U.S. patent application number 10/476503 was filed with the patent office on 2005-01-27 for dosage form containing a confectionery composition.
Invention is credited to Bunick, Frank J., Gilmor, Timothy P., LaBella, Gus B., Lee, Der-Yang, McNally, Gerard P., Sowden, Harry S., Thomas, Martin.
Application Number | 20050019376 10/476503 |
Document ID | / |
Family ID | 25512088 |
Filed Date | 2005-01-27 |
United States Patent
Application |
20050019376 |
Kind Code |
A1 |
McNally, Gerard P. ; et
al. |
January 27, 2005 |
Dosage form containing a confectionery composition
Abstract
A dosage form comprises an active ingredient and a confectionery
composition. In one embodiment the relative standard deviation of
the weight of the dosage form is less than 1%, and the dosage form
has at least one face. In another embodiment, a dosage form
comprising an active ingredient and a confectionery composition
wherein the dosage form has at least one face, does not have a free
formed surface, and has a mean polarized light transmission at the
angle of maximum extinction which is not greater than the mean
polarized light transmission of the dosage form at the angle of
maximum transmission. The active ingredient may be a
pharmaceutically active agent.
Inventors: |
McNally, Gerard P.; (Nerwyn,
PA) ; Bunick, Frank J.; (Randolph, NJ) ;
Sowden, Harry S.; (Glenside, PA) ; LaBella, Gus
B.; (Collegeville, PA) ; Gilmor, Timothy P.;
(Orefield, PA) ; Lee, Der-Yang; (Flemington,
NJ) ; Thomas, Martin; (Lake Worth, FL) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
25512088 |
Appl. No.: |
10/476503 |
Filed: |
May 17, 2004 |
PCT Filed: |
September 28, 2002 |
PCT NO: |
PCT/US02/31115 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10476503 |
May 17, 2004 |
|
|
|
09966939 |
Sep 28, 2001 |
|
|
|
Current U.S.
Class: |
424/440 |
Current CPC
Class: |
A61P 29/00 20180101;
B30B 11/34 20130101; A61K 9/2853 20130101; A61K 9/2893 20130101;
A61J 3/005 20130101; B30B 11/08 20130101; A61K 9/2873 20130101;
A61P 29/02 20180101; A23G 3/04 20130101; A23G 3/368 20130101; A61J
3/10 20130101 |
Class at
Publication: |
424/440 |
International
Class: |
A61K 009/68 |
Claims
1. A dosage form comprising at least one active ingredient and a
confectionery composition wherein the relative standard deviation
of the weight of the dosage form is less than 1%, and the dosage
form has at least one face.
2. A dosage form comprising at least one active ingredient and a
confectionery composition wherein the dosage form has at least one
face, does not have a free formed surface, and has a mean polarized
light transmission at the angle of maximum extinction which is not
greater than the mean polarized light transmission of the dosage
form at the angle of maximum transmission.
3. The dosage form of claim 2, in which the relative standard
deviation of the weight of the dosage form is less than 1%.
4. The dosage form of claim 1, in which the relative standard
deviation of the weight of the dosage form is less than 0.5%.
5. The dosage form of claim 1, in which the confectionery
composition comprises at least one component selected from the
group consisting of fat, amorphous sugar glass and fondant.
6. The dosage form of claim 1, in which the confectionery
composition does not contain a gelatin based composition.
7. The dosage form of claim 1, in which the confectionery
composition does not contain a gel based composition.
8. The dosage form of claim 1, in which the confectionery
composition comprises an amorphous sugar glass component and the
dosage form does not have a free formed surface.
9. The dosage form of claim 1, in which all the faces of the dosage
form have a surface gloss of about 200-300 gloss units.
10. The dosage form of claim 1, in which the dosage form has two or
more faces, and the difference in surface gloss between any two
faces is not more than about 20 gloss units.
11. The dosage form of claim 10 in which the difference in surface
gloss between any two faces is not more than about 15 gloss
units.
12. The dosage form of claim 10 in which the difference in surface
gloss between any two faces is not more than about 10 gloss
units.
13. The dosage form of claim 1 in which the dosage form has a mean
polarized light transmission at the angle of maximum extinction
which is not greater than the mean polarized light transmission of
the dosage form at the angle of maximum transmission.
14. The dosage form of claim 1, in which the dosage form has a mean
polarized light transmission between about 0 to 40 grayscale units
at the angle of maximum extinction.
15. The dosage form of claim 1 in which the confectionery
composition comprises an amorphous sugar glass component and the
dosage form does not have a free formed surface.
16. The dosage form of claim 1 in which the active ingredient is a
pharmaceutically active ingredient.
17. The dosage form of claim 1, in which the dosage form comprises
particles which comprise the active ingredient.
18. The dosage form of claim 17, in which the particles have an
average particle size of about 50 to about 2000 microns.
19. The dosage form of claim 17, in which at least a portion of the
particles are coated particles.
20. The dosage form of claim, in which the dosage form is a unitary
object.
21. The dosage form of claim 1, in which the dosage form does not
contain any seams on its surface.
22. The dosage form of claim 1 in which the confectionery
composition comprises an amorphous sugar glass component.
23. The dosage form of claim 1, in which the dosage form is
substantially free of pores having a diameter of 0.5 to 5.0
microns.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to dosage forms such as
pharmaceutical compositions comprising a confectionery composition.
More particularly, this invention relates to dosage forms
containing at least one active ingredient and a confectionery
composition such as fat, amorphous sugar glass, or fondant.
[0003] 2. Background Information
[0004] An important objective in designing pharmaceutical drug
delivery systems, especially for pediatric and geriatric
applications, is to make palatable, good tasting, dosage forms
which mask the unpleasant taste and/or texture of the active
pharmaceutical ingredient, to improve patient compliance with the
dosing regimen. Confectionery compositions offer great potential
for achieving these desired product attributes; however their use
in pharmaceutical applications has to date been quite limited.
[0005] The substantial differences in regulations governing the
confectionery and pharmaceutical industries has led to both
facilities and processes that are not directly transferable between
the two. The pharmaceutical developer desiring to apply the
benefits of confectionery compositions to drug delivery systems
must overcome major challenges in the areas of pharmaceutical "good
manufacturing practices" (GMP) and product quality standards.
[0006] Confectionery manufacturing facilities, for example, are not
commonly designed to allow for the rigorous controls on raw
material traceability required by the pharmaceutical industry, or
equipped for avoiding cross-contamination while processing multiple
drug active ingredients. A high-purity water source, closed
air-handling system, and on-site analytical laboratory are critical
for any pharmaceutical operation. Installing and validating these
systems entails substantial cost and complexity.
[0007] Most current commercial confectionery processes are designed
to meet the primary objectives of high-volume and low cost, while
aesthetic properties, consistency, uniformity, precision of dose,
and general appearance are secondary considerations. For
pharmaceutical dosage forms, there is a need for relatively
low-cost, high volume commercial scale processing methods which
also reliably and repeatably produce a highly precise dose which is
also a uniform, consistent, elegant looking product.
[0008] In typical current confectionery processes, for example, a
high percentage of scrap may be generated during processing without
compromising efficiency, because the unused portion of a batch can
be recycled into a future batch. In pharmaceutical processes, it
would not be considered GMP to routinely re-process waste, or
co-mingle batches.
[0009] Pharmaceutical dosage forms must have minimal variation in
the weight of individual dosage units to achieve a high degree of
drug content uniformity. Since many confectionery processes were
designed without the need for the high degree of precision and
reproducibility required for pharmaceuticals, a high degree of
variation is inherent in their design. Typical confectionery
rope-forming operations, for example, result in high product weight
variation due to entrained air, and variations in rope tensile
strength, viscosity, and plasticity with temperature. Conventional
confectionery cut and wrap operations result in high product weight
variation due to variation in flow and thickness of the rope.
Extruded confectionery compositions can vary in piece weight due to
changes in flow rate, and pulsations in the center fill pumping
operation which lead to variations in center fill content.
Additionally high weight variation is inherent in confectionery
depositing operations, which do not fill a fixed volume, so piece
weight depends on the reproducibility of the metered dose pumping,
which is subject to variability in viscosity, due to temperature
and material factors.
[0010] Product aesthetics represent another area of discrepancy
between the two industries. For example, typical confectionery
depositing operations produce a product which can have high
definition on only three sides, but necessarily has a "free-formed"
surface on one side. In such products, the degree of surface gloss
is higher on the free-formed surface than the molded sides.
Pharmaceutical products typically require a uniform and consistent
appearance implying a high degree of control in the manufacturing
process. It is thus desirable to have a manufacturing process which
can provide uniform high definition on all sides of the dosage
form.
[0011] The products produced by current confectionery methods are
not designed to withstand conventional packaging operations without
a substantial level of chipping, cracking, deformation, or
breakage, which would be unacceptable for pharmaceutical dosage
forms. For example typical rope forming operations entrain air
during the cooling and folding operations, and impart mechanical
stress to the glass during the roping operation. These
imperfections manifest as strain lines and air bubbles in the
finished product, which result in higher product fragility,
decreased product uniformity, and decreased visual appeal. In
particular, the areas of strain can serve as nucleation sites for
crystal formation, which decreases the shelf life of the product.
Entrained air additionally results in weight variation, and
detracts from overall consistency and visual elegance of the
product.
[0012] Chocolate-coatings over confectionery cores are typically
made by filling a cold mold to solidify the outer layer of
chocolate, then pouring out the excess, then injecting with the
center fill material, or alternatively by dipping the core material
into molten chocolate to form the bottom, then enrobing the
remainder of the piece by pouring molten chocolate over the top and
sides, then dripping off the excess. Such operations are inherently
high in weight variation because the coating level depends upon the
viscosity of the chocolate which will vary with raw materials,
temperature, humidity, etc. Thus these operations do not lend
themselves to pharmaceutical dosage forms. A need exists for
manufacturing processes which enable the reliable and repeatable
formation of a precise and consistent level of chocolate coating
over any type of center fill, to realize the benefits of these
types of compositions for pharmaceutical applications.
[0013] It is one object of this invention to provide a dosage form
comprising an active ingredient and a confectionery composition
wherein the relative standard deviation of the weight of the dosage
form is less than 1%, and the dosage form has at least one
face.
[0014] It is another object of this invention to provide a dosage
form comprising an active ingredient and a confectionery
composition wherein the dosage form has at least one face, the
dosage form does not have a free formed surface, and the dosage
form has a mean polarized light transmission at the angle of
maximum extinction which is not greater than the mean polarized
light transmission of the dosage form at the angle of maximum
transmission.
[0015] Other objects, features and advantages of this invention
will be apparent to these skilled in the art from the detailed
description of the invention provided herein.
SUMMARY OF THE INVENTION
[0016] In one embodiment, the dosage form of this invention
comprises at least one active ingredient and a confectionery
composition, the dosage form has at least one face, and the
relative standard deviation of the weight of the dosage form is
less than 1%, preferably 0.5%.
[0017] In another embodiment of this invention, the dosage form
comprises at least one active ingredient and a confectionery
composition wherein the dosage form has at least one face, does not
have a free formed surface, and has a mean polarized light
transmission at the angle of maximum extinction which is not
greater than the mean polarized light transmission of the dosage
form at the angle of maximum transmission.
[0018] In another embodiment, the relative standard deviation of
the weight of the dosage form is less than 0.5%.
[0019] In another embodiment, the confectionery composition
comprises at least one component selected from the group consisting
of fat, amorphous sugar glass and fondant.
[0020] In another embodiment, the confectionery composition does
not contain a gelatin based composition.
[0021] In another embodiment, the confectionery composition does
not contain a gel based composition.
[0022] In another embodiment, the confectionery composition
comprises an amorphous sugar glass component and the dosage form
does not have a free formed surface.
[0023] In another embodiment, all the faces of the dosage form have
a surface gloss of about 200-300 gloss units.
[0024] In another embodiment, the dosage form has two or more
faces, and the difference in surface gloss between any two faces is
not more than about 20 gloss units.
[0025] In another embodiment, the difference in surface gloss
between any two faces is not more than about 15 gloss units.
[0026] In another embodiment, the difference in surface gloss
between any two faces is not more than about 10 gloss units.
[0027] In another embodiment, the dosage form has a mean polarized
light transmission at the angle of maximum extinction which is not
greater than the mean polarized light transmission of the dosage
form at the angle of maximum transmission.
[0028] In another embodiment, the dosage form has a mean polarized
light transmission between about 0 to 40 grayscale units at the
angle of maximum extinction.
[0029] In another embodiment, the confectionery composition
comprises an amorphous sugar glass component and the dosage form
does not have a free formed surface.
[0030] In another embodiment, the active ingredient is a
pharmaceutically active ingredient.
[0031] In another embodiment, the dosage form comprises particles
which comprise the active ingredient.
[0032] In another embodiment, the particles have an average
particle size of about 50 to about 2000 microns.
[0033] In another embodiment, at least a portion of the particles
are coated particles.
[0034] In another embodiment, the dosage form is a unitary
object.
[0035] In another embodiment, the dosage form does not contain any
seams on its surface.
[0036] In another embodiment, the relative standard deviation of
the weight of the dosage form is less than 1.0%.
[0037] In another embodiment, the confectionery composition
comprises an amorphous sugar glass component.
[0038] In another embodiment, the dosage form is substantially free
of pores having a diameter of 0.5 to 5.0 microns.
[0039] In another embodiment, the dosage form of this invention
does not contain a gel-based composition or a gelatin-based
composition.
[0040] In another embodiment, the dosage form of this invention
comprises an amorphous sugar glass component and the dosage form
does not have a free formed surface.
[0041] In another embodiment, all the dosage form faces have a
surface gloss of about 200-300 gloss units.
[0042] In another embodiment, the dosage form has two or more
faces, and the difference in surface gloss between any two faces is
not more than about 20 gloss units, preferably not more than about
15 gloss units, most preferably not more than about 10 gloss
units.
[0043] In another embodiment, the dosage form has a mean polarized
light transmission between about 0 to 40 grayscale units at the
angle of maximum extinction.
[0044] In another embodiment, the active ingredient is a
pharmaceutically active ingredient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] FIG. 1A depicts a prior art composition and a composition of
the present invention viewed under normal polarized light.
[0046] FIG. 1B depicts a prior art composition and a composition of
the present invention viewed under polarized light at 90.degree.
filtering to the incident light.
[0047] FIG. 2A is a photograph of a two-piece hard candy lozenge
mold which may be used to prepare the dosage form of this
invention.
[0048] FIG. 2B is a photograph of the mold depicted in FIG. 2A
together with a lozenge dosage form which has been removed from the
mold.
[0049] FIG. 3A depicts an apparatus for measuring mean polarized
light transmission at the angle of maximum transmission.
[0050] FIG. 3B depicts an apparatus for measuring mean polarized
light transmission at the angle of maximum extinction.
[0051] FIG. 4A depicts typical photographic images taken at the
angle of maximum light transmission comparing hard candies made by
methods of the prior art and the dosage form of this invention.
[0052] FIG. 4B depicts typical photographic images taken at the
angle of maximum light extinction comparing hard candies made by
methods of the prior art and the dosage form of this invention.
[0053] FIG. 5 shows the greyscale intensity distribution for a
CHLORASEPTIC throat lozenge at both the angle of maximum light
transmission and the angle of maximum light extinction.
[0054] FIG. 6 shows the greyscale intensity distribution for the
product of the present invention at both the angle of maximum light
transmission and the angle of maximum light extinction.
DETAILED DESCRIPTION OF THE INVENTION
[0055] As used herein, the term "dosage form" applies to any solid
object, semi-solid, or liquid composition, designed to contain a
specific predetermined amount (i.e. dose) of a certain ingredient,
for example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, rectal
administration, topical, transdermal, or mucosal delivery, or
subcutaneous implants, or other implanted drug delivery systems; or
compositions for delivering minerals, vitamins and other
nutraceuticals, oral care agents, flavorants, and the like.
Preferably the dosage forms of the present invention are considered
to be solid, however they may contain liquid or semi-solid
components. In a particularly preferred embodiment, the dosage form
is an orally administered system for delivering a pharmaceutical
active ingredient to the gastro-intestinal tract of a human. In
another preferred embodiment, the dosage form is an orally
administered "placebo" system containing pharmaceutically inactive
ingredients, and the dosage form is designed to have the same
appearance as a particular pharmaceutically active dosage form,
such as may be used for control purposes in clinical studies to
test, for example, the safety and efficacy of a particular
pharmaceutically active ingredient.
[0056] The dosage form of this invention must be molded. The dosage
form comprises at least one active ingredient and a confectionery
composition.
[0057] Suitable active ingredients for use in this invention
include for example pharmaceuticals, minerals, vitamins and other
nutraceuticals, oral care agents, flavorants and mixtures thereof.
Suitable pharmaceuticals include analgesics, anti-inflammatory
agents, antiarthritics, anesthetics, antihistamines, antitussives,
antibiotics, anti-infective agents, antivirals, anticoagulants,
antidepressants, antidiabetic agents, antiemetics, antiflatulents,
antifungals, antispasmodics, appetite suppressants,
bronchodilators, cardiovascular agents, central nervous system
agents, central nervous system stimulants, decongestants,
diuretics, expectorants, gastrointestinal agents, migraine
preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof.
[0058] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0059] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubble gum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0060] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; stimulant laxatives, such as
bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,
castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures
thereof; H2 receptor antagonists, such as famotadine, ranitidine,
cimetadine, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; gastrointestinal cytoprotectives, such as
sucraflate and misoprostol; gastrointestinal prokinetics, such as
prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such
as ondansetron, analgesics, such as mesalamine.
[0061] In one embodiment of the invention, the active agent may be
selected from bisacodyl, famotadine, ranitidine, cimetidine,
prucalopride, diphenoxylate, loperamide, lactase, mesalamine,
bismuth, antacids, and pharmaceutically acceptable salts, esters,
isomers, and mixtures thereof.
[0062] In another embodiment, the active agent is selected from
analgesics, anti-inflammatories, and antipyretics: e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), including propionic
acid derivatives: e.g. ibuprofen, naproxen, ketoprofen and the
like; acetic acid derivatives: e.g. indomethacin, diclofenac,
sulindac, tolmetin, and the like; fenamic acid derivatives: e.g.
mefanamic acid, meclofenamic acid, flufenamic acid, and the like;
biphenylcarbodylic acid derivatives: e.g. diflunisal, flufenisal,
and the like; and oxicams: e.g. piroxicam, sudoxicam, isoxicam,
meloxicam, and the like. In a particularly preferred embodiment,
the active agent is selected from propionic acid derivative NSAID:
e.g. ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen,
indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin,
pranoprofen, suprofen, and pharmaceutically acceptable salts,
derivatives, and combinations thereof. In another embodiment of the
invention, the active agent may be selected from acetaminophen,
acetyl salicylic acid, ibuprofen, naproxen, ketoprofen,
flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib,
celecoxib, and pharmaceutically acceptable salts, esters, isomers,
and mixtures thereof. In another embodiment of the invention, the
active agent may be selected from acetaminophen, acetyl salicylic
acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac,
cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and
pharmaceutically acceptable salts, esters, isomers, and mixtures
thereof.
[0063] In another embodiment of the invention, the active agent may
be selected from pseudoephedrine, phenylpropanolamine,
chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine,
astemizole, terfenadine, fexofenadine, loratadine, desloratadine,
cetirizine, mixtures thereof and pharmaceutically acceptable salts,
esters, isomers, and mixtures thereof.
[0064] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260. As
used herein, the term "simethicone" refers to the broader class of
polydimethylsiloxanes, including but not limited to simethicone and
dimethicone.
[0065] The active ingredient or ingredients are present in the
dosage form in a therapeutically effective amount, which is an
amount that produces the desired therapeutic response upon oral
administration and can be readily determined by one skilled in the
art. In determining such amounts, the particular active ingredient
being administered, the bioavailability characteristics of the
active ingredient, the dose regime, the age and weight of the
patient, and other factors must be considered, as known in the art.
Preferably, the dosage form comprises at least about 85 weight
percent of the active ingredient. In one preferred embodiment, the
core comprises at least about 85 weight percent of the active
ingredient.
[0066] The active ingredient or ingredients may be present in the
dosage form in any form. For example, the active ingredient may be
dispersed at the molecular level, e.g. melted or dissolved, within
the dosage form, or may be in the form of particles, which in turn
may be coated or uncoated. If the active ingredient is in form of
particles, the particles (whether coated or uncoated) typically
have an average particle size of about 1-2000 microns. In one
preferred embodiment, such particles are crystals having an average
particle size of about 1-300 microns. In another preferred
embodiment, the particles are granules or pellets having an average
particle size of about 50-2000 microns, preferably about 50-1000
microns, most preferably about 100-800 microns.
[0067] If the active ingredient has an objectionable taste, and the
dosage form is intended to be chewed or disintegrated in the mouth
prior to swallowing, the active ingredient may be coated with a
taste masking coating, as known in the art. Examples of suitable
taste masking coatings are described in U.S. Pat. No. 4,851,226,
U.S. Pat. No. 5,075,114, and U.S. Pat. No. 5,489,436. Commercially
available taste masked active ingredients may also be employed. For
example, acetaminophen particles which are encapsulated with
ethylcellulose or other polymers by a coaccervation process may be
used in the present invention. Coaccervation-encapsulated
acetaminophen may be purchased commercially from Eurand America,
Inc. (Vandalia, Ohio) or from Circa Inc. (Dayton, Ohio).
[0068] The dosage form of the invention may also incorporate
pharmaceutically acceptable adjuvants, including, for example,
preservatives, high intensity sweeteners such as aspartame,
acesulfame potassium, cyclamate, saccharin, sucralose, and the
like; and other sweeteners such as dihydroalcones, glycyrrhizin,
Monellin.TM., stevioside, Talin.TM., and the like; flavors,
antioxidants, surfactants, and coloring agents.
[0069] In certain embodiments in which modified release of the
active ingredient is desired, the active ingredient may optionally
be coated with a release-modifying coating, as is well known in the
art. Commercially available modified release active ingredients may
also be employed. For example, acetaminophen particles which are
encapsulated with release-modifying polymers by a coaccervation
process may be used in the present invention as described
above.
[0070] The active ingredient or ingredients are preferably capable
of dissolution upon contact with a fluid such as water, stomach
acid, intestinal fluid or the like. In a preferred embodiment the
dissolution characteristics of the active ingredient meet USP
specifications for immediate release tablets containing the active
ingredient. In embodiments in which it is desired for the active
ingredient to be absorbed into the systemic circulation of an
animal, the active ingredient or ingredients are preferably capable
of dissolution upon contact with a fluid such as water, stomach
acid, intestinal fluid or the like. In one embodiment, the
dissolution characteristics of the active ingredient meet USP
specifications for immediate release tablets containing the active
ingredient. For example, for acetaminophen tablets, USP 24
specifies that in pH 5.8 phosphate buffer, using USP apparatus 2
(paddles) at 50 rpm, at least 80% of the acetaminophen contained in
the dosage form is released therefrom within 30 minutes after
dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2
phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at
least 80% of the ibuprofen contained in the dosage form is released
therefrom within 60 minutes after dosing. See USP 24, 2000 Version,
19-20 and 856 (1999). In another embodiment, the dissolution
characteristics of the active ingredient are modified: e.g.
controlled, sustained, extended, retarded, prolonged, delayed and
the like.
[0071] As used herein, the term "confectionery composition" means
an edible product comprising a sweet component. Confectionery
compositions generally include medicinal preparations made with
sugar, syrup, or honey, and sweet foods such as candy or pastry.
Suitable confectionery compositions are well known in the art and
include "sugar confectionery" such as hard candy (e.g. amorphous
sugar-glass, toffees, fudge, fondants, jellies, gummis, pasteils,
caramel, taffy, nougat, and chewing gum) as well as "fat-based
confectionery" such as chocolate (including, for example, milk
chocolate, dark chocolate, semi-sweet chocolate), and coatings
including, for example, chocolate compound coatings, pastel
compound coatings e.g. white chocolate, and the like.
[0072] Suitable sweet components include sugars such as sucrose,
glucose (dextrose), fructose; sugar-alcohols such as sorbitol,
mannitol, erythritol, xylitol, maltitol and the like; and
high-intensity sweeteners such as aspartame, acesulfame potassium,
cyclamate saccharin, sucralose, and the like; and other sweeteners
such as dihydroalcones, glycyrrhizin, Monellin.TM., stevioside,
Talin.TM., and the like.
[0073] In another embodiment, the confectionery composition may be
selected from fat-based confectionery compositions, such as
chocolate, including, for example, milk chocolate, dark chocolate,
semi-sweet chocolate; coatings including, for example, chocolate
compound coatings, pastel compound coatings e.g. white chocolate,
and the like. In such embodiments, the fat-based confectionery
composition may typically begin to melt at a temperature of about
25 to about 80.degree. C., e.g. about 25 to about 40.degree. C., or
about 34 to about 37.degree. C., or about 40 to about 80.degree.
C., and comprises a suitable low-melting material. Those skilled in
the art will recognize that the melting point of the composition
may vary according to the solid-fat indices of the various fat
components. Solid-fat index (SFI) is a method of characterizing fat
blends related to proportion of liquid fat in the blend at
different temperatures. IUPAC method 2.141 "Determination of the
Dilatation of Fats" details the method for measuring this
index.
[0074] In embodiments where the confectionery composition begins to
melt between 25-40.degree. C., suitable low-melting materials
include triglycerides such as lauric and non-lauric cocoa butter
substitutes, lauric (shorter chain fatty acids) fats, such as
coconut and palm kernal oils and derivatives thereof; non-lauric
(longer chain fatty acids) fats such as cocoa butter, palm oil,
soybean and cottonseed oils, and derivatives thereof; cocoa butter
equivalents; mono, and diglycerides; phospholipids; and water
soluble polymers such as polyethylene glycol. In one embodiment,
the low-melting material is a fractionated lauric fat selected from
palm kernal oil and coconut oil.
[0075] In embodiments where the composition begins to melt between
40-80.degree. C., suitable low-melting materials include waxes such
as carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac
wax, microcrystalline wax, and paraffin wax, water soluble polymers
such as polyethylene glycol, polyethylene oxides and derivatives,
and sucrose esters.
[0076] In yet another embodiment, the confectionery composition may
be a fondant. In such embodiments, the confectionery composition
comprises a crystalline carbohydrate of which at least about 90% of
the crystals have an average size from about 2 to about 15 microns,
and typically has a moisture content of about 5 to about 15%, e.g.
about 10 to about 12%.
[0077] In a preferred embodiment, the confectionery composition
comprises at least one component selected from fat, amorphous sugar
glass and fondant.
[0078] The dosage form of this invention may have any shape that is
suitable for molding. For example, in one embodiment the dosage
form may be in the shape of a truncated cone. In other embodiments
the dosage form may be shaped as a polyhedron, such as a cube,
pyramid, prism, or the like; or may have the geometry of a space
figure with some non-flat faces, such as a cone, cylinder, sphere,
torus, or the like. Exemplary shapes which may be employed include
tablet shapes formed from compression tooling shapes described by
"The Elizabeth Companies Tablet Design Training Manual" (Elizabeth
Carbide Die Co., Inc., p.7 (McKeesport, Pa.) (incorporated herein
by reference) as follows (the tablet shape corresponds inversely to
the shape of the compression tooling):
[0079] 1. Shallow Concave.
[0080] 2. Standard Concave.
[0081] 3. Deep Concave.
[0082] 4. Extra Deep Concave.
[0083] 5. Modified Ball Concave.
[0084] 6. Standard Concave Bisect.
[0085] 7. Standard Concave Double Bisect.
[0086] 8. Standard Concave European Bisect.
[0087] 9. Standard Concave Partial Bisect.
[0088] 10. Double Radius.
[0089] 11. Bevel & Concave.
[0090] 12. Flat Plain.
[0091] 13. Flat-Faced-Beveled Edge (F.F.B.E.).
[0092] 14. F.F.B.E. Bisect.
[0093] 15. F.F.B.E. Double Bisect.
[0094] 16. Ring.
[0095] 17. Dimple.
[0096] 18. Ellipse.
[0097] 19. Oval.
[0098] 20. Capsule.
[0099] 21. Rectangle.
[0100] 22. Square.
[0101] 23. Triangle.
[0102] 24. Hexagon.
[0103] 25. Pentagon.
[0104] 26. Octagon.
[0105] 27. Diamond.
[0106] 28. Arrowhead.
[0107] 29. Bullet.
[0108] 30. Barrel.
[0109] 31. Half Moon.
[0110] 32. Shield.
[0111] 33. Heart.
[0112] 34. Almond.
[0113] 35. House/Home Plate.
[0114] 36. Parallelogram.
[0115] 37. Trapezoid.
[0116] 38. FIG. 8/Bar Bell.
[0117] 39. Bow Tie.
[0118] 40. Uneven Triangle.
[0119] The dosage form surface may be substantially smooth, i.e.
may have indentations or protrusions at the microscopic level on
the order of less than about 20 microns in width, depth, or height.
Alternately the dosage form surface may be textured, i.e. having
indentations or protrusions greater than about 20 microns, e.g.
greater than about 50 microns, or greater than about 100 microns,
say greater than about 1000 microns in width, depth, or height. The
indentations or protrusions may be up to about 30,000 microns, e.g.
up to about 2,000 microns in width, depth, or height. In
embodiments wherein the dosage form surface is textured, the outer
surface of the dosage form may contain an embossed (raised) or
debossed (indented) design. For example, the outer surface of the
core may contain indentations, intagliations, letters, symbols or a
pattern such as a graphic or logo.
[0120] In one embodiment of this invention, the dosage form has at
least one face, and the relative standard deviation of the weight
of the dosage form is less than 1%, preferably less than 0.5%. As
used herein, relative standard deviation of the weight of the
dosage form may be determined as follows: The weights of 30
individual dosage forms are determined to the nearest 0.1 milligram
using an analytical balance. From the 30 individual weights for
each sample, a mean, sample standard deviation, and relative
standard deviation (% RSD) are calculated, as set forth in Example
5 herein. The relative standard deviation is the standard deviation
expressed as a percentage of the mean, as is well known in the
art.
[0121] In another embodiment of this invention, the dosage form has
at least one face, the relative standard deviation of the weight of
the dosage form is less than 1%, preferably less than 0.5%, and the
confectionery composition does not contain a gelatin based
composition or a gel based composition.
[0122] In another embodiment of this invention, the dosage form has
at least one face, the relative standard deviation of the weight of
the dosage form is less than 1%, preferably less than 0.5%, the
dosage form does not have a free formed surface, and the
confectionery composition comprises an amorphous glass sugar
component.
[0123] In another embodiment of this invention, the dosage form has
at least one face, and the relative standard deviation of the
weight of the dosage form is less than 1%, preferably less than
0.5%, and all the faces of the dosage form have a surface gloss of
about 200-300 gloss units. As used herein, "surface gloss" means a
measure of reflected light determined according to the method set
forth in Example 4 herein.
[0124] In another embodiment of this invention, the dosage form has
more than one face, the relative standard deviation of the weight
of the dosage form is less than 1%, preferably less than 0.5%, and
the difference in surface gloss between any two faces is not more
than about 20 gloss units, preferably about 15 gloss units, more
preferably about 10 gloss units.
[0125] In another embodiment of this invention, the dosage form has
at least one face, the relative standard deviation of the weight of
the dosage form is less-than 1%, preferably less than 0.5%, and the
dosage form has a mean polarized light transmission at the angle of
maximum extinction which is not greater than the mean polarized
light transmission of the dosage form at the angle of maximum
transmission.
[0126] "Mean polarized light-transmission" as used herein is
measured according the method set forth in Example 6 herein. In
summary, the system for measuring the mean polarized light
transmission consists of a light source followed by a first
polarizing filter, followed by the sample, followed by a second
polarizing filter, followed by a detector, such as, for example, a
digital camera.
[0127] The "angle of maximum transmission" as used herein is the
relative position of the polarizers that allows the maximum amount
of light to pass through the sample. This has been found to be an
angle of approximately zero degrees between the first and second
polarizers.
[0128] The "angle of maximum extinction" as used herein is the
relative position of the polarizers that allows the minimum amount
of light to pass through a sample. This has been found to be an
angle between the first and second polarizers of approximately 90
degrees, plus or minus about 20 degrees. The angle of maximum
extinction will vary with the composition of the sample because
different sugar-containing compositions rotate the plane of
polarized light by varying amounts, with the average being about
minus 15 degrees for a 100% glucose solution which corresponds to
an angle of maximum extinction of about 75 degrees between the
first and second polarizers.
[0129] The polarized light transmission is measured by plotting the
intensity of transmitted light across the 256 grayscale values of
the detected image. The mean polarized light transmission is
defined as the grayscale value at the midpoint of the area of peak
transmission intensity. The difference between the mean polarized
light transmission at the angle of maximum transmission and the
mean polarized light transmission at the angle of maximum
extinction is referred to herein as the "relative homogeneity
index." A sample which is free of strain lines and air bubbles will
have a high relative homogeneity index, while a sample containing
strain lines and air bubbles will have a low relative homogeneity
index.
[0130] In another embodiment of this invention, the dosage form has
at least one face, the relative standard deviation of the weight of
the dosage from is less than 1%, preferably less than 0.5%, the
dosage form has a mean polarized light transmission at the angle of
maximum extinction which is not greater than the mean polarized
light transmission of the dosage form at the angle of maximum
transmission, and the dosage form has a mean polarized light
transmission between about 0 to 40 grayscale units at the angle of
maximum extinction.
[0131] In another embodiment of this invention, the dosage form has
at least one face, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission.
[0132] In another embodiment of this invention, the dosage form has
at least one face, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission, and the relative standard deviation of the weight of
the dosage form is less than 1.0%, preferably less than 0.5%, more
preferably less than 0.5%.
[0133] In another embodiment of this invention, the dosage form has
at least one face, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission, and the confectionery composition does not contain a
gelatin based or gel based composition.
[0134] In another embodiment of this invention, the dosage form has
at least one face, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission and the confectionery composition comprises an
amorphous sugar glass component.
[0135] In another embodiment of this invention, the dosage form has
two or more faces, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission and all of the faces of the dosage form have a surface
gloss of about 200-300 gloss units.
[0136] In another embodiment of this invention, the dosage form has
two or more faces, does not have a free formed surface, and has a
mean polarized light transmission at the angle of maximum
extinction which is not greater than the mean polarized light
transmission of the dosage form at the angle of maximum
transmission, and the difference in surface gloss between any two
faces is not more than about 20 gloss units, preferably about 15
gloss units, most preferably about 10 gloss units.
[0137] In another embodiment, the dosage form comprises a
confectionery composition which may be a hard candy, such as for
example, an amorphous sugar-glass. In such embodiments the dosage
form has a mean polarized light transmission at the angle of
maximum extinction which is not greater than the mean polarized
light transmission of the dosage form at the angle of maximum
transmission.
[0138] In another embodiment, the dosage form of this invention is
a unitary object, that is, a single, undivided article or product
similar to a piece of hard candy, for example.
[0139] In another preferred embodiment, the dosage form of this
invention does not contain any seams on its surface.
[0140] In other embodiments, the dosage form of this invention is
substantially free of pores having a diameter of 0.5 to 5.0
microns. By "substantially free" it is meant that the dosage form
has a pore volume of less than about 0.02 cc/g, preferably less
than about 0.01 cc/g, more preferably less than about 0.005 cc/g,
in the pore diameter range of 0.5 to 5.0 microns. Typical
compressed materials have pore volumes of more than about 0.02 cc/g
in this pore diameter range.
[0141] Pore volume measurements may be obtained using a
Quantachrome Instruments PoreMaster 60 mercury intrusion
porosimeter and associated computer software program known as
"Porowin." The procedure is documented in the Quantachrome
Instruments PoreMaster Operation Manual. The PoreMaster determines
both pore volume and pore diameter of a solid or powder by forced
intrusion of a non-wetting liquid (mercury), which involves
evacuation of the sample in a sample cell (penetrometer), filling
the cell with mercury to surround the sample with mercury, applying
pressure to the sample cell by: (i) compressed air (up to 50 psi
maximum); and (ii) a hydraulic (oil) pressure generator (up to
60000 psi maximum). Intruded volume is measured by a change in the
capacitance as mercury moves from outside the sample into its pores
under applied pressure. The corresponding pore size diameter (d) at
which the intrusion takes place is calculated directly from the
so-called "Washburn Equation": d=-(4.gamma.(cos.theta.))/P where
.gamma. is the surface tension of liquid mercury, .theta. is the
contact angle between mercury and the sample surface and P is the
applied pressure.
[0142] Equipment used for pore volume measurements:
[0143] 1. Quantachrome Instruments PoreMaster 60.
[0144] 2. Analytical Balance capable of weighing to 0.0001 g.
[0145] 3. Desiccator.
[0146] Reagents used for measurements:
[0147] 1. High purity nitrogen.
[0148] 2. Triply distilled mercury.
[0149] 3. High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0150] 4. Liquid nitrogen (for Hg vapor cold trap).
[0151] 5. Isopropanol or methanol for cleaning sample cells.
[0152] 6. Liquid detergent for cell cleaning.
[0153] Procedure:
[0154] The samples remain in sealed packages or as received in the
dessicator until analysis. The vacuum pump is switched on, the
mercury vapor cold trap is filled with liquid nitrogen, the
compressed gas supply is regulated at 55 psi., and the instrument
is turned on and allowed a warm up time of at least 30 minutes. The
empty penetrometer cell is assembled as described in the instrument
manual and its weight is recorded. The cell is installed in the low
pressure station and "evacuation and fill only" is selected from
the analysis menu, and the following settings are employed:
[0155] Fine Evacuation time: 1 min.
[0156] Fine Evacuation rate: 10
[0157] Coarse Evacuation time: 5 min.
[0158] The cell (filled with mercury) is then removed and weighed.
The cell is then emptied into the mercury reservoir, and two
tablets from each sample are placed in the cell and the cell is
reassembled. The weight of the cell and sample are then recorded.
The cell is then installed in the low-pressure station, the
low-pressure option is selected from the menu, and the following
parameters are set:
[0159] Mode: Low pressure
[0160] Fine evacuation rate: 10
[0161] Fine evacuation until: 200 .mu. Hg
[0162] Coarse evacuation time: 10 min.
[0163] Fill pressure: Contact +0.1
[0164] Maximum pressure: 50
[0165] Direction: Intrusion And Extrusion
[0166] Repeat: 0
[0167] Mercury contact angle; 140
[0168] Mercury surface tension: 480
[0169] Data acquisition is then begun. The pressure vs. cumulative
volume-intruded 20 plot is displayed on the screen. After
low-pressure analysis is complete, the cell is removed from the
low-pressure station and reweighed. The space above the mercury is
filled with hydraulic oil, and the cell is assembled and installed
in the high-pressure cavity. The following settings are used:
[0170] Mode: Fixed rate
[0171] Motor speed: 5
[0172] Start pressure: 20
[0173] End pressure: 60 000
[0174] Direction: Intrusion and extrusion
[0175] Repeat: 0
[0176] Oil fill length: 5
[0177] Mercury contact angle: 140
[0178] Mercury surface tension: 480
[0179] Data acquisition is then begun and graphic plot pressure vs.
intruded volume is displayed on the screen. After the high pressure
run is complete, the low-and high-pressure data files of the same
sample are merged.
[0180] The differences between the prior art and the present
invention will be further understood with reference to FIGS. 1A and
1B. In FIG. 1A, Composition 1 is a Halls hard candy composition
commercially available from Warner-Lambert Co., Morris Plains,
N.J., and Composition 2 is dosage form according to the invention
in which the confectionery composition is amorphous sugar glass. As
show in FIG. 1A, when viewed under normal polarized light there are
no distinguishing differences between Compositions 1 and 2.
However, as shown in FIG. 1B, when viewed under polarized light at
90.degree. filtering to the incident light, Composition 1 exhibits
birefringence (i.e., refracted light) due to residual strain in the
glass portion of the composition, whereas Composition 2
advantageously appears uniform without residual strain.
[0181] The dosage form of this invention is produced by molding.
Several molding methods are known in the art, however it is
preferred that the dosage form be made using the thermal setting
molding method and apparatus described in copending U.S.
application Ser. No. 09/966, 450, pages 57-63, or the thermal cycle
molding method and apparatus described in copending U.S.
application Ser. No. 09/966,497, pages 27-51, the disclosures of
which are incorporated herein by reference.
[0182] In the thermal setting molding method, a starting material
comprising the ingredients for the dosage form is injected into a
molding chamber and molded into the desired shape. The starting
material preferably comprises, in addition to the active ingredient
and the confectionary composition, a thermal setting material at a
temperature above the melting point of the thermal setting material
but below the decomposition temperature of the active ingredient.
The starting material is cooled and solidifies in the molding
chamber into a shaped pellet (i.e., having the shape of the
mold).
[0183] According to this method, the starting material must be in
flowable form. For example, it may comprise solid particles
suspended in a molten matrix, for example a polymer matrix. The
starting material may be completely molten or in the form of a
paste. The starting material may comprise an active ingredient
dissolved in a molten material. Alternatively, the starting
material may be made by dissolving a solid in a solvent, and the
solvent is then evaporated from the starting material after it has
been molded.
[0184] The thermal setting material may be any edible material that
is flowable at a temperature between about 37 and about 250.degree.
C., and that is a solid or semi-solid at a temperature between
about -10.degree. C. and about 35.degree. C. In certain
embodiments, the thermal setting material may comprise all or a
portion of the confectionary composition as well, as some of the
same materials are useful for both. Preferred thermal setting
materials include water-soluble polymers such as polyalkylene
glycols, polyethylene oxides and derivatives, and sucrose esters;
fats such as cocoa butter, hydrogenated vegetable oil such as palm
kernel oil, cottonseed oil, sunflower oil, and soybean oil; free
fatty acids and their salts; mono- di- and triglycerides,
phospholipids, waxes such as camuba wax, spermaceti wax, beeswax,
candelilla wax, shellac wax, microcrystalline wax, and paraffin
wax; fat-containing mixtures such as chocolate; sugar in the form
on an amorphous glass, sugar in a supersaturated solution,;
low-moisture polymer solutions such as mixtures of gelatin and
other hydrocolloids at water contents up to about 30% such as those
used to make "gummi" confection forms. In a particularly preferred
embodiment, the thermal setting material is a blend of fats and
mono- and diglycerides.
[0185] In the thermal cycle molding method and apparatus of U.S.
patent application Ser. No. 09/966,497, a thermal cycle molding
module having the general configuration shown in FIG. 3 therein is
employed. The thermal cycle molding module 200 comprises a rotor
202 around which a plurality of mold units 204 are disposed. The
thermal cycle molding module includes a reservoir 206 (see FIG. 4)
for holding flowable material to make the core. In addition, the
thermal cycle molding module is provided with a temperature control
system for rapidly heating and cooling the mold units. FIGS. 55 and
56 of the '497 application depict the temperature control system
600.
[0186] In this embodiment, the mold units preferably comprise
center mold assemblies 212 and upper mold assemblies 214 as shown
in FIG. 26C of U.S. patent application Ser. No. 09/966,497, which
mate to form mold cavities having the desired shape of the dosage
form. As rotor 202 rotates, the opposing center and upper mold
assemblies close. Flowable material comprising the ingredients of
the dosage form, which is heated to a flowable state in reservoir
206, is injected into the resulting mold cavities. The temperature
of the flowable material is then decreased, hardening the flowable
material into dosage forms. The mold assemblies open and eject the
dosage forms.
[0187] FIG. 2A is a photograph of a two-piece hard candy lozenge
mold which may be used to prepare the dosage form of this
invention. The mold in FIG. 2A is a 2-piece aluminum mold made up
of first mold piece 2 and second mold piece 4. Mold pieces 2 and 4
have respective cavity portions 6 and 8 which form a cavity which
has been polished to a mirror finish. Mold pieces 2 and 4 also have
respective injection port portions 12 and 14 which define an
injection port for injecting flowable material into the mold, as
well as vent port portions 16 and 18 for venting air. FIG. 2B is a
photograph of the mold depicted in FIG. 2A together with a lozenge
dosage form 10 which has been removed from the mold.
[0188] This invention will be further illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
Molded Hard Candy Dosage Form
[0189] A batch of molded hard candy lozenges was prepared in the
following manner:
[0190] Hard Candy Pre-cook Formulation:
[0191] The following ingredients were used to prepare the
formulation:
1 Ingredient % mg/tab gms/batch Corn Syrup (42 DE) 45.35 170.06
498.85 Sugar (dry granular) 45.35 170.06 498.85 Purified Water USP
9.05 33.93 99.60 FD&C Red #40 0.05 0.20 0.50 Flavor 0.20 0.75
2.20 TOTAL 100.00 375.00 1100.0
[0192] The corn syrup was weighed into a tared non-stick 2-quart
saucepan. Purified water was then added to the same pan and the
mixture was warmed over low heat with stirring until homogeneous.
To the diluted corn syrup, dry granular sugar was added and stirred
to form a wet slurry.
[0193] Cook Step:
[0194] The sugar, water, corn syrup mixture was heated rapidly on a
gas-fired stove over high heat with gentle stirring until the
mixture appeared clear and began to boil. Heating continued until
the mixture reached a temperature of 120.degree. C. at which point
the heat was reduced to a medium flame. Heating was continued over
a medium flame until 140.degree. C. was reached at which point the
color was added to the batch and stirred in until uniformly
distributed. When the temperature reached 145.degree. C., the batch
was removed from the stove and the flavor was blended into the
batch. Subsequently, the batch was allowed to cool slightly without
mixing so that air bubbles would dissipate.
[0195] Molding Step:
[0196] While maintaining the batch in a fluid state by occasional
heating, the molten candy base was injected into a two piece metal
mold held together by thumbscrews (as shown in FIGS. 2A and 2B).
The mold, constructed from aluminum, had an injection port and a
vent port that allowed excess candy mass to exit the mold. The fill
cavity, in the shape of the desired lozenge piece, was polished to
provide a molded dosage form having a smooth shiny surface. The
injection device, a 10 cc plastic syringe having a cut off tip, was
used to transfer candy base from the cooked batch and inject the
candy base into the injection port of the molding apparatus. Once
filled, the mold was allowed to cool at room temperature for about
2 minutes before opening. Upon opening, the molded dosage form was
removed and any excess hard candy web from the fill and vent ports
was snapped off.
EXAMPLE 2
Hard Candy Dosage Form
[0197] A dosage form according to the invention is made following
the procedure stated in Example 1, except the hard candy pre-cook
formation is as follows:
2 Ingredient % mg/tab gms/batch Corn Syrup (42 DE) 44.99 170.06
498.85 Sugar (dry granular) 44.99 170.06 498.85 Purified Water USP
8.98 33.93 99.60 FD&C Red #40 0.05 0.20 0.50 Flavor 0.20 0.75
2.20 Benzydamine 0.79 3.00 8.80 TOTAL 100.00 378.00 1108.8
[0198] Here, the active ingredient, benzydamine, is added along
with the flavor after the batch is removed from the stove.
EXAMPLE 3
Hard Candy Menthol Lozenge Dosage Form
[0199] A commercial scale batch of hard candy menthol dosage forms
according to the invention is made using thermal cycle molding and
the formulation set forth below:
[0200] Hard Candy Pre-cook Formulation:
[0201] The following ingredients including menthol as the active
ingredient, are used to prepare the formulation:
3 Theory Ingredient Supplier Percent Mg/tab Kg/batch Sucrose
Florida Crystals, FL 46.91 1407..3 234.6 (dry granular) Corn Syrup
Archer Daniel Midland, 38.44 1153.2 192.2 42 DE CA Menthol A1
Menthol Century 0.40* 12.0* 2.00* Int'l, CA Purified Water 14.0
420.0 70.0 Flavor 0.20 6.00 1.00 Color 0.05 1.5 0.25 TOTAL 100.0
3000 500.0 *Includes a 17% overage for loss during processing.
[0202] Sucrose, corn syrup and water from the pre-cook formulation
is vacuum cooked by a batch method. Other suitable methods include
semicontinuous, and continuous vacuum cooking. Confectionery vacuum
cookers are manufactured by APV Baker (Peterborough, UK),
Kloeckner-Hansel GmbH (Cape Coral, Fla.), and Hosokawa Ter Braak B.
V. (Rotterdam, Netherlands).
[0203] Sugar and water are added to the syrup cooking pan of the
vacuum cooker and heated to about 110.degree. C. to completely
dissolve the sugar crystals. Subsequently, the corn syrup is added
and the mixture is cooked to about 138.degree. C. and then
discharged to the lower pan under vacuum (620 mm). In the lower
pan, color, flavor, and menthol are added and mixed into the
batch.
[0204] While still fluid, the cooked hard candy batch is
transferred to heated supply tanks or reservoirs, such as those
shown as 206 in FIG. 4 of copending U.S. application Ser. No.
09/966,497. The cooked hard candy batch is maintained within the
reservoirs at about 120.degree. C. without stirring. The reservoirs
206 are covered and pressurized to about 150 psi or sufficient
pressure to allow the fluid hard candy mass to flow to a thermal
cycle molding module as follows.
[0205] The dosage forms are then made in a thermal cycle molding
module thermal cycle molding module having the specific
configuration shown in FIG. 26A of copending U.S. application Ser.
No. 09/966,497. The thermal cycle molding module comprises center
mold assemblies 212 and upper mold assemblies 214 as shown in FIG.
26C, which mate to form mold cavities having the shape of a hard
candy. As rotor 202 rotates, the opposing center and upper mold
assemblies close. The fluid, cooked hard candy batch is injected
into the resulting mold cavities.
[0206] The mold assemblies are thermally cycled between about
120.degree. C. and about 90.degree. C. and receive the hot cooked
hard candy batch material when its cycle is in the high temperature
range. As the hot material fills the mold cavity, the mold
temperature is cycled to the low temperature range (i.e.
60-90.degree. C.) and cools the material to a temperature where it
is sufficiently solid that it no longer flows under its own weight.
Once set (i.e., for 1-60 seconds), the mold assemblies open and the
molded dosage form is ejected from the thermal cycle molding module
and conveyed to a tray to cool and completely harden.
[0207] Once cooled to room temperature (22.degree. C.), a batch of
molded hard candy lozenge dosage forms is ready to be transferred
in bulk to a packaging line.
EXAMPLE 4
Surface Gloss Comparisons
[0208] Commercially available molded lozenges were tested for
surface gloss using an instrument available from TriCor Systems
Inc. (Elgin, Ill.) under the tradename, "TRI-COR MODEL 805A/806H
SURFACE ANALYSIS SYSTEM" and generally in accordance with the
procedure described in "TriCor Systems WGLOSS 3.4 Model 805A/806H
Surface Analysis System Reference Manual" (1996), which is
incorporated by reference herein, except as modified below,
[0209] This instrument utilized a CCD camera detector, employed a
flat diffuse light source, compared tablet samples to a reference
standard, and determined average gloss values at a 60 degree
incident angle. During its operation, the instrument generated a
gray-scale image, wherein the occurrence of brighter pixels
indicated the presence of more gloss at that given location.
[0210] The instrument also incorporated software that utilized a
grouping method to quantify gloss, i.e., pixels with similar
brightness were grouped together for averaging purposes.
[0211] The "percent full scale" or "percent ideal" setting (also
referred to as the "percent sample group" setting), was specified
by the user to designate the portion of the brightest pixels above
the threshold that will be considered as one group and averaged
within that group. As used herein, "threshold" is defined as the
maximum gloss value that will not be included in the average gloss
value calculation. Thus, the background, or the non-glossy areas of
a sample were excluded from the average gloss value calculations.
The method disclosed in K. Fegley and C. Vesey, "The Effect of
Tablet Shape on the Perception of High Gloss Film Coating Systems",
which is available at www.colorcon.com as of 18 Mar., 2002 and
incorporated by reference herein, was used to minimize the effects
resulting from different dosage form shapes, and to report a metric
that was comparable across the industry. (The 50% sample group
setting was selected as the setting which best approximated
analogous data from tablet surface roughness measurements.)
[0212] After initially calibrating the instrument using a
calibration reference plate (190-228; 294 degree standard; no mask,
rotation 0, depth 0), a standard surface gloss measurement was then
created using gel-coated caplets available from McNEIL-PPC, Inc.
under the tradename, "EXTRA STRENGTH TYLENOL GELCAPS." The average
gloss value for a sample of 112 of such gel-coated caplets was then
determined, while employing the 25 mm full view mask (190-280), and
configuring the instrument to the following settings:
[0213] Rotation: 0
[0214] Depth: 0.25 inches
[0215] Gloss Threshold: 95
[0216] % Full Scale (% ideal): 50%
[0217] Index of Refraction: 1.57
[0218] The average surface gloss value for the reference standard
was determined to be 269.
[0219] Each face of each sample molded lozenge was then
independently tested in accordance with the same procedure. For the
deposited samples, the "free-formed" face was designated as "Face
1." The opposing face was designated as "Face 2". A 31 by 31 pixel
area (corresponding to an area on the sample of about 3.1
mm.times.3.1 mm, or 9.61 square millimeters) was chosen to minimize
contribution from air bubbles. HALLS PLUS lozenges available from
Warner-Lambert Company, Morris Plains, N.J. were selected as
exemplary of lozenges manufactured by a conventional uniplasting
process (Sample A). Cepacol.RTM. Sore Throat Lozenges, available
from J. B. Williams Co., Glen Rock, N.J., and JOLLY RANCHER HARD
CANDY available from Hershey Foods Corp, Hershey, Pa. were selected
as exemplary of lozenges manufactured by conventional depositing
methods (Samples B and C, respectively). Injection molded lozenges
made according to the method of Example 1 were designated as Sample
D. The results obtained were as follows:
4 Gloss - Manufacturing Gloss - Gloss - Difference Sample Method
Face 1 Face 2 (gloss units) A (Halls Plus .RTM.) Uniplast .TM. 225
210 15 punch molded B (Cepacol .RTM.) Deposited 282 261 21 C (Jolly
Rancher .RTM.) Deposited 296 256 40 D (Example 1) Injection 291 297
6 Molded
[0220] The results indicate that lozenge-type dosage forms
according to the invention have a small difference in surface gloss
between the two faces. In contrast, commercially available lozenges
molded by depositing had surface glosses on their free-formed faces
at least about 21 gloss units higher than the surface gloss on
their molded faces. Lozenges made by the Uniplast punch method also
showed less difference in surface gloss between their 2 major faces
than those prepared by depositing.
EXAMPLE 5
Weight Variation of Comparative Products
[0221] Variation in piece weight of various commercially available
confectionery forms, representative of conventional confectionery
processing methods was measured by the following method. The weight
of 30 individual pieces of each form was determined to the nearest
0.1 milligram using an analytical balance. From the 30 individual
piece weights for each sample, a mean, sample standard deviation,
and relative standard deviation (% RSD) were calculated. Note the
relative standard deviation is the standard deviation expressed as
a percentage of the mean, as known in the art.
5 Relative Standard Mean Piece Standard Deviation in Deviation in
piece Product Supplier Weight (g) piece weight (g) Weight (%) Jolly
Rancher .RTM. Hershey Foods Corp, 5.9108 0.1972 3.34 Hard Candy
Hershey, PA Tootsie Roll .RTM. Tootsie Roll Industries, 6.5572
0.1248 1.90 Inc, Chicago, IL Hershey .RTM.'s Hershey Foods Corp.
4.6323 0.1523 3.29 Kisses .RTM. Hershey, PA Halls .RTM. Cough
Warner-Lambert 3.7859 0.0652 1.72 Suppressant Company, Morris
Plains, Drops NJ Werther .RTM.'s Storck USA L.P., 5.1829 0.1294
2.50 Original Hard Chicago, IL Candy Kraft .RTM. Caramels Nabisco
Inc., East 7.9660 0.3844 4.83 Hanover NJ
EXAMPLE 6
Visualization and Quantification of Strain in Hard Candy Glass
[0222] Samples of hard candy glass were viewed and photographed
under plane polarized light to quantify the relative strain in the
candy glass. Sample A was a Halls Plus.RTM. lozenge commercially
available from Warner-Lambert Co., Morris Plains, N.J. Sample B was
an injection molded lozenge made according to Example 1 herein.
Sample C was a Chloraseptic lozenge commercially available from
Prestige Brands International, Inc., Bonita Springs, Fla. Samples A
and C are exemplary of Uniplast.TM. punch molded hard candy glass
products. Typically, injection molded and deposited hard candy show
no intrinsic strain whereas punch or roller molded hard candy
retain residual strain that is visible when viewed under a strain
viewer. The equipment used was as follows:
[0223] 1) Camera--Scalar Portable Digital Microscope DG-1 fitted
with the 1X lens with a C-mount adapter.
[0224] 2) Strain Viewer--The strain viewer used was fabricated
using:
[0225] Portable light box containing an 8 watt florescent lamp
(Apollo--model LB 101, Ronkonkoma, N.Y. 11779).
[0226] Two 5".times.3" pieces of linear polarizing filters.
Available from the 3M Company e.g., HN32--Neutral linear polarizer
or other suitable for stress analysis.
[0227] As depicted in FIGS. 3A and 3B, a first filter 300 was
secured to the middle of a light box 302 with cellophane tape and a
second filter 304 was held by hand, parallel above the first filter
302. Samples (306 and 308) being analyzed were placed on top of the
first filter 300 but beneath the second filter 304. Light
transmission was regulated by rotating the second filter 304 while
maintaining its parallel position above the first filter 300, as
shown in FIG. 3B.
[0228] Alternatively, strain viewers are commercially available
from: Strainoptic Technologies, Inc., 108 W. Montgomery Ave., North
Wales, Pa. 19454, or from Sharples Stress Engineers, LTD, Unit 29
Old Mill Industrial Estate, School Lane, PR5 6SY Lancashire,
UK.
[0229] Photographs of the samples were recorded using a digital
camera. The pictures were taken through the second filter at both
the maximum light transmission angle and the minimum light
transmission angle (maximum extinction) with respect to the sample
image (not the filter).
[0230] FIGS. 4A and 4B depict typical photographic images for a
punch molded hard candy (Sample A) and an injection molded or
deposited hard candy (Sample B) when viewed as described at maximum
and minimum light transmission through a pair of polarizing
filters.
[0231] Subsequently, image analysis software (Sigma Scan Pro 5
available from SPSS, Inc.) was used to quantitatively characterize
the observed strain in the hard candy glass. Equivalent areas of
the color images (free of bubble defects and cracks) were converted
into gray scale and displayed as a histogram of pixel elements
ranging in value from 0 (black) to 255 (white). For purposes of
resolution, sample illumination and digital image exposure is
adjusted to maximize the peak separation between the transmission
and extinction states.
[0232] As seen in FIGS. 5 and 6, a converted image appears as a
peak-like distribution of gray scale pixels. Moreover, the peak
maximum for a given sample differs when the polarization filters
are at maximum light transmission (0.degree.) versus maximum light
extinction (.about.90.degree.). Drop roll or punch molded hard
candy samples, such as the Chloraceptic.RTM. Lozenge (Sample C)
depicted in FIG. 5, brighten as polarization reaches the point of
maximum extinction and their gray scale peaks shift to higher
values. Conversely, in the case of injection molded and deposited
hard candy samples, their images darken and their gray scale peaks
shift to smaller values as the polarized light reaches high
extinction levels.
[0233] Although this invention has been illustrated by reference to
specific embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made which
clearly fall within the scope of this invention.
* * * * *
References