Note: Descriptions are shown in the official language in which they were submitted.
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HYDROXYPROPYLCELLULOSE AND ANIONIC POLYMER COMPOSITIONS
AND THEIR USE AS PHARMACEUTICAL FILM COATINGS --
The present invention relates to film forming compositions and more
particularly it relates to compositions comprising hydroxypropylcellulose and
sodium
carboxymethylcellulose.
15 Bac round of the Invention
Coating tablets, granules and beads with polymeric film forming compositions
is well known in the pharmaceutical industry. In addition to pharmaceutical
books,
manuals and technical literature, patent publications in this field include:
U.S. Patent
No. 4,931, 286 disclosing high gloss pharmaceutical tablet which comprises an
2o active ingredient in a binder matrix as a core with an outermost coating of
sodium
carboxymethylcellulose (SCMC) having a degree of substitution (DS) of 0.2-14
and a
degree of polymerization (DP) of 150-400 and a polyethylene glycol (PEG)
plasticizer. The outermost coating is applied from a water solution by spray
coating.
The tablet has a much higher gloss than other cellulosic polymers. This
eliminates
2s the need to increase the gloss by an additional coating. In addition, only
very small
amounts of sodium carboxymethylcellulose are needed, thus providing an
unexpected economic advantage in terms of raw material costs and processing
times. Further, sodium carboxymethylcellulose films dissolve much more rapidly
than films e.g. hydroxypropymethyl cellulose and so are less likely to
interfere with
3o the dissolution of drug from a coated tablet.
Hydroxypropylcellulose has been used very successfully in aqueous film
coatings to enhance the utility of hydroxypropylmethylcellulose (The Use of
Klucel
hydroxy-propylcellulose (HPC), NF, to increase the Utility of
hydroxypropylmethylcellulose (HPMC) in Aqueous Film Coating, Aqualon Technical
3s Bulletin VC-556A). Hydroxypropylmethylcellulose has high tensile strength
and a
very low percent elongation. When Klucel HPC, with its high percent
elongation, is
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added to the traditional hydroxypropylmethylcellulose film coating, the film
flexibility
and substrate adherence is greatly increased.
U.S. Patent No. 4,316,884 discloses that indoprofen can be used in increased
safety at its effective anti-inflammatory dose in humans and that the activity
of
indoprofen is greatly prolonged by micro encapsulating micro particles of
indoprofen
in a solid protective coating of a cellulose ether such as ethylcellulose.
According to the present invention there is provided a compos':tion comprising
io hydroxypropylcellulose and at least one anionic polymer e.g. carboxymethyl
ether
salts of cellulose, methacrylic acid polymers and copolymers, carboxyvinyl
polymers
and copotymers, alginic acid salts, pectinic acid salts, pectic acid salts,
carrageenan,
agar and carboxylic acid salts of polysaccharides.
Further provided is a composition comprising a substrate and a coating
is comprising hydroxypropylcellulose and at least one anionic polymer.
Still further provided is a process for coating a substrate comprising (a)
preparing an aqueous solution of hydroxypropylcellulose and anionic polymer
and
(b) applying said solution to the substrate.
As used herein the term "consisting essentially of" means that the named
2o ingredients are essential, however, other ingredients which do not prevent
the
advantages of the present invention from being realized can also be included.
!t has been found that compositions of hydroxypropylcellulose and anionic
2s polymer, such as sodium carboxymethylcellulose, have film-forming
characteristics.
Films of these compositions show good tensile strength and percent elongation
as
well as provide high gloss film coatings.
Anionic polymers suitable for use in the present invention are carboxymethyl
ether salts of cellulose, preferably SCMC, methacrylic acid polymers and
3o copolymers, carboxyvinyl polymers and copolymers, alginic acid salts ,
pectinic acid
salts, pectic acid salts, carrageenan, agar and carboxylic acid salts of
polysaccharides.
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Sodium carboxymethyl cellulose suitable for use in the present invention has
a degree of substitution (DS) of at least 0.2 and preferably at least about
0.5. The
degree of substitution of the sodium carboxymethyl cellulose can be up to
about 2.5,
preferably up to about 0.9. The degree of polymerization (DP) of the sodium
carboxymethylcellulose is at least about 100, preferably at least about 200.
The
sodium carboxymethylcellulose degree of polymerization can be up to about
4,000,
preferably up to-about 1,000.
Hydroxypropylcellulose suitable for the present invention has a weight
average molecular weight of at least about 80,000. The molecular weight of the
io hydroxypropylcellulose can be up to about 1,150,000, preferably up to about
95,000.
The degree of substitution for the sodium carboxymethyl cellulose is given by
carboxymethyl groups based on 3.0 as total substitution of available
androhexoic
sites. Sodium carboxymethylcellulose is a cellulose gum available as Aqualon~
SCMC from Hercules Incorporated. As a 99.5% purity free flowing powder it
meets
is all specifications of the US PHARMACOPEIA.
Hydroxypropylcellulose is a cellulose gum available as Klucel~
hydroxypropylcellulose from Hercules Incorporated. As a free flowing powder it
meets all specifications of the US PHARMACOPEIA.
The weight ratio of hydroxypropylcellulose to sodium carboxymethylcellulose
2o is at least about 1:20, preferably at least about 1:4. The
hydroxypropylcelluloseaodium carboxymethylcellulose weight ratio can be up to
about 20:1, preferably up to about 4:1.
Optionally, plasticizer can also be present in the composition of the present
invention. Suitable plasticizers are ethanolamines, ethylene glycol, glycerol,
1,2,6-
2s hexanetriol, mono-, di-, and triacetin, 1,5-pentanediol, sorbitol,
polyethylene glycol
(weight average molecular weight up to about 600), propylene glycol and
trimethylolpropane. The preferred plasticizer is polyethylene glycol,
preferably
having a molecular weight of about 400. When present, the plasticizer is at
least one
percent by weight based on the total composition, preferably at least about
5.5
3o percent by weight. The plasticizer, when present, can be up to about 50% by
weight,
preferably up to about 20 percent by weight based on the total composition.
The composition of the present invention is particularly suitable for use as a
coating on substrates e.g. for the coating of tablets, granules, beads etc.
One
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speck area of use is for the coating of pharmaceutical substrates e.g. tablets
containing pharmaceutically active ingredients, or may be applicable for novel
pharmaceutic dosage forms. In this type of application pharmaceutically
approved
plasticizer, such as polyethylene glycol can be used.
Other ingredients can also be incorporated in the coating composition, such
as active pharmaceutical ingredients, active cosmetic ingredients, nutritional
supplements, colorants, opacifying materials, surfactants, stabilizers,
silicas,
silicones, preservatives, surface treatment agents, flavorants, crosslinking
agents,
and other polymers deemed necessary and useful in promoting the utility, value
and
io ease of preparation or coating of the tablets, granules, beads and other
novel
pharmaceutical dosage forms.
Representative types of active medicaments include antacids, anti-
inflammatory substances, (including but not limited to non-steroidal anti-
inflammatory
drugs, NSAIDs, vasodilators, coronary vasodilators, cerebral vasodilators, and
is perpheral vasodilators), anti-infectives, phsychotropics, antimanics,
stimulants,
antihistamines, laxatives, decongestants, vitamines, gastrointestinal
sedatives,
antidiarrheal preparations, antianginal drugs, antiarrhythmics,
antihypertensivs
drugs, vasoconstrictors and migraine treatments, anticoagulants and anti-
thrombotic
drugs, analgesics, anti-pyretics, hypnotics, sedatives, antiemetics, anti-
nauseants,
2o anticonvulsants, neuromuscular drugs, hyper and hypoglycemic agents,
thyroid and
antithyroid preparations, diuretics, antispasmodics, uterine relaxants,
mineral and
nutritional additives, anti-obesity drugs, anabolic drugs, erythropoietic
drugs,
antiasthmatics, expectorants, cough suppressants, mucolytics, antiuricemic
drugs,
and other drugs or substances acting locally in the mouth, such as topical
2s analgesics, local anesthetics, polypeptide drugs, anti-HIV drugs,
chemotherapeutic
and antineoplastic drugs etc.
Examples of specific active medicaments include aluminum hydroxide,
prednisolone, dexamethasone, aspirin, acetaminophen, ibuprofen, isosorbide
dinitrate, nicotinic acid, tetracycline, ampicillin, dexbrompheniramine,
3o chlorpheniramine, albuterol pseudophedrine, loratadine theophylline,
ascorbic acid,
tocopherol, pyridoxine, methoclopramide, magnesium hydroxide, verapamil,
procainamide hydrochloride, propranolol, captopril, ergotamine, flurazepam,
diazepam, lithium carbonate, insulin, furosemide, hydrochlorothiazide,
guaiphenesin,
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dextromethorphan and benzocaine, although any active medicament which is
physically and chemically compatible with the hydroxypropyl cellulose and
anionic
polymer blend and other tablet ingredients.
Formulations containing NSAIDs (including for the purposes of this application
acetaminophen) may also contain therapeutic amounts of other pharmaceutical
actives conventionally employed with NSAID including but not limited to
decongestants or bronchodilators (such as pseudoephedrine,
phenylpropanolamine,
phenylephrine and pharmaceutically acceptable salts thereof), antitussives
(such as
caraminophen, dextromethorphan and pharmaceutically acceptable salts thereof),
io antihistamines (such as chlorpheniramine, brompheniramine,
dexchlorpheniramine,
dexbrompheniramine, triprolidine, doxylamine, tripeiennamine, cyproheptadine,
pyrilamine, hydroxyzine, promethazine, azatadine and pharmaceutically
accptable
salts thereof), non-sedating antihistamines (such as acrivastine, astemizole,
cetirizine, ketotifen, loratidine, temelastine, terfenadine (including the
metabolites
is disclosed in U.S. Pat. Nos. 4,254,129 and 4,285,957 hereby incorporated by
reference and pharmaceutically acceptable salts thereof), muscle relaxants
(such as
glycerylmonether SMRs, methocarbamol, mephenesin, mephenesin carbamate,
cyclobenzaprine, chlorzoxazone, mephenesin acid succinate, chlorphenesin
carbamate, or pharmaceutically acceptable salts thereof) and adjuvants (such
as
2o diphenhydramine, caffeine, xanthine derivatives (including those disclosed
in U.S.
Pat. No. 4,558,051, hereby incorporated by reference) and pharmaceutically
acceptable salts thereof, nutritional supplements and combinations of any of
the
aforesaid pharmaceuticals. The aforesaid pharmaceuticals may be combined with
acetaminophen for the treatment of allergies, cough, colds, cold-like and/or
flu
2s symptoms in mammals including humans. However, these pharamaceuticals maybe
combined with acetaminophen as sleep aids (such as diphenhydramine), or for
other
known purposes.
Anionic polymers, such as sodium carboxymethyl cellulose cross-link in the
presence of certain polyvalent canons. Sodium carboxymethylcellulose (SCMC) is
so an anionic water-soluble polymer. The chemical and physical properties of
SCMC
make it useful in a wide range of applications, such as food, pharmaceuticals
and
personal care. Treatment of aqueous solutions of SCMC with certain polyvalent
salts results in its precipitation. However, the gradual release of polyvalent
cations,
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such as AI+3, to SCMC solutions leads to uniform cross-linking of the polymer
molecules through carboxymethyl groups. This produces a gel. The nature of the
gel depends in turn, on the amount of cross-linking agent present, the
concentration
and the DP of the polymer molecules. The rate at which gelation occurs depends
upon how quickly the AI'3 ions are allowed to dissociate into the aqueous
system.
The ultimate qualities of the gel and gelling times can be controlled by
varying the
viscosity grade and amount of SCMC used, the proportion of a polyvalent ration
and
the pH of the medium.
The active ingredients that can be incorporated in the coating composition
io and in the substrate (e.g. tablets, granules, beads etc.) can be
pharmaceutically
active ingredients such as hypnotics, sedatives, antiepileptics, awakening
agents,
psychoneurotropic agents, neuromuscular blocking agents, antispasmodic agents,
antihistaminics, antiallergics, cardiotonics, antiarfiythmics, diuretics,
hypotensives,
vasopressors, antitussive expectorants, thyroid hormones, sexual hormones,
is antidiabetics, antitumor agents, antibiotics, chemotherapeutics, and
narcotics.
The coating composition and the substrate (e.g. tablets, granules, beads etc.)
may contain cosmetically active agents such as breath freshening compounds
like
menthol, other flavors and fragrances commonly used for oral hygiene, and for
dental and oral cleansing like quaternary ammonium bases. The effect of
flavors
2o may be enhanced using flavor enhancers like tartaric acid, citric acid,
vanillin, or the
like.
The composition of the present invention is preferably applied from aqueous
solution for the coating of substrates such as tablets.
The preferred process for coating the substrate with the composition ofithe
2s present invention comprises preparing an aqueous solution of
hydroxypropylcelluiose and anionic polymer, e.g. sodium carboxymethylcellulose
and applying the aqueous solution to the substrate. Optionally, plasticizer as
indicated above can also be present in the coating composition. In making the
aqueous solution of sodium carboxymethylcellulose, hydroxypropyicellulose and
3o plasticizer, the solutions can be made up together or alternatively can be
made up
separately. Suitable coating weight will preferably be at least about 0.5%,
more
preferably at least about 0.75% by weight based on the total weight of the
coated
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substrate. The coating weight can be up to about 10% by weight preferably up
to
about 2% by weight of the total coated composition.
High gloss pharmaceutical tablets generally comprise at least one
pharmaceutically active ingredient in a binder matrix core having a coating of
anionic
polymer, e.g., sodium carboxymethylcellulose, hydroxypropylcellulose and
optionally
a plasticizer.
The composition of the present invention has industrial applicability in the
manufacturing of pharmaceutical formulations.
The following examples are given for the purpose of illustration only and are
io not intended to limit the scope of the present invention. All parts and
percentages
are by weight unless otherwise indicated.
In this example, an air suspension column coater, Glatt GPCG5/9, available
is from Glatt Air Techniques was set up as follows:
Spray Gun: Port size, mm 1.2
Spacer ring, mm 3.0
Atomization air pressure, bar 1.8
Pump, Peristaltic
Delivery rates, g/min 28
Column
2s Inlet air damper setting open
Outlet air damper setting, % 45
Batch size, kg 3
Inlet air temperature, C 60
Outlet air temperature, C 48
The tablets are pneumatically fluidized through a cylindrical coating
partition
past a spray nozzle which is mounted in the center of the bottom orifice plate
of the
product chamber. As the tablets pass through the spray they are coated with
the
aqueous solution. The region outside the partition is the down bed. The air
flow in
3s this region keeps the tablets in near weightless suspension so that they
can move
rapidly downward and can be drawn horizontally in to the gap at the base of
the
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coating partition. This process continues until the tablets have achieved the
desired
coating.
With stirring, 24.8 g of sodium carboxymethyl cellulose, available from
Hercules Inc. as Aqualon~ 7L2P CMC; and 24.8 g of hydroxypropylcellulose,
s available from Hercules Inc. as Klucel~ EF hydroxypropylcellulose, was mixed
with
906.5 g of deionized water. Mixing was continued until the solution cleared.
Then
7.7 g of polyethylene glycol, available from Union Carbide as PEG 400, was
added
to the solution and mixed until a uniform solution was obtained. Solution
viscosity
was measured to obtain a value between 125 and 300 cps in order to provide
good
io coating using the Glatt GPCG-5 coater.
Two kg of biconvex placebo tablets were charged to the fluid bed and allowed
to warm up for five minutes. The coating solution was then applied to the
tablets.
The weight gain was 1.9%. The disintegration time of these tablets was 4:00
minutes. The gloss of these tablets was higher than those obtained with
is hydroxypropyi-cellulose/hydroxypropylmethylcellulose coating.
Gloss was measured on a Multi Angular Reflectometer ASTM D523-89
Gloss
20 60 ~ 80.5
HPC/HPMC 1/1 13.7 30.9 43.1
HPC/CMC 1/1 8.1 26.9 51.2
HPC/CMC 2/1 15.0 54.2 90.8
HPC/CMC 1/2 36.3 68.8 89.3
8.7% PEG 400, based
on polymer weight
2o With stirring 24.8 g of Aqualon~ 7L2P sodium carboxymethyl cellulose was
added to 595.2 g of deionized water, and 24.8 g of Klucel~ EF
hydroxypropylcellulose was mixed with 235.2 g of deionized water. Mixing was
continued until the solution cleared. Then 3.9 g of polyethylene glycol,
available
from Union Carbide as PEG 400, was added to both solutions and mixed until
2s uniform solutions were obtained. 3.1 g of aluminum chloride was dissolved
in 50 g of
deionized water. This solution was added to the hydroxypropylcellulose
solution and
s
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mixed until a uniform solution was obtained. Solution viscosity was measured
to
obtain a value between 125 and 175 cps in order to provide good coating using
the
Glatt GPCG-5 were charged to the fluid bed and allowed to warm up for five
minutes.
The spraying was begun with a layer of sodium carboxymethyl cellulose followed
by
a layer of hydroxypropylcellulose. These layers were alternated and the final
layer
was sodium carboxymethyl cellulose. The weight gain was 1.7%.
The disintegration time of the layered tablets was 8:10 minutes.
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