U.S. patent application number 10/430142 was filed with the patent office on 2004-02-05 for chemical delivery device.
Invention is credited to Chopra, Sham.
Application Number | 20040022852 10/430142 |
Document ID | / |
Family ID | 26772456 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040022852 |
Kind Code |
A1 |
Chopra, Sham |
February 5, 2004 |
Chemical delivery device
Abstract
The invention provides a controlled release dissolution and
diffusion devices which can deliver an active ingredient at a
constant or controlled-variable rate comprising an active
ingredient and dissolution modifiers and/or an insoluble matrix.
The compressed core is coated, except for at least one exposed
face, with a coating containing an insoluble polymer or a mixture
of an insoluble polymer and pore-forming elements said pore-forming
elements having a dissolution rate slower that the release rate so
that the pore formation is completed after release of the active
ingredients and the residual inert structures disintegrate.
Inventors: |
Chopra, Sham; (Brampton,
CA) |
Correspondence
Address: |
Patrick H. Higgins
Mathews, Collins, Shepherd & McKay
Suite 306
100 Thanet Circle
Princeton
NJ
08540
US
|
Family ID: |
26772456 |
Appl. No.: |
10/430142 |
Filed: |
May 6, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10430142 |
May 6, 2003 |
|
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10085234 |
Feb 28, 2002 |
|
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60293701 |
May 25, 2001 |
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Current U.S.
Class: |
424/468 ;
424/471 |
Current CPC
Class: |
A61K 9/2866 20130101;
A61K 9/2846 20130101; A61K 9/2086 20130101; A61K 9/2893
20130101 |
Class at
Publication: |
424/468 ;
424/471 |
International
Class: |
A61K 009/22; A61K
009/24 |
Claims
What is claimed is:
1. A dissolution-controlled chemical delivery device providing
controlled variable release of at least one biologically active
ingredient into a medium throughout a substantial portion of a
delivery period which composition comprises (i) a shaped core (a)
having at least one release face wherein dissolution at said face
causes a surface area of said face to vary throughout a substantial
portion of the delivery period, and (b) containing the biologically
active ingredient mixed with at least one dissolution regulator
operable to release the biologically active ingredient from said
release face, and; (ii) a coating surrounding and adhering to said
core except the release face(s), said coating containing an
insoluble polymer or a mixture of an insoluble polymer and
pore-forming elements operable to create channels in said
impermeable coating to permit disintegration of the coating after
release of said active ingredient is completed.
2. A device according to claim 1 wherein said core is a circadian
configuration.
3. A device according to claim 2 which comprises two release
faces.
4. A device according to claim 2 wherein said polymer coating is
selected from a group consisting of ethyl cellulose, cellulose
acetate, cellulose acetate butyrate and cellulose acetate
phthalate, polyvinyl alcohol, polyvinyl acetate and methacrylic
acid copolymers.
5. A device according to claim 2 wherein said pore-forming element
is selected form a group consisting of dextrose, fructose, glucose,
dextrates, sorbitol and carbowax.
6. A device according to claim 2 wherein said dissolution regulator
is selected from a group consisting of hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, methyl cellulose, soluble modified starches,
gelatin, and acacia.
7. A device according to claim 2 where the active ingredient is a
pharmaceutical agent for human use.
8. A device according to claim 7 where the active ingredient is
selected from a group consisting of psychotherapeutic agents,
antidiabetic drugs, anticonvulsants, cardiovascular drugs, stroke
treatment agents, respiratory therapies, anti-infective agents,
migraine therapies, urinary tract agents, contraceptives,
analgesics, cholesterol reducers, antiarthritic agents,
gastrointestinal products, muscle-relaxants, muscle-contractants,
anti-Parkinson agents, anti-inflammatory agents, hormonal agents,
diuretics, electrolytes, serotonin agonists and antagonists
H2-antagonists muscle relaxants.
9. A device according to claim 8 where the active ingredient is
selected based on a suitable half-life and adsorption
characteristics from a group consisting of aspirin, bupropion
hydrochloride, buspirone hydrochloride, carbamazepine, carbidopa,
cephalosporin, cimetidine hydrochloride, citalopram hydrobromide,
clarithromycin, clonidine, diclofenac sodium, diltiazem
hydrochloride, dipyridamole, divalproex sodium, doxazosin mesylate,
enalapril maleate, ethinyl estradiol, etodolac, fexofenadine
hydrochloride, glipizide, haloperidol, ibuprofen, indomethacine,
isosorbide dinitrate, isradipine, ketoprofen, labetalol,
lansoprazole, levodopa, lithium carbonate, loratidine, lovastatin,
methascopolomine chloride, metformin hydrochloride, metronidazole,
methylphenidate hydrochloride, metoprolol succinate, morphine
sulfate, naproxen sodium, nifedipine, nisoldipine, norethindrone
acetate, omeprazole, oxybutynin chloride, oxycodone hydrochloride,
penicillin, pentoxifylline, potassium chloride, pseudoephedrine
hydrochloride, rabeprazole sodium, ranitidine hydrochloride,
salbutamol, terfenadine, theophylline, tramadol hydrochloride,
trandolapril, venlafaxine hydrochloride, verapamil hydrochloride,
and alternative or pharmaceutically acceptable salts thereof.
10. A device according to claim 2 where said active ingredient is a
pharmaceutical agent for veterinary use.
11. A device according to claim 2 where said active ingredient is
an insecticide or fungicide.
12. A device according to claim 2 where said active ingredient is a
biocide or disinfectant.
13. A process for the preparation of a chemical delivery device
according to claim 2 by dry granulation process comprising the
steps of: (a) blending said active ingredient and a dissolution
regulator and optionally with a diluent; (b) optionally milling and
sieving the resulting blend with a mesh size suitable for the
specific application; (c) mixing said blend with a soluble or
insoluble lubricant and compressing said blend into tablet with an
appropriate shape in a punch machine; (d) coating said tablet with
a coating containing an insoluble polymer or a mixture of an
insoluble polymer and pore-forming elements using a
compression-coating machine.
14. A process for the preparation of a chemical delivery device
according to claim 2 by wet granulation process comprising: (a)
blending said biologically active ingredient and a dissolution
regulator with water, an organic solvent or a mixture of water and
an organic solvent and optionally with a diluent; (b) drying the
resulting blend at an appropriate temperature, milling and sieving
the resulting blend with a mesh size suitable for the specific
application; (c) mixing said blend with a soluble or insoluble
lubricant and compressing the blend into tablet into an appropriate
shape in a punch machine; (d) coating said tablet with a mixture
containing an insoluble polymer or a mixture of an insoluble
polymer and pore-forming elements using a compression-coating
machine.
15. A method of delivering an active ingredient with a controlled
variable release of an active compound into a medium comprising:
(a.) incorporating at least one biologically active ingredient into
a tablet having: (i) a shaped core (a) having at least one planar
release face wherein the dissolution of said face causes at least
one of the dimensions of said face to vary thereby increasing or
decreasing the surface area of said face throughout a substantial
portion of the delivery period wherein said core is a circadian
configuration, and (b) containing a compressed mixture of the
biologically active ingredient homogeneously mixed with at least
one dissolution regulator operable to release the biologically
active ingredient from said release face; and, (ii) a coating
surrounding and adhering to said core except the release face(s),
said coating containing an insoluble polymer or a mixture of an
insoluble polymer and pore-forming elements operable to create
channels in said impermeable coating to permit disintegration of
the coating after release of said active ingredient is completed
said coating disintegrating over a substantially longer period of
time than is required for said dissolution regulator to release
said biologically active ingredient; and, (b) placing said tablet
in a fluid medium in need of the presence of said active
ingredient.
Description
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/085,234, filed Feb. 28, 2002, which claims
priority to U.S. Provisional Patent Application Ser. No.
60/293,701, filed May 25, 2001.
FIELD OF THE INVENTION
[0002] The present invention relates to controlled release chemical
delivery devices, and more particularly to a controlled release
drug delivery device, with a geometrically shaped body coated with
a mixture of an insoluble polymer, optionally containing
water-soluble pore-forming material(s) said pore-forming
material(s) having a dissolution rate slower that the release rate
so that the pore formation is completed after release of the active
ingredients and the residual inert structures disintegrate.
BACKGROUND OF THE INVENTION
[0003] Effective drug therapy generally requires maintained drug
levels in the blood stream for extended periods of time. Standard
tablets, however, generally disintegrate quickly and release all
the active components over a relatively short period of time. With
these dosage forms drug levels are maintained by administering the
tablets several times a day. This is inconvenient and frequently
leads to poorer patient compliance. Thus it is desirable to
identify drug delivery systems which will produce constant drug
levels in the blood for extended time periods. It is thought that
to obtain a constant drug level in the blood a drug delivery system
must release the drug at a constant rate. To achieve this constant
rate, several mechanisms including osmosis, diffusion and
dissolution, and dosage form modifications have been investigated,
for example as described in Ho-Wah Hui et al., Chapter 9 in
"Controlled Drug Delivery": Fundamentals and Applications (2.sup.nd
Ed.), Marcel Dekker, New York, 1987. There remains, however, a
clear and continuing need for simple inexpensive dosage forms which
efficiently and reliably deliver active compounds over extended
time periods. Drug delivery systems frequently include passive
impermeable coatings which surround a core composition containing
the active drug substance and excipients. This coating frequently
plays an important role in maintaining the structural integrity of
the device during the drug release period. If the impermeable
coating does not dissolve or disintegrate prior to passage through
the gastrointestinal system, a "ghost" residue will remain which
can be uncomfortable or undesirable to void. Furthermore, passage
of these residual coatings through the GI tract potentially can
damage the intestinal mucosa.
[0004] Attempts have been made to achieve constant rates of drug
release by controlling the surface area of tablets. Examples of
such attempts are described in Stephenson et al. (UK Patent No.
1,022,171), Reid (U.S. Pat. No. 3,279,995) and DePrince (U.S. Pat.
No. 4,663,147). However, such systems have not been completely
successful usually either due to improper design of the system or
due to a lack of appropriate and available manufacturing
technology.
[0005] Another approach has been to coat the active component with
impermeable coatings which limit access of the fluid media to the
active component and slow dissolution of the core. Staniforth (U.S.
Pat. No. 5,004,614) employs a coated tablet containing holes in the
coating to limit contact with the surrounding medium. Both
dissolution and diffusion process can be exploited to attempt to
regulate drug release from delivery devices. Ranade (U.S. Pat. No.
4,803,076) has disclosed a dissolution and diffusion device for the
controlled release of a substance into a fluid media at a
substantially constant rate wherein the substance is contained in a
shape substantially that of a truncated cone in which the sides and
base (but not the top) of the cone are coated with an impermeable
wall or coating. A related design was disclosed by Cremer (U.S.
Pat. No. 6,264,985). McMullen (U.S. Pat. No. 4,816,262) describes a
controlled release tablet which includes a solid core having a
hydrophilic releasable agent. The core has a central hole and is
coated on all faces except that formed by the central hole. The
thickness gradually increases from the central hole to the outer
border and forms a concave disk containing a hydrophilic releasable
agent. Chopra (U.S. Pat. No. 5,342,627) describes a tablet shaped
core in which the thickness decreases from the center of the tablet
to the periphery and the exposed surface from which release occurs
is a cylindrical band around the outer perimeter of the tablet. Kim
(U.S. Pat. No. 6,110,500) has disclosed a tablet for controlled
release of an active ingredient from a core having a donut-like
configuration with a cylindrical hole extending through the center
of the core. The core comprises a releasable substance and at least
one hydrophilic, water-soluble polymeric carrier. These hydrophilic
polymeric carriers are swellable and/or erodable. Swelling of the
polymer, however, can deform the controlled release device and
alter the release rates. The core is coated with a hydrophobic
water insoluble material except the area defined by the cylindrical
hole through the core. Cremer (U.S. Pat. No. 5,853,760) teaches a
device for the controlled release of active substances into fluid
media from an active substance-containing matrix, the active
substance releasing surfaces of which are, at least partially,
covered by an erodible solid. The delivery characteristics depend
on the surfaces coated and the thickness and geometry of the
coating which erodes over the delivery period to expose additional
surfaces of the matrix to the fluid medium. Shah and Britten (U.S.
Pat. No. 5,922,342) disclose a controlled release composition with
a compressed core having two parallel planar surfaces containing at
least 90% of a non-disintegrating therapeutic agent(s) and
optionally containing 0-10% of non-disintegrating ingredients that
are conventional in tablet making such as binders, lubricants,
compression aids, flow aids and the like. The device allows
zero-order release of a drug throughout the delivery period. The
core is free of materials that can cause swelling or disintegrate.
A seal coating consisting of a film of impermeable material
surrounds the core except the two parallel planar surfaces (i.e. on
all the later surfaces. The seal coating serves to protect the
lateral surfaces of the core.
[0006] The osmotically driven systems (e.g. U.S. Pat. No.
4,111,202) release the drug at a constant rate for as long as the
concentration of the osmotic agent in the system is at the
saturation point. When the concentration of the osmotic agent falls
below the saturation point, the release rate declines parabolically
towards zero as described in F. Theeuwes et al. Elementary Osmotic
Pump for indomethacin, J. Pharm. Sci., 72, 253, (1983).
[0007] Dissolution-controlled and diffusion controlled devices
consist of a pharmaceutical agent mixed with inert ingredients
compressed into tablets. A dissolution-controlled device contains a
shaped core, optionally partially coated with an insoluble
polymeric coating, in which the exposed portion of the core
dissolves into or is eroded by the surrounding media whereby the
active compound is released into the media. The shaped core
contains the active ingredient optionally combined with
release-modifying agents, buffers and binders. A dissolution device
is suitable for formulating hydrophobic and hydrophilic compounds
whereas a diffusion device is especially suited to deliver
hydrophilic compounds. A diffusion-controlled device contains a
pharmaceutical agent uniformly distributed in an insoluble porous
polymeric matrix. The insoluble matrix is present throughout the
delivery period and the dimensions of the device remain constant.
As the drug becomes depleted in proximity of the exposed surface,
the release rate also becomes a function of the diffusion path
length through the insoluble matrix through which the remaining
drug must diffuse to reach the exposed surface in contact with the
dissolution media.
[0008] Some therapeutic regimens require administering a varying
quantity of the active substance. Attempts have been made to design
dosage forms which produce variable release rates or pulsatile
release but these have not been reliable or cost effective since
they frequently possess complex architectures which are difficult
to fabricate and are structurally weak. For example, Chopra (U.S.
Pat. No. 5,342,627) teaches that "the geometrical profile of the
cavity and core of the diffusion device may be such that `pulses`
of the active substance are release at predetermined points in the
total dissolution time. Thus, the profile of the cavity `walls` may
be varied to provide pre-determined changes in the surface are so
as to provide pulses of activity." There is, however, no
explanation of geometries which will produce nonlinear release nor
does the geometry of the device allow for ready modification.
[0009] The release rate of a chemical from a compressed soluble
disc in a dissolution-controlled device, dm/dt, can be expressed
as: 1 m t = AC x t ( Equation 1 )
[0010] where:
[0011] A is the surface area;
[0012] C is the concentration of the chemical; and
[0013] dx/dt is the mass erosion rate.
[0014] Equation (1) predicts that the release rate will be
proportional to the exposed surface area if the mass erosion rate
is constant and the chemical substance is uniformly distributed
throughout the core of the tablet. In reality, however, the rate of
dissolution is not a simple function of surface area alone, rather
it is a complex function of changing size and the shape of the disc
itself, as well as fluid dynamics of the adjacent solvent layer as
described in F. J. Rippie and J. R. Johnson, Regulation of
Dissolution Rate by Pellet Geometry, J. Pharm. Sci., 58, 428
(1969). Nevertheless, if the device is designed to provide a
constant surface area over a substantial portion of the delivery
period, a constant dissolution rate can be expected. (D. Brooke and
R. J. Washkuhn, Zero-order Drug Delivery Systems: Theory and
Preliminary Testing, J. Pharm. Sci., 1979 66:159)
[0015] In the diffusion mechanism, the release of chemical from a
solid matrix by diffusion can be represented by Equation 2: 2 q t =
- DA c t ( Equation 2 )
[0016] where
[0017] q is the mass of chemical being transferred;
[0018] t is the time;
[0019] c is the chemical concentration;
[0020] r is the diffusion path length;
[0021] A is the area for the mass transport; and,
[0022] D the diffusion coefficient of the chemical.
[0023] According to the above equation, the chemical release rate
decreases as the diffusion path length r increases. Since r cannot
be kept constant, a constant release rate can be maintained by
increasing the concentration of active compound by exposing greater
surface area to compensate for the increase in diffusion distance
through the matrix.
[0024] Existing devices have features that limit their
applicability and practical production of effective controlled
release agents has proven difficult. Devices which do not provide
for adequate quantities of a dissolution regulator have limited
flexibility to optimize the delivery rate. Water-soluble compounds
will be released too rapidly when present in very high
concentration in dissolution devices. Devices which do not provide
for insoluble modifiers are incapable of functioning as diffusion
devices which are desirable when delivering hydrophobic compounds.
If improperly designed, the release rate from controlled release
devices may vary over the release period. Osmotic devices have a
lag time until the desired release rate is achieved whereas the
present devices begin to deliver the active chemical upon contact
with the fluid medium. The release from osmotic systems also
decreases suddenly once the osmotic regulant is depleted from the
device leaving residual active compound in the device.
Diffusion-controlled devices in which the active compound must
diffuse through an insoluble matrix may have a lag time or slow
release rate and be voided intact before the complete release of
the active ingredient. Premature separation of the impermeable
coating from the core can cause "dose dumping" as the uncoated core
disintegrates Impermeable coatings in existing devices have no
reliable disintegration mechanism which can lead to evacuation of
the intact coating or release device. Furthermore the amount of
active substance which can be accommodated by these known devices
is often limited by practical difficulties scaling the size and
geometry of these architecturally complex devices. The rate of
release from devices with a swellable and/or erodible polymer
decrease in the later stages of drug release whereas dissolution
devices afford constant release throughout the delivery period. The
release rate from swellable cores also can be erratic due to the
hydrodynamic conditions in the gastro-intestinal tract as the
swellable polymers are easily abraded. Release from an erodible
matrix decreases as the surface area of the erodible surface
decreases. Diffusion devices often exhibit non-zero order release
as the diffusion path between the residual active substance and the
fluid medium increases. A variety of geometrical designs have been
suggested to overcome these problems; however, implementing these
designs has often been problematical.
[0025] The release rate from these devices is dependent on a
variety of factors. The geometrical shape of the matrix is an
important parameter. Other factors include, but not limited to, the
specific properties of the substances used, e.g., molecular mass,
solubility, swelling temperature and glass transition temperature
of the components of the device. When the release requires
diffusion through a matrix, the main parameters include the size of
the surface, the matrix volume, the diffusion coefficient, the
concentration and solubility of the active substance in the matrix,
the porosity and tortuosity of the matrix, and the diffusion
resistance between the matrix and the fluid medium.
[0026] Many controlled release delivery devices incorporate
polymeric coatings that are essentially water insoluble and
consequently have low permeability to both water and the active
component in the device. Depending upon the physical principles
utilized to control delivery of the active ingredient, these
coatings may be modified to alter their permeability. Several
approaches to controlled drug delivery devices utilize a core
containing the active ingredient with an impermeable polymeric coat
containing particulate pore-forming materials which are soluble in
water or in gastrointestinal fluids. Lindahl and Erlandsson (U.S.
Pat. Nos. 4,557,925; 4,629,619 and 4,629,620) utilize pore-forming
materials that dissolve or leach out of the coating which creates
paths or channels allowing ingress of the surrounding fluids which
dissolve the active compound and produce saturated solutions of the
active compound in the core which subsequently egress through the
same channels. The release rates in these relatively simple devices
are predominantly a function of the time required for dissolution
of the particles and the size and density of the channels. These
variables depend on the solubility and particle size of the
pore-forming material and the concentration in the impermeable
coat. Berliner and Nacht (U.S. Pat. No. 5,849,327) disclosed
delivery devices in which the pore-forming materials are degraded
by colon specific bacteria resulting in release of the active
ingredient in the colon. Lindahl and Ekland (U.S. Pat. No.
4,824,678) describe delivery devices utilizing this principle by
incorporating the active ingredient in the core and in the
pore-creating particles which produces a burst of active ingredient
as the pores are formed.
[0027] Osmotic delivery devices also have incorporated pore-forming
materials within impermeable or semipermeable polymeric coatings to
provide channels for osmotic pumping of the contents into the
external medium. For example, Haslam and Rork (U.S. Pat. No.
4,886,668) describe an osmotic device wherein pore-forming
materials are incorporated with a semipermeable coating. Ingress of
water occurs through the semipermeable coating and dissolution or
leaching of the pore-forming materials provides egress channels for
the concentrated solution of active component formed in the
core.
[0028] Regardless of the physical principles underlying the design
and operation of the delivery device, the pore-forming compounds
are incorporated to provide a pathway to move fluids through the
impermeable polymeric coating.
[0029] There remains a need for effective and adaptable systems for
controlled release of active chemicals with improved performance.
The devices in the present invention can be readily scaled to
different proportions that will accommodate differing quantities of
the active chemical and which, therefore, have the capacity for
longer release periods. With the present system the core is slow
dissolving, which means that "dose dumping" is not as prevalent as
in other chemical delivery systems, and there is minimal effect of
hydrodynamic conditions prevailing in the stomach as only the
peripheral face of the core is exposed. The present system also
provides a reliable and predictable means to insure disintegration
of the insoluble impermeable coating to avoid elimination of the
intact device. Furthermore the rate of disintegration of the
coating can be manipulated by adjusting the size, density and
composition of the pore-forming materials.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] Other objects and features of the present invention will
become apparent from the following detailed description considered
in connection with the accompanying drawing which discloses several
embodiments of the present invention. It should be understood,
however, that the drawing is designed for the purpose of
illustration only and not as a definition of the limits of the
invention.
[0031] FIGS. 1A-G show different embodiments of a geometrically
shaped core of the present invention that maintain a constant
surface area throughout the delivery process.
[0032] FIG. 2A illustrates one embodiment of the core that is
rectangular.
[0033] FIGS. 2B-D show the coated core of FIG. 2A at varying stages
of chemical release.
[0034] FIG. 2E is a cross-section view of a typical dissolution
delivery device containing pore-forming elements in the coat.
[0035] FIG. 3 illustrates an embodiment of the invention where the
core is two frustums of a cone that are joined at the larger base.
This geometry results in increasing quantities of drug delivered
per unit time throughout the release period in a dissolution device
or zero-order delivery from a diffusion device.
[0036] FIG. 4 illustrates an embodiment of the invention where the
core is two frustums of a cone that are joined at the smaller base.
This geometry results in decreasing quantities of drug delivered
per unit time throughout the release period in a dissolution device
or a diffusion device.
[0037] FIG. 5a illustrates an embodiment of the invention where the
core is a truncated bipyramid. This geometry results in increasing
quantities of drug delivered per unit time throughout the release
period in a dissolution device or zero-order delivery from a
diffusion device. FIGS. 5b and 5c show the core at various stages
of the release process.
[0038] FIG. 6 illustrates the release profile of a zero-order
sustained release of nifedipine and glipizide tablets from a device
with a shaped core coated with a slowly disintegrating coating.
[0039] FIG. 7 shows a sectioned view an example circadian
configuration embodiment of the present invention.
[0040] FIGS. 8A-E show an example "circadian configuration"; a
specially shaped delivery core having a specifically designed
dosage structure to yield a release profile, for example, of a
relatively rapid drug release, followed by a maintenance dose,
followed by a rapid drug release.
DETAILED DESCRIPTION OF THE INVENTION
[0041] Although many approaches have been taken to design
controlled release systems which release a pharmaceutical agent
according to a predetermined release profile, there remains an
unfilled need for simple and reliable dissolution- and
diffusion-controlled delivery devices that are manufactured with
relative ease and acceptable cost. One embodiment of the present
invention is a new simple chemical delivery device. The delivery
device produces linear (zero-order) kinetics for releasing a
chemical compound over a desired period. The delivery device
comprises a geometrically shaped core with at least one planar
release face exposed to the fluid medium, at least one chemical
compound and at least one dissolution regulator dispersed within
the core. The core is surrounded by an insoluble polymer coating
and water-soluble pore-forming material(s) that leach out of the
coat and that introduce mechanical instability and allow the coat
to disintegrate after release of the active compound is complete.
The disintegration rate of this coating can be manipulated by
changing the concentration and/or size of pore-forming material(s),
the water-solubility of the material(s) and the thickness and
composition of the coating. Another embodiment of the present
invention is a chemical delivery device which can independently
release more than one chemical ingredient. In the present invention
this can be achieved by incorporating one substance into the shaped
core and a second substance into the coating which erodes at a
substantially slower rate than the core resulting in a release rate
different from the drug in the core. Alternatively the core can be
comprised of multiple layers with each compound in one of the
layers or two compounds can be mixed within a single shaped core.
In this embodiment of the invention the relative surface area of
the exposed face of each layer will determine the relative release
rate for the chemical compound contained therein.
[0042] The chemical compounds used in the present invention may
include, but are not limited to, therapeutically active compounds
for human and veterinary applications, pesticides useful in
agriculture such as insecticides and fungicides, disinfectants and
biocides to control growth of undesired organisms, active compounds
used in water treatments in swimming pools and toilets and any
other application in which the release of a chemical at a
controlled rate is required.
[0043] The phrase "a" or "an" entity as used herein refers to one
or more of that entity; for example, a compound refers to one or
more compounds or at least one compound. As such, the terms "a" (or
"an"), "one or more", and "at least one" can be used
interchangeably herein.
[0044] The terms "comprising", "including" and "having" are used
interchangeably. Furthermore, a compound "selected from the group
consisting of" refers to one or more of the compounds in the list
that follows, including mixtures (i.e., combinations) of two or
more of the compounds.
[0045] The terms "controlled-release", "sustained-release" and
"slow-release" are to be considered as synonyms in the context of
the present invention. The term "controlled release", as used
herein means that the release of the therapeutically active agent
occurs such that blood levels are maintained within a desired
therapeutic range over an extended period of time, e.g., at least
about 6 and preferably from about 12 to about 24 hours.
[0046] The term "core" as used herein can be interchanged with the
term "body", and is used to describe the part of the tablet that
contains the active ingredient(s) and excipients and that is
covered by a slowly dissolving or disintegrating coat, preferably a
coat that dissolves or disintegrates only after the active
ingredient is released from the core. The term "exposed surface" or
"release surface" as used herein means the uncoated surfaces of the
core in direct contact with the external fluid medium. One
embodiment of the invention is a shaped core covered by a coating
comprising soluble and insoluble components whereby the soluble
components can leach out or dissolve and render the insoluble
coating porous and structurally weak allowing it to disintegrate
after the all the active compound is released but before the tablet
is evacuated.
[0047] The term "dissolution regulator", "release modifying agent"
or "soluble diluents" as used herein means a chemical compound
included in the core to surround the particles of the active
compound and modify its inherent dissolution rate.
[0048] The term "dissolution-controlled" as used herein means the
components of the shaped-core erode or dissolve away from the
original exposed surface of the device. There is no limitation on
the mechanism or physical processes whereby the erosion occurs.
[0049] The term "diffusion-controlled" as used herein means the
active compound(s) is (are) disposed in an insoluble matrix and the
shape and dimensions of the matrix remain substantially unchanged
during the delivery period. In a diffusion-controlled device the
"dissolution front" or "dissolution surface", where active compound
is released into the fluid medium, is within the insoluble matrix
and only coincident with the exposed surface at the initial point
in the release profile. During the release period the dissolution
front moves away from the exposed face of the matrix and the active
substance released from the dissolution front within the insoluble
matrix must diffuse through pores of the insoluble matrix to reach
the surface, i.e., "release front", exposed to the fluid
medium.
[0050] The term "diffusion path length" as used herein refers to
the distance between the dissolution surface and the surface
exposed to the external fluid media through which the active
compound must diffuse.
[0051] The term "erosion" or "eroded" as used herein denotes a
process whereby mass is removed from the exposed faces by
mechanical degradation (e.g. surface disintegration) or by
dissolution of the dissolution regulator or by a more complex
process including, but not limited to a chemical reaction, e.g.
hydrolysis, of matrix components.
[0052] The term "pore-forming material(s)", "pore-forming
element(s)" or "pore former(s)" as used herein refers to water
soluble materials which are embedded throughout the insoluble
coating and which dissolve, erode or leach out of the coating. The
pore-forming materials can be in solid or liquid form embedded in
the coat. These pores do not alter the drug release rate and are
designed to form after the drug release period is substantially
completed and allow disintegration of the device and coating prior
to passage put of the colon.
[0053] The term "substantially constant" as used herein means that
release of the active ingredient does not deviate by more than
.+-.20% from the theoretical release rate and preferably does not
deviate by more than .+-.10% from the theoretical release rate. The
term "delivery period" as used herein refers to time period
expected for complete release of the active compound. A
"substantial portion of the delivery period" as used herein means
that 70-80% of the active ingredient has been delivered. It is
understood that this can vary widely with the precise application
and the manufacturing conditions. Devices for oral delivery of a
pharmaceutical compound will typically release within 24 hours to
avoid evacuation of the device with unreleased active ingredient
remaining therein. Agricultural applications may require
significantly longer release periods for the active compound.
Biocidal and disinfectant applications will preferably have very
slow release rates to maximize the effective lifetime of the
device. Manufacturing variables such as compression force will
effect the dissolution times of the core and the useful delivery
period; and, these parameters must be optimized for a specific
application and specific components.
[0054] The delivery device of the present invention can be based on
the dissolution mechanism. As shown in FIGS. 1A-G and 2A-E, the
device preferably consists of a geometrically shaped core 10,
preferably a rectangular, cubical or cylindrical shaped core. The
core 10 contains a uniformly dispersed chemical compound or
compounds including an active ingredient 20 and a dissolution
regulator 22; preferably the uniformly dispersed active ingredients
are therapeutically active compound(s). The compressed core can
optionally be scored 18 to secure the slowly dissolving or
disintegrating coating to the compressed core. A slowly dissolving
or disintegrating coat 12 optionally containing pore-forming
material 16 surrounds all but at least one face 14 of the core as
shown in FIG. 2B. As the two exposed surfaces erode the two faces
recede inwards until the core 10 is dissolved as shown in FIG. 2D.
The chemical release occurs only from the exposed face(s) 14 whose
surface area dictates the rate of release of chemical. Throughout
the dissolution process, the surface area of the dissolution front
is constant in these geometrical shapes and therefore the release
substantially approximates zero-order kinetics. Because the exposed
face(s) are in immediate contact with the fluid medium, the active
ingredient is released immediately no lag time is observed. The
volume of the core can be increased or decreased to accommodate
different quantities of the active ingredient and excipients. The
release rate, however, will be determined by the rate of erosion of
the exposed surfaces and will be zero-order as long as the exposed
surface of a dissolution device, or the ratio of the dissolution
front to the diffusion path in a diffusion device, is constant.
Another advantage of the present invention is the complete release
of the active ingredient followed by the disintegration of
remaining inert components of the delivery device. This is in
contrast to many diffusion-based matrices, which leave a "ghost
residue".
[0055] The invention is not restricted to cubical, rectangular and
cylindrical objects. As depicted in FIG. 1, a variety of prismatic
solids afford geometries in which exposed surfaces can dissolve
without altering the surface area of the exposed face and are,
therefore, considered to be within the scope of the current
invention. This system has the advantage over other oral delivery
systems that the chemical release profile can be easily modulated
in a predictable manner simply by changing the geometrical
configuration of its core thereby altering the exposed surface area
of the shaped core. The amount of chemical compound(s) included in
the core of the device will depend on the application for which it
is being used, for example in the case of a therapeutically active
compound, the amount will depend on the amount of chemical that is
required to be delivered to the patient. Quantities of the
therapeutically active compounds required to produce a
pharmacological effect are well know to those skilled in the
formulation art.
[0056] Impermeable coatings are common elements in many
formulations. Impermeable coatings add mechanical strength and
stability to the dosage form. They are also barriers which restrict
contact between the external medium and the active ingredient and
permit controlled release of the active material into the medium.
Problems exist with presently available coatings. After active
ingredient is released the remaining plastic coating may be
excreted substantially unchanged which is unnecessary and
objectionable. The mechanical properties of coatings vary and
traditional spray coated polymers produces a polymeric film subject
to stretching and cracking which allows shaped core to separate
from the coating prior to complete release of the active
ingredient. The present invention uses compression coating
techniques to produce coatings with increased mechanical strength.
The compression coating is optionally applied with a pore-forming
material(s) which dissolve, leach or erode out of the polymer coat
after delivery of the active compound is complete which introduces
mechanical instability and the device and coating disintegrates or
dissolves and is not excreted intact. The pores do not alter the
release rate of the active ingredient.
[0057] In another embodiment of the present invention the
dissolution- or diffusion-controlled delivery device consists of a
truncated bipyramid core (FIG. 5) or a two frustums of a cone
joined at either the larger base (FIG. 3) or the smaller base (FIG.
4). In a dissolution-controlled release device, the surface area of
the exposed face(s) in these geometries varies throughout the drug
delivery resulting in a variable release rate.
[0058] Altering the three dimensional shape of the core to produce
a desired surface area profile permits a release profile of an
active compound to be modified in a controlled fashion. According
to Equation 1 the release rate of active ingredient is proportional
to the surface area of the exposed face(s). In this embodiment that
surface area either increases or decreases during a delivery period
which results in a corresponding increase or decrease in the rate
of drug release. The core geometries in FIGS. 3 and 5 result in
increasing release rates during the release period whereas the
release rate from the geometry in FIG. 4 decreases during the
release period. One skilled in the art would recognize alternative
shapes which would be equally effective and are considered part of
the present invention. In this embodiment of the invention the core
is again initially coated with an insoluble polymer containing a
pore-forming material to limit exposure of the core to the medium
during release of the active ingredient and to introduce mechanical
instability into the coating after release of the active substance
is completed.
[0059] Embodiments of the present invention are therefore based on
a drug delivery device which accurately and effectively release a
drug. The release is regulated by controlled rate of change of the
surface area of the release face(s) during the release process
(dissolution). Particularly, a delivery device is provided
comprising a core with at least one release face. The release
face(s) may be circular, semi-spherical, elliptical,
semi-elliptoid, oblong, oblong with a rounded surface, square,
triangular, hexagonal, or practically any other shape or geometric
shape that is feasible to manufacture. Flat (planar) faces are
preferred. A coat, that disintegrates after the core has dissolved
or that has a dissolution rate that is slower than that of the
core, covers all the faces of the device, except the release
face(s). Drug release occurs from the release face(s), whose
surface area dictates the rate of release of the drug. The
variability of the exposed surface area of the release faces
throughout the release process accordingly controls the release
kinetics. As the releasing face(s) regress during dissolution, as
is indicated in the figures, e.g., FIGS. 8B-8E, the surface area
increases or decreases, periodically, relative to a previous
surface area, depending upon the desired amount of drug to be
delivered at various times during the dosage period.
[0060] FIG. 8A shows an example "circadian configuration"; a
specially shaped delivery core having a specifically designed
dosage structure to yield a release profile, for example, of a
relatively rapid drug release, followed by a maintenance dose,
followed by a rapid drug release. The profile of the circadian
configuration core therefore generally shows varying thickness,
depending upon the desired rate and timing of dosage delivery.
Circadian configuration cores comprise at least one release face.
Although the circadian configuration core shown in FIG. 8A
demonstrates two release faces (di-bar), circadian configuration
cores are contemplated herein that have a plurality of active
release faces, e.g., tri-bar, quadra-bar (e.g., cross shape), or
more. Active release face(s) thus generated, vary in size, and may
vary in basic shape, during the release process or dosage period.
The face(s) may be circular, elliptical, oblong, square,
triangular, hexagonal, or practically any other shape or geometric
shape that is feasible to manufacture.
[0061] This type of "circadian configuration" device may be used
for chronotherapy. The rationale behind chronotherapy products is
that many disease processes follow very predictable circadian
rhythms and tend to occur with great predictability at certain
times of the day (e.g. elevated cholesterol at 6 PM and heart
failure at 3 AM). Chronotherapy products are designed to deliver a
maintenance dose of drug throughout the day, complemented with a
burst release, pulse release, and other rates, around the
clinically critical time of day. The number of high release rate
periods may be increased if desired. Accordingly, an increasing or
decreasing surface area during the release process will result in
increasing or decreasing drug release profiles respectively.
Indeed, embodiments described herein can be configured to give any
desired release profile provided the required core can be
compressed and coated. Accordingly, a dissolution-controlled
chemical delivery device providing controlled variable release of
at least one biologically active ingredient into a medium
(preferably aqueous, preferably physiological fluid) throughout a
substantial portion of the delivery period is provided--which
comprises a shaped three dimensional core having at least one
release face, preferably planar, wherein the dissolution at said
face causes at least one dimension (e.g., radius) of said face to
vary thereby increasing or decreasing the surface area of the
release face throughout a substantial portion of the delivery
period, and wherein said core contains at least one biologically
active ingredient mixed, preferably homogeneously, with at least
one dissolution regulator operable to release the biologically
active ingredient from said release face, and wherein the device
comprises a coating surrounding and adhering to said core except
the release face(s), said coating containing an insoluble polymer
or a mixture of an insoluble polymer and pore-forming elements
operable to create channels in said impermeable coating to permit
disintegration of the coating after release of said active
ingredient is completed.
[0062] One "circadian configuration" di-bar device, e.g., FIG. 8A,
for example, may be two fused cores (symmetrical) comprised of
separate active ingredients. Such a di-bar device may be
symmetrical as shown in FIG. 8A or may be asymmetrical. Asymmetry
in such a device may be employed to deliver separate drugs
(combination therapy) at separate rates of dissolution as otherwise
described herein. Accordingly, a tri-bar device described herein,
for example, may be used to deliver either a single therapeutic
agent, two separate therapeutic agents, or three separate
therapeutic agents.
[0063] Manufacturing may involve, in one embodiment, granulating
the drug with slow dissolving materials followed by compressing the
blend into shaped cores on a conventional tabletting press using
specially designed tooling. The coating material used to encase the
active core is prepared by mixing a blend of soluble and insoluble
polymers with appropriate plasticizers. The surface of the active
core, excluding the peripheral edge, is then coated using a
compression-coating machine with a specially designed transfer
mechanism. The devices herein described use pharmaceutically
compatible ingredients in compressed tablet and compression coating
form. There are consequently no toxicological issues with the
technologies. The core consists of the active and standard
tabletting excipients including a lubricant. The coating consists
of polymers, plasticizers, and a lubricant.
[0064] In yet another embodiment of the present invention there is
provided a diffusion delivery device. In contrast to dissolution
devices, the geometries depicted in FIGS. 3 and 5 produce a
substantially constant release rate in a diffusion-controlled
device. The diffusion device is particularly effective for
delivering water soluble ingredients and typically comprises a
compressed core containing the active ingredient and an insoluble
matrix. The surface area of the dissolution front and the diffusion
path length vary throughout the delivery period and the dependence
of the release rate on the area of the dissolution front is given
by Equation 2. This embodiment of the invention the core is also
coated with an insoluble polymer containing a pore-forming
material. The insoluble matrix in a diffusion release device leaves
a depleted ghost residue which will be voided intact unless means
for disintegration are incorporated into the device. Dissolution or
disintegration of the coating permits the insoluble structural
elements to disintegrate.
[0065] Still another embodiment of the present invention provides
for zero-order release of the active ingredient from a
geometrically shaped core that is comprised of less than 90% of a
therapeutic compound. The core is surrounded by a coating
comprising an insoluble or slowly soluble polymer and, optionally,
a soluble component which leaches out of the coat rendering it
porous, weak and susceptible to disintegration shortly after
release of the active ingredient is complete. Earlier devices
disclosed cores comprised of greater than 90% of the active
component; however, such cores afford limited opportunity to
control the release rate. Hydrophilic drugs require the presence of
dissolution regulators to prevent rapid and immediate dissolution
of the entire core. This embodiment allows the release rate to be
optimized for different active ingredients. The core coating
remains intact throughout the delivery period but disintegrates
prior to evacuation from the colon.
[0066] Examples of some chemical compounds that may be used
include, but are not limited to, therapeutically active compounds,
active compounds used in insecticides, active compounds used in
pesticides, and active compounds used in water treatments in
swimming pools and toilets, and other applications in which the
release of a chemical or chemicals is required at a controlled
rate. Examples of some chemical compounds that may be used include,
but are not limited to, inorganic and organic pharmaceutical agents
such as psychotherapeutic agents, anti-diabetic drugs,
anticonvulsants, cardiovascular drugs, stroke treatment agents,
respiratory therapies, anti-infective agents, migraine therapies,
urinary tract agents, contraceptives, analgesics, cholesterol
reducers, anti-arthritic agents, gastrointestinal products,
muscle-relaxants, muscle-contractants, anti-Parkinson agents,
anti-inflammatory agents, hormonal agents, diuretics, and
electrolytes. Examples of drugs that can be formulated into the
dissolution based or diffusion based device include aspirin,
bupropion hydrochloride, buspirone hydrochloride, carbamazepine,
carbidopa, cephalosporin, cimetidine hydrochloride, citalopram
hydrobromide, clarithromycin, clonidine, diclofenac sodium,
diltiazem hydrochloride, dipyridamole, divalproex sodium, doxazosin
mesylate, enalapril maleate, ethinyl estradiol, etodolac,
fexofenadine hydrochloride, glipizide, haloperidol, ibuprofen,
indomethacin, isosorbide dinitrate, isosorbide mononitrate,
isradipine, ketoprofen, labetalol, lansoprazole, levodopa, lithium
carbonate, loratidine, lovastatin, methascopolomine chloride,
metformin hydrochloride, metronidazole, methylphenidate
hydrochloride, metoprolol succinate, morphine sulfate, naproxen
sodium, nifedipine, nisoldipine, norethindrone acetate, omeprazole,
oxybutynin chloride, oxycodone hydrochloride, penicillin,
pentoxifylline, potassium chloride, pseudoephedrine hydrochloride,
rabeprazole sodium, ranitidine hydrochloride, salbutamol,
terfenadine, theophylline, tramadol hydrochloride, trandolapril,
venlafaxine hydrochloride, verapamil hydrochloride, and the like,
and alternative or pharmaceutically acceptable salts thereof.
[0067] Examples of polymers that are either soluble polymers or
polymers that produce clear colloidal dispersion in water that may
be used include, but are not limited to: hydroxypropyl cellulose,
hydroxyethyl cellulose, hydroxypropyl methylcellulose;
polyvinylpyrrolidone, methyl cellulose, soluble modified starches,
gelatin, acacia, polyethyleneoxide, and polyethyleneglycol. Water
insoluble polymers that may be used, but are not limited to,
include: cellulose acetate, cellulose acetate butyrate, polyvinyl
alcohol, ethyl cellulose, methacrylic acid copolymers, insoluble
modified starches, and polypropylene oxide. Biodegradable polymers
that may be used include: polyglycolide, poly-L-lactide,
poly-D,L-lactide, caprolactone, polyamino acids, polyorthoesters
and polyanhydrides. One skilled in the art will recognize other
polymers with similar properties which also may be used and the
invention is not limited to the specific polymers listed above.
[0068] Examples of suitable pore-forming materials include, but are
not limited to, alkali and alkaline earth metal salts, organic
compounds such as polysaccharides, organic aliphatic alcohols
including diols, polyols; polyhydric alcohol, polyalkylene glycol,
polyglycol, .alpha.,.omega.-alkylenediols, and the like. The
pore-forming elements can have a size of about 0.1 to 200 microns.
In a presently preferred embodiment, the means or wall comprises 1
to 50% of pore former based on the weight of the polymer. Preferred
pore-forming materials include sugars, e.g., dextrose, fructose,
glucose, dextrates, sorbitol, propylene glycol, glycerin and
carbowax.
[0069] Examples of suitable soluble diluents that may be
incorporated into the core include, but are not limited to,
lactose, sucrose, carbowax, dextrates, glucose, fructose, soluble
starch, sorbitol, mannitol, hydroxypropyl cellulose, hydroxyethyl
cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone,
methyl cellulose, soluble modified starches, gelatin, acacia.
Examples of biodegradable diluents that may be incorporated into
the core include, but are not limited to, polyglycolide,
poly-L-lactide, poly-D,L-lactide, caprolactone, polyamino acids,
polyorthoesters, and polyanhydrides. Examples of pH sensitive
diluents diluents include cellulose acetate phthalate,
hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate
and polymethacrylate. Examples of suitable insoluble diluents that
may be used include, but are not limited to, calcium sulfate,
dicalcium phosphate, microcrystalline cellulose, insoluble modified
starches and starch.
[0070] Examples of suitable lubricants that may be used include,
but are not limited to, stearic acid, sodium stearate, calcium
stearate, magnesium stearate and sodium lauryl sulfate.
[0071] Yet another embodiment of the current invention further
provides a process for manufacturing the chemical delivery device.
The manufacturing process comprises the steps of forming a mixture
of at least one chemical compound and at least one rate modifier,
and then compressing the mixture into a geometrically shaped core
comprising at least one exposed face. The process further includes
coating the shaped core with an inactive coat, the coat covering
all the faces of the core except at least one exposed face. In one
embodiment of the invention the shaped core is scored to assist in
securing the coating to the core.
[0072] The dissolution-based cores are composed primarily of
soluble excipients whereas diffusion based cores may contain
soluble and insoluble excipients. Granules for the bodies are
prepared using conventional, dry or wet granulation methods and the
bodies are compressed on a conventional press. No special tooling
is required in this system for the compression of the active
core.
[0073] A dry process does not require the use of solvents for the
compression coating. Coating formulations for both diffusion and
dissolution-based systems are composed of insoluble
pharmaceutically acceptable polymers and soluble plasticizers or
soluble compounds. Granules for coating may be prepared either by
dry granulation or wet granulation method.
[0074] The pre-compressed bodies are then compression coated using
a core-coater fitted with a specially designed tooling for placing
bodies precisely in the dyes. Approximately fifty percent of the
required coating material is transferred to the die and the core is
placed precisely at the desired location on the top of the granules
in the die. The remaining fifty-percent of the coating granules are
then placed on top of the core. The punches are then brought closer
together to compress all the components of the device. An example
of a suitable core-coater is manufactured by Korsche Pressing. Any
machine can be used that allows the geometrically shaped core to be
coated, preferably a machine that uses a device to pick up the
bodies for the precise placement in the center of the dye.
[0075] Although specific methods for manufacturing the chemical
delivery devices are described below, numerous modifications and
alternative process steps will be apparent to those skilled in the
art. Accordingly, this description is to be construed as
illustrative only and is for the purpose of teaching those skilled
in the art methods to prepare the invention. These processes may be
varied substantially without departing from the spirit of the
invention and the exclusive use of all modifications which come
within the scope of the appended claim is reserved.
EXAMPLE 1
Dry Granulation Method for Core Compression
[0076] In an appropriate blender, the chemical is blended with a
dissolution regulator which comprises the dissolution-based core.
If required a soluble or insoluble diluent may also be added.
Suitable polymers and diluents are known in the art and examples
are described above. The blend may be milled and sieved, if
desired, through a sieve with an appropriate size mesh, the mesh
size is chosen according to the application. The blend is then
mixed with a lubricant and the lubricated blend is compressed on a
conventional rotary or single punch machine, examples of which are
known in the art, into a tablet core of the appropriate shape and
size.
EXAMPLE 2
Wet Granulation Method for Core Compression
[0077] In an appropriate blender, the chemical is blended with
either a slow dissolving polymer which comprise the shaped core. If
required a soluble or insoluble diluent may also be added. The
blend is subsequently granulated with water or an organic solvent
or a mixture of water and an organic solvent. Alternatively a slow
dissolving or dispersing polymer may be dissolved or dispersed in a
solvent and added to the blend while mixing continuously. The
mixture thus granulated is then dried at a suitable temperature and
milled through a screen with an appropriate opening. The granules
prepared are then mixed with a soluble or insoluble lubricant. The
lubricated granules are compressed into a tablet core of the
appropriate shape. Examples of suitable core compressing machines
that may be used are known in the art and supplied by, for example
Killian & Co. Inc. (Pennsylvania, USA), Thomas Engineering
(Illinois, USA) and Fette America Inc. (New Jersey, USA).
EXAMPLE 3
Dry Granulation Method for Coating
[0078] An insoluble polymer and optionally a pore-former and/or a
plasticizer are mixed in a suitable blender, and then the blend may
be milled through a screen with an appropriate size mesh. The
milled blend is lubricated with a soluble or insoluble lubricant.
The core is covered with the blend and the coating applied by
compression.
EXAMPLE 4
Wet Method for Coating
[0079] An insoluble polymer and optionally a pore-former and/or a
plasticizer are blended together, and then the blend may be milled
through a screen with appropriate size mesh. The blended material
is granulated with a solution of a polymer in water. The granules
are dried at a suitable temperature and screened through a mesh of
appropriate size. The coating blend is lubricated with a soluble or
insoluble lubricant. The core is covered with the blend and the
coating applied by compression.
EXAMPLE 5
Nifedipine Tablets
[0080] Nifedipine (60 g.), lactose monohydrate (112.5 g.) and
hydroxypropyl methylcellulose 5 cps (124.5 g.) were blended in a
Diosna High Speed Blender for 2 min and sized through a 20 mesh
screen. The blend was granulated with water and dried at 60.degree.
C. and then milled through a 20 mesh screen. The milled material
was lubricated with magnesium stearate (3 g.). The lubricated blend
was compressed under a compression force of 23 kilonewtons into a
10 mm diameter and 6 mm thick cylindrical core weighing 300 mg. All
but two surfaces of the core were compression coated with a blend
of 50 g methacrylate S-100, 50 g methacrylate RSPO and 7.5 g
triethylcitrate and 5 g fine sorbitol. The coated tablets were
heated at 80.degree. C. for one hour.
EXAMPLE 6
Glipizide Tablets
[0081] Glipizide (8 g.), lactose monohydrate (95 g.) and
hydroxypropyl methylcellulose 5 cps (95 g.) were blended in a high
speed blender and sized through a 20 mesh screen. The blend was
granulated with water, dried at 60.degree. C. and then milled
through a 20 mesh screen. The milled material was lubricated with
sodium stearate 2 g.). The lubricated blend was compressed into a
4.times.4.times.10 mm rectangular core weighing 250 mg. All but two
surfaces of the core were compression coated with a blend of 25 g
cellulose acetate, 65 g ethyl cellulose and 6 g dextrate, 3 g ethyl
lactate and 1 g fine magnesium stearate. The coated tablets were
heated at 80.degree. C. for one hour. The total weight after
coating is 500 mg.
EXAMPLE 7
Nifedipine and Glipizide Release Profiles
[0082] The release profile of nifedipine and glipizide were
determine in simulated gastric fluid containing 1% sodium lauryl
sulfate using apparatus 2 described in the U.S. Pharmacopeia
<XXIV> incorporated herein by reference. The data is depicted
in FIG. 3. Nifedipine and glipizide were completely release in 20
and 19 hours respectively. The release rates and correlation
coefficient for the data for both nifedipine and glipizide were
3.13 mg/hr (0.99858) and 0.528 mg/hr (0.99882) respectively. Both
compounds exhibited constant first order release.
[0083] Although this invention has been described with reference to
specific embodiments thereof, it is understood that other
embodiments and variations of the invention as described and
exemplified may be made by those skilled in the art without
departing from the true spirit of the invention. It is intended
that the appended claims be construed to include all such
embodiments and variations.
* * * * *