Note: Descriptions are shown in the official language in which they were submitted.
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AHp-9914 /Cl
PH~RMACE~TICAL COATED CORES
This invention relates to solid pharmaceutical or medicament
coated cores which are essentially water soluble, the coating
material being applied as a liquid to the solid core such that
the core is wetted and partially dissolved by the coating
material, and then dried. The pharmaceutical coated cores are
for oral administration dissolved in hot or cold water or other
pharmaceutically acceptable liquid.
Sugar coated pharmaceuticals are old in the art, the sugar
coating generally being used to mask the taste of the usually
insoluble pharmaceutical core. The sugar coating, however, is
usually applied to a core which has previously been coated with
a sealing coat to prevent inter mixture of the pharmaceutical
containing core and the sugar coat. Note, for example, Example
12 of U.S. Patent Number 4,904,477 to Ho et al.
Other patents of interest are U.S. Patent 4,946,684 to Blank
et al and U.S. Patent 4,371,516 to Gregory et al described
therein. These patents deal with Fast Dissolving Dosage Forms
comprising an open matrix network carrying a pharmaceutical,
wherein the open matrix network is comprised of a water-soluble
or water-dispersable carrier material. The carrier material can
be gelatin, hydrolysed dextran, dextrin or mannitol. The carrier
~5 material and the pharmaceutical, which can be chlorpheniramine
maleate, are dissol~ed or dispersed in water, and the solution
or admixture is freeze dried to form solid dosage forms.
Many patents exist which disclose coating of nonpareil
seeds, i.e. sugar pellets, with a pharmaceutical as a first step
in the preparation of a core for further processing to make
~: sustained release medicaments. Such patents include U.S. Patents
2,921,883 and 4,810,501, the first of which discloses in Example
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3 the coating of nonpareil seeds in a coating pan with a coating
solution, formed by dissolving chlorprophenpyridamine maleate in
a 10% gelatin solution, to form drug pellets which are then
- coated with a fat-cellulosic coating solution to form a delayed
release medicament. Patent 4,810,501 discloses in the example
the spray coating of nonpareil seeds with a coating solution
formed by mixing with water kaolin, diphenhydramine hydrochloride
and hydroxypropyl cellulose. The drug layered pellets were then
coated with ethyl cellulose to form sustained release pellets.
The pharmaceutical dosage forms of this invention, however, are
for immediate release.
U.S. Patent No. 4,177,254 discloses solid penicillin dosage
forms wherein an aqueous suspension of a penicillin and a binder
is sprayed onto a fluidized bed comprising sucrose. The binder
can be sucrose such that the binder admixed with the insoluble
penicillin forms a layer on the sucrose particles in the
fluidized bed, which layer comprises particles of penicillin
dispersed throughout the binder. The solid dosage forms can be
reconstituted with water to form a syrup.
This invention provides
a f;nely divided solid pharmaceutical dosage form for
oral administration dissolved or suspended in a
pharmaceutically acceptable liquid, the pharmaceutical
dosage form consisting of a pharmaceutical coat;ng on a
core wherein:
a) the core comprises about 90% to 100% by weight of
a crystalline or granular water soluble or water
dispersible material or mixtures thereof based on
the weight of the core, said material having a
particle size of 600~m-250um (30-60 U.S.) mesh
and the core comprising about 90% to about 99% by
weight of the pharmaceutical dosage form;
b) the pharmaceutical coating comprises about 25% to
about 50% by weight of a water soluble or water
dispersible material whlch may be the same or
d;fferent material as the core based on the dry
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weight of the coating and about 50% to about 75%
by weight of at least one water-soluble
pharmaceutical based on the dry weight of the
coating and the coating compr;sing about 1% to
about 5% by weight of the pharmaceutical dosage
form;
and
c) the pharmaceutical coating having been applied to
the core from an aqueous solution of the water
soluble or water dispersible material and the
water-soluble pharmaceutical containing about 50%
to 80% by weight of water by pan coating such
. that the surface of the core is dissolved and
intimately admixed with the coating solution
thereby forming an ;ntimate bond between the core
and the water-soluble pharmaceutical.
This invention is an improved solid pharmaceutical dosage
form for oral administration dissolved or suspended in a liquid
25 and having a core such as sugar the surface of which has been
: wetted with an aqueous base pharmaceutical coating solution and
; then dried such that the surface of the core is dissolved and
~:` intimately admixed with the coating solution thereby forming an
3 intimate bond between ~he core and the pharmaceutical upon
drying. In a preferred embodiment, the sugar core consists
essentially of about 90% to 100% by weight of sugar based on the
; weight of the sugar core, the sugar core comprising about 90% to
about 99% by weight of the pharmaceutical dosage form. In said
embodiment, the pharmaceutical coating consists essentially of
about 25% to about 50% by weight of sugar based on the weight of
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the coating and about 50% to about 75% by weight of
pharm~ceutical based on the weight of the dry coating, and the
dry coating comprises about 1% to about 5% by weight of the
pharmaceutical dosage form. In said preferred embodiment, the
pharmaceutical coating is applied by pan coating to the sugar
core from an aqueous solution o~ the sugar and a water-soluble
pharmaceutical containing about 50% to about 80% by weight of
water, preferably at least about 70% by wei~ht of water. Too
much water requires a longer processing time and too little water
lG inhibits formation of the intimate bond between the sugar core
and the water soluble pharmaceutical upon drying.
The invention is described in relation to the practice of
its preferred embodiment, i.e. wherein the core and coating
solution comprise sugar. However, as explained below, other
suitable materials may be utilized in the practice of the present
invention. Furthermore, it should be noted that the core and the
solute of the coating solution may be non-identical materials.
The pharmaceuticals or medicaments useful in the invention
include, for example, nonnarcotic analgesics such as
acetaminophen; antihistamines such as terfenadine,
chlorpheniramine maleate, phenylephrine hydrochloride,
diphenhydramine hydrochloride, bromopheniramine maleate and
pheniramine maleate; nonsteroidal antiinflammatories such as
ibuprofen, ketoprofen, etodolac and indomethacin; decongestants
such as pseudoephedrine hydrochloride , phenylpropanolamine
hydrochloride and ephedrine hydrochloride; cough suppressants
such as dextromethorphan hydrobromide and guaifenesin;
bronchodilators such as epinephrine, isoproterenol hydrochloride
and theophylline; and stimulants such as caffeine~
When more than one pharmaceutical is employed, they may be
divided between the pan charge and the coating solution. The
water-soluble pharmaceuticals are used as an ingredient of the
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coating solution and water-insoluble or difficultly dispersible
pharmaceuticals are used as an ingredient with sugar in the pan
charge. The water-soluble pharmaceuticals generally include the
acid addition salts, ie the inorganic and organic acid addition
salts such as the hydrochlorides, the hydrobromides and the
maleates. The nonnarcotic analgesics and the antiinflammatories
generally have limited solubility, as do terfenadine and
epinephrine. Since the coating solution is at least about 70~
water and relatively large proportions are used, pharmaceuticals
such as guaifenesin and theophylline can be used since they are
` soluble to the extent required especially in warm water. At
about 50Y to 60QC guaifenesin is quite soluble in such warm water
and does not precipitate out at lower temperatures of about 25QC.
Accordingly, water-soluble pharmaceuticals are those that are
soluble to an extent such that 12 to 20 grams of the final
pharmaceutical dosage form will provide an adequate adult dosage
of the water-soluble pharmaceutical.
In addition to the sugar and the pharmaceuticals, the pan
charge can contain a water-soluble polymer to promote
agglomeration of the sugar particles. Such polymers useful in
this invention include water soluble polymers which are nontoxic
and pharmacologically acceptable, particularly for oral
administration~ Illustrative of such polymers are
polyvinylpyrrolidone, hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, methyl cellulose, block co-polymers of
ethylene oxide and propylene oxide and polyethylene glycol.
Other polymers include the natural gums such as xanthan gum,
karaya gum, and the like.
Similarly the coating solution can contai~ other water-
soluble ingredients such as colors, flavors, binders, and thelike, in addition to the pharmaceutical.
After the coating step is completed, water insoluble agents
such as anticaking agents can ~e added. These include colloidal
silicon dioxide and tricalcium phosphate. Also flavoring agents
such as citric acid can be added at this point.
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The sugars which are both useful in the practice of the
invention, and preferred as the core material and in the
production of the coating solution, include sucrose, dextrose,
glucose, fructose, lactose, and mannose. Sucrose is the
preferred sugar primarily because of its availability and low
cost. However, materials other than sugars are also useful.
Generally, these materials must be either crystalline or
granular. Further, they must be water-soluble or water
dispersible. These include cellulosic derivatives such as sodium
carboxy methyl cellulose, ethyl hydroxymethyl cellulose and
methyl hydroxypropyl cellulose. These also include non-caloric
sugars such as sorbitol, mannitol and zylitol. Also useful are
low molecular weight polyethylene glycols, such as those having
molecular weights of about 1000 to about 1500. The weight ratio
of sugar to pharmaceutical is about 90:10 to about 98:2 such that
the amount of a single adult dose of the dosage form of the
invention will be about 12 to 20 grams, an amount that can
readily be mixed with or dissolved in the pharmaceutically
acceptable liquid, and can be packaged in individual sachet
2G dosages.
The invention will now be further described in the following
examples.
EXA~PLE 1
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~` In the following example a finely divided solid dosage form
` was prepared having three pharmaceutical ingredients. The charge
to the coating pan contained acetaminophen in addition to the
sucrose and the coating solution contained pseudoephedrine HCI
and dextromethorphan HBr as well as the sucrose. The coating pan
was a 60 inch Pellegrini Model T-300 and the pump for the coating
solution was a Graco-Monark 5:1 airless sprayer equipped with an
0.043 cm (0.017) inch tip and with an 45.72 cm (18 inch) fan
width delivering approximately 380-400 ml of coating solution per
minute. The drying air inlet temperature was set at 50QC and
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` full air flow was 59.m3 (2100 feet3) per minute and partial air
flow was 31.13 (1100 feet3) per minute. The coating pan was set
to rotate at 12RPM.
The ingredients used were as follows:
Pan Charge: Sucrose Cane NF (extra fine) 30-60 mesh 244 kg
Hydroxypropylmethylcellulose E-5 (HPMC) 512 g
Compap L (90% Acetaminophen) 9,074 g
lG The sucrose comprised about 95.3~ of the pan charge and the
pharmaceutically comprised about 3.2~.
Coating Pseudoephedrine, HCl 1,008 g
Solution: Dextromethorphan ~Br 504 g
Sucrose, Cane NF (extra fine)
30-60 mesh 1,008 g
Water 7,560 g
Appearance: Clear Solution
~ The sucrose comprised about 40% of the coating solids and
:` the pharmaceutical comprised about 60~ of the coating
solids.
The 60" Pellegrini Pan was prewarmed for 20 minutes with
full air (50QC) and then charged with sucrose, Compap L and HPMC.
With the door cover '1On" and exhaust outlet "off" the batch was
then tumbled for five (5) minutes at 12 RPM to insure a uniform
dry blend before the start of the spraying process.
The goal of the spraying process was to apply the coating
solution as fast as possible to keep the batch as wet as possible
without triggering the formation of sugar lumps.
The coating cycles, all at 12 RPM, were as follows and the
total process time for coating was 127.5 minutes.
30 CYCLE NO AIR
~ 8pray Time Tumble Full AirPart ~ir
1 8'00" 3'00" 8'00"
2 4'00" 2'00" 9'00"
3 4'30" 2'00" 17'00"
4 2'30" 2'00" 7'00"
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2'00~' l'oo" 4'00"
6 2'00" 1'30" 13'00"
7 30'00" (40~c) 5'00" (40QC)
The coated core through Cycle #7 comprised about 95.4% by
weight of sucrose and about 4.1% by weight of pharmaceutical.
At the end of Cycle #7, the moisture content was 0.21%. At
- this point anticaking additives were added, colloidal silicon
dioxide in the amount of 128 grams and tricalcium phosphate in
the amount of 38~ grams. After tumbling for an additional 5
minutes, the moisture content was 0.15%. The total yield was 250
kilograms, i.e. about 98%.
The product was sub~ected to a screen analysis, i.e. a loO
gram sample, Rotap, for 5 minutes, and is compared to a screen
analysis of the sucrose raw material as follows:
~p~ Mc~ib (U~./am~ 211/850 30/600 40/425 60/251) 80/180 Pan
Sucr~ O Trace 13 40 42 4
~penmcnt 14 Mcsh (U~ 20/850 30/600 40/425 60/250 ~ Pan
` Batcb: 0 2.7 3~ 51 14 0.2 r~cc
2 0
Due to agglomeration of sugar grains during the coating
process, the comparison set forth above indicates a shift from
the finer to the coarser end. This is a clear indication that
the water from the coating solution is not only dissolving the
2 5 surface of the substrate but also causing a bond between the
grains as well.
EXAMPLL 2
_0 In the following example a finely divided solid dosage form
o~ the invention was prepared having four pharmaceutical
ingredients. The charge to the coating pan contained
acetaminophen in addition to the sucrose, and the coating
solution contained pseudoephedrine hydrochloride,
diPhenylhydramine hydrochloride and dextromethorphan
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hydrochloride as well as the sucrose. The equipment was the same
as that used in Example 1.
- The ingredients used were as follows,
Pan Charge: Sucrose, Cane NF (30-60 U.S./600 - 250 ~m mesh)
233 kg
Hydroxypropylmethyl cellulose E-5 (HPMC) 600 g
Compap L (90% Acetaminophen) 13600 g
The sucrose comprises about 94.3% of the pan charge and the
pharmaceutical comprises about 4.9% of the pan charge.
Coating Pseudoephedrine, HC1 750 g
10 Solution: Diphenylhydramine HCl 630 g
Dextromethorphan HBr 378 g
D&C Yellow #10 3024 mg
FD&C Yellow #6 636 mg
Sucrose, Cane NF 756 g
~; Water 7560 ml
The sucrose comprised about 30% of the coating solids and
the pharmaceuticals comprised about 70% of the coating
solids.
- Sweetener Blend: Sucrose, Cane NF 720 g
Nutrasweet 730 g
Blended in bag for 1 minute
~Q Flavor Blend; Sucrose, Cane NF 3360 g
Natural Lemon Flavor #16774900 g
Natural Honey Flavor 1200 g
Blend half of sucrose with lemon flavor in bag for 1
` minute.
Blend other half of sucrose with honey flavor in bag for 1
~` 25 minute.
Flavor/Anticaking Citric Acid, Fine Granular 7200 g
` Blend: Tri Calcium Phosphate 288 g
Colloidal Silicon Dioxide 144 g
The 60" Pellegrini pan was prewarmed for 20 minutes with
full air (50QC) and then charged with sucrose, Compap L and HPMC.
With the door cover "on" and exhaust outlet "off" the batch was
then tumbled for five (5) minutes at 12 RPM to insure a uniform
dry blend before the start of the spraying process.
' The water was heated in a 113.6 1 (30 gallon) kettle to 55Q-
60QC and there were dissolved therein the dyes, all of the
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sucrose, the diphenylhydramine hydrochloride, the
dextromethorphan hydrobromide and the pseudoephedrine
hydrochloride and the admixture was mixed to a clear solution.
The coating solution was held at a temperature of above 22~C
until application.
The goal of the spraying process was to apply the coating
solution as fast as possible to keep the batch as wet as possible
without triggering the formation of sugar lumps.
The drying air inlet temperature was set at 50QC and full
lG air flow was 59.5 - 61.3 m3 (~100-2200 feet3) per minute, partial
air flow was 42.5 - 44.3 m3 (1500-1600 feet3) per minute, and
exhaust was 22.2 m3 (800 feet3) p~r minute.
The coating cycles, all at 13 RPM, were as follows and the
total process time for coating was about 156.5 minutes.
Step No Air Partial
# Spray Time Tumble FUll Air Air
1 8'00" 3'00" 12'00"
2 4'00" 2'00" 16'00"
3 4'00" 2'00" 12'00"
0 4 Sprinkle sweetener blend
~- 2'00" (Exhaust open)
3'00" 2'00" 12'00"
6 Sprinkle lemon blend
3'00" (Exhaust open)
7 2'00" 1'30" 9'30"
8 Sprinkle honey flavor blend
3'00" (Exhaust open)
9 3'00" 1'30" 17'00"
10. Sprinkle 15 kg sucrose over a period of 3 minutes with no
air tumbling, exhaust open, for dusting purposes, at a pan speed
of 9RPM.
11. Partial air drying for 30 minutes at 9RPM and at the end of
cycle 11 the moisture content was 0.28~ but after an additional
ten minutes with partial air tumbling, the moisture content was
O. 09% .
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AHY-9914/C1
12. The flavor/anticaking blend was added to the batch with
tumbling for five minutes at 13 RPM.
13. The pan was unloaded and the batch was screened through a
#10 mesh screen and no lumps were observed. The yield was 259
kg, i.e. 98%.
After about 13-14 minutes of full air during step 9, some
sticking was noticed on the pan sides. This sticking was
alleviated by the dusting step 10 and the problem disappeared.
The coated core through step 9 comprised about 93.6% by
weight of sucrose and about 5.6% by weight of pharmaceutical.
The finished dosage form through step 11 comprised about 92.97%
by weight of sucrose and about 5.15% by weight of
pharmaceutical.
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