Note: Descriptions are shown in the official language in which they were submitted.
~972zo TH7
This invention relates to a novel improved controlled
release tablet for medicaments comprising an active ingredient
which is dispersed in a water soluble permeable matrix~
A controlled release tablet or the administration
of medicinal agents over a prolonged period of up to about
eight hours is described in U. S. Patent ~o. 3,458,622,
July 29, 1969 to John A. Hill. This patent discloses a
compressed tablet for the prolonged release of a medicament
containing that medicament in a core formed Erom a polymeric
vinyl pyrrolidone, preferably polyvinyl pyrrolidone (Pve),
and a carboxyvinyl hydrophilic polymer such as those marketed
under the trademark Carbopol. The core material formed from
the two polymeric substances provides the con-trolled release
effect by forming a complex under the action of water or gas-
tric fluid. This complex is gel-like in conslstency and re-
tards the diffusion of active ingredient from the tablet.
It has been found, however, that there is a tendency
for an initial surge of medicament to occur so -that the first
amount of drug released may be larger than subsequently. This
may be due to the short delay until water or gastric fluid
acts on the polymeric blend and the gel which provides the
delaying action forms.
It is therefore an object of thls invention to improve
the characteristics of controlled release tablets formed from
a blend of polymers such as those in the Hill patent re~erred
to above by reducing the tendency for an initial surge in the
release of medicament.
The present invention provides an lmproved controlled
release tablet which comprises a compressed matrix com-prising
an effective amount of medicament dispersed in a blend of poly-
~ meric vinyl pyrro]idone and a carboxyvinyl hydrophilic polymer
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and a substantially water insoluble, water permeable, rup~turable film coating on the matrix oompris:ing a blend of
hydrophobic polymer which is slightly soluble in water and
hydrophilic polymer which is water solublel,
The improvement comprises coating an insoluble
swalling type delayed release matrix with a rupturable film
which is water permeable and substantially insoluble in water
comprising a combination of hydrophobic and hydrophilic poly-
mers to modify the drug release rate.
In the water-insoluble matrix of tha type described
in the Hill patent referred to above, the controlled release
rate of the drug is dependent upon the interaction of the
two principal ingredients, the polymer and the hydrocolloid,
in the presence of water to form a gummy complex of low solu-
bility. Since little of the gummy complex i~ present initially,
the drug at or near the surface dissolves fairly rapidly and
there is an initial surge wherein a relatively larga amount
o drug is released in~the beginning or a period of about one
hour. As the colloid complex is formad, once aqueous solution
:
penetrates the surface of the tablet, the gel r~tards the dis-
solution of the drug out of the tablet.
According to this inven~ion, the delayed release
:
charactexistic of a water insoluble ma~rix of the type des-
cri~ed in the Hill patent is improved by coating suah a matrix
with a ~ilm o~ the kind describad below. Initially, while the
film lS~ intact, the ralease of the drug contained in the matrix
is pri~arily controlled by diffusion of solvent and soluta
molecules through the film~ As watar or gastric fluid permeates
through the film, the gummy complex forms and the slight swell-
ing of -the complex causes the film to rupture or erode. The
release rate is then controlled by the gummy complex. The appli-
. . .
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cation of a relatively water lnsoluble, water permeable film
primarily controls the drug release rate ~lile the matrix
gel is being generated and a smoother, gradual, more uniform
release rate is achieved during -the entire period of about
eight to twelve hours, approaching a zero order release pat-
texn. The release pattern of the core, upon application of
the film, can be varied over a range by varying -the composi-
tion and amount of film forming mixture.
The controlled release tablets are prepared, accord-
ing to this invention, by forming a tablet-like matrix in
which the active ingredient ls dispersed and then coatiny this
matrix with a water permeable film of low wa-ter solubility.
The film is a combination of hydrophobic polymer which is
slightly soluble in water and hydrophilic polymer which is
water soluble. When combined, they constitutè a relatively
insoluble blend.
The matrix comprises a polymer blend. One component
of the polymer blend is a vinyl polymer, e.g., polyvinyl py-
rrolidone ~Merck Index, 8th ed., 1968, page 849) having a
molecular weight o~ about 5,000 to 80,000, preferably about
40,000, generally referred to as PVP. The second component
of the polymer blend is a carboxypolymethylene hydrocolloid
polymer of the type described in U. S~ Patent No. 2,909,462,
October 10, 1959 ~see also Chem. Eng. News 36, No. 39, page ~;
64 (Sept. 29, 1958)], a carboxyvinyl hydrophilic polymer of ;~
acrylic acid cross-linked with polyalkenyl polyether and
having active carboxyl groups, particularly acrylic acid
cross-linked with polyallyl sucrose. Such carboxyvinyl hydro-
philic polymers are marketed under -the trademark Car~opol
with designations 934, 940 941 by B. ~. Goodrich Chemical Co.
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972 % 0 TH7
Controlled release of the medicament ~rom tablet
matrices formed from such polymer blends can be aahieved
with relatively small proportions of the release controll-
ing substances In general, the polymer blend comprises
less than 50% by weight o~ the matrix and, indeed, weight
of the complete tablet. The proportions by weight of the
two polymeric substances in the blend which forms the matrix
is about 1:10 to 10:1 (by weight) of vinyl polymer to car-
boxypolymethylene polymer. The preferred ratio is about
1:1 to 1.5:1. The ratio tby weight) of carboxyvinyl poly-
mer to active drug ingredient is less than 0~5:1, preferablyabout 0.1 to 0.45:1~ The combined weight of the two polymers
in the blend may exceed half the weight of active medicament, ~-
but is preferably below about 75% of the weight of active ~ ~
drug.~ These proportlons refer to the matrix. ;~ ~`
~ Finished tablets having a tot~l weight of up to
about l gm can be prepared.~ Of this total weight,~the coat-
ing described in detail below comprlses about 5 to 15
Thus the~controlled release tablet matrix preferably
compri~es a blend of an effective amount of medicament which
is preferably at least about 50% of the totaI matrix weight,
vinyl polymer, preferably PVP, and a carboxyvinyl hydrophilic
polymer of acrylic cross~linked with polyalkenyl polyether,
preferably a polymer of acrylic acid cross-linked with poly-
allyl sucrose and especially Carbopol. The release control
substance is a gel formed by the interaction of the polymers
in the presence of water.
~ The ratio by weight of vinyl polymer to carboxypoly-
methylene polymer is about 1:10 to 10:1, preferably about 1:1.
The ration by weight of carboxyvinyl polymer to active drug
ingredient is less than 0.5:1, preferably about 0.1 to 0.45:1.
1(;~9722~ TH7
The combined weight oE the polymers is below about 75% of
the weight oE the active drug ingredient.
To form the tablet matrix or core~ a dry granula-
tion technique ls preferred. All of the ingredlents are
blended in dry form, made more dense by s].ugginy or com-
paction and reducing to a granulation by grinding. The
ground particles are then compressed into tablet foxm which
can take any of the conventional shapes, e.g., round, elon-
gated, oval, etc. A tablet press fitted with 5Ui tably sized
punches and dies are used to form a tabIet core o any de-
sired weight, shape and composition.
In carrying out the dry granulation procedure various ;~
other conventional ingredients can be included as required~
For example, a diluent or filler may be included for welght
adjustment~ Such diluents includej for example, lactose,
mannitol, ~orn starch, particularly, various cellulose deri-
vatives such as wood cellulose (Solkafloc) and especially
microcrystalline cellulose~marketed under the trademark
- Avicel (see U. S. Patents 2,978,446 and 3,141,875). Other
additives may include lubricants like stearic acid, pa]mitic
.:
acid, magnesium stearater calcium stearate, ta}c, carnauba
wax or the like. Silica flow conditioners or glidants may
.
also be included. Colors acceptable in drugs such as the
various F.D. & C. colors can be added at various stages, in-
cluding spray coatings o the finished core.
As an alternative, though not preerred, the wet
granulation technique can also be used. ~ccording to this
procedure, the dry active ingredient, vinyl polymer and poly-
methylene polymer and other diluents are blended, for example,
in a planetary mixer. The powders are wetted with a granulating
3Q liquid like methylene chloride, chloroorm, methyl chloroform,
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pure or denatured ethyl alcohol, isopropyl alcohol, 1,1-
dichloroethane, 1,2-dichloroethane, l,l,l-trichloroethana
or the like. Binders such as zein, ethyl cellulose, beta-
pinene polymers, gelatin, shellac or the like may be inclu-
ded in the granulating liquid. The moist mass is granulated,
e.g., by ~orcing thxough a screen of suitable mesh size, driedt
and if desired, the particles further reduced in size~ The
granulate is then compressed in conventional manner, using
lubricants, glidants, etc., as required.
When the tablet matrix has been ~ormed and, optionally
the color has been applied, a film is applied according to
this invention. The film comprises a combination of hydro-
phobic and hydrophilic polymers which permits the entry of
water and hydration of the matrix so that there is not a
large initial surge in the release of medlcament.
The hydrophllic polymers are water soluble~polymers
(lmder pH 5.5). They include cellulose methyl ethers like
me~hyl cellulose, hydroxypropylmethyl cel~lulose, hydroxy-
methyl celluIose phthalate, also hydroxypropyl cellulose,
cellulose acetate phthalate or polyvinyl alcohol.
The hydrophobic poLymers are slightly soluble in water,
` (By slightly soluble is meant the definitlon in USP XIX,~page 6,
;~ although polymers up to 3% solubLe ln water can be used.~ They
include cellulose ethyl~esters like ethyl cellulose, also cellu-
lose acetate, polyvinyl alcohol-maleic anhydride copolymers,
.
pinene polymers (Picolyte), glycerol esters of wood resins
like glycerol ester of partially dimerized rosin, ~lycero}
ester of partially hydrogenated wood rosin, glycerol ester of
polymeriæed rosin, hydroxypropyl methyl cellulose phthalate,
etc.
.
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Preferred are combinations of methyl cellulose and ethyl
cellulosa ox hydroxypropylmethyl cellulose and ethyl cellulose.
One or more members of each class of polymer can be
used. The proportion of hydrophilic polymer or polymers to
hydrophobic polymer or polymers is within the range of about
4:1 to about 1:4 (by weight) preferably about 1.5:1 to 1 1.
These polymers are best combined in a proportion which re-
sults in rupture in about one hour. ~ film of about 1 to 15
mil (.001 to 0.015 inches) preferably 3 to 7 mil, in thickness
is sufficient to achieve the purpose.
1~ The film formers are applied by spraying a system
containing them on the core by conventional ~llm coating tech-
niques. The film formers are dissolved in a solv~nt or mixture
of solvents in which both types are solubl~ or form a solvent.
Such solvents include alcohols like methyl alcohol, ethyl alco~
hol or isopropyl alcohol, ketones like acetone,~ methyl~thyl
, .
ketone, chlorina-ted hydrocarbons like methylene chloride, di~
chloroethane, l,lgl-trichloroethane, atc. Preferred are methyl-
ene chloride plus isoprcpyl alcohol or methylene chloride plus
methyl alcohol (preferably 70~:30%).
~he ilm forming composition may optionally inclu~e
plasticizers such as triethyl citrate, diethyl phthalate,
propylene glycol, glycerin, butyl phthalate, castor oil or
the like to provide the desired balanced characteristics.
Preferably, the ~olor! if used, is applied in this fil~ coat-
ing composition. ~hese colors include F.D. & C. approved
colors or lakes. Opacifiers such as titanium dioxide can
also be included.
A wide variety of medicaments which are orally ad-
ministered in tablet form can be used in the form of tab-
lets pxepared according to this invention. These include,
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for example, adrenergic agents such as ephedrine, desoxy-
ephedrine, phenylephrine, epinephrine and the like, cholinergic
agents such as physostigmine, neostigmine and the like,
antispasmodic agents such as a-tropine, methanetheline,
papaverine and the like, curariform agents such as chlorisondamine
and the like, tranquilizers and muscle relaxants such as
fluphenazine, chlorpromaæine, triflupromazine, mephenesin,
meprobamate and the like, antidepressants like amitrip-tyline,
nortriptyline, and the like, antihistamines such as
diphenylhydramine, dimenhydrinate, tripelennamine, perphenazine,
chlorprophenazine, chlorprophenpyridamine and the like,
hypotensive agents such as rauwolfia, reserpine and the
like, cardioactive agents such as benzydroflumethiazide,
flumethiazide, chlorothiazide, aminotrate, propranolol,
procainamide and the like, steroids~such as testosterone,
prednlsolone, and the like, antibacterial agents, e.g.,
sulfonamides such as sulfadiazine, sulfamerazine, sulfametha-
zine, sulfisoxazole and the like, antimalarials such as
chloroquine and the like, antlbiotics such as the tetra-
cyclines, nystatin, streptomycin, cephradine and other
cephalosporlns, penlcillin, semi-synthetic penicillins,
griseofulvin and the like, sedatives such as chloral
hydrate, phenobarbital and other barbiturates, glutethimide,
antitubercular agents such as isoniazid and the like,
analgesics such as aspirin, propoxyphene, meperidine and the
like, etc. These substances are frequently employed either
as the free compound or in a salt form, e.g~, acid addition
salts, basic salts like alkali metal salts, etc. Other
therapeutic agents having the same or di.fferent physiological
activity can also bc em~loycd in pharrllaccutical preparatioJls
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within the scope of the present .invention.
The invention is particularly ada,pted for controlled
release tablets eontai.n.ing the an~iarrhythmic agent procai.namide
(usually formulated in the Eorm of its hydrochlorideJ.
The following examples are il.lust:rative of the
invention and constitute preferred embodiments. They also
serve as models for additional compositions within the ~:
scope of the invention.
Example 1 ~ :~
~ ,
The following ingredients are used to make
1000 tablets each containing 500 mg. of procainamide
hydrochloride:
A. Compressed Tablet ;~
Procainamide HCl S00 gm.
Polyvinylpyrrolidone
(pharmaceutical grade)144 gm.
Carbopol 934 -
(carboxypolymethylene polymer) 96 gm.
Avicel
(microcrystalline cellulose) 23.4 gm.
Carnauba wax (~.S.P.No. 1
yellaw powdered, 100 mesh) 15.6 gm.
Stearic acid (food gradeJ 7.8 gm. ~ ~ -
*Syloid 244 Grade 68
~silica glidantJ3.95 gm.
B Coating Solution
:
Per ~iter -
Methocel 60 HG 15 cps.
(hydroxypropylmethyl cellulose) 30 gm.
Ethyl cellulose 20 gm>
T.riethyl Citrate 2 gm.
Isopropyl Alcohol 99%
~30% v/v of solventJ2~4.4 ml.
_ g _
* Trade Mark
~'^" i
" ~, :
~97~:ZC~
1`~17
Methylene Chloride q.s. 1 liter
(ca. G64 ml.)
All of the ingredients under A above, except the
stearic acid and Syloid are h:lendecl in t:he dry form. The
dry blend is compacted on a tablet press then reduced by
grinding to about 20 mesh. The stearic acid lubricant
and glidant are added to the dry granu].a-te and blended
-thoroughly. The mixture is then compressed on a tablet
press to form biconvex oval tablet matrices with slightly
flattened ends weighing 790 mg. each.
The coating solution B is then applied to the
tablet matrices by airless spray in a back outlet rotary
coating pan. The coating is applied until a 3.5 to 4 mil.
coating is obtained.
Example 2
Tablet matrices are prepared as described in
Example l.
A~color coat solution is prepared by adding 400 ml.
of Opaspray Yellow (a dispersion of F.D. & C. yellow ~5 & 6 ~;~
lakes, titanium oxide and hydroxypropylmethyl cellulose in
SD3A Alcohol) to the coating solution B in Example l and
mixing. The compressed tablet matrices are then sprayed as
in Example l to obtain yellow coated tablets each weighlng
a total of 840 mg. and containing 500 mg. of procainamide
HCl (core = 791 mg.).
Example_3_
The following ingredients are used to make l000
tablets each containing 570 mg. of cephradine:
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~ * Trade Mark
,, .
. - , .
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A. Compressed Tablet
Cephradine 570.6 gm.
Lactose anhydrous274.4 gm.
Plasclone (PVP) ~-3060.0 g~.
Carbopol 934 40.0 gm.
Ethyl cellulose 6.0 gm.
Talc 39.7 grn.
*Emersol 9.3 gm.
Methylene chloride qs~
lQ B. Coatin~ Solution
Per Liter
Hydroxypropylmethylcellulose 50 ym.
phthalate (XD-55)
Methocel 60 HG
- premium 15 cps. 25 gm.
Methanol ca 12.5~ q.s.
Isopropyl Alcohol 15% q.s
Methylene chloride ca 65% q.s.
* *
The cephradine, lactose, Plasdone and Carbopol are ~-
mixed. The mixture is granulated with the ethyl cellulose and
methylene chloride. The granulation is dried and reduced
to 20 mesh size. The talc and Emersol are added and the
mixture is compressed into tablets (1000). The coating
solution is well mixed and sprayed onto the compressed cores
to a thickness of 3 - 4.5 mil.
Example 4
The release rate of active drug determined for
the uncoated cores and the film coated tablets prepared
according to Example 1 by the U.S.P. XIX dissolution method
(p.651) using l liter of water at 37 C. with the basket
rotated at 50 rpm. is as follows:
:, .,
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Trade Mark i ~ ~
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TABLE I
P6 Procainamide ReLeased
Per HQur_ _
HourYi].m Coated Tablet Uncoated Core
1 14.6 ~ ~0.0 %
2 20.1 ~1.8
3 13~3 14.4
4 20.0 9.8
S 1.5 ~ 3.6
6 6.3 3.2
7 5.7 3.0 :
8 2.1 0 ~ :;
3-10 9.9 6.1
Example 5
The release rate of cephradlne de-termined for the ~ :
coated tablets of Example 3 is as follows-
;~ TABLE II
: % Cephradine Released
.
Per Hour
HourPer~ent
: : 1 26
2 ~ 15
3 12
4 : 10
6 ~ 8
~ -12-
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