Note: Descriptions are shown in the official language in which they were submitted.
CA 02223014 1997-12-02
WO 96/40080 PCT/US96/08869
CONTROLLED RELEASE FORMULATION HAVING A PREFORMED
PASSAGEWAY
BACKGROUND OF THE INVENTION:
~ The present invention relates to a novel orally
administrable controlled release unit dose formulation
- for the administration of pharmaceuticals. In the prior
art many techniques have been used to provide controlled
and extended release pharmaceutical dosage forms in order
to maintain therapeutic serum levels of medicaments and
to minimize the effects of missed doses of drugs caused
by a lack of patient compliance.
Certain prior art extended release tablets
containing osmotic tablets have been described and
manufactured which have had an osmotically active drug
core which expands when contacted with gastric fluids and
extrudes out a separate layer that contains an active
drug. The core is divided into two layers one of which
contains the active drug and the other contains a push
layer of pharmacologically inactive ingredients which are
osmotically active in the presence of gastrointestinal
fluids. These tablets are provided with an aperture that
is formed by punching or drilling a hole in the surface
using a mechanical or laser drilling apparatus. A product
of this type is disclosed in U.S. 4,783,337 and is sold
commercially as Procardia XL ~.
The osmotic dosage forms that are disclosed in
U.S. 4,783,337 are described as having a passageway which
includes an aperture, orifice, hole, porous element,
hollow fiber, capillary tube, microporous insert, pore,
microporous overlay or bore which extends through the
semipermeable lamina, the microporous lamina, or through
the laminated wall. The patent also states that the
passageway may be formed by mechanical drilling, laser
drilling, eroding an erodible element, extracting,
dissolving, bursting or leaching a passageway-former from
the wall of the osmotic dosage form (col. 14, line 35 et
seq.) which are implicitly~pre-formed in the tablet
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WO 96/40080 PCT/US96/08869
during the manufacturing process. The only exemplified
technique of forming a passageway in U.S. 4,783,337 is
the use of a laser to drill a hole in the outer layer of
the tablet.
U.S. 4,285,987 described an osmotic tablet
which had a laser drilled aperture into the core of the
tablet. The laser drilled hole was plugged with leachable
sorbitol which was leached out in the presence of
gastrointestinal fluid.
The present invention is concerned with
providing an osmotic tablet having an aperture but does
not have a separate "push" layer in the core~which
contains no medicament. In addition, a coating process
has been invented which applies an insoluble coating to a
tablet having an aperture without causing the aperture to
become coated or clogged by the coating.
SUMMARY OF THE INVENTION
The present invention is directed to a
controlled release pharmaceutical tablet having at least
one passageway which extends from the outside surface
into the core, said tablet comprising:
(a) a compressed core which comprises:
(i) a medicament;
(ii) an amount of a water soluble
osmotic agent which is effective to cause the
medicament to be delivered from said
passageway in the presence of aqueous media;
(iii) a water-swellable pharmaceutically acceptable
polymer; and
(b) a membrane coating around said core tablet which
comprises a water insoluble pharmaceutically
acceptable polymer.
It is an object of the invention to provide a
a controlled release pharmaceutical tablet having an
aperture which extends from the outside surface of said
2
CA 02223014 2004-11-25
tablet into an osmotic core which is covered with an
external polymeric membrane.
Tt is also an object ofi the invent:ion to
provide a dosage formulation that provides i:herapeutic
blood levels with once a day administration.
2t is also an object of the present invention
to provide a controlled release pharmaceutical tablet
that has a water insoluble coating on the exterior
surface and no coating on the pre-formed aperture which
extends from the exterior surface of the tablet into the
core of said tablet.
Tt is also an object of this invention to
provide a controlled release pharmaceutical tablet having
a single component osmotic core wherein the core
component may be made using ordinary tablet compression
techniques.
In a broad aspect, then, the present invention
is directed to a controlled release pharmaceutical tablet
having at least one preformed passageway which extends
from the outside surface into the core, said tablet
comprising: (a) a single component compressed core having
a passageway that extends from the outside surface into
the compressed core, said compressed core comprising a
mixture of: - a medicament, - an amount of a water
soluble osmotic agez~.t which is effective to cause the
medicament to be delivered from said passageway in the
presence of aqueous media; and - poly(ethylenc oxide)
having a weight average molecular weight of 100,000 to
8,000,000, and (b) a membrane coating around said single
component compress core which coats said core except for
the passageway which extends frarn the outside surface
into the compressed core, said coating consisting of a
water insoluble pharmaceutically acceptable polymer, a
plasticizer and 1-30 weight percent of a channelling
agent wherein the weight percent of the channelling agent
is based on the weight of the water insoluble polymer.
3
CA 02223014 2004-11-25
These and other objects of the invention will
become apparent from the appended specification.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig, 1 is a graph which compares the in vitro release
rate, in 0.25wt.~ sodium lauryl sulate, of n nifedipine
tablet prepared according to Example 1 of the present
application (a), with the commercial product Procardia XL°~
(b) .
Fig. 2 is a graph which compares the in vitro release
rate, in simulated intestinal fluid, of a glipizide
tablet prepared according to Example 2 of the present
application (a), with the commercial product Glucotrol XL~
(b) .
Fig. 3 is a graph which compares the in vitro release
25 rate, in distilled water, of a pseudoephedrine HC~. core
containing 180mg of pseudoephedrine HC1 which was
prepared according to Example 3 of the present
3a
CA 02223014 1997-12-02
WO 96/40080 PCT/US96/08869
application (a), with the commercial product
Efidac/24~(b) which was modified by washing off the
immediate release layer.
DETAILED DESCRIPTION OF THE INVENTION
The controlled release osmotic tablet
formulation of the invention provides performance which
is equivalent-to much more complicated prior art
controlled release dosage formulations which require a
complex segmented osmotic core and an aperture which is
formed after a water insoluble coating is applied to the
core.
The core of the controlled release tablet of
the present invention may be made by direct compression
of the core components or by initially forming granules
by combining a medicament and a water soluble osmotic
agent with conventional excipients and a water soluble
polymeric binder. Thereafter, the granules are blended
with a water swellable polymer and suitable excipients to
form a composition which may be compressed into tablets.
A tabletting machine is used to compress the core forming
components into a core tablet which is subsequently
coated with a water insoluble polymeric membrane to form
the controlled release tablet of the invention. The
passageway may be formed before or after the water
insoluble polymeric membrane is placed on the tablet.
The water insoluble coating is applied to
tablets which have a preformed aperture. The coating
technique comprises the use of a fluidized bed coater in
which a water insoluble resin is applied as a dispersion
or solution in a highly volatile organic solvent. It has
been found that using the proper residence time in a
particular type of a fluidized bed coater with a properly
selected solvent, the coating will not be deposited
within the preformed aperture of the tablet in such a ,
manner that the release of the drug from the core will be
affected by coating. ,
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WO 96/40080 PCT/US96/08869
Although the inventor does not wish to be bound
by any theory by which the present ._>ention operates, it
is believed that the application of the water insoluble
polymer, to form the external membrane around the core of
the tablet, does not coat the interior walls of the
aperture of the tablet or cause the outer opening of the
aperture to become clogged because the coating solution
has a low viscosity and is applied under fluidized bed
coating conditions where the finely divided or atomized
i0 coating solution volatilizes before any liquid coating
solution penetrates into the aperture of the_tablet. When
the tablet is placed in an aqueous medium, water is taken
up through the passageway and into the core of the
tablet, the water swellable polymer expands as the water
soluble osmotic agent dissolves and increases the osmotic
pressure inside the tablet causing the core component to
extrude out of the tablet via the passageway.
The controlled release tablet of the invention
is intended to be used to administer medicaments which
are water soluble to practically insoluble in water. The
term practically insoluble is used to include those
substances which are soluble at a level of 1 of solute to
from 100 to more than 10,000 parts of water per part of
solute. The term water soluble includes those substances
which are soluble at level of one part of solute to 5
parts of water or less.
Examples of categories of water insoluble
medicaments which may be utilized, at therapeutic dose
levels, in the controlled release tablets of the
invention include anti-hypertensives, calcium channel
blockers, analgesics, anti-neoplastic agents, anti-
microbials, anti-malarials, non-steroidal anti-
inflammatory agents, diuretics, anti-arrythmia agents,
hypoglycemic agents and the like. Specific examples of
medicaments include nifedipine, nisoldipine, nicardipine,
nilvadipine, felodipine, bendroflumethazide,
acetazolamide, methazolamide, chlorpropamide,
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WO 96/40080 PCT/US96/08869
methotrexate, allopurinol, erythromycin, hydrocortisone,
triamcinolone, prednisone, prednisolone, norgestrel,
norethindone, progesterone, norgesterone, ibuprofen,
atenolol, timolol, cimetidine, clonidine, diclofenac,
glipizide, and the like. Useful water soluble medicaments '
include various therapeutic agents such as decongestants,
antihistamines, analgesics, sedatives, anti-inflammatory, '
anti-depressants, antihypertensives and the like at
therapeutic~dosage levels.
Examples of specific medicaments which may be
utilized, at therapeutic dose levels, in the controlled
release tablets of the invention include ephedrine,
pseudoephedrine, phenylpropanolamine, chlorpheniramine,
diphenhydramine, dimenhydramine, indomethacin, labetalol,
albuterol, haloperidol, amitriptyline, clofenac,
clonidine, terfenadine, fentanyl, and the like which are
in the form of a water soluble salt such as the
hydrochloride or sodium salt or in the from of an ester,
ether, amide, complex or the like.
The water soluble osmotic agent is any non-
toxic pharmaceutically acceptable compound which will
dissolve sufficiently in water and increase the osmotic
pressure inside of the core of the tablet. The osmotic
agents are used in effective amounts, which are from 5 to
55~ by weight of the total weight of the core, and
preferably from 10 to 50~ by weight of the total weight
of the core tablet. When the drug is water soluble,
lesser amounts of the osmotic agent will be employed.
These osmotic agents include sodium chloride, potassium
chloride, magnesium sulfate, magnesium chloride, sodium
sulfate, lithium sulfate, urea, inositol, sucrose,
lactose, glucose, sorbitol, fructose, mannitol, dextrose,
magnesium succinate, potassium acid phosphate and the
like as well as osmopolymers such as polyethylene oxide
having a weight average molecular weight of 50,000 to
300,000; polyvinyl pyrrolidone and the like.
If granules are prepared a binder may be
6
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WO 96/40080 PCT/US96/08869
optionally employed. The binders include any
pharmaceutically acceptable material which can be
utilized to bind the powder mixture together with an
adhesive, instead of by compaction, in order to form
granules for making compressed tablets. These polymers
include polyvinyl pyrrolidone, carboxyvinyl polymer,
A
methylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, low molecular weight polyethylene
oxide polymers, hydroxypropylmethylcellulose, dextrin,
maltodextrin and the like. These materials may be used as
a dry solid binder or formed into a dispersion or
solution in water or other solvent system at a sufficient
concentration to have a binding effect on the osmotic
agent, the medicament and any excipient.
Generally the binder is used in a sufficient
amount so that when it is combined with a suitable
solvent, combined with the water soluble osmotic agent
and agitated, granules will be formed which may be
compressed into a tablet core. If a binder is used , it
should be used at a level of 5 to l5wt~ based on the
total weight of the core components.
Prior to compressing the granules, a water
swellable polymer and one or more conventional
pharmaceutical diluents may be added such as
microcrystalline cellulose, lactose, dextrose and the
like are added to the granule forming mixture in an
amount which will aid in forming granules which are
compressible to form a tablet core. Generally, if a
diluent is added, it will be added at a level which
ranges from about 5 to 50wt~ based on the weight of the
compressed core.
Suitable pharmaceutically acceptable, water
swellable polymers include polyethylene oxide having a
molecular weight of 100,000 to 8,000,000; poly(hydroxy
alkyl methacrylate) having a molecular weight of from
30,000 to 5,000,000; polyvinyl) alcohol, having a low
acetal residue, which is cross-linked with glyoxal,
7
CA 02223014 2000-08-24
formaldehyde or glutaraldehyde and having a degree of,
polymerization of from 200 to 30,000; a mixture of methyl
cellulose, cross-linked agar and carboxymethyl cellulose;
a water insoluble, water swellable copolymer produced by
forming a dispersion of a finely divided copolymer of
malefic anhydride with styrene, ethylene, propylene,
butylene or isobutylene cross-linked with from 0.001 to
0.5 moles of saturated cross-linking agent of saturated
cross-linking agent per mole of malefic anyhydride in the
copolymer; Carbopol~ carbomer which is as acidic carboxy
polymer havi.ig a molecular weight of 450,000 to
4,000,000; Cyanamero polyacrylamides; cross-linked water
swellable indene-malefic anhydride polymers; Goodrichm
polyacrylic acid having a molecular weight of 80,000 to
200,000; starch graft copolymers; Aqua-Keepsm acrylate
polymer polysaccharides composed of condensed glucose
units such as diester cross-linked polyglucan and the
like; Amberliteo ion exchange resins; Explotab~ sodium
starch glycolate; and Ac-Di-Sol~ croscarmellose sodium.
Other~polymers which form hydrogels are described in U.S.
3,865,108; U.S. 4,002,173 and U.S. 4,207,893,
The pharmaceutically acceptable, water swellable polymers
may be employed in an effective amount that will control
the swelling of the tablet core. These amounts will
generally be from about 3 to l2wt%, preferably from about
5 to lOwt% based an the weight of the compressed tablet.
core.
The membrane coating around said core consists
essentially of a plasticized or unplasticized water
insoluble pharmaceutically acceptable polymer.. Suitable
water insoluble polymers include cellulose esters,
cellulose ethers and cellulose esterethers. The
cellulosic polymers have a degree of substitution greater
than 0 up to 3. The degree of substitution is calculated
as the average number of original hydroxyl groups on the
anhydroglucose unit which makes up the cellulose polymer
which are replaced with a substitute group. These
8
CA 02223014 2001-09-18
materials include cellulose acylate, cellulose ethyl
ether, cellulose diacylate, cellulose triacylate,
cellulose acetate, cellulose diacetate, cellulose
triacetate, mono-, dl- and triceilulose alkan, mono-, di-
and tricellulose aroyl and the like. Cellulose triacetate
is the preferred polymer. Other water insoluble polymers
are disclosed in U.S. 4,765,989. If desired other polymers
may be combined with the water insoluble polymer to modify
the permeability of the membrane coating around the core.
These include hydroxymethyl cellulose, hydroxypropyl
cellulose or cellulose per se. Generally, the membrane
coating around the core will comprise from about 4 to 12 wt%
preferably about 6 to 10 wt% based on the total weight of
the core tablet.
The water insoluble polymer may optionally
contain a plasticizer or a water soluble channeling
agent. The water soluble channeling agent is a material
that dissolves in water to form a porous polymer shell
that allows water to be imbibed into the core. This
material is used in a sufficient amount that channels
will form in the water insoluble polymer. These materials
include water soluble organic and inorganic compounds
such as sucrose, lactose, dextrose, sodium chloride,
sorbic acid, potassium chloride, polyethylene glycol
(weight av.. molecular weight 380-420), propylene glycol;
hydroxypropyl methylcellulose, hydroxypropyl cellulose,
polyvinylpyrrolidone and mixtures thereof.
The water insoluble polymer may be plasticized
with a plasticizing amount of a plasticizer. The
preferred plasticizer is triacetin but materials such as
acetylated monoglyceride, rape oil, olive oil, sesame
oil, acetyltributylcitrate, acetyltriethylcitrate,
glycerin sorbitol, diethyioxalate, diethylmalate,
diethylfumarate, dibutylsuccinate, diethylmalonate,
dioctylphthalate, dibutylsebacate, triethylcitrate,
tributylcitrate, glyceroltributyrate, and the like.
9
CA 02223014 2004-11-10
Depending on the particular plasticizer or water soluble
channeling agent, amounts of from 1~ to 40~, and
preferably 10 to 30~ of the modifier based on the total
weight of the water insoluble polymer, water soluble
channelling agent and the modifier may be utilized.
In the preparation of the tablets of the
invention, various conventional well known solvents may
be used to prepare the granules and apply the external
coating to the tablets of the invention. In addition,
various diluents, excipients, lubricants, dyes, pigments,
dispersants etc. which are disclosed in Remington's
Pharmaceutical Sciences, 1985 Edition may be used to
optimize the formulations of the invention.
Generally the depth of the aperture should be
from twice the thickness of the coating layer to two-
thirds of the thickness of the tablet. The aperture may
be sized to be from 0.2 to 3.Omm. in diameter and from
0.2 to 3mm. in depth. If desired, the passageway may be
extended all of the way through the tablet. The
passageway may be farmed by punching or drilling the ,
passageway using a mechanical or laser apparatus or using
a properly sized projection on the interior of the tablet
punch to form the passageway. A preferred manner of
forming the passageway is by the use of a cylindrical or
frustroconical pin which is integral with the inside
surface of the upper punch of the punch which is used to
form the tablet.
For certain applications, it may be desirable
to add a further coating layer aver the water insoluble
membrane coating for the purpose of providing an
immediate release drug layer for the purpose of providing
an initial loading or therapeutic dose of a drug. The
drug in such an immediate release layer may be the same
or different from the drug which is placed in the core of
the tablet. A example of an immediate release coating,
which may be placed on the outer membrane of the tablet
which is disclosed in Example 3, is as follows:
CA 02223014 1997-12-02
WO 96/40080 PCT/US96/08869
Immediate release coating
pseudoephedrine HC1 8l.lwt~
hydroxylpropyl cellulose, NF 13.5wt~
i 5 (Klucel~ EF)
polysorbate 80 5.4wt$
water* (the weight of water is equal to the weight
of the tablets)
* water is evaporated during the coating process
The immediate release coating is applied to the
tablets by coating the tablets with the immediate release
coating solution. The coating is applied using a fluid
bed coater or a perforated coating pan until the tablets
exhibit a weight gain of 19.8.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
EXAMPLE 1
Tablets having the following formula are prepared as
follows:
I Core Tablet:
nifedpine l2wt~
polyethylene oxides l0~wt~
polyethylene oxide2 20~wt~
sodium starch glycolate 30wt~
lactose, NF 27wt~
magnesium stearate lwt~
'' Polyox WSR 303; weight average molecular weight
=7,000,000; 2 Polyox WSR N80; weight average molecular
weight =200,000;
(a) The nifedipine, the polyethylene oxides, the
sodium starch glycolate and the lactose are dry blended
for 15 minutes and then mixed with the magnesium stearate
for an additional 5 minutes. The powder mixture was then
directly compressed into 0.3438" round tablets (275mg)
with a 1.3mm hole (2.5mm deep) in the center of the
tablet using a specially designed upper punch having a
11
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WO 96/40080 PCT/US96/08869
cylindrically shaped projection which forms the hole in
the tablet.
II Sustained release coating
Core tablets weighing a total of 300g were then coated in '
a Glatt fluidized bed coating apparatus with the
following coating composition:
cellulose acetate 80wt~
polyethylene glycol 400 5wt$.
sugar, confectioner's 6X (micronized) lOwt~
triacetin 5wt~
acetone* (10 times the weight of the coating materials)
The coating conditions for this batch are as follows:
spraying rate: 6m1/min.;inlet temperature: 24-28°C;
atomization pressure: 1 bar. The coating procedure is
carried out until a weight gain of 7.5$ is obtained. The
coated tablets were dried in the fiuidized bed apparatus
for an additional 5 minutes at 28°C.
*The acetone is evaporated during the coating process
The dissolution profiles of the coated tablets and
Procardia XL~ in 0.25 sodium lauryl sulfate, in a USP
Type 2, paddle apparatus, at 100rpm and 37°C are set
forth in Fig. 1.
EXAMPLE 2
Tablets having the following formula are prepared as
follows:
a_
I Core Tablet
glipzide 4wt$
polyethylene oxides l0~wt~
polyethylene oxidez 20~wt%
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WO 96/40080 PCT/US96/08869
sodium starch glycolate 30wt~
hydroxypropyl methylcellulose lOwt$
lactose, NF 34wt~
magnesium stearate lwt~
1 Polyox WSR 303; weight average molecular weight
=7,000,000; 2 Polyox WSR N80; weight average molecular
Weight =200,000;
(a) The glipzide, polyethylene oxides, sodium
starch glycolate, hydroxypropylmethylcellulose and the
lactose were mixed for 15 minutes and were then mixed
with the magnesium stearate for an additional 5 minutes.
The powder mixture was compressed into the same size
tablets having the same passageway as the tablets
described in Example 1. The tablets were then coated
using the same procedure and coating suspension that was
used to coat the tablets of Example 1.
The dissolution profiles of the tablets of Example 2 are
shown on Fig.2.
EXAMPLE 3
A tablet having the following formula is prepared:
I Granulation
pseudoephedrine HC1 74.80wt~
microcrystalline cellulose, NF 10.27wt~
sodium chloride, USP powder 9.73wt$
povidone', USP 5.20wt~
purified water* (10 times the amount of povidone)
weight average molecular weight = 55,000; freely soluble
h in water (1g in 1-lOml of water); dynamic viscosity
(10~w/v solution at 20°C) - 5.5-8.5 m Pa s
*water is evaporated during the granulation process.
(a) The povidone is dissolved in water to make
a lOwt.~ solution. Then the pseudoephedrine
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WO 96/40080 PCT/C1S96/08869
hydrochloride, sodium chloride and microcrystalline
cellulose are mixed and placed in a granulator and the
povidone solution is sprayed onto the mixture to form
granules. The drying cycle is initiated after the
granulation process is completed. The drying cycle is
continued until the moisture loss on drying (LOD) is not
more than 2.0~ at about 50°C. Then, the dry granules are
sized with a 40 mesh (USS) screen in an oscillating
granulator.
II Tabletting Case I Case II
granules (from I) 79wt~ 89wt~
polyethylene oxide2 20wt~ lOwt~
magnesium stearate l.Owt~ l.Owt~
Polyox WSR 303; weight average mol. wt. 7,000,000
(b) A tablet core is made by adding the
polyethylene oxide and the magnesium stearate to the
granules prepared in step (a). Core tablets weighing
305mg each for Case I and 271mg each for Case II are
prepared using a tablet press machine using 0.3438"
standard concave punches with a projection as described
in Example 1 in the upper punch.
The core tablets were then coated according to the
procedure of Example 1.
While certain preferred and alternative
embodiments of the invention have been set forth for
purposes of disclosing the invention, modifications to
the disclosed embodiments may occur to those who are
r
skilled in the art. Accordingly, the appended claims are
intended to cover all embodiments of the invention and
modifications thereof which do not depart from the spirit
and scope of the invention.
14
