Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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11692-2/A3
METHOD FOR DELIVERING AN ACTIVE INGREDIENT
BY CONTROLLED TIME RELEASE UTILIZING A NOVEL
DELIVERY VEHICLE WHICH CAM BE PREPA~ED BY A
PROCESS UTILIZING THE ACTIVE INGREDIENT AS A POROGEN
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the present invention relates
generally t,o deliyery vehicles used in a time relaase
method for delivering an active ingredient and process-
es for producing such vehicles.
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2. Description of the Prior Art
-
There are a wide variety of controllad re-
lease products presently being utilized in numerous
applications, including pharmaceutical, agricultural
and veterinary app~ications. Generally speaking, an
~20 active ingredient is released over time. The active
ingredient may be contained in a variety of media, such
as coated particles (e.g., sphere, aggregate, multiple
coating or pill), solid solutions te.g., beadlet, film,
bandage or cube), compositions (e.g., sphere, tablet,
pills or strip), containers (e.g., capsule, breakable
ampule or capillary), and combinations (e.g.,~ in a li~-
uid, in a~capsule or in a pill).
Microencapsulation is the most common process
for preparing a time release delivery vahicle. Gener-
alLy speaking, microencapsulation utilizes a coating tocontain the active ingredient which is then released by
rupture or dissolution of the coating. Alternatively,
the coa-ting or membrane may be semipermeable or porous
to allow the active ingredient to diffuse out of the
microencapsule.
Uni-ted States Patent No. 4,322,311 describes
an encapsulation technique for producing semi-permeable
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or controlled porosity microcapsules. An active ingre-
dient and a monomer in a first solution are emulsified
in a hydrophobic solvent. A monomer complementary to
the first monomer which is soluble in the hydrophobic
solvent is added to the emulsion to initiate interfacial
polymerization about the aqueous droplets. During the
course of reaction, the affinity of the continuous phase
for the first monomer is varied by adding a solvent to
the continuous phase to vary its polarity. This promotes
diffusion into the continuous phase resulting in a porous
membrane. Since the patent describes the use of an
amine monomer, some amine monomer may remain encapsulated
within the microcapsule.
Another encapsulation technique is described
15 in United States Patent No. 4,444,699 wherein minute
capsules are manufactured en masse. The process uti-
es polycondensation of melamine with formaldehyde or
~` in situ polymerization of methylol melamine or esterified
methylol melamine, or a low molecular weight polymer
thereof, in an aqueous vehicle and the reaction is con-
ducted in the presence of polyelectrolyte material and
- certain salts. However, this process will typically
leave some residue of formaldehyde which may pose a
health problem.
Other examples of encapsulation techniques
include, by way of example only, United States Patent
Numbers: 4,324,683; 4,353,809; 4,353,888; 4,353,962;
4,391,909; 4,396,670; 4,407,957; 4,439,488; and
4,464,271. The microcapsules produced by these type of
processes will typically possess limited mechanical
strength and will release all of the active ingredients
at once if the membrane is ruptured. The limited me-
chanical stability can create problems with incorporat-
ing the microcapsules into a medium and will also limit
the shelf life of these delivery vehicles. In addi-
tion, the microcapsules will typically contain reactive
groups which can crea-te problems of chemical stability.
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Another delivery vehicle for an active ingre-
dient is described in United States Patent No. 3,985,298
which utilizes a process to impregnate an active ingre-
dient into and within a cellulosic polymer-liquid com-
posite material as a par~ of or all of the liquid phase.The active ingredient is released from the gel matrix
which shrinks or collapses as the active ingredient is
removed. The gel structure is not mechanically strong
and therefore it suffers some of the mechanical problems
associated with microspheres.
Accordingly, there exists a need for an eco-
nomical time-release delivery vehicle with high mechan-
ical strength useful in a controlled-release applica-
tion.
SUMMARY OF THE INVENTION
The invention relates to a method for deliv-
ering an active ingredient by controlled time release.
In another aspect of the present invention, a composi-
tion of matter and a process for preparing the composi-
tion of matter useful in the method of the instant in-
vention are disclosed.
In the instant invention, a delivery vehicle
comprised of a polymeric bead having a network of pores
with the active ingredient held within the network is
utilized to provide a controlled time release of the
active ingredient. The active ingredien-t might be a
~ lubricant, an emollient, a moisturizer, a pigment, an
; insect or flea repellant, a fragrance, a vitamin, a
drug or any other functional ingredient. The delivery
vehicle may be incorporated in a medium, such as a gel,
a cream, a lotion, an ointment, a liquid or the like,
- which may then be applied to a surface. The active
ingredient may then be released by pressure, diffusion
or volatilization. Thus, the delivery vehicle is uniq-
uely suited for use ln a wide variety of applications
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in which it is desirable to release an active ingredient
by one or more methods.
A delivery vehicle according to the present
invention has increased mechanical stability over a
microencapsulated or gel delivery vehicle. The network
of pores of a bead according to the present invention
will not be subject to osmotic shock which might occur
in prior art delivery vehicles. In addition, the in-
creased mechanical stability allows a delivery vehicle
to be manufactured, processed and handled under more
severe conditions, such as mechanical stirring, which
might otherwise rupture or damage prior art gel or micro-
encapsulated delivery vehicles. Thus, a delivery vehi-
cle according to the present invention can easily be
incorporated in certain media in which it would prove
difficult or more expensive to incorporate delivery
~ ~ vehicles of the prior art.
-~ When a delivery vehicle according to the present
invention is polymerized from styrene and divinylbenzene,
the delivery vehicle will possess greater chemical sta-
bility over previous delivery vehicles because the sty-
rene divinylbenzene polymeric bead will not contain
reactive groups and will consist essentially of hydro-
carbon backbone with benzene rings. Because the styrene
divinylbenzene polymeric bead does not contain reactive
groups, the bead will not readily undergo unwanted re-
actions and the bead will be stable over a very wide pH
range, the bead will resist moderate oxidation and re-
duction, the bead will be stable to higher temperatures,
the bead will not be subject to attack by moisture, and
; the bead will have a longer shelf life. In addition,
in contrast to some prior art delivery vehicles, a sty-
rene divinylbenzene polymeric bead of the present inven-
tion does not contain any reactive groups or polymeric
structure which may cause a problem of toxicity, irri-
tation or the like when applied topographically to skin.
When a delivery vehicle is prepared in accor-
dance with the present invention, the active ingredient
12833SS
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is trapped in the network of pores during polymeriza-
tion of the bead. Thus, in contrast to a process which
might adsorb an active ingredient into a preformed ma-
trix, the active ingredient in a delivery vehicle of
the present invention should have a substantially uni-
form concentration throughout the network of pores.
This uniformity helps to create a more controlled time
release of the active ingredient from the network of
pores over a given period of time. Further, the deliv-
ery vehicle of the instant invention is capable of pro-
viding a sustained release over a period of time as
compared to a total release when the membrane of a micro-
encapsulated delivery vehicle is broken.
Another advantage of a delivery vehicle pre-
pared in accordance with the present invention is thesubstantial absence of unreacted monomer. Thus, in a
microencapsulation delivery vehicle it may be difficult
to remove unreacted monomer because it might become
encapsulated along with the actïve ingredient inside of
the membrane. This problem is especially acute in some
prior art delivery vehicles w~ich utili~e urea-formal-
dehyde microencapsules which can create potential health
problems.
Accordingly, it is a primary object of the
present invention to provide a delivery vehicle for
delivering an active ingredient by controlled time re-
lease over a period of time.
This and further objects and advantages of
the present invention will become apparent to one of
ordinary skill in the art in connection with the de-
tailed description of the preferred embodiments set
forth below.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is a photomicrograph of a plurality
of delivery vehicles produced according to the present
invention.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In accordance with the present invention, an
active ingredient is released from a network of pores
by controlled time relaase. The active ingredient can
5 be defined as a functional ingredient or an ingredient
which is released from the network of pores to perform
some function. Thus, for e~ampl~, when the active in-
gredient is a drug used in a dermatologic medication,
the active ingredient might comprise anti-infectives
10 (such as antibioticsj ungicides, sca~icides pediculi-
cides or miscellaneous anti-infectives such as iodine),
anti-inflammatory agents, antipruritics, astringents,
anti-hidrotics, keratoly-tic agents and caustics, kerato-
plastic agents, rubefacients-, sunscreens, pigmentation
- 15 agents, emollients, demukents, protectants and decergents.
- In ~ddition to use as a dermatologic medication, the
active .ingredient might be used in a variety of other
applica-tions such as beauty aids, including cosmetic
and toiletry applications, and the active ingredient
} 20 may be incorporated in a medium such as a gel~ a cream,
a lotion, an ointment, a liquld or the like. The de-
livery vehicle containing the active ingredient might
be incorporated into cosmetic preparations such as hand
-~ creams, acne products, deodorants~ antiperspirants,
25 baby powders, foot powders, lip ices, lip sticks, baby
creams and loti~ns, mouthwashes, dentifrices, medicated
facial creams and lotions, shampoos, shaving creams,
pre- and after-shave lotions, depilatories and hairgroom-
~ing preparations. The active ingredient may be comprised
30 of a carrier and an agent wherein the carrier is used
to deliver the agent and the agent is the functional
ingredient. Thus, for example, the agen-t might be a
solid suspended in an agent. Accordingly, the term
active ingredient is meant to encompass a whole host of
35 possible compositions or subs-tances so long as the ac-
tive ingredient is held within the network of pores of
a porous béad according to the present invention.
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A delivery vehicle according to the present
invention can be prepared by polymerizing one or more
polymers by a free radical suspension polymerization
process. A tnonomer or pair of comonomers i.s dissolved
in an inert porogen, which is also the active ingredi-
ent, to form a solution which is suspended in a phase
or solvent incompatible with the solution.
- An example of a phase or solvent might be
water with stabilizing additives. After the solution
is suspended in the phase, the solution and phase are
agitated to form a plurality of droplets of solution
suspended in the phase. After the formation of the
piurality of droplets, the monomer or monomers in the
plurality of droplets are activated to initiate a poly-
merization reaction in which a monomer is cross-linked
or two or more monomers are polymerized to form porous
' ~ beads having a network of pores with the porogen hald
within the network of pores. The activation may be
triggered by an initiator which is soluble in the mon-
- 20 omer solution. Alternatively, activation may be trig-
gered by an energy source such as radiation; The inert
~;~ ; porogen will serve as an internal diluent during poly-
mPrization to introduce the desired sponge-like macro-
porous struc~ure or network of pores into the finished
delivery vehicle. The inert porogen should not react
~ with the monomer present during polymerization or inhibit
'~ the polymerization. The bead of the delivery vehicle
may or may not swell in the inert porogen. After the
formation of the porous beads, the beads are separated
from the phase and subjected to one or more purification
steps, such as washing, to remove any unreacted monomer
or impurity from the beads. The purification of the
beads should not be designed to remove the porogen from
the network of pores in each of the beads. Af-ter puri-
fication, the beads may be dried to obtain a powder-like
substance comprised of the beads which have retained
the porogen within the network of pores to serve as an
333~i5
active ingredient when the beads are used as a time-
release delivery vehicle.
The process of the present invention can be
designed so as to control porosity and the particle
diameter of the beads which may be considered substan-
tially spherical. Under identical polymerization con-
ditions, the porosity can be increased by increasing
the calcula-ted or theoretical cross-linking density or
by increasing the porogen concentration in the solu-
tion. An increase in porosity will increase the sur-
~ace area of the bead and hence the weight percent of
the porogen which can be held within the bead. To de-
crease the particle diameter under identical polymer-
ization conditions, the agitation or the concentration
of dispersion agents in the phase should be increased.
By controlling the porosity and the particle diameter
of the bead, a delivery vehicle suitable for use in the
method of the present invention can be obtained. Gen-
erally speaking, it has been found that it is prefera-
ble for-the bead to have a diameter from about 10 mi-
~;; crons to about 100 microns, and have a calculated cross-
linking in excess of about 10%. The active ingredient
should comprise between approximately 5% to approximately
60% of the total weight of the composition or delivery
vehicle comprising the polymeric bead and the active
ingredient.
To distinguish whether a composition possess-
es sufficient mechanical strength to be used as a de-
; livery vehicle for providing controlled time-release of
the active ingredient, the composition can be subjected
to a wetting test. If the composition has a calculated
cross-linking density and an active ingredient concen-
tration such that substantially all of the active in-
gredient will be released from the network of pores
when the bead is placed in a solvent, in which the ac-
tive ingredient is soluble, for a sufficient length of
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time to wet the bead, then the composition can be uæed
in the method of the present invention.
A wetting test can be performed by weighlng a
; dry sample of material to be tested containing an orig-
inal amount of active ingredient. The dry sample is
then mixed with a solvent in which the active ingredi-
ent is soluble to form a wet sample. The wet sample is
then agitated for a sufficient length of time to wet
the bead if the dry sample is comprised of a delivery
IO vehicle according to the present invention. The amount
of act:ive ingredient released into the solvent is then
determined. The amount of active ingredient released
into the solvent will be substantially the same as the
original amount of active ingredient if the dry sample
consisted essentially of the delivery vehicle, whereas
the released amount will be substantially less than the
original amount if the dry sample contained a substan-
tial amount of gel product or a microencapsulated prod-
uct.
; ~0 The process of the present inven-tion can be
conducted without-using expensive and en~ironmentally
to~ic solvents sueh as chloroform or other chlorinated
solvents which are often used in in*erfacial polymer-
i~ation. Further, since it i5 desired to leave the
'; ~ 25 porogen held within the nekwork of pores, there is no
; ~ need for an additional washing step in which the porogen
~ ~ must be dissolved to be removed from the network of
:;
pores. Accordingly, the process of the present invention
can be very economical with a minimal exposure of pos-
sible environmental pollution when a suitable activatorand phase or solvent are selected.
To utilize a delivery vehicle ln accordance
with the method of the present invention, the delivery
~ vehicle is mixed with a medium to form a mixture which
; 35 is applied to a surface. The active ingredlent is then
released from the network of pores by a force or ener-
gy. The controlled time release might occur through
~3L2133~55
diffusion or volatilization, both of which are attrib--
utable to changes in kinetic energy. Alternatively,
the active ingredient may be released by a force such
as pressure. Pressure release may be gradual and con-
tinuous. Pressure release may also be triggered byintermittent pressure which may vary the concentration
of active ingredient released from the network of pores.
A delivery vehicle of the present invention
is mechanically strong because of the polymeric struc-
ture of the bead and the degree of cross-linking or
copolymerization. It is believed that the ~ead can be
`~ conceptualized as a rigid sponge, i.e., a structural
network formed by three dimensional cross-linking or
copolymerization which leaves random spaces or holes
which collectively form the network of pores. The pol-
~ ymer structure or bead physically holds the active in-
- gredient in the network of pores because the active
; ingredient diffuses into the polymeric structural net-
work being formed during polymerization of the bead,
and is then held or trapped unti~ an external force or
energy releases the porogen from the netwo~k of pores
in the polymerized bead. However, unlike a gel in which
; the polymeric structural network collapses when the
material held within said network is removed or released,
~ 25 a delivery vehicle according to the present invention
- ~ must possess a certain minimum degree of calculated
cross-linking density for a given active ingredient
concentration so as to give the entire structure or
bead sufficient strength to prevent substantial shrink-
ing or collapse of the bead when porogen is removed
from the network of pores.
The invention will be further illus-trated in
the example that follows wherein the delivery vehicle
is copolymerized from styrene and divinylbenzene which
is an especially preferred comonomer pair because of
the chemical stability of styrene divinylbenzene. As
would be apparent to one skilled in th- art, the term
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"divinylbenzene" as used in this description, as well
as in the appended claims, is meant to include pure
divinylbenzene as well as commercial divinylbenzene
which is really a mixture of divinylbenzene and ethyl-
vinylbenzene. Other preferred comonomer pairs are vinylstearate and divinylbenzene, and methylmethacrylate and
ethylene gl~col dimethylmethacrylate. In the following
example the active ingredient and porogen is mineral
oil which is an especially preferred wetting agent in
many beauty aids. Other similar wetting agents might
include vegetable oils or sunflower oil.
EXAMPLE 1
A 2,000 ml four - necked reaction flask equip-
ped with a stirrer, condenser, thermometer, and nitrogen
inlet was evacuated and charged with nitrogen. 900 ml
deionized water, 7.2 grams of gum arabic and 7.2 grams
of a lignosulfonate available from the American Can Co.
under the trademark Marasperse N-22, were charged into
the reaction flask. The mixture was stirred and heated
in an oil bath at about 60 C until the dispersants
dissolved to form a phase. To this mixture was added a
freshly prepared solution of 90.8 grams of styrene (99.8%
purity), 45.2 grams commercial divinylbenzene (S5.6%
divinylbenzene, 42.3% ethylvinylbenzene), 2.5 grams
benzoyl peroxide (70% active ingredient and 30% water),
and 1~6.0 grams of mineral oil. The initiator benzoyl
peroxide was dissolved in monomer before mineral oil is
added because mineral oil does not readily dissolve
benzoyl peroxide unless benzoyl peroxide is dissolved
in a monomer. The phase and solution were agitated by
a mechanical stirrer whose stirring rate was adjusted
; to obtain a plurality of droplets having a droplet di-
ameter in the range of 5 to 80 microns. The gum arabic
and lignosulfonate serve to stabilize the plurality of
droplets. The reacti.on mixture was then heated to about
95 C and maintained at that temperature for about 18
to 20 hours at the adjusted stirring rate to form porous
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beads of styrene divinylbenzene having a network of
pores with mineral oil held within the network of pores.
The mixture was then cooled, the porous polymeric beads
were removed from the reaction flask by filtration,
washed initially three times with one liter of water to
- remove gum arabic and lignosulfonate, followed by three
washes of 1 liter of methanol to remove residual or
unreacted monomer. The purified product was then dried
to remove methanol and the resulting polymeric delivery
vehicles ~"ere white and opa~ue indicating their macro-
porosity.
The calculated or theoretical cross-linking
density of the purified beads is 18.5%. This density
is calculated by mutliplying the weight of divinylben-
~5 zene (45.2 g) by the purity of the divinylbenzene (.556)to get the actual weight of pure divinylbenzene which
is then divided by the totaL weight of monomer (45.2 g
go.8 ~)-
The surface area of a sample of the purified
- 20 beads w~s d~termined by t~e B.E.T. mPthod to be 7.25
meters2/gram while the pore volume was determined by
nitrogen adsorption isotherm to be 0.1028 ml./gram.
The B.E.T. method is described in detail in Brunauer,
S. Emme~, P.~., and Teller, E., J.Am.Chem.Soc., 60,
309-16 ~1938~. The nitrogen adsorption isotherm method
is described in detail in Barrett, E.P., Joyner, L.G.
and Helenda, P.P., J.Am.Chem.Soc., 73, 373-80 (1951).
The sample used in these methods was prepared by dis-
solving the mineral oil in ethylacetate to~remove the
mineral oil from the network of pores.
A sample of the purified delivery vehicles
was also subjected to a ~etting test. 2.0 grams of the
purified beads was accurately weighted and then placed
into a 250 ml. glass stoppered flask. 100.0 ml. of
hexane was added to the flask by a pipet. A stopper
was then placed in the flask which was clamped to a
Burrel brand mechanical shaker set at its highest speed
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(10) for 5 ~ 1 minutes. The liquid was immediately
filtered through Whatman paper #54. A 20 ml. sample
was removed by pipet and placed into a tared glass con~
tainer which was placed on a steam bath or under a heat
lamp until the hexane was evaporated. The container
was then placed in an oven maintained at a temperature
of 105 C for 30 minutes. The container was then cooled
and weighed. The percentage of free oil was calculated
as follows:
% F~ee Oil ~ wt. of residue x 100 x 5
wt. of sample
The % free oil was 50% of the total weight of the sam-
ple. Since the sample or delivery vehicle was comprised
of approximately 50% by weight bead and approximately
15- 50% by weight mineral oil, substantially all of the
active ingredient was released from the network of pores
- of the beads into the solvent.
The particle size of the beads was determined
by an optical microscope to be 40 microns or less with
an average particle size diameter within the range from
about 10 microns to about 30 microns.
- Another dry sampIe of the purified delivery
vehicles was placed into a capped glass bottle and stored
in a shelf wi-th a glass door for approximately one year.
The bottle was air tight. Ater approximately one year
the bottle was opened and no change in visual charac-
teristics of the sample was observed. A wetting test
was performed on a sample obtained from the bottle.
The picture was-ta~en on an electron microscope with a
magnification of 6000~. The picture is rPproduced in
Figure 1.
EXAMPLES II-IV
These examples were carried out under idanti-
cal reaction conditions as those of Example I except
for the weight of the monomers and mineral oil utilized
in the reaction. These values are set forth in Table
I.
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TABLE I
ExampleStyrene DVB Mineral Oil
II 41.0 9.0 55.0
III 61.4 73.6 146.0
IV 13.6 36.4 55.0
Samples obtained from Examples II-IV had an average
particle size diameter within the range of from about
10 microns to about 50 microns. Samples from these
Examples were subjected to the wetting test described
in Example 1 and substantially all of the mineral oil
was released from the network of pores of the beads of
each of the Examples. The calculated cross-linking
density, surface area and pore volume of each of Exam-
ples II through IV were obtained according to the pro-
cedures described in Example I and the data is set forth
in Table II.
TABLE II
Cross-linking,
ExampleD.V B. Surface Area Pore Volume
% M2/gram ml/g
II 10.0 3.65 0.6130
III 30.0 14.97 0.1010
~ ~ IV 40.0 ~49.0 0.7585
c~ EXAMPLE V
30~ Once again, this example was carried out un-
der identical reaction conditions as those of Example I
except for the weight of the monomers and mineral oil
utilized in the reaction. The example used 42.7 grams
of styrene, 7.3 grams of divinylbenzene (DVB) and 55.0
grams of mineral oil. The theoretical cross-linking
density was 8.0 and the surface area was 1.93 me-
ters2/gram while the pore volume was 0.0284 ml/gram.
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The average particle size diameter was within the range
of from about 10 microns to about 50 microns. However,
when a sample of the composition was subjected to the
wetting test described in Example I, the percentage of
free oil was found to be 10~ indicating that the compo-
sition is a gel bead which is not macroporous and would
not be acceptable for use in the method of controlled
time-release o~ the instant invention.
Having fully described the present invention,
; 10 it will be apparent from the above description and draw-
ing that various modifications in the specific composi-
tions, procedures, methods and processes may be made
within the scope of the invention. Therefore, the inven-
tion is not intended to be limited to the particular
compositions, processes or methods except as may be
re~uired by the lawful scope of the!following claims.
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