U.S. patent number 3,909,444 [Application Number 05/169,230] was granted by the patent office on 1975-09-30 for microcapsule.
This patent grant is currently assigned to NCR Corporation. Invention is credited to Jerrold L. Anderson, Thomas C. Powell.
United States Patent |
3,909,444 |
Anderson , et al. |
September 30, 1975 |
**Please see images for:
( Certificate of Correction ) ** |
Microcapsule
Abstract
An enterically active, controlled release microcapsule is
disclosed which includes: (a) an internal phase or capsule core of
a continuous matrix of water-soluble polymeric material having
finely-divided particles of an active contained material and
finely-divided particles of an enteric contained material mixed
throughout; and (b) a seamless external coating of capsule wall of
a water-insoluble polymeric material which prevents disintegration
of the internal phase in aqueous liquids but which is permeable to
aqueous solutions.
Inventors: |
Anderson; Jerrold L. (Dayton,
OH), Powell; Thomas C. (West Alexandria, OH) |
Assignee: |
NCR Corporation (Dayton,
OH)
|
Family
ID: |
22614736 |
Appl.
No.: |
05/169,230 |
Filed: |
August 5, 1971 |
Current U.S.
Class: |
428/402.24;
252/184; 424/486; 424/494; 427/212; 427/213.36; 428/403; 428/407;
502/159; 8/526; 424/485; 424/488; 424/497; 427/213.35; 427/222;
436/829 |
Current CPC
Class: |
A61K
9/1652 (20130101); B01J 13/02 (20130101); A61K
9/5047 (20130101); Y10S 436/829 (20130101); Y10T
428/2991 (20150115); Y10T 428/2989 (20150115); Y10T
428/2998 (20150115) |
Current International
Class: |
A61K
9/16 (20060101); A61K 9/50 (20060101); B01J
13/02 (20060101); B01J 013/02 () |
Field of
Search: |
;252/316 ;117/1A
;424/22,35 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Lovering; Richard D.
Attorney, Agent or Firm: Shafer; Robert J. McKinney; E.
Frank
Claims
What is claimed is:
1. A microcapsule consisting of an internal phase and a water
soluble capsule wall permeable to aqueous solutions wherein the
internal phase comprises an individual particle of a continuous
matrix of water-soluble material and, distributed substantially
evenly throughout the continuous matrix, a plurality of
finely-divided particles of an active material and a plurality of
finely-divided particles of enteric material and wherein the water
insoluble capsule wall permeable to aqueous solutions comprises a
thin coating of water-insoluble polymeric material substantially
evenly covering the particle of continuous matrix material
preventing disintegration of the internal phase.
2. A minute, enterically active, microcapsule having a capsule wall
permeable to aqueous solutions and consisting essentially of
hydrophobic polymeric film-forming material insoluble in aqueous
systems and a solid core of finely-divided water-soluble active
material and finely-divided enteric material intimately combined
with a matrix of water-soluble binder material wherein the enteric
material is relatively insoluble in acidic aqueous systems and is
relatively more soluble in aqueous systems of decreased acidity and
wherein the capsule wall prevents disintegration of the solid
core.
3. The capsule of claim 2 wherein the hydrophobic polymeric
film-forming capsule wall material is ethyl cellulose.
4. The capsule of claim 3 wherein the enteric material is cellulose
acetate hydrogen phthalate.
5. A capsule consisting of:
a. a substantially water insoluble capsule wall permeable to
aqueous solutions and
b. an internal phase comprising
i. a water-soluble, continuous, matrix binding
ii. a multitude of particles of finely-divided active material
and
iii. a multitude of particles of finely-divided enteric
material
wherein the enteric material and the active material are
substantially homogeneously dispersed in and bound by the matrix
and the capsule wall prevents disintegration of the internal
phase.
6. The capsule of claim 5 wherein the capsule wall consists
essentially of a film of water insoluble, hydrophobic, polymeric
material permeable to aqueous solutions and encasing the internal
phase in conformance with the internal phase shape and preventing
disintegration of the internal phase.
7. The capsule of claim 6 wherein the particle of active material
are water soluble and of a size substantially the same as the
particles of enteric material.
8. The capsule of claim 6 wherein the internal phase is
substantially spherical and of a size more than about 100 microns
and less than about 1000 microns.
9. The capsule of claim 8 wherein the internal phase constitutes 85
to 98 percent, by weight, of the capsule;--the remainder being
capsule wall material.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an enterically active microcapsule which
provides controlled release of a contained material in aqueous
environments. It more particulary pertains to a microcapsule which
exhibits rapid but controlled release of contained material in
alkaline aqueous environments and which exhibits relatively slow
release of contained material in acid aqueous environments. The
slow release in acid environments is release as it would be
expected from a microcapsule having a low internal phase content,
but without enteric activity.
The microcapsule of this invention consists of an internal phase
and a capsule wall encasing the internal phase;--the internal phase
being a substantially homogeneous combination of water-soluble
polymeric matrix material with finely-divided particles of an
active material and of an enteric material mixed therethroughout.
The enteric material is selected to be relatively insoluble in
aqueous acid and relatively soluble in aqueous base. The capsule
wall material is selected to be substantially insoluble in, but
permeable to, all aqueous solutions thereby preventing
disintegration of the internal phase in aqueous solutions. The
matrix material, the enteric material and the capsule wall material
operate in combination to produce the unexpected effect of
providing rapid but sustained release of the active material in
alkaline environments and of providing relatively slow release of
the active material in acid environments. The microcapsule of this
invention finds particular utility in the pharmaceutical and
medical fields where it may be desired or required that an active,
capsule-contained, medicament material pass through the
acid-condition of the stomach with a relatively low, but definite,
amount of solution to then be released, relatively rapidly, but in
a sustained manner, in the relatively basic environment of the
intestinal tract. The rate controlling factor for release of active
material in acid environments is the barrier of enteric particles
coupled with diffusion of dissolved material through the capsule
walls and the rate controlling factor for release of active
material in alkaline environments is diffusion through the capsule
walls. The microcapsule of this invention finds utility in fields
other than the pharmaceutical and medical fields and the term
"enteric" is used simply as a matter of convenience. For purposes
of this invention, the meaning of the word "enteric" is expanded to
include progressively increased solubility with decreased acidity
in aqueous environments, whether in a gastrointestinal tract or
not. Also, for purposes of this invention, the "active"
capsule-contained material is the material to be released from the
capsule. The "active" material is the material of the internal
phase excluding the matrix material and the enteric material.
2. Description of the Prior Art
In the past, several schemes have been developed for providing
small particles of material with some degree of enteric activity or
prolonged period of solution.
Examples representative of the prior art include: U.S. Pat. No.
2,553,544 issued May 22, 1951 on the application of Herman H. Bogin
which discloses granular particles of a continuous, single-phase,
matrix of gelatin, a plasticizer, and an enterically active
material. The matrix is disclosed to contain, distributed
therethroughout, droplets of a liquid vitamin compound. The
granules disclosed by Bogin comprise a relatively homogeneous
mixture of an enterically active, continuous, matrix with vitamins
dispersed therein and with no covering film to form capsules. The
granular particles disclosed by Bogin disintegrate and release
their vitamin contents very rapidly in an aqueous system of
alkaline pH. The particles disclosed by Bogin contain 30 to 40
percent, by weight, vitamin material;
U.S. Pat. No. 2,656,298 issued Oct. 20, 1953 on the application of
Leo Loewe which discloses an enterically active medicament
composition for oral administration which can include solid
particles of a medicament dispersed in a continuous matrix of
formalized protein. The continuous matrix is coated, externally, by
enteric anion exchange resin. In all embodiments, the anion
exchange resin is disclosed to be utilized as an enclosing material
for the medicament to be protected;
U.S. Pat. No. 2,809,916 issued Oct. 15, 1957 on the application of
Victor M. Hermelin which simply discloses a sustained release
medicament composition comprising granules of intermixed binder and
medicament. The binder can be enteric in nature and the process for
producing the product is repeated granulation and;
U.S. Pat. No. 3,115,441 issued Dec. 24, 1963 on the application of
Victor M. Hermelin discloses a tabletted composition comprising
particles of medicament covered by several individual layers of
enteric coating material and included in a matrix of medicament and
filler. Enteric activity is provided only at the surface of
individual particles.
The present invention represents a substantial improvement over the
prior art and provides a microcapsule construction with a
combination of material properties not before recognized or
utilized. The active contained material is included in a continuous
matrix of water-soluble polymeric material and the matrix is
encapsulated by a water-insoluble polymeric film permeable to
aqueous solution. The matrix also includes particles of an enteric
material. Release of the active material is accomplished by
solution and diffusion through the capsule wall and, very
importantly, to the extent that the undissolved enteric material
blocks solution or diffusion, release of the active material is
slowed.
SUMMARY OF THE INVENTION
At times, a method is desired or required for releasing a material
into a liquid system in a controlled manner wherein the liquid
system has certain predetermined characteristics. As an example, in
the administration of medicines, it is sometimes advantageous to
provide a medicament in a special form such that the medicament
will be passed through the patient's stomach with only a slight
dosage there and then pass on into the intestine where the
remainder is released in a relatively rapid but prolonged manner.
This form of administration is especially advantageous when the
medicament is in danger of being hydrolyzed or otherwise destroyed
in an acid environment such as is usually found in a patient's
stomach or, when release of a large amount of the medicament into a
patient's stomach would cause unnecessary discomfort or
irritation.
As further examples of the utility of selectively releasing active,
capsule-contained materials, the rapid release of an encapsulated
catalyst or reagent in a chemical reaction only during times when
conditions in the system are correct for conducting the reaction
may be mentioned, as can the release of an additive, such as a dye,
to indicate change of conditions or presence of a new condition in
a system.
It is an object of this invention to provide a microcapsule which
is partially enterically active to exhibit slow release of
contained material in acid aqueous conditions, as though the
material to be released were in a non-enteric binder, and to
exhibit relatively more rapid, controlled, released in alkaline
aqueous conditions.
It is a further object of this invention to provide a microcapsule
having a construction comprising a capsule internal phase of a
water-soluble, polymeric, matrix binder containing a multitude of
particles of enteric material and a multitude of particles of
active material enclosed by a capsule wall of water-insoluble but
permeable polymeric material.
It is a further object of this invention to provide the above
microcapsule wherein the insoluble but permeable polymeric material
prevents disintegration of the microcapsule in aqueous solution and
wherein the finely-divided active material is included in a matrix
of water-soluble polymeric material along with finely-divided
enteric material, which enteric material serves, in aqueous acid
environment, as a partial barrier to solution and consequent
diffusion of the active material.
The inventors have not discovered and herein disclose and claim a
microcapsule to accomplish the above objects and other objects as
will be made apparent to those skilled in the art.
The novel microcapsule has a capsule wall and contains an internal
phase. The internal phase includes finely-divided particles of
active material, finely-divided particles of enteric material and a
continuous matrix of water-soluble polymeric material which also
serves as a binder for the particles. "Enteric material", as is
referred to throughout this patent, means material which is
relatively water insoluble in acidic conditions and is relatively
water soluble in basic conditions. The capsule wall material is a
water-insoluble polymer and provides a film barrier which prevents
disintegration of the internal phase on immersion of the capsules
in water. Additionally, the capsule wall material permits release
of water-dissolved capsule contents by transfer through the capsule
wall film. All release of active material from the capsule of this
invention occurs by transfer of a solution of the material through
the capsule wall. Each entity of capsule internal phase includes a
multitude of finely-divided particles of active material and a
multitude of finely-divided particles of enteric material; -- all
of the particles being bound together by the matrix of
water-soluble polymeric material. The rate of release of the active
material is controlled by the rate at which the active material is
made available at the capsule wall and by the rate of transfer
therethrough. An important feature of the present invention and
what is considered to be patentable herein, is the capsule as
above-described having four essential elements and providing a
release rate which is slow and controlled by a barrier of insoluble
enteric particles at an acid pH and is more rapid and controlled by
transfer rate through the capsule wall material at an alkaline pH.
The four essential elements are particles of active material and
particles of enteric material bound together as granules by
water-soluble matrix material; -- the granules being encapsulated
by a water-insoluble but permeable film of polymeric material. The
novel capsule is individual and discrete alone or among others of
its kind and is minute in size; --individual capsules having a size
range of from 200 microns to 1000 microns or perhaps slightly
larger.
Enteric materials eligible for use in this invention as a contained
material include any material soluble at certain selected
environmental conditions and insoluble at others. The microcapsules
of this invention are normally used in aqueous systems and the
enteric materials are selected to be soluble in water at alkaline
pH and insoluble in water at acid pH. Examples of such materials
include partial esters and half-esters of maleic anhydride
copolymers such as poly(methylvinylether-co-maleic anhydride) and
poly(ethylene-comaleic anhydride) and specifically include methyl,
ethyl, n-butyl, isobutyl, and 2-ethylhexyl half and partial esters
of maleic anhydride copolymers. Further examples of such materials
include polycarboxylic acid partial esters of cellulose esters of
lower aliphatic monocarboxylic acids including esters derived from
combination of an aromatic polycarboxylic acid such as phthalic
acid and an aliphatic acid such as acetic, propionic, butyric, and
the like, acids. Preferred ones of those mentioned above are
partial esters and half-esters of cellulose acetate phthalate,
cellulose propionate phthalate, and cellulose butyrate phthalate.
The above materials derive their enteric properties from being
partial esters, that is, from having free carboxyl groups in some
positions on the molecules. Although it is not required that each
repeating unit of the enteric material molecule contain a free
carboxyl group, the material as a whole should contain from about 5
to about 25 percent, by weight, free carboxyl groups. A free
carboxyl group content from about 8 to about 15 percent, by weight,
has been found to be most preferable for use in practicing this
invention. It must be remembered, of course, that the enteric
activity of the above materials is controlled by, among other
things, the free carboxyl content; and that if desired or required
for a particular use or effect, enteric materials can be used which
have carboxyl contents outside the abovementioned ranges. Other
materials eligible for use as the enteric material of this
invention include: shellac, derivatives of shellac; certain fats,
fatty acids, and waxes; esters of starch, methylcellulose,
ethylcellulose, and ethyl(hydroxyethyl) cellulose; phthalates of
sugars such as glucose, sucrose, sorbitol and dextrin; zein; and
like materials.
Water-soluble polymeric matrix materials (also referred to, herein,
as binder materials) eligible for use in this invention include:
methyl cellulose; ethyl(hydroxyethyl) cellulose; poly(vinyl
alcohol); gum arabic; gelatin, especially of low Bloom strength;
poly(vinylpyrrolidone); completely hydrolyzed esters of maleic
anhydride copolymers such as poly(methylvinylether-co-maleic
anhydride) and poly(ethylene-co-maleic anhydride), and the like.
Although not specifically polymeric, sugars and similar organic
materials such as glucose, sucrose, sorbitol, and dextran are
eligible for use. In short, any water-soluble polymeric, or
equivalent, material is eligible for use as the matrix material of
the present invention.
Polymeric materials eligible for use in this invention as capsule
wall material include any material which is both substantially
insoluble in the environmental conditions for use of the novel
capsules and permeable to aqueous solutions of the materials to be
contained within the capsule walls. The microcapsules of this
invention are normally used in aqueous systems and the capsule wall
material is, therefore, selected to be substantially insoluble in
water. The selected capsule wall material, when used in a thin film
such as found as capsule walls, must be permeable to aqueous
solutions of the capsule-contained material. Examples of such
eligible capsule wall materials include polymeric materials such
as: poly(acrylics); --poly(methacrylates), poly(acrylates), and the
like; celluloses; --cellulose acetate propionate, cellulose acetate
butyrate, ethylcellulose, cellulose acetate, cellulose nitrate, and
the like; poly(vinyls); --poly(vinyl acetate), poly(vinyl
butyrate), poly(vinylidene chloride) and the like; poly(olefins);
--polyethylene, polypropylene, and the like, including materials
having the various forms of stero-regularity; poly(halocarbons);
--poly(tetrafluoroethylene), poly(trifluorochloroethylene),
fluorinated poly(ethylene), fluorinated poly(propylene), and the
like; poly(styrenes) and copolymers of poly(styrenes) with other
materials such as acrylonitrile or butadiene; poly(amides);
poly(esters); poly(epoxides); and silicone resins. Preferred
capsule wall materials are the cellulosic materials disclosed above
and, in the present practice, most preferred of those is
ethylcellulose.
Active material eligible to be contained by the microcapsule of
this invention includes any material which can be included as a
dispersion of fine particles in the matrix binder material without
dissolving therein or reacting therewith. As has been previously
disclosed, the capsule of this invention finds its normal utility
in controlled release of the contained material in an aqueous
environment. The preferred form of the invention is directed toward
capsules containing water soluble materials which water soluble
materials can be released by permeation of aqueous solution through
the capsule wall material. A most preferred form of the invention
is directed toward containing water soluble medicaments.
Any acid-sensitive medicament substance, as a class, is eligible
for use, such as, for example: penicillin salts, aureomycin,
chloromycetin, streptomycin, bacitracin, subtilin, polymyxin,
dihydrostreptomycin; and other acid-sensitive materials such as
acetylsalicyclic insulin, adrenalin, heparin and the like. Other
eligible materials include acetylsalicyclic acid, digitoxin,
pyralimine, caffeine, phenobarbital, stilbesterol, methyl
testosterone, scopolamine methylbromide, pentaerythritol
tetranitrate, hexamethonium chloride, N-acetyl-p-aminophenol, and
veratrum viride, d-amphetamine sulfate, pentobarbituric acid,
mephobarbital, mannitol hexanitrate, pyralimine maleate, and the
like. Of course, other materials physiologically active or not,
acid sensitive or not, may be employed in the present invention as
desired or required to a particular use. Such a use may be in
controlled provision of a catalyst or coreactant in certain pH
environments or in controlled release of a dye or indicator
material under certain conditions,
The method for manufacturing microcapsules of this invention is not
important and forms no part of the invention. Particles of internal
phase can be manufactured, for example, by granulating a paste of
the matrix binder material mixed with finely-divided particles of
the material to be contained and finely-divided particles of the
enteric material. The paste if kneaded or otherwise mixed until
homogeneous and then granules of the desired size are made and
dried. Liquid to make the paste can be a solvent which dissolves
the matrix material but does not dissolve the active material or
the enteric material or it can be a solvent which dissolves the
matrix material and the active material to the saturation of the
active material.
The granules or particles, when manufactured, by whatever method,
are coated by the polymeric film of capsule wall material. Any of
several known methods can be used to apply the capsule wall
material. Well-known examples of eligible capsule wall coating
methods include: pan-coating, wherein a solution of the capsule
wall material is sprayed onto internal phase particles which are
tumbling in a rotating bowl; impingement coating, wherein the
internal phase particles are impinged onto and cast through a
liquid film of the capsule wall material and thereby become coated
with the material; and encapsulation by liquid-liquid phase
separation of the capsule wall material wherein the internal phase
particles are distributed in a two-phase liquid capsule
manufacturing system consisting of a phase of continuous suspending
liquid and a phase of dispersed liquid droplets of the capsule wall
material which droplets coat the internal phase particles to yield
capsules. The phase separation method for coating the intended
phase particles is preferred and will be used herein to teach
practice of the invention.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 depicts a microcapsule of this invention in partial
cross-section. The figure is a schematic representation and no
attempt has been made to show relative dimensions or actual shapes
of any components. A microcapsule of this invention may be more or
less spherical than the representation of the figure.
FIG. 2 depicts a release comparison between active materials
contained in capsules of this invention and active materials
contained by prior art means.
Returning to FIG. 1, the novel capsule 10 comprises a homogeneous
combination of active material 11 (hatching upward to the left),
enteric material 14 (hatching upward to the right) and matrix
binder material 13, all encased in a polymeric capsule wall 12. The
particle sizes of the active material 11 and the enteric material
14 can be larger or smaller, in relation to the capsule size as a
whole, than the particle size in the figure; and the concentration
of active material 11 and enteric material 14 in the matrix binder
material 13 can be greater or less. The ratio of active material 11
to enteric material 14 can be adjusted to any desired or required
relation depending on the result to be achieved. Particle size for
the active and enteric contained materials is usually less than 250
microns; a preferred size range being from a few microns to 150
microns. The contained materials are normally from about 85 to
about 98 percent, by weight, of the internal phase; --about 90 to
about 95 percent being preferred. The active material normally
constitutes about 20 to 80 percent of the contained
materials--about 50 percent being preferred. The polymeric capsule
wall 12 is a seamless film substantially conforming to the shape of
the internal phase particle. The thickness of the polymeric capsule
wall 12 can be varied over a considerable range. The thickness may
even change as the capsule is produced or used by virtue of the
capsule wall material either absorbing or losing liquid. As used
herein the words "internal phase" mean all material enclosed by a
capsule wall and the words "contained material" mean the active and
enteric material granulated into the matrix binder to yield
internal phase.
The graph of FIG. 2 is a schematic representation of the release of
contained material in an aqueous environment. The ordinate
represents percent, by weight, (on a logarithmic scale) of
contained material remaining in a composition being tested. The
abscissa represents passage of time and a secondary ordinate,
designated as i, represents a time when the pH of the aqueous
environment is changed from 1.2 to 7.5 as is customary in some in
vitro laboratory tests. Curves A and B depict the release expected
for unencapsulated granules of active material in a non-enteric,
insoluble, binder material and in an enteric, insoluble, binder
material, respectively. It should be noted that curves A and B are
located in the pH 1.2 region of the graph and that, in that region,
the preferred enteric materials exhibit solubility characteristics
substantially identical with non-enteric materials.
Curve B' depicts the release for granules with enteric binder in pH
7.5 aqueous medium. Time begins at the i axis for the curves A' and
B'. What is intended to be represented by curve B' is the slightly
greater rate of release for granules having enteric binder when
placed in alkaline media as compared to release in acid media.
Curve A' depicts a release relatively slower than that of curve B'
and represents the release to be expected from granules having
non-enteric binder material immersed in an alkaline medium. The
release depicted by curve A and curve A' is substantially equal.
Note that release from granules is quite rapid.
Curve C depicts the release expected for encapsulated granules of
active material in a non-enteric, water insoluble, binder material
with no enteric material added. It should be noted that the rate of
release is substantially independent of pH and that the rate of
release is substantialy slower than the unencapsulated granules of
Curves A and B. The slope of curve C can vary considerably
depending upon the type of non-enteric matrix, whether water
soluble or not, the concentration of active contained material, and
the like. Curve C evidences the fact that an insoluble capsule wall
provided prolonged release of contained materials by virtue of the
need for contained materials to be permeated through the capsule
walls as liquid solution.
Curve D depicts the release expected for the capsule of this
invention. It should be noted that a "knee" occurs in the release
curve at the time of pH change;--the release rate in the alkaline
medium being much greater than the release rate in the acid medium.
Additionally, it is noted that release from the capsule of this
invention is slower than release from the granules by reason of the
rate controlling feature of transfer through the capsule wall
material.
DESCRIPTION OF PREFERRED EMBODIMENT
An example of this invention, to be complete, will describe both,
preparation of particles containing matrix, enteric material and
active material and encapsulation of the particles in a water
insoluble polymer wall. The processes utilized in this example are
to be considered as representative and not as limiting the
invention, which invention resides in the final product and can be
manufactured by any of many processes including those disclosed
hereinabove.
In this example, gum arabic is used for the water soluble matrix
binder material; cellulose acetate hydrogen phthalate (CAP) is the
enteric material; and N-acetyl-p-aminophenol (APAP) is the active
material. Two hundred grams of dry CAP, powdered to an average
particle size of less than about 50 microns, is combined with 200
grams of dry APAP having a similar average particle size. The
powders are blended dry to achieve a substantially homogeneous
mixture and then a 10 percent, by weight, aqueous solution of the
binder is added in small incremental portions and under continued
blending force. The binder solution is added until a pasty,
granulable, mass is achieved; --about 400 grams usually sufficing.
The mass is granulated by being force through a coarse (10 mesh)
screen or by using a wet granulator which yields particles of about
1500 to 2500 microns in average diameter. The particles are dried,
the dried particles are forced through a screen having openings of
about 1200 microns, and the material retained on a screen having
openings of about 500-600 microns is collected for use. The "fines"
can be recycled through the granulating process to forestall waste
of the materials. Internal phase particles could be used in the
size range of from about 100 to more than about 1000 microns in
average diameter.
The hydrophobic polymeric capsule wall material of this example is
ethylcellulose. To accomplish encapsulation, 350 grams of
cyclohexane, 105 grams of the granulated particles, 7 grams of
ethylcellulose (as below specified) and 7 grams of polyethylene (as
below specified) are added to a vessel equipped for heating and
agitation. The ethylcellulose has an ethoxyl content of 48.0-49.5
percent and exhibits a viscosity of about 90-105 centipoises when
tested at 20.degree. centigrade as a 5 percent, by weight, solution
in a 4/1, toluene/ethanol solvent. (An example of such material is
sold by The Dow Chemical Co., Midland, Michigan as a commercially
available, standard material, carrying the designation Grade 100.)
The polyethylene of this example serves as a
phase-separation-inducing polymer, has a molecular weight of about
7000 and a ring and ball softening point of about 100.degree.
centigrade determined according to Specification D-36-26 of the
American Society for Testing Materials, (An example of such
material is sold under the trademark, Epolene C-10, by Eastman
Chemical Products, Inc., New York, N. Y.)
Agitation is commenced to disperse all of the solid materials.
Agitation is continued while the system is heated to about
80.degree. centigrade and then slowly cooled to about 25.degree.
centigrade. During the course of heating and cooling, capsules are
formed wherein droplets of a liquid, separated phase, concentrated
in ethylcellulose, wraps, as capsule wall material, about
individual particles of the granulated material at the high
temperature and wherein the liquid wall material solidifes as the
temperature is lowered. The capsules are separated from the
cyclohexane capsule manufacturing vehicle by filtration, are washed
by two portions of cyclohexane, and the residual cyclohexane is
removed by evaporation.
As a test of capsules made in the example above, release of active
material was measured in aqueous media of acid, basic, and varied
pH. In an aqueous solution, buffered at pH 1.2, release of the
active material was as follows:
Time (hours) Cumulative Release (percent)
______________________________________ 0.5 24 1.0 45 2.0 70 3.5 88
______________________________________
At the low pH, the enteric material is insoluble and acts as a
barrier to the release of active material, Thus, at low pH, release
of the active material is slowed by the combination of hydrophobic
capsule wall material and by the interference caused by insoluble
particles of the enteric material.
Release in aqueous solution buffered at pH 7.5 was as follows:
Time (hours) Cumulative Release (percent)
______________________________________ 0.5 52 1.0 83 2.0 99
______________________________________
The release is rapid due to solubility of the enteric material;
--the active material being slowed only by solution transfer
through the capsule wall.
Release was as follows in an aqueous solution wherein the pH was
increased as the test progressed:
Time (hours) pH Cumulative Release (percent)
______________________________________ 0.5 1.2 21.5 1.0 1.7 39.8
1.5 5.7 64.4 2.0 6.0 80.7 2.5 7.0 93.0 3.0 7.5 100.0
______________________________________
The release is slow in the early portion of the test at low pH;
--the enteric material serving to block release of the active
material. As the pH is increased, the release is more rapid; --the
active material being held only by the capsule wall.
These tests represent a significant exhibition of the invention
described and claimed herein in that there is actual demonstration
of the effect of the combination of hydrophobic capsule wall
material and particulate enteric barrier material in release of
active encapsulated material at a variety of pH levels.
The use of particulate enteric material in a water soluble binder
is important to permit at least a partial release in acid aqueous
environments. The hydrophobic polymeric capsule wall material is
important to provide sustained release by diffusion and to prevent
disintegration of the granules which would render release
instantaneous.
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