymeric chemical that degrades above a certain
temperature, exposing a colored indicator layer underneath. In
another embodiment, the bead is coated with a polymeric chemical
that fractures at or below 0 degrees Celsius revealing a colored
indicator layer underneath. In another embodiment the bead is
coated with a polymeric chemical that will degrade when exposed to
low pH, revealing a colored indicator layer underneath. In another
embodiment the bead is coated with a polymeric chemical that will
degrade when exposed to high pH, revealing a colored indicator
layer underneath.
[0025] The disclosure also provides a method of administering an
active pharmaceutical ingredient to a subject with difficulty
swallowing comprising formulating the active pharmaceutical
ingredient, thereby alleviating difficulty swallowing the active
pharmaceutical ingredient in the subject with difficulty
swallowing. In one embodiment, the subject in need thereof suffers
from dysphagia. In another embodiment, the composition, that is
designed and formulated specifically for compatibility, safety and
efficacy when mixed with food, is administered to the subject in
food, beverage or cosmetic.
[0026] In other embodiments, the method also includes sprinkling
the formulated active pharmaceutical ingredient that is designed
for administration in food, into or onto the food, beverage or
cosmetic. In additional embodiments, the method also includes
mixing the formulated active pharmaceutical ingredient that is
designed for administration in food, into or onto the food,
beverage or cosmetic.
[0027] According to some embodiments, the mouthfeel, taste, smell
or texture of the food, beverage and/or cosmetic is not
substantially changed from food, beverage or cosmetic not sprinkled
or mixed with the formulated active pharmaceutical ingredient.
[0028] In certain embodiments, the microformulating step comprises
coating beads with the active pharmaceutical ingredient. In other
embodiments, the beads are between 50 and 200 or 50 and 100 .mu.m
in diameter or have an average diameter between 50 and 200 or 50
and 100 .mu.m.
[0029] In other embodiments, the method also includes adding an
indicator to the formulated active pharmaceutical ingredient. In
certain embodiments, the indicator provides information regarding
pH, temperature changes and the occurrence of freeze-thaw.
According to some aspects of this embodiment, the indicator
provides information regarding lowering of pH below about 8.0, 7.5,
7.0, 6.5, 6.0, 5.5 or 5.0. According to other aspects of this
embodiment, the indicator provides information regarding raising of
pH above about 5.0, 5.5, 6.0, 6.5, 7.0 7.5 or 8.0.
[0030] In another embodiment, the indicator provides information
regarding a temperature change wherein the temperature drops below
10 or 5.degree. C. In yet another embodiment, the indicator
provides information regarding a temperature change wherein the
temperature rises above 30 or 50.degree. C.
[0031] In certain embodiments, the indicator changes color in order
to provide information. The color change can be from white or gray
to red, green, blue, orange, yellow or violet. In other more
specific embodiments, the indicator is selected from the group
consisting of: a dark blue and light blue indicator once sold under
the trademark REFLEX BLUE.TM., Black Pantone 7C 2x, Red 192,
Process Magenta, Orange 165, Green 349, green C, Purple 2735,
Yellow 100U, gentian violet, leucomalachite green, thymol blue,
methyl yellow, bromophenol blue, congo red, methyl orange, screened
methyl orange, bromocresol green, methyl red, azolitmin,
bromocresol purple, bromothymol blue, phenol red, a eurhodin dye
once sold under the trademark NEUTRAL RED.TM., naphtholphthalein,
cresol red, phenolphthalein, thymolphthalein and alizarene yellow
R.
[0032] In some embodiments the indicator may be comprised of a
colored layer that is exposed when an outer layer or layers is
changed by the environmental conditions. In one embodiment the bead
is coated with a polymeric chemical that degrades above a certain
temperature, exposing a colored indicator layer underneath. In
another embodiment, the bead is coated with a polymeric chemical
that fractures at or below 0 degrees Celsius revealing a colored
indicator layer underneath. In another embodiment the bead is
coated with a polymeric chemical that will degrade when exposed to
low pH, revealing a colored indicator layer underneath. In another
embodiment the bead is coated with a polymeric chemical that will
degrade when exposed to high pH, revealing a colored indicator
layer underneath.
[0033] According to some embodiments, the active pharmaceutical
ingredient coats a first group of beads and the indicator coats a
second group of beads. In another embodiment, the subject is a
mammal In some aspects of the embodiment, the subject is a human.
In other aspects of this embodiment, the human is greater than 65
years in age.
DETAILED DESCRIPTION
[0034] The disclosure provides pharmaceutical compositions that are
easier to swallow than solid oral dosage forms. In certain
embodiments, the pharmaceuticals described herein can be
administered less frequently than solid oral dosage forms.
[0035] According to further embodiments, the pharmaceutical
compositions described herein also include an "indicator"
capability that warns of certain potential issues relating to
product identity, integrity, food compatibility and medication
co-administration compatibility. In certain embodiments, indicators
provide signals showing the identity of an API associated with the
indicator. In other embodiments, indicators can also change in
signal when changes in the API integrity, compatibility of the API
with food or other medications that are co-administered with the
API occur. In certain embodiments, more than one type of indicator
is used. In certain specific embodiments, indicators that show
identity of an API are used with indicators that show changes in
status of the integrity, food compatibility and medication
co-administration compatibility of the API.
[0036] In certain embodiments, the pharmaceutical compositions
described herein is a powder, coated bead or granular technology,
which offers the greatest flexibility in terms of drugs that can be
incorporated while meeting the specific administration to subjects
with dysphagia. These compositions can be combined with various
types of food, beverage and/or cosmetics to aid in administration
of APIs to subjects with dysphagia. Particularly, the
pharmaceuticals can be combined with various types of food or
beverage. In other embodiments, the pharmaceuticals can be combined
with various types of food.
I. Dysphagia
[0037] Subjects with dysphagia have difficulty swallowing. Subjects
with dysphagia can have oropharyngeal dysphagia, esophageal
dysphagia or functional dysphagia. Oropharyngeal dysphagia can
arise from abnormalities of muscles, nerves or structures of the
oral cavity, pharynx, and upper esophageal sphincter. Esophageal
dysphagia can arise from the body of the esophagus, lower
esophageal sphincter, or cardia of the stomach, usually due to
mechanical causes or motility problems. Functional dysphagia is
when a subject has trouble swallowing but no organic cause of the
dysphagia can be found. Functional dysphagia is more common in the
geriatric population because the ability to swallow usually
deteriorates with old age. The compositions and methods described
herein can be used to administer active pharmaceutical ingredients
(API; drug substance; medicine) to subjects with any form of
dysphagia.
[0038] Symptoms of dysphagia include difficulty controlling food in
the mouth, inability to control food or saliva in the mouth,
difficulty initiating a swallow, coughing, choking, frequent
pneumonia, unexplained weight loss, gurgly or wet voice after
swallowing and nasal regurgitation. Dysphagia occurs more often in
elderly subjects, subjects who have suffered strokes and subjects
admitted to acute care hospitals or chronic care facilities. Other
causes of dysphagia include head and neck cancer, progressive
neurologic diseases such as Parkinson's disease, dementia, multiple
sclerosis, multiple system atrophy, or amyotrophic lateral
sclerosis. The compositions and methods described herein can be
used to more easily administer API to subjects with any of the
above pathologies or symptoms or to geriatric patients, mitigating
the discomfort and pain associated with swallowing solid oral
dosage forms (e.g. pills, tablets).
[0039] As used herein, "geriatric patients" refers to human
subjects of greater than 50 years of age suffering from a pathology
or dysfunction that requires help from a medical professional.
According to other embodiments, geriatric patients are human
subjects of greater than 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,
61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,
78, 79 or 80 years old. Geriatric patients can also refer to
mammalian non-human subjects of advanced age that are suffering
from a pathology that requires help from a veterinary professional.
Geriatric patients that are mammalian non-human subjects have
advanced through greater than 60% of the normal life expectancy for
their species. In other embodiments, the mammalian non-human
subjects have advanced through greater than 65, 70, 75, 80, 85, 90
or 95% of the normal life expectancy for their species.
II. Beads
[0040] In certain embodiments, the APIs administered according to
this disclosure are associated with beads. The size of the beads
allows the API to be administered with a food, beverage or cosmetic
without changing the texture, smell and/or taste of the food,
beverage or cosmetic.
[0041] Beads appropriate for use according to the compositions and
methods described herein are smaller than 1000 .mu.m in diameter.
According to other embodiments, the beads appropriate for use
according to the compositions and methods described herein are
smaller than 1000, 950, 900, 850, 800, 750, 700, 650, 600, 550,
500, 450, 400, 350, 300, 290, 280, 270, 260, 250, 240, 230, 220,
210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 90, 80,
70, 60, 50, 40, 30, 20 or 10 .mu.m in diameter. According to other
embodiments, the beads appropriate for use according to the
compositions and methods described herein are between 50 and 300
.mu.m in diameter.
[0042] In certain embodiments, beads appropriate for use according
to the compositions and methods described herein are smaller than
300 .mu.m in diameter. According to other embodiments, the beads
appropriate for use according to the compositions and methods
described herein are smaller than 290, 280, 270, 260, 250, 240,
230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110,
100, 90, 80, 70, 60, 50, 40, 30 20 or 10 .mu.m in diameter.
According to other embodiments, the beads appropriate for use
according to the compositions and methods described herein are
between 50 and 300 .mu.m in diameter. Smaller beads are
particularly useful for being associated with API Smaller beads
have less of an effect on mouthfeel, texture and taste when the
beads are mixed with food, beverage or cosmetics.
[0043] According to other embodiments, the beads appropriate for
use according to the compositions and methods described herein are
between 70 and 200 .mu.m in diameter. According to other
embodiments, the beads appropriate for use according to the
compositions and methods described herein are between 10 and 50, 50
and 100, 100 and 150, 150 and 200, 200 and 250, 250 and 300, 50 and
250, 50 and 200, 50 and 150, 70 and 250, 70 and 150, 70 and 100 or
100 and 200 .mu.m in diameter.
[0044] API can be associated with beads according to any method
known in the art. The bead API compositions can be made on
microparticles of the API, itself. In other embodiments, the API is
associated with beads of various compositions.
[0045] The bead compositions described herein can be manufactured
according to any method known in the art. Methods known in the art
include extrusion and spheronization, drug layering, hot melt
extrusion, mini-tabs, spray congealing, direct pelletization and
high shear melt pelletization. In certain embodiments, the bead
compositions described herein are manufactured by extrusion and
spheronization or drug layering or hot melt extrusion or
pelletization. Extrusion and spheronization involves a multi-step
process including dry mixing, wet massing, extrusion,
spheronization and drying steps. Wet massing uses high
shear/planetary/Hobart/sigma blade mixer. Extrusion uses various
screen sizes. Spheronization is accomplished with a marumizer with
different sizes of cross hatch plates. Beads can be coated with
various layers of coatings. Drug layering involves deposition of
successive layers of drug from solution or suspension on substrates
which may be crystals or granules of the same material or inert
beads. Sugar spheres or MCC (non-pareil seeds) are the most common
starting materials. Drug particles are dissolved/suspended in the
binding liquid and sprayed on to the sugar spheres in a fluid bed
coater equipped with Wurster column. Hot melt extrusion involves
solid dispersion of active pharmaceutical ingredients (APIs) in a
polymeric matrix. The goal is to disperse drugs in a matrix at the
molecular level to form solid solutions or dispersions. It is a
single step continuous process that produces pellets/beads with
solid solution/dispersion of API in excipients. Functional
excipients can be matrix polymers such as PVP, PVP-VA, polyethylene
co-vinyl acetate, polyethylene glycols, cellulose ethers and
acrylates, polyethylene oxides, PLGA, low melting waxes, bees wax,
carnauba wax, cetyl palmitate, gleceryl behanate, gleceryl
monostearate, hydrogenated castor oil, stearic acid, stearic
alcohol. Plasticizers can be used including but not limited to low
molecular weight polyethylene glycols. Bulking agents and other
ingredients such as colors and anti-oxidants can be included.
Pelletization can include direct pelletization-rotogranulation, and
high shear melt pelletization. Rotogranulation is where dry blended
material containing API is wetted with solvent or binder system and
subjected to centrifugal motion simultaneously producing
agglomerates. High shear melt includes pelletization by heating and
massing a dry powder mixture. API, binder and other excipients are
mixed and heated to beyond the melting point of the binder. Binders
can be stearic acid, glycerol monostearate, hydrated castor oil and
polyethylene glycols or others.
III. Indicators
[0046] The compositions described herein can also include
indicators. These indicators are used to monitor various parameters
associated with API administration, particularly when the API is
first mixed with or sprinkled on food, beverage or cosmetic. The
parameters that can be monitored include pH, temperature and
freeze/thaw. The indicators operate by creating a signal when a
threshold for a parameter is reached. In certain embodiments, this
signal is a color change. However, any signal method known in the
art could be used. These methods include signals based on changes
in fluorescence, magnetic properties, ionic properties,
electrochemical properties or resonance properties. Indicators have
a home configuration wherein a first signal is produced and at
least a first threshold configuration wherein a second signal is
produced. The indicator changes from a home to a first threshold
configuration upon passing a threshold in a measured parameter.
According to certain embodiments, the indicators used herein have
more than one threshold. In certain embodiments, the indicators
described herein have 2, 3, 4, 5, 6, 7, 8, 9, 10 or more threshold
configurations that are reached through exposing the indicator to a
given parameter as different ranges.
[0047] In one example, an indicator operates as follows. For the
purposes of this example, an indicator detected pH changes. The
indicator is in its home configuration when it is exposed to a pH
between 6.5 and 7.5. At this pH range, the indicator is a neutral
color. At a pH<6.5 the indicator's first threshold is reached.
In the first threshold configuration, the indicator changes color
to red. At a pH>7.5 the indicator's second threshold is reached.
In the second threshold configuration the indicator changes color
to blue.
[0048] In certain embodiments, when a threshold is reached, the
indicator retains the color associated with the configuration
caused by passing that threshold, even if the conditions the
indicator is exposed to change so that the indicator is no longer
exposed to a value of a parameter that is beyond the threshold. For
example, an indicator that has a first threshold of pH<6.0 is
exposed to a pH of 5.5. The indicator attains its first threshold
configuration and changes color, here to red. Later, the pH the
indicator is exposed to increases to 7.3. In this example, the
indicator would retain the color associated with its first
threshold configuration. In other embodiments, the color of the
indicator reflects the value of the parameter that it is presently
exposed to. Thus, in this example, an indicator would change from
the color associated with its first threshold and back to the color
associated with its home configuration if conditions changed from
those that trigger the first threshold configuration and then back
to conditions that are associated with the home configuration.
[0049] The color used for each configuration can be any known in
the art as long as the colors for the various configurations can be
distinguished from each other. Colors that can be used include
white, black, brown, grey, red, orange, yellow, green, blue or
violet. However, any color across the visible spectrum could be
used. Indicators that differentially reflect light outside the
visible spectrum (e.g. ultraviolet and infrared) could also be
used. In certain embodiments, the color used for the home
configuration is neutral so that the indicator is not detectable to
the naked eye when mixing the indicator with food, beverage or
cosmetics. In these embodiments, the first and other threshold
configurations are represented by colors that are detectable to the
human eyes. In other embodiments, the indicator is detectable to
the human eye in its home configuration as well as in threshold
configurations. In other embodiments, the indicator is detectable
in its home configuration but not in at least some threshold
configurations.
[0050] According to certain embodiments, the indicators used with
the compositions and methods described herein are used to detect
changes in pH. In certain embodiments, the indicators are used to
detect acidity, to prevent hydrolytic degradation of APIs mixed
with the indicator by hydrolysis. In certain embodiments, the
indicator shows a change in pH when it passes below 8.0, 7.9, 7.8,
7.7, 7.6, 7.5, 7.4, 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5,
6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2,
5.1, 5.0, 4.9,4.8, 4.7, 4.6, 4.5, 4.4, 4.3 4.2, 4.1 or 4.0. In
other embodiments, the indicators are used to detect the presence
of basic conditions. In certain embodiments, the indicator shows a
change in pH when it passes above 6.0, 6.1, 6.2, 6.3, 6.4, 6.5,
6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8,
7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1,
9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0. In certain
embodiments, indicators transition from their home configuration to
a first threshold configuration when pH changes to be outside of a
certain pH range. These ranges include pH of 6.0-8.0, 6.5-7.5, 5.0-
7.0, 7.0-8.0, 7.2-7.6, or 7.0-9.0. In certain embodiments, whether
the pH became higher or lower than the desired range, the indicator
would transition to its first threshold configuration. According to
other embodiments, the indicator could transition to a first
threshold configuration if the indicator were exposed to an
environment with a pH lower than a desired range and transition to
a second threshold configuration if the indicator were exposed to
an environment with a pH higher than a desired range. The first and
second threshold configurations could be represented by different
colors to be differentiated.
[0051] According to other embodiments, the indicators used with the
compositions and methods described herein are used to detect
changes in temperature. In certain embodiments, the indicators are
used to detect exposure to high temperatures. Certain APIs become
less effective when exposed to high temperatures. In certain
embodiments, the indicator shows a change in temperature when it
passes above 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 100, 105, 110, 115 or 120 .degree. C. This temperature could be
achieved when the indicator is added to a food, beverage or
cosmetic that is subject to heating. In other embodiments, the
indicators are used to detect exposure to low temperatures. Certain
APIs become less effective when exposed to low temperatures,
especially if they are exposed to freeze thaw cycles. In certain
embodiments, the indicator shows a change in color when it passes
below 20, 15, 10, 5, 0, -5, -10, -15, -20, -25, 30, -35 or -40
.degree. C. In certain embodiments, indicators transition from
their home configuration to a first threshold configuration when
exposed to temperature outside of a certain range. These ranges
include 10-25, 25-50, -5-5, 0-5, -5-0, 25-50, 90-110.degree. C. In
certain embodiments, whether the temperature was higher or lower
than the desired range, the indicator would transition to its first
threshold configuration. According to other embodiments, the
indicator could transition to a first threshold configuration if
the indicator were exposed to an environment with a temperature
lower than a desired range and transition to a second threshold
configuration if the indicator were exposed to an environment with
a temperature higher than a desired range. The first and second
threshold configurations could be represented by different colors
to be differentiated.
[0052] In other embodiments, the indicator is able to detect
exposure to freezing and/or thawing. In certain embodiments, an
indicator can detect the temperature change that accompanies a
freeze thaw cycle. In some embodiments, when the indicator has been
exposed to a freeze thaw cycle, a first threshold is reached and
the color of the indicator changes. In certain embodiments, if the
indicator is then exposed to higher or lower changes, it retains
the color associated with the first transition configuration
triggered by the freeze/thaw event. In other embodiments, the
indicator reaches a second, third or additional thresholds with
subsequent freeze/thaw events. Thus, the indicator can show a
different color depending on the number of freeze/thaw events it is
exposed to. In certain embodiments, the indicator need only be
exposed to freezing temperatures to show a freeze/thaw event. In
other embodiments, the indicator must be exposed to freezing
temperatures and then temperatures above freezing to register a
freeze/thaw event. Different aqueous and organic solutions have
different freezing temperatures. In some embodiments, the
freeze/thaw indicator is sensitive to freezing at 0.degree. C. In
other embodiments, the freezing temperature is selected from -10,
-9, -8, -7, -6, -5, -4, -3, -2, 1, 1, 2, 3, 4, 5, 6, 7, 8, 9 or
10.degree. C.
[0053] Indicators can be associated with beads. According to
embodiments in which the indicators are administered with an API,
the API and indicators can be associated with the same beads or
they can be associated with different beads. According to some
embodiments, when the APIs and indicators are associated with
different beads the beads can be of the same type or different
types.
[0054] In certain embodiments, beads associated with indicators can
be between 300 and 1000 .mu.m in diameter. In other embodiments,
the beads associated with indicators can be 300-500, 500-750 or
750-1000 .mu.m in diameter. These larger beads are particularly
useful for indicators that show the identity of an API that they
are associated with. The greater size of the beads allows the
signal (e.g. color) from the indicators to be more easily
perceived. These larger sized beads can enhance the signal produced
by any type of indicator.
[0055] In certain embodiments, the compositions described herein
contain only bead associated indicators. These bead associated
indicators can then be later mixed with an API to show its identity
or used in situations where changes in the values of particular
parameters are necessary. Examples of these parameters are provided
above.
[0056] IV. Kits
[0057] The disclosure also provides kits consistent with
administration of the compositions described herein. These kits
include APIs associated with beads that are coded by indicators. In
certain embodiments, the indicators encode the associated beads by
color. The color provided by the indicator can be used to color
code the pharmaceutical associated with that indicator for ease of
selecting and administering pharmaceuticals to a patient population
and also providing a quality assurance step by allowing
identification of the beads drug product in food or other
administration matrices and allowing differentiation from admixed
crushed solid oral drug products.
[0058] In certain embodiments, each container contains a single
dose of API. These doses can be associated with beads and/or
indicators. The indicators can also be associated with beads of the
same or different type from the API associated beads.
[0059] In certain embodiments each container contains a single dose
of multiple APIs. These doses can be associated with beads and/or
indicators. The indicators can also be associated with beads of the
same or different type from the API associated beads.
[0060] In certain embodiments, each API is associated with one type
of bead. In other embodiments each API is associated with multiple
types of beads. These various API associated beads can be mixed to
provide various API dosing regimens including time release or
various dose amounts. Kits can also include indicators independent
of an API. These indicators can be associated with beads of their
own or free in solution or suspension. These indicators can be
mixed with APIs and potentially the APIs associated beads for any
of the detecting needs described above. Thus, an API that needs to
have an indicator for pH can be mixed with that appropriate
indicator in that situation. APIs will need different indicators
depending on the specific API and the mode of administration. The
necessary indicator may also be dependent upon the specific food,
beverage or cosmetic that the API is being administered in.
[0061] In another embodiment, the kits make up a system in which
several APIs are associated with beads in separate containers. In
some embodiments, each container contains one API. Each API can be
associated with beads. In certain embodiments, each of the APIs is
associated with an indicator that shows a different color for ease
of identification. These APIs could also be associated with
specific indicators for detection of any of the properties shown
above. In certain embodiments, the system also includes indicators
in separate containers such that one container may contain one
population of indicators for one environmental parameter, or
combinations of two or more indicators to detect two or more
parameters. In some embodiments, each container contains one
indicator. Each indicator is capable of detecting a different
parameter. The system can be used to provide different combinations
of APIs associated with beads with different indicators. In certain
embodiments, the indicators are also associated with beads
independent of the beads that the APIs are associated with. Each
API and/or indicator can be associated with differing or similar
beads depending on the specific API or indicator.
[0062] In certain embodiments, the containers for the APIs or
indicators described herein are transparent to reveal the color of
the APIs or indicators or the APIs mixed with indicator. In other
embodiments, the containers, themselves, are color coded for easy
identification of APIs or combinations of APIs and indicators or
indicators. The containers can also include identifying marks for
quality control purposes. For instance, identifying marks include
labels, bar codes or RFID tags. The identifying marks can be
readily integrated into the systems already used in medical care
facilities. These medical care facilities can be hospitals,
hospices, clinics or elder care facilities.
V. Food, Beverage or Cosmetic
[0063] According to certain embodiments, the bead associated APIs
and in some embodiments, indicators, are sprinkled on or mixed with
food, beverage or cosmetics. In certain embodiments, food, beverage
and cosmetics are used that fit the temperature and pH limitations
of the APIs that are added to them. For instance, some APIs are
heat or pH sensitive and lose efficacy if exposed to extremes in
temperature or pH. In some embodiments, the food, beverage or
cosmetic is heat treated either prior to mixing with the API,
during mixing with the API or after mixing with the API.
[0064] Foods that can be mixed with the bead associated APIs
described herein include soups, cereals, breads, pretzels, chips,
popcorn, cooked and or pureed vegetables, corn, carrots, cabbage,
lettuce, tomatoes, potatoes, greens, broccoli, cucumbers, celery,
mushrooms, radishes, nuts, peanuts, walnuts, pecans, almonds,
cashews, cheese, cheddar cheese, Swiss cheese, brie, blue cheese,
meats, pastas, fish, white sauce, meat sauce, demi-glace sauce,
tomato sauce, curry, stew, cream soup, minestrone, Worcestershire
sauce, middle-thick sauce, thick sauce, pork cutlet sauce,
seasoning soy sauces, Chinese noodles, buckwheat noodles, jams,
jellies, preserves, nut butters, (e.g. peanut, almond, Nutella)
yogurt plain or flavored, puddings, white wheat noodles, chops,
rice, dumplings, dressings, dried seasoning powder, dipping sauces,
frozen foods, ready-to-eat foods, instant foods, beef, chicken,
lamb, pork, and others. Beverages include, water, tea, coffee,
soda, soda water, tonic water, juice, alcoholic beverages, beer,
wine, spirits, milk, pedialyte, electrolyte replenishment drinks
and others. Cosmetics include shaving cream, chewing gum,
toothpaste, eye drops, make-up, sun block, skin lotion, mouthwash,
mints, aftershave lotion, soap, shampoo, conditioner and
others.
[0065] In certain embodiments, the bead compositions described
herein would not substantially change the taste or flavor of the
food, beverage or cosmetic it is administered with. In other
embodiments, the bead compositions described herein would not
substantially change the texture of the food, beverage or cosmetic
it is administered with. In other embodiments, the bead
compositions described herein would not substantially change the
appearance of the food, beverage or cosmetic it is administered
with. In other embodiments, the bead compositions described herein
would not substantially change the color of the food, beverage or
cosmetic it is administered with unless a threshold was reached on
a parameter of an indicator included with the beads.
[0066] In certain embodiments, APIs cannot be mixed with hot, cold,
frozen, acidic or basic foods.
VI. Methods of Administration
[0067] The compositions described herein are administered through
adding and mixing the bead-associated API with food, beverage
and/or cosmetics. In certain embodiments, the compositions
described herein are administered through adding and mixing the
bead-associated API with food or beverage. In certain embodiments,
the compositions described herein are administered through adding
and mixing the bead-associated API with food. The bead-associated
API can also be associated with an indicator. The indicator can
also be associated with its own population of beads such that this
population of beads contains an indicator or indicators or other
ingredients to otherwise inform potential product safety issues,
efficacy issues and quality assurance, but that contains no API
(i.e. this is a placebo population of indicator beads). This
population of indicator placebo beads may be administered
separately from the API-containing beads, such as with other
medicinal products, that may be administered and mixed with
API-containing beads either as a combined drug product or
separately.
[0068] According to certain embodiments, each API is associated
with beads and one or more indicators in one container. In this
embodiment, specific indicators that show the identity, integrity
and/or efficacy of the API are present with the API in one pre-made
dosage form. In other embodiments, the API is associated with
beads, but the indicators are added to the bead-associated API
later. The indicators can be added by a health care professional or
someone else in the supply chain for the bead associated API.
Indicators can be added to the bead associated API depending on the
context in which it will be administered. These contexts could vary
depending on the specific food, beverage or cosmetic the bead
associated API is administered with, the types of drugs the
intended patient population tends to be taking or the conditions
the bead associated API may experience during transport and
storage. The indicators to be added to the bead associated APIs may
themselves be associated with their own beads. These indicators may
be presented in color coded or transparent containers. The
containers and/or the beads themselves may be color coded for easy
identification of the indicators. Any of the indicators described
above may be used according to these embodiments.
[0069] The bead associated APIs may be sprinkled into food,
beverage or cosmetics. The bead associated APIs can be mixed with
the food, beverage or cosmetics according to any method known in
the art.
VII. Pharmaceutical Compositions
[0070] In certain embodiments, the APIs described herein are
further formulated with a pharmaceutically acceptable carrier. In
preferred embodiments, pharmaceutical compositions and formulations
described herein are administered orally, transmucosally or
transdermally The pharmaceutical compositions can be formulated in
any way and can be administered in a variety of unit dosage forms
depending upon the condition or disease and the degree of illness,
the general medical condition of each patient, the resulting
preferred method of administration and the like. Details on
techniques for formulation and administration of pharmaceuticals
are well described in the scientific and patent literature, see,
e.g., Remington: The Science and Practice of Pharmacy, 21st ed.,
2005.
[0071] The APIs described herein can be administered alone or as a
component of a pharmaceutical formulation (composition). The
compounds may be formulated for administration, in any convenient
way for use in human or veterinary medicine. Wetting agents,
emulsifiers and lubricants, such as sodium lauryl sulfate and
magnesium stearate, as well as coloring agents, release agents,
coating agents, sweetening, flavoring and perfuming agents,
preservatives and antioxidants can also be present in the
compositions.
[0072] Pharmaceutical formulations of the invention can be prepared
according to any method known to the art for the manufacture of
pharmaceuticals. Such drugs can contain sweetening agents,
flavoring agents, coloring agents and preserving agents. A
formulation can be administered with nontoxic pharmaceutically
acceptable excipients which are suitable for manufacture.
Formulations may comprise one or more diluents, emulsifiers,
preservatives, buffers, excipients, etc. and may be provided in
such forms as liquids, powders, emulsions, lyophilized powders,
sprays, creams, lotions, controlled release formulations, tablets,
pills, gels, on patches, in implants, etc.
[0073] Aqueous suspensions can contain an active agent in admixture
with excipients suitable for the manufacture of aqueous suspensions
for mixing with beads. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethylene oxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
(e.g., polyoxyethylene sorbitol mono-oleate), or a condensation
product of ethylene oxide with a partial ester derived from fatty
acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan
mono-oleate). The aqueous suspension can also contain one or more
preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or
more coloring agents, one or more flavoring agents and one or more
sweetening agents, such as sucrose, aspartame or saccharin.
Formulations can be adjusted for osmolarity.
[0074] In certain embodiments, oil-based pharmaceuticals are used
for mixing APIs with beads. Oil-based suspensions can be formulated
by suspending an active agent in a vegetable oil, such as arachis
oil, olive oil, sesame oil or coconut oil, or in a mineral oil such
as liquid paraffin; or a mixture of these. See e.g., U.S. Pat. No.
5,716,928 describing using essential oils or essential oil
components for increasing bioavailability and reducing inter- and
intra-individual variability of orally administered hydrophobic
pharmaceutical compounds (see also U.S. Pat. No. 5,858,401). The
oil suspensions can contain a thickening agent, such as beeswax,
hard paraffin or cetyl alcohol. Sweetening agents can be added to
provide a palatable oral preparation, such as glycerol, sorbitol or
sucrose. These formulations can be preserved by the addition of an
antioxidant such as ascorbic acid. As an example of an injectable
oil vehicle, see Minto (1997) J. Pharmacol. Exp. Ther.
281:93-102.
[0075] In certain embodiments, the APIs are mixed with beads in
oil-in-water emulsions. The oily phase can be a vegetable oil or a
mineral oil, described above, or a mixture of these. Suitable
emulsifying agents include naturally-occurring gums, such as gum
acacia and gum tragacanth, naturally occurring phosphatides, such
as soybean lecithin, esters or partial esters derived from fatty
acids and hexitol anhydrides, such as sorbitan mono-oleate, and
condensation products of these partial esters with ethylene oxide,
such as polyoxyethylene sorbitan mono-oleate. The emulsion can also
contain sweetening agents and flavoring agents, as in the
formulation of syrups and elixirs. Such formulations can also
contain a demulcent, a preservative, or a coloring agent. In
alternative embodiments, these injectable oil-in-water emulsions of
the invention comprise a paraffin oil, a sorbitan monooleate, an
ethoxylated sorbitan monooleate and/or an ethoxylated sorbitan
trioleate.
[0076] In certain embodiments, the pharmaceutical compositions and
formulations are delivered transdermally, by a topical route,
formulated as applicator sticks, solutions, suspensions, emulsions,
gels, creams, ointments, pastes, jellies, paints, powders, and
aerosols.
[0077] In certain embodiments, the pharmaceutical compositions and
formulations are delivered as beads for slow release in the body.
For example, beads can be administered via intradermal injection of
drug which slowly release after administration, or beads can be
administered orally which slowly release in the gut after ingestion
see, e.g., Eyles (1997) J. Pharm. Pharmacol. 49:669-674.
[0078] In certain embodiments, sustained-release polymers for use
in the beads described herein include alkylcelluloses such as
ethylcellulose, acrylic and methacrylic acid polymers and
copolymers; and cellulose ethers, especially hydroxyalkylcelluloses
(especially hydroxypropylmethylcellulose) and
carboxyalkylcelluloses. Preferred waxes include for example natural
and synthetic waxes, fatty acids, fatty alcohols, and mixtures of
the same (e.g., beeswax, carnauba wax, stearic acid and stearyl
alcohol). Certain embodiments utilize mixtures of any of the
foregoing sustained release materials in the matrix of the core.
However, any pharmaceutically acceptable hydrophobic or hydrophilic
sustained-release material that is capable of imparting
sustained-release of the active agent may be used in accordance
with the beads described herein.
[0079] In certain embodiments, suitable coating materials for
effecting delayed release include, but are not limited to,
cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose,
hydroxypropyl methyl cellulose acetate succinate,
hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl
cellulose, cellulose acetate, cellulose acetate phthalate,
cellulose acetate trimellitate and carboxymethylcellulose sodium;
acrylic acid polymers and copolymers, preferably formed from
acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate,
methyl methacrylate and/or ethyl methacrylate, and other
methacrylic resins that are commercially available under the
tradename EUDRAGIT.RTM.. (Degussa AG, Dusseldorf, Germany),
including EUDRAGIT.RTM. L30D-55 and L100-55 (soluble at pH 5.5 and
above), EUDRAGIT.RTM. L-100 (soluble at pH 6.0 and above),
EUDRAGIT.RTM. (soluble at pH 7.0 and above, as a result of a higher
degree of esterification), EUDRAGITs.RTM. NE, RL and RS
(water-insoluble polymers having different degrees of permeability
and expandability) and EUDRAGIT.RTM. FS3OD a tercopolymer of
methacrylic acid, methyl acrylate and methylmethacrylate; vinyl
polymers and copolymers such as polyvinyl pyrrolidone, vinyl
acetate, vinylacetate phthalate, vinylacetate crotonic acid
copolymer, and ethylene-vinyl acetate copolymer; enzymatically
degradable polymers such as azo polymers, pectin, chitosan, amylose
and guar gum; zein and shellac. Combinations of different coating
materials can also be used. Multi-layer coatings using different
polymers can also be applied. The preferred coating weights for
particular coating materials can be readily determined by those
skilled in the art by evaluating individual release profiles for
tablets, beads and granules prepared with different quantities of
various coating materials. It is the combination of materials,
method and form of application that produce the desired release
characteristics, which can be determined by those of skill in the
art, considering the nature of the compound to be adsorbed, as well
as other relevant factors.
[0080] In other embodiments, the coating composition can include
conventional additives, such as plasticizers, pigments, colorants,
stabilizing agents, glidants, etc. A plasticizer is normally
present to reduce the fragility of the coating, and will generally
represent about 10 wt. % to 50 wt. % relative to the dry weight of
the polymer. Examples of typical plasticizers include polyethylene
glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate,
tributyl citrate, triethyl acetyl citrate, castor oil and
acetylated monoglycerides. A stabilizing agent is preferably used
to stabilize particles in the dispersion. Typical stabilizing
agents are nonionic emulsifiers such as sorbitan esters,
polysorbates and polyvinylpyrrolidone. Glidants are recommended to
reduce sticking effects during film formation and drying, and will
generally represent approximately 25 wt. % to 100 wt. % of the
polymer weight in the coating solution. One effective glidant is
talc. Other glidants such as magnesium stearate and glycerol
monostearates can also be used. Pigments such as titanium dioxide
can also be used. Small quantities of an anti-foaming agent, such
as a silicone (e.g., simethicone), can also be added to the coating
composition.
[0081] The amount of pharmaceutical composition adequate to
accomplish this is a therapeutically effective dose. The dosage
schedule and amounts effective for this use, i.e., the dosing
regimen, will depend upon a variety of factors, including the stage
of the disease or condition, the severity of the disease or
condition, the general state of the patient's health, the patient's
physical status, age and the like. In calculating the dosage
regimen for a patient, the mode of administration also is taken
into consideration.
[0082] The dosage regimen also takes into consideration
pharmacokinetics parameters well known in the art, i.e., the active
agents' rate of absorption, bioavailability, metabolism, clearance,
and the like (see, e.g., Hidalgo-Aragones (1996) J. Steroid
Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51
:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J.
Pharm. Sci. 84: 1 144-1 146; Rohatagi (1995) Pharmazie 50:610-613;
Brophy (1983) Eur. J. Clin. Pharmacol. 24: 103-108; Remington: The
Science and Practice of Pharmacy, 21st ed., 2005). The state of the
art allows the clinician to determine the dosage regimen for each
individual patient, active agent and disease or condition treated.
Guidelines provided for similar compositions used as
pharmaceuticals can be used as guidance to determine the dosage
regimen, i.e., dose schedule and dosage levels, administered
practicing the methods of the invention are correct and
appropriate. Single or multiple administrations of formulations can
be given depending on for example: the dosage and frequency as
required and tolerated by the patient, the degree and amount of
cholesterol homeostasis generated after each administration, and
the like. The formulations should provide a sufficient quantity of
active agent to effectively treat, prevent or ameliorate
conditions, diseases or symptoms, e.g., treat obesity.
[0083] In certain embodiments, pharmaceutical formulations for oral
administration are in a daily amount of between about 1 to 100 or
more mg per kilogram of body weight per day. Lower dosages can be
used, in contrast to administration orally, into the blood stream,
into a body cavity or into a lumen of an organ. Substantially
higher dosages can be used in topical or oral administration or
administering by powders, spray or inhalation. Actual methods for
preparing parenterally or non-parenterally administrable
formulations will be known or apparent to those skilled in the art
and are described in more detail in such publications as Remington:
The Science and Practice of Pharmacy, 21st ed., 2005.
EXAMPLES
[0084] The present invention is further illustrated by the
following examples, which should not be construed as further
limiting. The contents of and all references, patents and published
patent applications cited throughout this application are expressly
incorporated herein by reference.
Example 1. Bead Drug Product
[0085] A composition (of one of a series) of bead drug product is
described herein. The generic medicinal chemical Metoprolol
succinate (indicated for the treatment of hypertension) as well as
a population of placebo-containing indicator beads (capable of
indicating the potential for product degradation due to
environmental factors or compromise of drug release
characteristics) are combined. This drug product can be used as a
system to facilitate drug oral delivery to hypertensive patients
with dysphagia, using beads designed for administration in
foodstuffs. The drug product helps alleviate pain and other
difficulties associated with swallowing solid oral medicinal
products experienced by patients with dysphagia.
Current Approach
[0086] Metoprolol succinate is formulated as a solid oral dosage
form (tablet). The Metoprolol succinate tablets are ingested whole,
with accompanying symptoms of dysphagia, once daily (long acting
once daily formulation; this formulation cannot be crushed under
any circumstances). Alternatively the tablets are given twice daily
(immediate release formulation) and are crushed manually or using a
device and admixed with foodstuffs, exposing the active
pharmaceutical ingredients to food contents. Crushing tablets
adulterates the pharmacology and compromises dosing accuracy
introducing toxicity and efficacy issues for patients and safety
issues for drug administration staff.
Bead Based Approach
[0087] In one embodiment, Metoprolol succinate active
pharmaceutical ingredient is made into drug product beads by
rotogranulation. In one embodiment the beads are round in shape and
300 microns in diameter on average. In one embodiment the drug
substance beads are coated with ethylcellulose in order to regulate
dissolution rate and in order to protect the drug from exposure to
food. The dissolution rate and other physical and chemical
parameters of the drug substance beads are based on the existing
data for the reference product that will be used to establish
bio-equivalence consistent with regulatory requirements. In one
embodiment the drug substance beads are coated with a white
coating. In one embodiment the white coating is overlaid with a
blue coating to uniquely identify the API contained therein, and
that blue coating will dissolve after a period of time to reveal
the white color underneath. The appearance of white color indicates
that the protective coating(s) on the beads have been dissolved and
that the API is in imminent danger of being exposed to foodstuffs
and other drugs mixed in the foodstuffs (i.e. signals the potential
of drug product compromise). In one embodiment the beads have a
clear coat as the most external layer. In another embodiment the
finished drug product beads have a diameter of 240 microns on
average. In another embodiment the finished drug product beads
provide a single daily dose consistent with the reference product
and regulatory requirements. Appropriate testing will establish
dissolution rate and other pharmacological parameters,
bio-equivalence, and food compatibility.
[0088] In other embodiments, a population of indicator beads is
added to the drug product beads to comprise the final drug product.
In one embodiment the indicator beads are placebo (i.e. they
contain no active pharmaceutical ingredient). In another
embodiment, the indicator beads are added at a ratio of
approximately 10:1 (active drug product: placebo indicator). In
another embodiment, the indicator beads are approximately round in
shape and approximately 200 microns in diameter on average. In
another embodiment, the indicator beads are composed of
sub-populations of some indicator beads for environmental
temperature and some indicator beads for environmental acidity. The
indicators allow detection of potential product compromise or
degradation in foodstuffs. In another embodiment, all of the
indicator beads are blue in color. In another embodiment, the
temperature indicator beads (sub-population of indicator beads)
turn from blue to white and stay white if there has been an
excursion beyond the tested product stability upper limit of 37
degrees Celsius. In another embodiment, the freeze/thaw indicator
beads turn from blue to white and stay white if the beads have been
exposed to temperatures lower than 0 degrees Celsius and
subsequently warmed. In another embodiment, the pH indicator beads
turn from blue to white and stay white if the beads have been
exposed to pH>6.
[0089] In further embodiments, the final drug product, designed and
formulated for safety and efficacy in food, contains a population
of beads that is comprised of a once daily administration
population of round Metoprolol succinate containing beads, blue in
color (soluble blue layer), averaging 240 microns in diameter, with
white undercoating (to indicate solubilization when exposed). The
final drug product is also comprised of a population of placebo
indicator beads, blue in color, round and approximately 100 microns
in diameter on average, at a ratio of approximately 1:10
(indicator: active) which is in turn comprised of sub-populations
of indicators that turn white when exposed to pH>6, temperatures
below 0 degrees Celsius, and temperatures above 37 degrees
Celsius.
Example 2. Bead Drug Product
[0090] A composition (of one of a series) of bead drug product is
described herein. The generic medicinal chemical Nifedipine
(indicated for the treatment of hypertension and angina) as well as
a population of placebo-containing indicator beads (capable of
indicating the potential for product degradation due to
environmental factors or compromise of drug release
characteristics) are combined. This drug product can be used as a
system to facilitate drug oral delivery to hypertension or angina
patients with dysphagia, using beads designed for administration in
foodstuffs. The drug product helps alleviate pain and other
difficulties associated with swallowing solid oral medicinal
products experienced by patients with dysphagia.
Current Approach
[0091] Nifedipine is formulated as a solid oral dosage form
(tablet), both long acting (once daily) or immediate release forms
(three times daily). The Nifedipine tablets are ingested whole,
with accompanying symptoms of dysphagia, once daily (long acting
once daily formulation; this formulation cannot be crushed under
any circumstances) Immediate release tablets are not recommended
for administration to the elderly according to the Beers List, a
recognized published listing of medications that may be dangerous
and/or inappropriate in the elderly. The only approved option for
Nifedipine patients, therefore, is to ingest whole once daily
tablets.
Bead Based Approach
[0092] In one embodiment, Nifedipine active pharmaceutical
ingredient is made into drug product beads by hot melt extrusion.
In one embodiment the beads are round in shape and 250 microns in
diameter on average. In one embodiment the drug substance beads are
coated with wax layers in order to regulate dissolution rate and in
order to protect the drug from exposure to food. The dissolution
rate and other physical and chemical parameters of the drug
substance beads are based on the existing data for the reference
product that will be used to establish bio-equivalence consistent
with regulatory requirements. In one embodiment the drug substance
beads are coated with a white coating. In one embodiment the white
coating is overlaid with a red coating to uniquely identify the API
contained therein. The red coating is comprised of red color and
polymers that degrade when exposed to pH<4. The appearance of
white color indicates that the API is in imminent danger of being
exposed to an acidic environment (i.e.).
[0093] In one embodiment the beads have a clear coat as the most
external layer. In another embodiment the finished drug product
beads have a diameter of 280 microns on average. In another
embodiment the finished drug product beads provide a single daily
dose consistent with the reference product and regulatory
requirements. Appropriate testing will establish dissolution rate
and other pharmacological parameters, bio-equivalence, and food
compatibility.
[0094] In further embodiments, the final drug product, designed and
formulated for safety and efficacy in food, contains a population
of beads that is comprised of a once daily administration
population of round Nifedipine-containing beads, red in color,
wherein the red color layer is comprised of red color and a
pH-sensitive polymer. In certain aspects the red layer is such that
it will dissolve when exposed to pH<4 exposing the white layer
underneath, indicating the API is in imminent danger of being
exposed to an acidic environment and signaling the potential of
drug product compromise.
Example 3. Bead Drug Product
[0095] A composition (of one of a series) of bead drug product is
described herein. The generic medicinal chemical Isosorbide
mononitrate (indicated for the treatment of angina) as well as a
population of placebo-containing indicator beads (capable of
indicating the potential for product degradation due to
environmental factors or compromise of drug release
characteristics) are combined. This drug product can be used as a
system to facilitate drug oral delivery to hypertensive patients
with dysphagia, using beads designed for administration in
foodstuffs. The drug product helps alleviate pain and other
difficulties associated with swallowing solid oral medicinal
products experienced by patients with dysphagia.
Current Approach
[0096] Isosorbide mononitrate is formulated as a solid oral dosage
form (tablet). The isosorbide mononitrate tablets are ingested
whole, with accompanying symptoms of dysphagia, once daily (long
acting once daily formulation; this formulation cannot be crushed
under any circumstances). Alternatively the tablets are given twice
daily (immediate release formulation; this formulation cannot be
crushed under any circumstances) and are ingested whole, with
accompanying symptoms of dysphagia. Crushing any solid oral
formulation of Isosorbide mononitrate is contraindicated.
Bead Based Approach
[0097] In one embodiment, active pharmaceutical ingredient is made
into drug product beads by extrusion and spheronization. In one
embodiment the beads are round in shape and 250 microns in diameter
on average. The dissolution rate and other physical and chemical
parameters of the drug substance beads are based on the existing
data for the reference product that will be used to establish
bio-equivalence consistent with regulatory requirements. In one
embodiment the drug substance beads are coated with a white
coating. In one embodiment the white coating is overlaid with a
yellow coating to uniquely identify the API contained therein, and
that yellow coating will dissolve after a period of time to reveal
the white color underneath. The appearance of white color indicates
that the protective coating(s) on the beads have been dissolved and
that the API is in imminent danger of being exposed to foodstuffs
and other drugs mixed in the foodstuffs (i.e. signals the potential
of drug product compromise). In one embodiment the beads have a
clear coat as the most external layer. In another embodiment the
finished drug product beads have a diameter of 280 microns on
average. In another embodiment the finished drug product beads
provide a single daily dose consistent with the reference product
and regulatory requirements. Appropriate testing will establish
dissolution rate and other pharmacological parameters,
bio-equivalence, and food compatibility.
[0098] In other embodiments, a population of indicator beads is
added to the drug product beads to comprise the final drug product.
In one embodiment the indicator beads are placebo (i.e. they
contain no active pharmaceutical ingredient). In another
embodiment, the indicator beads are added at a ratio of
approximately 15:1 (active drug product: placebo indicator). In
another embodiment, the indicator beads are approximately round in
shape and approximately 250 microns in diameter on average. In
another embodiment, the indicator beads are composed of
sub-populations of indicator beads for environmental temperature.
The indicators allow detection of potential product compromise or
degradation in foodstuffs. In another embodiment, all of the
indicator beads are yellow in color. In another embodiment, the
indicator beads are comprised of two sub-populations of beads. In
one aspect of this embodiment, one sub-population of indicator
beads has a yellow outer layer comprised of yellow color and
polymers that degrade above 30 degrees Celsius. In another aspect
of this embodiment the yellow indicator layer overlays a white
layer such that when the yellow layer is exposed to high
temperature and degrades, then the white layer is exposed. This
indicates a critical temperature excursion and signals the
potential of drug product compromise. In another aspect of this
embodiment, one sub-population of indicator beads has a yellow
outer layer comprised of yellow color and polymers that fracture
below 0 degrees Celsius. In another aspect of this embodiment the
yellow indicator layer overlays a white layer such that when the
yellow layer is exposed to freezing and thawing it degrades, and
the white layer is exposed.
[0099] In further embodiments, the final drug product, designed and
formulated for safety and efficacy in food, contains a population
of beads that is comprised of a once daily administration
population of round Isosorbide mononitrate-containing beads, yellow
in color (soluble yellow layer), averaging 280 microns in diameter,
with white undercoating (to indicate solubilization when exposed).
The final drug product is also comprised of a population of placebo
indicator beads, yellow in color, round and approximately 250
microns in diameter on average, at a ratio of approximately 1:15
(indicator: active) which is in turn comprised of two
sub-populations of indicators that turn white when exposed to
freeze/thaw conditions or temperatures above 30 degrees
Celsius.
Example 4. Bead Indicator Product (Medicinal Use)
[0100] A composition (of one of a series) of bead indicator product
for medicinal use is described herein. The indicator beads are
intended to mix with other forms of powdered or beaded drugs that
will be administered to patients admixed with foodstuffs. The bead
indicator contains no active medicinal ingredient and allows for
detection of environmental conditions that could degrade or
compromise the drug products being administered, such as
freeze/thaw, high temperature and high or low pH.
Current Drug Administration in Elderly
[0101] Drugs are often administered to the elderly in foodstuffs.
Most drugs are crushed, added to food and then administered.
Drug Administration using Indicator Beads
[0102] In certain embodiments, indicator beads are added to the
drug product before or during mixing with food. In certain
embodiments the indicator beads are added at the time of primary
packaging. In other embodiments the indicator beads are added at
the time of drug administration when the drugs and indicator beads
are mixed together in food. In one embodiment, the indicator beads
are added at a ratio of approximately 10:1 (active drug product:
placebo indicator). In another embodiment, the indicator beads are
approximately round in shape and approximately 250 microns in
diameter on average. In another embodiment, the indicator beads are
composed of sub-populations of indicator beads for environmental
temperature and pH. The indicators allow detection of potential
product compromise or degradation in foodstuffs. In another
embodiment, all of the indicator beads are red in color. In another
embodiment, the indicator beads are comprised of three
sub-populations of beads. In one aspect of this embodiment, one
sub-population of indicator beads has a red outer layer comprised
of red color and polymers that degrade above 30 degrees Celsius. In
another aspect of this embodiment the red indicator layer overlays
a white layer such that when the red layer is exposed to high
temperature and degrades, then the white layer is exposed. This
indicates a critical temperature excursion and signals the
potential of drug product compromise. In another aspect of this
embodiment, one sub-population of indicator beads has a red outer
layer comprised of red color and polymers that fracture below 0
degrees Celsius. In another aspect of this embodiment the red
indicator layer overlays a white layer such that when the red layer
is exposed to freezing and thawing it degrades, and the white layer
is exposed. In another aspect of this embodiment, one
sub-population of indicator beads has a red outer layer comprised
of red color and polymers that degrade below pH 4. In another
aspect of this embodiment the red indicator layer overlays a white
layer such that when the red layer is exposed to low pH it
degrades, and the white layer is exposed.
Example 5. Bead Indicator Product (Food Industry Use)
[0103] A composition (of one of a series) of bead indicator product
for use in the quality assurance of food is described herein. The
indicator beads are intended to mix with foodstuffs. The bead
indicator contains no active medicinal ingredient and allows for
detection of environmental conditions that could degrade or
compromise or result from the degradation or compromise of the
food, such as freeze/thaw, high temperature and high or low pH.
Quality Assurance of Foodstuffs Using Indicator Beads
[0104] In certain embodiments, indicator beads are added to the
food product. In certain embodiments the indicator beads are added
at the time of primary packaging. In other embodiments the
indicator beads are added at some point during manufacture. In
other embodiments indicator beads are added by the consumer. In one
embodiment, the indicator beads are approximately round in shape
and approximately 350 microns in diameter on average. In another
embodiment, the indicator beads are composed of sub-populations of
indicator beads for environmental temperature and pH. The
indicators allow detection of potential product compromise or
degradation in foodstuffs. In another embodiment, all of the
indicator beads are blue in color. In another embodiment, the
indicator beads are comprised of three sub-populations of beads. In
one aspect of this embodiment, one sub-population of indicator
beads has a blue outer layer comprised of blue color and polymers
that degrade above 30 degrees Celsius. In another aspect of this
embodiment the blue indicator layer overlays a white layer such
that when the blue layer is exposed to high temperature and
degrades, then the white layer is exposed. This indicates a
critical temperature excursion and signals the potential of drug
product compromise. In another aspect of this embodiment, one
sub-population of indicator beads has a blue outer layer comprised
of blue color and polymers that fracture below 0 degrees Celsius.
In another aspect of this embodiment the blue indicator layer
overlays a white layer such that when the blue layer is exposed to
freezing and thawing it degrades, and the white layer is exposed.
In another aspect of this embodiment, one sub-population of
indicator beads has a blue outer layer comprised of blue color and
polymers that degrade above pH 7. In another aspect of this
embodiment the blue indicator layer overlays a white layer such
that when the blue layer is exposed to high pH it degrades, and the
white layer is exposed.
* * * * *