U.S. patent application number 09/426140 was filed with the patent office on 2002-03-21 for hydrogel microbeads having a secondary layer.
Invention is credited to QUONG, DOUGLAS.
Application Number | 20020034550 09/426140 |
Document ID | / |
Family ID | 23689476 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020034550 |
Kind Code |
A1 |
QUONG, DOUGLAS |
March 21, 2002 |
HYDROGEL MICROBEADS HAVING A SECONDARY LAYER
Abstract
A microbead having a matrix core comprising a hydrophilic matrix
and droplets of active material entrained therein, and a secondary
layer adjacent to the outer surface of the matrix core. The
secondary layer may be ionically complexed or hydrogen bonded to
the matrix core surface. Compositions comprising the microbeads
suspended in solution may be sprayable. The microbeads of the
invention may be controllable by exposing the microbeads to high or
low humidity or moisture.
Inventors: |
QUONG, DOUGLAS; (LONDON,
CA) |
Correspondence
Address: |
ATTENTION: ARLENE L HORMILLA
OFFICE OF INTELLECTUAL PROPERTY COUNSEL
3M INNOVATIVE PROPERTIES COMPANY
P O BOX 33427
ST PAUL
MN
551333427
|
Family ID: |
23689476 |
Appl. No.: |
09/426140 |
Filed: |
October 22, 1999 |
Current U.S.
Class: |
424/489 |
Current CPC
Class: |
A61K 8/042 20130101;
A61Q 13/00 20130101; A61K 8/736 20130101; B01J 13/10 20130101; A61K
8/342 20130101; A61Q 19/00 20130101; B01J 13/14 20130101; B01J
13/0052 20130101; A61K 2800/614 20130101; A01N 25/28 20130101; A61K
8/733 20130101; A61K 2800/56 20130101; A61K 8/0245 20130101; A61K
8/35 20130101; A61K 8/37 20130101 |
Class at
Publication: |
424/489 |
International
Class: |
A61K 009/14 |
Claims
What is claimed is:
1. A microbead comprising a hydrophilic matrix core having a
plurality of active material droplets entrained in said matrix
core, said core having an outer surface, and a secondary layer
adjacent and ionically complexed to said outer surface.
2. The microbead of claim 1 wherein said secondary layer is
discontinuous.
3. The microbead of claim 1 wherein said secondary layer is a
continuous layer permeable to liquid.
4. The microbead of claim 1 wherein said secondary layer comprises
a material selected from the group consisting of chitosan,
poly(hexamethylene co-guanidine), poly(methylene co-guanidine),
polyethyleneimine and combinations thereof.
5. The microbead of claim 1 wherein said secondary layer is
hydrophobic.
6. The microbead of claim 1 wherein said hydrophilic matrix core is
made from a polysaccharide.
7. The microbead of claim 8 wherein said polysaccharide is selected
from the group consisting of alginate, chitosans, carrageenan, gum
and agar.
8. The microbead of claim 1 wherein said active material is
selected from the group consisting of pheromone,
mercaptan-containing compound, herbicide, pesticide, and
pharmaceutical material.
9. The microbead of claim 1 wherein said microbead has an average
diameter of about 1 micrometers (.mu.m) to about 1000 .mu.m.
10. The microbead of claim 1 wherein said microbead has an average
diameter of about 1 .mu.m to about 500 .mu.m.
11. The microbead of claim 1, wherein said microbead further
comprises a surfactant.
12. The microbead of claim 1 wherein said microbead further
comprises an oil absorbent.
13. The microbead of claim 1 wherein said active material is
present in an amount between about 0.1 wt % to about 60 wt % of the
total weight of said microbead.
14. The microbead of claim 1 wherein said active material is
present in an amount between about 0.2 wt % to about 40 wt % of the
total weight of said microbead.
15. The microbead of claim 1 wherein said active material is
present in an amount between about 0.3 wt % to about 20 wt % of the
total weight of said microbead.
16. The microbead of claim 1 wherein said hydrophilic matrix core
is an alginate, said active material is a pheromone, and said
secondary layer is formed using chitosan or a co-guanidine
containing compound.
17. A microbead comprising a hydrophilic matrix core having a
plurality of active material droplets entrained in said matrix
core, said core having an outer surface, and a secondary layer
adjacent and hydrogen bonded to said outer surface.
18. The microbead of claim 17 wherein said secondary layer is
discontinuous.
19. The microbead of claim 17 wherein said secondary layer is a
continuous layer permeable to liquid.
20. The microbead of claim 17 wherein said secondary layer is
hydrophobic.
21. The microbead of claim 17 wherein said secondary layer
comprises a material selected from the group consisting of
polyurea, polymethylene urea, and polyurethane.
22. The microbead of claim 17 wherein said hydrophilic matrix core
is made from a polysaccharide.
23. The microbead of claim 22 wherein said polysaccharide is
selected from the group consisting of alginate, chitosans,
carrageenan, gum and agar.
24. The microbead of claim 17 wherein said active material is
selected from the group consisting of pheromone,
mercaptan-containing compound, herbicide, pesticide, and
pharmaceutical material.
25. The microbead of claim 17 wherein said microbead has an average
diameter of about 1 .mu.m to about 1000 .mu.m.
26. The microbead of claim 17 wherein said microbead has an average
diameter of about 1 .mu.m to about 500 .mu.m.
27. The microbead of claim 17 wherein said microbead further
comprises a surfactant.
28. The microbead of claim 1 wherein said microbead further
comprises an oil absorbent.
29. The microbead of claim 17 wherein said active material is
present in an amount between about 0.1 wt % to about 60 wt % of the
total weight of said microbead.
30. The microbead of claim 17 wherein said active material is
present in an amount between about 0.2 wt % to about 40 wt % of the
total weight of said microbead.
31. The microbead of claim 17 wherein said active material is
present in an amount between about 0.3 wt % to about 20 wt % of the
total weight of said microbead.
32. The microbead of claim 17 wherein said hydrophilic matrix core
is an alginate, said active material is a pheromone, and said
secondary layer is polyurea.
33. A sprayable composition comprising a plurality of the
microbeads of claim 1 suspended in a solution.
34. The composition of claim 33 further comprising adhesive
material selected from the group consisting of hollow tacky
adhesive microspheres, solid tacky adhesive microspheres, latex,
and combinations thereof.
35. The composition of claim 33 wherein said microbeads further
comprise an additive selected from the group consisting of
preservatives, humectants, stabilizers, UV protectants, and
combinations thereof.
36. A sprayable composition comprising a plurality of the
microbeads of claim 17 suspended in a solution.
37. The composition of claim 36 further comprising adhesive
material selected from the group consisting of hollow tacky
adhesive microspheres, solid tacky adhesive microspheres, latex,
and combinations thereof.
38. The composition of claim 36 wherein said microbeads further
comprise an additive selected from the group consisting of
preservatives, humectants, stabilizers, UV protectants, and
combinations thereof.
39. A method of delivering and releasing active material comprising
the steps of: a) suspending a plurality of said microbeads of claim
1 in a solution; b) delivering said solution comprising said
microbeads onto a substrate; and c) allowing said microbeads to
dehydrate.
40. The method according to claim 39 further comprising the steps
of: d) exposing said microbeads to humidity; and e) allowing said
microbeads to rehydrate.
41. The method according to claim 39 wherein said active material
is a pheromone and said hydrophilic matrix core is an alginate.
42. The method according to claim 40 wherein said step of exposing
said microbeads to humidity is performed by wetting the surfaces of
said microbeads with a solution.
43. The method according to claim 40 wherein said step of exposing
said microbeads to humidity is performed by adding moisture to the
ambient air.
44. The method according to claim 40 wherein said steps c) thru e)
are repeated sequentially.
45. A method of delivering and releasing active material comprising
the steps of: a) suspending a plurality of said microbeads of claim
17 in a solution; b) delivering said solution comprising said
microbeads onto a substrate; and c) allowing said microbeads to
dehydrate.
46. The method according to claim 45 further comprising the steps
of: d) exposing said microbeads to humidity; and e) allowing said
microbeads to rehydrate.
47. The method according to claim 45 wherein said active material
is a pheromone and said hydrophilic matrix core is an alginate.
48. The method according to claim 46 wherein said step of exposing
said microbeads to humidity is performed by wetting the surfaces of
said microbeads with a solution.
49. The method according to claim 46 wherein said step of exposing
said microbeads to humidity is performed by adding moisture to the
ambient air.
50. The method according to claim 46 wherein said steps c) thru e)
are repeated sequentially.
Description
FIELD OF THE INVENTION
[0001] The invention relates broadly to immobilization and release
of active material within hydrogel microbeads having a secondary
layer. The hydrogel microbeads can be used to immobilize water
soluble and water insoluble actives such as oils, fragrances,
lubricants, and agricultural chemicals such as pheromones,
herbicides, insecticides and pesticides.
BACKGROUND
[0002] Methods of eliminating unwanted pests from orchards, crops
and forests frequently entail the use of organophosphate
insecticides. Alternative methods involve insect mating disruption,
where insect pheromones are used to control pests and protect
agricultural crop. In insect mating disruption methods, the mating
pheromone plume of a female insect is typically masked with other
pheromone point sources. This reduces the likelihood of a male
insect finding a female, and subsequently disrupts and reduces
larvae production. The insect population of the next generation is
thus decreased, as well as potential crop damage.
[0003] Conventional sprayable pheromone formulations are generally
provided in liquid filled microcapsules containing an active.
Typically, the microcapsules have a polyurea membrane that can be
formed using an interfacial process involving an isocyanate and an
amine. Microencapsulation by this method has been described for
example in U.S. Pat. No.4,487,759 (Nesbitt et al., 1984). These
polyurea membranes allow actives to be released into the atmosphere
for up to a total of 2-3 weeks for most insect pheromones.
[0004] Use of interfacial condensation to encapsulate substances
such as pharmaceuticals, pesticides and herbicides is taught in
U.S. Pat. No. 3,577,515. The encapsulation process involves two
immiscible liquid phases (typically water and an organic solvent),
one being dispersed in the other by agitation, and the subsequent
polymerization of monomers from each phase at the interface between
the bulk (continuous) phase, and the dispersed droplets.
Polyurethanes and polyureas are materials suitable for producing
the microcapsules. The microcapsules comprise a polymeric sphere
and a liquid centre, ranging from 30 micron to 2 mm in diameter,
depending on monomers and solvents used.
[0005] Highly viscous and thickened hydrogels have been used to
deliver pheromones, fragrances and other non-water soluble actives.
U.S. Pat. No. 4,755,377, for example, describes a process of
encapsulating perfume or fragrant material within an aqueous-based
gel composition. The resulting material is in the form of a highly
viscous semi-solid. U.S. Pat. No. 5,645,844 describes the use of
chitosan paste for delivery of pheromones to disrupt insect mating,
where the material can be dispensed by an apparatus such as a
caulking gun. Due to their thickness and high viscosity, these
materials, however, are generally unsprayable compositions.
[0006] Most hydrogels are safe and non-toxic to humans. Hydrogels
are have been used for the encapsulation of biological materials
whereby the formulation is non-lethal to the viability of the
cells, proteins, and related materials. U.S. Pat. No. 4,689,293,
describes the process of encapsulating living tissue or cells in
alginate beads. The encapsulation shell permits the passage of
materials and oxygen to the cells and permits the diffusion of the
metabolic by-products from the gel. In U.S. Pat. No. 5,635,609, the
encapsulation art described involves one esterified polysaccharide
(i.e., alginate) and one polyamine (i.e. chitosan) whereby the
outer surface membranes are formed through covalent amide bonds.
U.S. Pat. No. 4,439,488 teaches a process of encapsulating
pheromone whereby the biological agents are dissolved or dispersed
in an aqueous paste of a gel-forming polyhydroxy polymer. By adding
boric acid to an alkaline pH, the paste transforms into a gel
thereby entrapping the agents in a protective matrix.
[0007] Japanese patent S 60-252403 describes a method of forming
sprayable, slow release pheromone agent obtained by emulsification
co-polymerization. In Japanese patent H-9-1244-08, the outer
surface of the delivery system (i.e., synthetic resin or inorganic
substance) is coated by a water-proof material. The water-proof
agent can be a silicon, fluroine, or paraffin hydrogen carbide type
material.
SUMMARY OF THE INVENTION
[0008] A method of delivering active material using a plurality of
microbeads suspended in solution is provided, where the microbeads
comprise a hydrophilic matrix having droplets of active material
entrained therein and a secondary layer adjacent to the surface of
the matrix. Furthermore, the matrix is capable of immobilizing a
broad spectrum of active materials, either water soluble or
non-water soluble. In one aspect of the invention, the hydrophilic
matrix may be made from a naturally occurring material to provide
an environmentally friendly microbead.
[0009] In an aspect of the invention, the active entrained in the
matrix diffuses through the hydrophilic matrix and the secondary
layer, and is released into the environment over an extended
period.
[0010] In another aspect, the microbeads are capable of
re-hydrating after an initial dehydration and release of active.
Thus, the release and longevity of the active can be controlled by
adjusting the humidity of the environment in which the microbeads
have been delivered.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a cross-sectional illustration depicting a
preferred embodiment of a microbead of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0012] In view of the increasing awareness of insecticide toxicity
to humans and other environmental concerns, it would be
advantageous to provide an active delivery system having an
extended release life and having a hydrogel material in order that
it be non-toxic and bio-degradeable. It would also be advantageous
to provide a system for sprayable long lasting active delivery that
would be applicable to a broad spectrum of actives thereby
eliminating the issue of reactivity of the active with one of the
membrane components.
[0013] The present invention provides microbeads having a secondary
layer, where the microbeads are made of a hydrophilic matrix core
having droplets of active material entrained and immobilized
therein. Surprisingly, it has been found that release of the active
from within the microbeads can be altered by adding a secondary
layer onto the microbead surface to alter the diffusion pathway of
the active and subsequently extend and improve the active release
properties. Furthermore, the secondary layer advantageously
provides physical protection to the hydrogel matrix with the active
entrained therein, from rupturing forces, UV, and other external
environmental conditions.
[0014] The secondary layer can be a membrane, web, coating, film,
or other material that is positioned outside and adjacent to the
outer surface of the matrix core. For simplicity, the term
"secondary" layer is used herein to describe the layer that lays
immediately outside the surface of the matrix core. Thus, it is
contemplated, that the microbeads of the invention can have
multiple layers.
[0015] The microbeads of the invention comprise a matrix forming
material, and is preferably substantially spherical. The matrix
forming materials of the microbead core are hydrophilic and water
soluble. Entrained or finely dispersed within the matrix are
micro-sized droplets of active material. Active materials that can
be immobilized within the hydrogel microbeads include acetates,
aldehydes, alcohols, esters, epoxy compounds, ethers, and ketones,
especially reactive ketones in which the double bond of the
carbonyl group is conjugated with one or more double bonds, for
example acetophenone where the carbonyl group is conjugated with
double bonds of the aromatic ring.
[0016] Advantageously, the hydrogel matrix core is preferably made
from environmentally or biologically friendly materials to provide
sufficient immobilization of oil soluble actives such that the
active can be delivered and sprayed by conventional techniques. By
utilizing a hydrophilic matrix core, the hydrogel microbeads entrap
micro-sized droplets of active material within the matrix. This is
in contrast to delivery systems that solely utilize
microencapsulation of actives, achieved by interfacial
condensation. Immobilizing active material in a hydrophilic matrix
core advantageously imparts the capability of the hydrogel
microbeads to immobilize oil-soluble active materials and minimizes
the risk of undesired reactivity between the active and its
immobilizer. Thus, immobilization of active materials by use of the
microbeads of the invention does not render the immobilized
material inert or ineffective.
[0017] It has also been surprisingly found that the microbeads of
the invention provide a method of controlling release of active(s)
by cyclically hydrating and re-hydrating the microbeads. This is a
result of the surprising benefit from immobilizing active
ingredients in hydrogel microbeads, where the microbead is able to
"swell" under humid conditions and shrink under dry conditions. As
used herein, "swell" is descriptive of the behavior of a microbead,
wherein the size (volume) is enlarged (increased) due to absorption
of water. The microbeads' ability to swell is likely due to the
hydrophilic nature of the matrix forming materials used to
immobilize the active material.
[0018] In the presence of humidity, the hydrogel microbeads are
surprisingly found to be capable of absorbing moisture,
rehydrating, and consequently releasing active material contained
within the microbead. This behavior can be cyclical. Thus, by
controlling the humidity (or dryness) of the ambient air, the
release rate of active material from the microbeads can be
controlled such that specific periods of release can be generally
predicted. It is therefore possible with the present invention to
release the active material on demand from the microbead. Release
on demand, or "smart release," can be advantageous in those
instances where release is preferred at certain times. The
microbeads' ability to release more active out from the matrix may
increase the longeveity of the release period. Preferably, the
microbeads are delivered to an intended environment in effective
amounts to obtain the desired effect. For example, microbeads
having pheromones entrained therein, are preferably delivered to a
desired area in amounts such that mating disruption is effected and
release is accomplished for more than 4 weeks, more preferably, the
microbead can release for more than about 6 weeks; and most
preferably more than about 8 weeks.
[0019] During the drying process (i.e dehydration) a surface film
layer will form as a result of water evaporation from the
hydrophilic matrix. Both initially and during use, the microbeads
are characterized by a large surface area to volume ratio, which
helps maintain the rate of diffusion of the active material during
use. Thus, it has been found that microbeads made according to the
method of present invention provide excellent delivery systems as
they are capable of releasing active material for extended periods.
Furthermore, since the active is dispersed within a water-based
matrix, additional protection from environmental conditions (i.e.,
UV) can be provided.
[0020] Although it has been found that microbeads of the invention
can be made having a diameter of up to about 5 millimeters (mm), it
is preferred that the microbeads be between about 1 micrometers
(.mu.m) to about 1000 .mu.m and more preferably between about 1
.mu.m to about 500 .mu.m in diameter to ensure that the microbeads
are easily sprayable from conventional spray nozzles. Most
preferably, to ensure minimal clogging in conventional nozzles, the
microbeads are less than about 400 .mu.m in diameter. It is
contemplated, however, that with the advent of larger spray nozzles
not yet realized in the industry, the microbeads can be provided in
much greater diameters.
[0021] For spraying applications, particularly aerial spraying, it
is desirable that the microbeads be capable of remaining suspended
in solution (e.g., water) to ensure that the microbeads do not
sink, settle, or coagulate in the suspension. A uniform suspension
ensures an even spray coverage. Preferably, the microbeads of the
invention are able to remain in suspension, thus minimizing if not
eliminating the need to agitate during application (and storage).
Various suspension aids can also be included in the suspension
containing the microbeads of the invention. Examples of suitable
suspension aids include rhamsam gum, xanthum gum, gellan gum,
pectin, and gum arabic.
[0022] Owing to the handling to which the microbeads are subjected,
it is desirable that the microbeads of the present invention should
be somewhat elastic, and not frangible. For example, typical
atomization of a suspension during a spray application will force
the suspension through two rotating perforated discs that are
immediately upstream of the discharge nozzle. Sufficient elasticity
of the microbeads minimizes physical damage to the microbeads as
they pass through the discs.
[0023] The microbeads of the present invention comprise a
hydrophilic matrix core having active material droplets entrained
therein, and a secondary layer adjacent matrix forming material and
active material. Referring now to FIG. 1, a preferred embodiment is
shown, where a plurality of active material droplets 10 is
entrained within the hydrogel matrix 12, and a layer 14 adjacent to
outer surface 16 of the matrix 12. As seen in FIG. 1, active
material droplets are preferably located between and within the
hydrogel matrix, where the matrix provides an immobilizing network
around the droplets. The degree and extent of agitation as well as
the type of surfactant used to form the microbeads can affect the
size and the dispersity of the pheromone droplets within
microbead's matrix. Droplets are preferably between about 0.01 mn
to about 200,000 nm in diameter. More preferably, the droplets are
between about 1 to about 1000 nm.
[0024] The matrix-forming material useful in the present invention
are biocompatible, water-soluble, have pendant functional groups,
and complex with ions (e.g., polyvalent cations and/or anions) to
form hydrogels. Functional groups of the matrix forming material
include for example, carboxyls, hydroxyls, primary or secondary
amines, aldehydes, ketones, esters, or combinations thereof.
Preferably, the matrix-forming material of the hydrophilic matrix
core can be made from natural occurring polysaccharides, such as
alginates, chitosans, gums, agars, carrageenans, or the matrix can
be made synthetic, water soluble monomers, oligomers or polymers,
such as, for example, polyvinyl alcohol,
poly(N-isoproylacrylamide), acrylamides, acrylates, methacrylates
or combinations thereof.
[0025] Suitable naturally occurring polysaccharides include the
water-soluble salts of alginic, pectic and hyaluronic acids, the
water-soluble salts or esters of polyglucuronic acid, polymanuronic
acid, polylygalacturonic acid and polyarabinic acid, and gum
kappa-carrageenan. The preferred polysaccharides are the ammonium,
magnesium, potassium, sodium and other alkali metal salts of
alginic acid, and the most preferred polysaccharide is sodium
alginate.
[0026] "Alginate" is the general name given to alginic acid and its
salts. Alginates are composed of D-mannosyluronic (mannuronic -
"M") and L-gulopyranosyluronic (guluronic - "G") acid residues. The
ratio of mannuronic to guluronic acid residues is known as the M:G
ratio. The alginate used to immoblize active droplets should be
carefully selected to ensure proper microbead formation, ensure the
stability of the microbeads during storage and delivery
applications, and ensure that the microbeads are able to shrink and
swell appropriately to deliver the desired active material over an
extended period of time (preferably 4-6 weeks). Preferably, an
alginate is chosen such that the matrix formed is sufficient in
strength to withstand the shear forces (conditions) placed upon the
microbeads during application via a spray nozzle - i.e., the
microbeads are resistant to rupture during the spray
application.
[0027] For strength and stability of the microbeads, it is
desirable to choose a proper molecular weight of the alginate, as
well as an appropriate M:G ratio. Although alginates high in
mannuronic acid are generally useful for thickening applications,
whereas alginates with a high level of guluronic acid are often
used for forming gels, both alginate categories (individually or a
mixture thereof) are suitable for the microbeads of the invention.
A preferred alginate that imparts strength and rupture resistance
is an alginate that has a high level of guluronic acid, e.g.,
greater than about 30 percent by weight. Alginate compositions with
excessive levels of mannuronic acid could result in less stable and
less rigid microbeads than high guluronic acid gels. However, high
mannuronic acid alginates impart to the microbeads the capability
of swelling and absorbing more water than microbeads of high
guluronic acid content. Thus, a careful balance of the advantages
imparted by each of M and G residues should be considered when
choosing a suitable alginate.
[0028] It has been surprisingly found that alginates preferably
having a molecular weight in the range of about 100,000 kg/mol to
about 2,500,000 kg/mol, more preferably about 200,000 kg/mol to
about 1,500,000 kg/mol. Furthermore, the alginates preferably have
an M:G ratio in the range of about 0.2 to about 3.5; more
preferably about 0.3 to about 1.85.
[0029] Suitable alginates that have a high level of guluronic acid,
for example are alginates from the algae Laminaria hyperborea,
stem, whole plant or frond. Preferred alginates with high levels of
mannuronic acid include Ascophyllum nodosum, for example.
[0030] Gel matrices formed by crosslinking polysaccharides bearing
pendant carboxylate groups are also useful in the present
invention. These compounds are composed of water-insoluble
alginates which include, with the exception of magnesium and the
alkali metal salts, the group II metal salts of alginic acid. The
water-insoluble alginate gels are typically formed by the chemical
conversion of water-soluble alginates, in an aqueous solution, into
water-insoluble alginates. This conversion usually is accomplished
by the reaction of a water-soluble alginate with polyvalent cations
released from a soluble di- or trivalent metal salt.
[0031] Water-soluble alginates can include the ammonium, magnesium,
potassium, sodium, and other alkali metal salts of alginic acid.
Water-insoluble di-or trivalent metal salts suitable for the
present invention should satisfy two requirements: (1) that the
water-insoluble metal salt contain a di-or trivalent metal ion
capable of complexing with the pendant carboxylate groups of the
water-soluble polysaccharide to cause the formation of a
water-insoluble polysaccharide gel; and (2) that the
water-insoluble metal salt reacts with a water-soluble acid to form
a water-soluble metal salt.
[0032] A common and suitable alginate gel is composed of calcium
aliginate.
[0033] Sources for the crosslinking calcium ions used in the
formation of alginate gels include, for example, calcium carbonate,
calcium sulfate, calcium chloride, calcium phosphate, calcium
tartrate, calcium nitrate, and calcium hydroxide. Other acceptable
crosslinkers may include lanthanum chloride, ferric chloride,
cobaltous chloride, as generally are other compounds with
multivalent cations, such as calcium (Ca++), copper (Cu++), barium
(Ba++), strontium (Sr++) and the like.
[0034] The time of gelation of the calcium alginate gels can be
accomplished by regulating the concentration of free calcium ions
in the solution. Typically the concentration of free calcium ions
is controlled by manipulation of the ionization rate of the calcium
salt and/or by the inclusion of other compounds in the solution
which react with the free calcium ions.
[0035] It has been advantageously found that it is possible to
immobilize and deliver a wide range of active materials, including
non-water soluble materials as well as alcohols.
[0036] Preferred active materials entrained in the matrix core are
partially water-miscible organic molecules of compounds that have a
molecular weight in the range of between about 100 to about 400,
preferably between about 150 to 300. The compounds contain a
heteroatom that confers some degree of water-miscibility. For many
compounds of interest the sole heteroatom is oxygen, and there may
be up to three heteroatoms per molecule in, for instance,
hydroxy-substituted or keto-substituted carboxylic acids.
Unsubstituted carboxylic acids of course contain two oxygen atoms
and simple aldehydes, ketones and ethers contain only one oxygen
atom. Compounds that contain nitrogen and/or sulphur atoms are also
of interest.
[0037] Of particular interest are biologically active compounds.
For purposes of the present invention, the term "biologically
active" means materials that affect the life processes of
organisms. Materials that are biologically active include
herbicides, pesticides, pharmaceuticals, and semiochemicals,
including naturally and artificially produced pheromones and
synthetic pheromone analogs. Materials of this nature that are of
particular interest are those materials that interfere with a life
process essential to the survival of a target pest.
[0038] The method of the invention can be used to immobilize
pheromone with functional groups such as acetates, aldehydes,
ketones, alcohols, esters, ethers, epoxies or combinations thereof.
Pheromones may be defined as compounds which, when naturally
produced, are secreted by one member of an animal species which can
influence the behaviour or development of another member of the
same animal species. Pheromones generally are species-specific and
therefore the application of pheromones for insect behaviour
modification has minimal effect on non-target pests. Pheromones
supplied for modification of insect behaviour interfere with the
"mate finding process" by releasing point sources of pheromone,
which may compete with or camouflage the pheromone plume of a
female. This latter type of action differs from chemical
insecticides or insect growth regulators or hormones, in that
pheromones target future generations of insects, not present ones.
As pheromones are very species-specific and are used only in small
quantities, their use is more environmentally acceptable than
broadcasting of pesticides.
[0039] Many pheromones have an ester terminal group, for example
and acetate or formate group. Typically these substances are
water-immiscible and incorporation of them into microcapsules by
known methods presents no particular problem. Many other pheromones
have an aldehyde or an alcohol terminal group. In general, these
are partially water-miscible and potentially reactive with the
reactants used to encapsulate by prior, conventional methods. In
particular, it is difficult to achieve high degrees of
encapsulation of materials that have some degree of water
solubility, as the material partitions between the small amount of
organic solvent and the relatively larger amount of water that
constitutes the continuous phase. Furthermore, these compounds can
be expected to react with the reactants used to encapsulate.
Aldehydes and ketones react with amines to form aldimines and
ketimines, respectively. Alcohols, carboxylic acids and mercaptans
react with isocyanates. Epoxy compounds react both with amines and
with isocyanates. Thus, the present invention overcomes the
limitation of delivering partially water-miscible substances such
as alcohols, aldehydes, carboxylic acids, ketones, ethers,
including epoxy compounds, and mercaptans.
[0040] Pheromones useful in the inventive microbeads are preferably
insect pheromones. In describing the structure of the a pheromone,
the following notation is used: the type (E (trans)or Z(cis)) and
position of the double bond or bonds are given first, the number of
carbon atoms in the chain is given next and the nature of the end
group is given last. To illustrate, the pheromone Z-10 C19 aldehyde
has the structure; 1
[0041] Pheromones can be mixtures of compounds with one component
of the mixture predominating, or at least being a significant
component. Partially water-miscible significant or predominant
components of insect pheromones, with the target species in
brackets, include, for example: E/Z-11 C14 aldehyde (Eastern Spruce
Budworm), Z-10 C19 aldehyde (Yellow Headed Spruce Sawfly), Z-l 1
C14 alcohol (Oblique Banded Leafroller), Z-8 C12 alcohol (Oriental
Fruit moth) and E,E-8,10 C12 alcohol (Codling moth), E-1 1 C14
acetate (Sparganothis Fruitworm), and Z-11 C14 acetate (Blackheaded
Fireworm).
[0042] An example of a ketone that is a pheromone is E or Z
7-tetradecen-2-one, which is effective with the oriental beetle. An
ether that is not a pheromone but is of value is 4-allylanisole,
which can be used to render pine trees unattractive to the Southern
pine beetle.
[0043] Preferred embodiments of the invention are described with
reference to immobilization of partially water-miscible and water
immiscible pheromones, but it should be appreciated that the
invention extends to immobilization of materials other than such
pheromones and to microbeads containing materials other than
pheromones. Those materials may, or may not, be biologically
active.
[0044] For example, alternatively, active materials containing
mercaptans can be immobilized in the microbeads of the invention,
such as what is found in urine of animals. These compounds are
preferable in situations where animals mark their territory by
means of urine, to discourage other animals from entering the
particular territory. Examples of such animals include preying
animals such as wolves, lions, dogs, etc. By dispersing hydrogel
microbeads containing the appropriate mercaptans, it is possible to
define a territory and discourage particular animals from entering
that territory. For example, the urine of a wolf includes a
mercaptan, and distribution of microbeads from which this mercaptan
is gradually released to define a territory will discourage deer
from entering that territory. Other active materials useful in
discouraging approach of animals include essences of garlic,
putrescent eggs and capsaicin.
[0045] Other active compounds that can be included in the
microbeads of the invention include perfumes, fragrances,
flavouring agents and the like.
[0046] Optionally, oil absorbents can be incorporated into the
active droplets. These absorbents can help retain the active
droplets within the microbeads, resulting in longer lasting
formulations. Clays and starches could also be used for this
purpose.
[0047] The concentration of active material in the microbeads of
the invention should be at a level such that the matrix forming
material can still provide a strong, rupture resistant network and
deliver an effective amount of the active material to the
environment to which it is intended. Thus, the active material is
preferably present in an amount between about 0.1 wt % to about 60
weight percent (wt %) of the total weight of the microbead. More
preferably, the amount of active material is present in the
microbead at between about 0.2 wt % to about 40 wt %; and most
preferably between about 0.3 wt % to about 20 wt %.
[0048] Microbeads of the invention comprise at least one layer
(hereinafter referred to as a "secondary layer") adjacent to the
outer surface of the hydrophilic matrix core. To provide diffusion
and release of the active into the atmosphere, the secondary layer
can be a discontinuous layer, or alternatively, a continuous layer
permeable to liquid (moisture). The secondary layer that is applied
onto the microbead surface can be performed by chemical processes
such as ionic complexation or alternatively in-situ polymerization
which involves hydrogen bonding of the layer to the matrix core. It
is preferable that the material used to form the secondary layer is
chosen such that the path of diffusion of the active material is
altered to provide extended release of the active. Suitable
materials that can be used for the secondary layer include
hydrophilic, hydrophobic, inorganic or organic materials or
combinations thereof. Preferably, the secondary layer is
biocompatible and easily biodegradeable in the environment.
[0049] In a preferred aspect, the secondary layer can be ionically
complexed with the outer surface of the hydrophilic matrix core.
Advantageously, an ionically complexed layer provides a different
permeability and diffusion profile of the active through the
secondary layer, than that of a secondary layer that is covalently
bonded to a matrix core. The permeability and diffusion of the
actives delivered by the compositions and methods of the invention
provide extended release periods.
[0050] Formation of the secondary layer by ionic complexation is
achieved by binding opposing charged groups (i.e.
negatively-charged groups and positively-charged groups) of the
matrix core materials and the secondary layer. Thus, the selection
of the material to form the secondary layer depends on the surface
charge of the hydrophilic matrix core. If the hydrophilic matrix
core is comprised of a negatively charged hydrophilic material,
then the counter charged material should be a positively-charged
material, and vice-versa.
[0051] Negatively charged groups suitable for use in the invention,
include for example, hydroxyl, carboxyl, sulphate, and phosphate
groups. Preferred biocompatible negatively-charged hydrophilic
materials include, for example a polysaccharide. Suitable
polysaccharides include, for example, an alginate, a carrageenan,
in particular kappa-carrageenan, a gelable pectin, in particular a
low methoyxyl pectin, agar, gellan gum, or combinations
thereof.
[0052] Positively-charged hydrophilic materials suitable for use in
the invention include, for example, proteins, polylysines,
polypeptide, polyamino acids, polysaccharide bearing amino groups
such as chitosan and carboxymethyl cellulose, aliphatics, alicyclic
or aromatic organic substances bearing several primary or secondary
amino groups, such as ethylenediamine, hexamethylenediamine,
piperazine, phenylenediamine, polyethyleneimine, poly(hexamethylene
co-guanidine), or poly(methylene co-guanidine), or combinations
thereof. Of these, chitosan and co-guanidine-containing compounds
are particularly preferred. Chitosan, obtained by the deacetylation
of chitin, is an amino-polysaccharide and a biopolymer widely
distributed in nature. Chitosan is a linear polysaccharide composed
of .beta.-1,4 linked D-glucosamine residues. In nature, the polymer
is partially acetylated, and it includes a wide range of polymers
corresponding to various proportions of D-glucosamine and
N-acetyl-glucosamine residues. The properties of chitosan in
solution depend on molecular weight, the degree of deacetylation,
pH and ionic strength.
[0053] The ionic complexation reaction generally requires an
aqueous solvent. The concentration of the solute (acid or alkaline)
is preferably about 0.01 wt % to about 10 wt %, more preferably
about 0.05 wt % to about 4 wt %. The solvent is preferably chosen,
and its pH adjusted, to avoid precipiation yet ensure satisfactory
complexation of the counter-charges materials. For example, in a
preferred embodiment where chitosan solution is used to complex
with an alginate, the pH is preferably between about 1.0 and 6.0,
more preferably between about 5.0 and 6.0.
[0054] The concentration of the secondary layer forming material is
preferably about 0.01 wt % to about 10.0 wt %, more preferably
about 0.02 wt % to 4.0 wt % based on the total solution weight.
[0055] In another preferred aspect, the secondary layer can be
adjacent to and hydrogen bonded to the outer surface of the
hydrophilic matrix core. This method is performed in-situ, where
the secondary layer is deposited onto the surface of the
hydrophilic matrix core. Alternatively, the in situ formation of a
secondary layer may be formed by a reaction between a
water-immiscible polyisocyanate and a water-miscible polyfunctional
amine. The polyisocyanate may be dispersed within the hydrogel
forming emulsion mixture or dissolved in or within the active
droplet. Layers formed by the in situ methods can be continuous and
preferably permeable. Suitable materials for use in the in-situ
method include for example, polyurea, polyurethane, or
polyureamethylene urea.
[0056] The polyisocyanate may be aromatic or aliphatic and may
contain two, three or more isocyanate groups. Examples of aromatic
polyisocyanates include 2,4- and 2,6-toluene diisocyanate,
naphthalene diisocyanate, diphenylmethane diisocyanate and
triphenylmethane-p, p', p"-trityl triisocyanate.
[0057] Aliphatic polyisocyanates may optionally be selected from
aliphatic polyisocyanates containing two isocyanate
functionalities, three isocyanate functionalities, or more than
three isocyanate functionalities, or mixtures of these
polyisocyanates. Preferably, the aliphatic polyisocyanate contains
5 to 30 carbons. More preferably, the aliphatic polyisocyanate
comprise one or more cycloalkyl moieties. Examples of preferred
isocyanates include dicyclohexylmethane-4,4'-diisoc- yanate;
hexamethylene 1,6-diisocyanate; isophorone diisocyanate;
trimethyl-hexamethylene diisocyanate; trimer of hexamethylene
1,6-diisocyanate; trimer of isophorone diisocyanate;
1,4-cyclohexane diisocyanate; 1,4-(dimethylisocyanato) cyclohexane;
biuret of hexamethylene diisocyanate; urea of hexamethylene
diisocyanate; trimethylenediisocyanate; propylene-1,2-diisocyanate;
and butylene-1,2-diisocyanate. Mixtures of polyisocyanates can be
used.
[0058] Particularly preferred polyisocyanates are polymethylene
polyphenylisocyanates of formula 2
[0059] wherein n is 2 to 4. These compounds are available under the
trade-mark Mondur-MRS. The mole equivalent ratio of total primary
amine functionality to isocyanate functionality in the system is
preferably about 0.8:1 to 1:1.2, and more preferably about
1:1.1.
[0060] The polyfunctional amine, in the amount used, is preferably
freely soluble in the water present in the reaction mixture.
[0061] The polyfunctional compound containing amine and/or hydroxy
functional groups may contain at least two functional groups
selected from primary amine, secondary amine and hydroxy groups.
Examples of suitable compounds include ethylene diamine, diethylene
triamine and compounds of the general formula 3
[0062] wherein m takes a value from 1 to 8, and each R is
independently hydrogen or methyl. Also useful are compounds whose
structure is similar to the above formula, but which have one or
more oxygen atoms present in ether linkages between carbon atoms.
It is preferred that R is hydrogen, especially at the terminal
amino groups. Aromatic diamines, for example toluene diamine, can
be used. Mixtures of polyfunctional compounds can be used.
Tetraethylene pentamine (TEPA) and pentamethylene hexamine are
particularly preferred.
[0063] A suitable amine for use in this invention is
trimethylamine, a tertiary amine. This compound, and its C.sub.2,
C.sub.3 and C.sub.4 homologues can be used in the microbeads of the
invention. Other suitable tertiary amines include those containing
a mixture of alkyl groups, for instance methyldiethylamine. The
tertiary amine can contain more than one tertiary amine moiety. It
may also contain other functional groups provided that those other
functional groups do not interfere with the required reaction, or
the functional groups participate beneficially in the required
reaction. As an example of a functional group that does not
interfere there is mentioned an ether group. As examples of groups
that participate beneficially there are mentioned primary and
secondary amine groups, which will form urea moieties with
isocyanate groups, and hydroxyl groups, which will form urethane
moieties with isocyanate groups. Examples of suitable tertiary
amines include compounds of the following structures:
[0064] N[CH.sub.2(CH.sub.2).sub.nCH.sub.3].sub.3, where n is 0, 1,
2 or 3 4
[0065] Of the tertiary amines triethylamine (TEA) is preferred.
[0066] In another aspect of the in situ formation of the secondary
layer, a water-insoluble non-thermoplastic synthetic resin may be
used. Polymerization of the resin generally requires a pre-polymer.
Prepolymers suitable to the present invention are partially
etherified urea-formaldehyde prepolymers with a high solubility in
the organic phase and low solubility in water. In its
non-etherified form, the prepolymer contains a large number of
methylol groups, --CH.sub.2OH, in its molecular structure.
Etherification is the replacement of the hydroxyl hydrogens with
alkyl groups; and is preferably achieved by condensation of the
prepolymer with an alcohol. Complete etherification is preferably
avoided, however, since hydroxyl groups are needed for the in situ
self-condensation polymerization, which occurs in the layer forming
step. The secondary layer of this invention may comprise a
water-soluble urea resin where at least one of the prepolymers is a
mixture of formaldehyde and at least one compound selected from the
group consisting of urea, melamine and thiourea.
[0067] The microbeads of the present invention can be placed into
suspension in aqueous or solvent-based solutions. For environmental
and biologically-friendly reasons, it is preferred that aqueous
suspensions be used. Suspension aids are preferably included in the
suspension formulations to ensure the microbeads remain suspended
in solution.
[0068] Preferably, the suspension solution is substantially free of
monovalent cations, such as sodium, to avoid degradation or
breakdown of the secondary layer or the hydrogel matrix. In a
preferred aspect, a concentration of approximately 50 millimolar of
a crosslinker such as calcium chloride is maintained in a stored
solution comprising the microbeads of the invention.
[0069] Optionally, adhesive material can be included in the
compositions of the invention. The adhesive material can be
provided in various forms, such as for example, latex or a tacky
microspheres. Adherent properties imparted to the hydrogel
microbeads should result in the microbeads being able to still
retain their suspended state and minimize aggregation or
coagulation in the aqueous suspension. Furthermore, any adhesive
material used to impart adherent properties should not affect the
integrity of the particles; it should not dissolve or weaken the
microbeads.
[0070] A suitable adhesive material that may be included in the
compositions of the invention is adhesive latex. The adhesive latex
may be any suitable water-dispersible adhesive available in the
art. In the agricultural business, such latex compositions are
often called stickers or spreaders. Stickers are used to help
non-encapsulated agriculture chemicals adhere to plants. Spreaders
are used to help disperse non-encapsulated agriculture chemicals on
application. Preferred adhesives are acrylate-based adhesives. One
suitable latex is available from Rohm & Haas under the
trade-mark Companion. Another is available from Deerpoint
Industries under the trade-mark DPI S-100 (a proprietary
sticker/spreader). Examples of such adhesives are polymers made
from the "soft" monomers such as n-butyl acrylate, isooctyl
acrylate, or the like, or copolymers made from a soft component,
such as isobutylene, n-butyl acrylate, isooctyl acrylate, ethyl
hexyl acrylate, or the like; and a polar monomer such as acrylic
acid, acrylonitrile, acrylamide, methacrylic acid, methyl
methacrylate or the like. Non-spherical polyacrylate adhesives are
commercially available, for example, as the Rohm and Haas RhoplexTM
line of adhesives. Preferably, the non-spherical polyacrylate
adhesive is present in an amount of about 10-35% by weight of the
total suspension.
[0071] Tacky microspheres of adhesive may alternatively be used to
help adhere the hydrogel microbeads of the invention to an intended
substrate. The tacky microspheres have sufficient adhesive
properties to provide the desired adhesive function, yet there is
no danger of completely coating the microbead which may lead to
potentially inhibiting the release characteristics of the
microbead. The combination of microbeads and tacky microspheres may
be applied without the need to modify the orifices of conventional
sprayers with minimal clogging or plugging problems. Furthermore,
the incorporation of tacky (adhesive) microspheres to the
(formulation) suspension of microbeads allows the microbeads'
surfaces to become tacky. The beads can therefore stick to intended
surfaces, such as, foliage and branches, for example. The adhesive
microspheres, especially if they are hollow, may also absorb some
of the active material into its own body, thus providing a second
mechanism of release of the active material. This could result in
an overall alteration, preferably an enhancement, of the release
profile.
[0072] Preferably, the adhesive material is an acrylate- or
methacrylate-based adhesive system comprising infusible, solvent
dispersible, solvent insoluble, inherently tacky, elastomeric
copolymer microspheres as disclosed in U.S. Pat. No. 3,691,140.
Alternatively, this adhesive composition may comprise hollow,
polymer, acrylate, infusible, inherently tacky, solvent insoluble,
solvent dispersible, elastomeric pressure-sensitive adhesive
microspheres as disclosed in U.S. Pat. No. 5,045,569. Other
suitable adhesives are the tacky microspheres having pendant
hydrophilic polymeric or oligomeric moieties that are disclosed in
U.S. Pat. No. 5,508,313.
[0073] Alternatively, the adhesive comprises between about 60-100%
by weight of hollow, polymeric, acrylate, inherently tacky,
infusible, solvent-insoluble, solvent dispersible, elastomeric
pressure-sensitive adhesive microspheres having a diameter of at
least 1 micrometer, and between about 0-40% by weight of a
non-spherical polyacrylate adhesive. The hollow microspheres are
made in accordance with the teaching of European Patent Application
371,635.
[0074] The compositions of the present invention may also include
one or more adjuvants including, for example, gelling aids,
preservatives, dyes, humectants, fixatives, emulsifiers, extenders,
and freeze/thaw stabilizers such as polyhydric alcohols and their
esters. These materials are present in an amount effective to
achieve their extended function, generally less than about 5%
typically less than 2%, by weight of the composition.
[0075] Incorporation of a light stabilizer can be included in the
microbeads of the invention. Suitable light stabilizers include the
tertiary phenylene diamine compounds disclosed in Canadian Patent
No. 1,179,682, the disclosure of which is incorporated by
reference. The light stabilizer can be incorporated by dissolving
it, with the active, in a water-immiscible solvent. Alternatively,
a light stabilizer can be incorporated in the microbeads as taught
in Canadian Patent No. 1,044,134, the disclosure of which is also
incorporated by reference.
[0076] The process of making the microbeads of the invention,
preferably comprises, initially, the formation of a microemulsion
and the dispersion of the active material in the hydrogel material.
The microemulsion is then mechanically atomized to create
substantially spherical droplets which are subsequently gelled
(hardened) to form a hydrogel microbead having an active material
dispersed therein.
[0077] In a preferred method of making the microbeads of the
invention, an emulsion of an oil active within a water soluble
solution comprising a hydrogel is first formed. This emulsion is
then followed by a mechanical microbead forming step that can be
performed by, for example, spray method or emulsification. The
droplets are then hardened or cured either by chemical means (i.e.,
polymer cross-linking) or by non-chemical means (i.e., temperature,
pH, pressure). The resulting microbead is a hydrogel microbead,
having greater than about 30% water initially, and the active would
be finely dispersed and entrained within the water-polymer matrix.
The microbeads tend to be more spherical in shape when the spray
method is used, as compared to the emulsification method. The size
of the microbeads is generally governed by the intrinsic properties
of the emulsion solution, the feed rate and the coaxial airflow
rate.
[0078] The droplets which are atomized can then be allowed to
free-fall directly into a reacting bath. The reacting bath cures or
sets the hydrogels so that they solidify. Reaction bath curing can
be achieved through chemical or non-chemical means. For the case of
sodium alginates, calcium ions are used to cross-link the polymer
chains. A preferred crosslinker is calcium chloride.
[0079] The emulsification method is another technique that can be
used for producing hydrogel microbeads. In selecting the continuous
phase material, it is preferable that it be immiscible with both
the aqueous polymer and oil active.
[0080] The matrix-forming material preferably has a range of
concentrations usable in practicing the invention. The
concentration should be chosen to optimize ease of handling,
gelling time, the strength of the hydrogel microbead around the
active material droplets. For example, a sodium alginate solution
can preferably be prepared in a concentration of about 1 to about
10% (w/v) in water, more preferably about 1.5 to about 5% and most
preferably from about 1 to 3%. However, if the hydrogel agent
concentration is too great, the solution may be so viscous as to
hinder the formation of spherical microbeads.
[0081] Alternatively, hydrogel microbeads of the invention can be
formed, for example, by adding the matrix forming material solution
drop-wise to a selected crosslinker. For example, a method can be
used whereby droplet formation and crosslinker addition is
completed as a one step process by a vibrating nozzle which ejects
a hydrogel droplet from one source and coats the droplet with a
crosslinker from another. U.S. Pat. No. 4,701,326 teaches use of
this method.
[0082] In the preferred aspect where alginates are used to
immobilize an active material, a crosslinker is preferably made up
in solution at a concentration of 1 to 1000 millimolar, more
preferably 20 to 500 millimolar and most preferably from 50 to 100
millimolar. The concentration ranges may have to be adjusted,
depending on the nature of a crosslinker and matrix-forming
material.
[0083] The microbeads containing matrix material and active
material can be treated with the crosslinker solution by soaking,
spraying, dipping, pouring or any of sever other methods which will
deposit an amount of the complexing agent on the droplet. When
soaking, the time in solution may be from 1 second to 24 hours,
preferably 1 minute to 1 hour, and more preferably from 10 to 30
minutes.
[0084] The temperature for hydrogel microbead formation is
preferably chosen as to avoid damage or alteration to the active
material. For example, in the preferred aspect where alginates are
utilized, the temperature is preferably in the range of about
1.degree. C. to about 70.degree. C.; more preferably between about
10.degree. C. to about 40.degree. C., and most preferably between
about 15.degree. C. to about 30.degree. C.
[0085] Forming the secondary layer of the microbead may be
accomplished in various methods. In one aspect, both the secondary
layer and the hydrophilic matrix core can be produced substantially
simultaneously. In this process, the ionically complexed layer is
formed while the crosslinker diffuses into the matrix-forming
material to form (gel) the matrix core.
[0086] In a preferred method utilizing ionic complexation to form
the secondary layer, the active material is emulsified and
entrained into the matrix-forming material with the aid of
surfactants. The intact beads are then placed into an ionically
complexing solution containing opposing charges (either positively
or negatively charges), depending on the selection of the
hydrophilic matrix forming material for a specified period of
time.
[0087] The reaction time or the length of incubation time of the
secondary layer forming material and the matrix forming material
should be sufficient to complex to the hydrogel bead. Preferably,
the reaction time is between 5 min to 3 hours, preferably between 5
min and 1 hour, and even more preferably is 30 min.
[0088] In a preferred method where in situ polymerized polyurea
(PU) membranes are formed as the secondary layer, the
polyisocyantes are first dispersed within the matrix forming
material and/or along with the active material. The microbeads can
then be formed in a crosslinking solution, where the secondary
layer is formed substantially simultaneously as the matrix core
with active droplets entrained therein.
[0089] In another preferred method where in situ polymerized
polymethylene urea membranes (PMU) are formed on hydrogel
microbeads, the matrix core with active droplets entrained therein
is formed prior to forming the secondary layer. The secondary layer
is then preferably formed by providing an aqueous solution of a
water-soluble, low-molecular weight urea-aldehyde precondensate
comprising predominantly low molecular weight reaction products of
urea, melamine or thiourea and formaldehyde and adding acid thereto
in amount to provide a pH for the dispersion in the range of about
1 to 6.0 and more practically about 1.0 to 3, thereby promoting
acid catalysis of the precondensate. Polymerization of the
precondensate to a water-insoluble urea-formaldehyde polymer can be
continued by agitation within a preferable temperature range of
about 20 to about 90.degree. C. for at least about one hour. The
polymerized layer can then be neutralized using sodium
hydroxide.
[0090] Prior to adding the microbeads a suspending solution, the
microbeads are preferably washed and filtered using, for example, a
Buchner type funnel.
[0091] Surfactants can be used in the process of forming the
microbeads. The incorporation of different surfactants will offer
different types of microemulsion drop sizes of the active within
the hydrogel as well as dictate the amount of free oil lost in the
reacting bath solution. A preferred surfactant has a high critical
micelle concentration, such as for example, a product available
under the product designation DISPONIL SUS IC 875 (CMC.about.1%).,
available from Henkel (Ambler, Pa.).
[0092] Particularly preferred surfactants are nonionic. Examples of
suitable surfactants include polyvinylpyrrolidone (PVP) and
poly(ethoxy)nonylphenol. PVP is usable and available at various
molecular weights in the range of from about 20,000 to about
90,000. PVP having a molecular weight of about 40,000 is preferred.
Poly(ethoxy)nonylphenols are commercially available under the trade
designation IGEPAL from Rhone-Poulenc (Cranbury, N.J.), with
various molecular weights depending on the length of the ethoxy
chain. Poly(ethoxy)nonylphenols having the formula: 5
[0093] where n has an average value from about 9 to about 13 can be
used. A preferred poly(ethoxy)nonylphenols is available
commercially under the product name IGEPAL 630, from Rhone-Poulenc
(Cranbury, N.J.)--630 is indicative of the approximate molecular
weight of the compound. Other examples of suitable surfactants
include polyether block copolymers, such as those available under
the trade designations PLURONIC and TETRONIC, both available from
BASF (Washington, N.J.), polyoxyethylene adducts of fatty alcohols,
such as BRIJ surfactants available from ICI (Wilmington, Del.), and
esters of fatty acids, such as stearates, oleates, and the like.
Examples of such fatty acids include sorbitan monostearate,
sorbitan monooleate, sorbitan sesquioleate, and the like. Examples
of the alcohol portions of the fatty esters include glycerol,
glucosyl and the like. Fatty esters are commercially available as
surfactants under the trade designation ARLACEL C from ICI
(Wilmington, Del.) Various properties of the surfactant, such as
for example, chain length, functional groups, and hydrophobic
regions, can affect the size of the active droplets formed within
the microbeads. For example, use of PVP (having a molecular weight
of 40,000) tend to result in production of larger sized active
droplets than use of poly(ethoxy)nonylphenols (IGEPAL 630).
[0094] Ionic surfactants can alternatively be used in the processes
of the invention. Examples of suitable ionic surfactants partially
neutralized salts of polyacrylic acids such as sodium or potassium
polyacrylate or sodium or potassium polymethacrylate.
[0095] The active material entrained in the microbeads of the
invention are released gradually over time. While not being bound
by this theory, it is believed that a mechanism of release of the
active in the microbeads of the invention involves water
evaporation from the matrix core and then diffusion of active
through the secondary layer. In another aspect, the active may be
released by entrainment with the hydrogel matrix as the water
evaporates, in addition to release by diffusion through the
secondary layer. Where multiple layers are optionally included in
the microbeads of the invention, the active preferably diffuses
though each layer.
[0096] In preferred applications, these hydrogel microbeads would
be sprayed followed by water evaporation within the gel. As the
hydrogel bead dehydrates, the matrix shrinks in size and releases
its active with time. The degree of shrinkage of the microbead from
its original size, depending on the components used in the
formulation. Preferably, the microbeads shrink about 10 to about
90% from its original size, more preferably from about 40 to about
80%, and most preferably from about 50% to about 70%.
[0097] Active release from the microbeads of the invention has
surprisingly been found to be controllable by controlling the
humidity (and dryness) of the environment in which the microbeads
are in. Advantageously, the microbead, upon re-exposure to
humidity, can swell and rehydrate itself by absorbing water.
Re-exposure to humidity can be performed in various ways. For
example the microbeads' surfaces can be contacted directly with
water or other aqueous solutions. In agricultural applications
where pheronomes are used as the active material, a farmer or
caretake can irrigate the plants and foliage to re-hydrate the
hydrogel microbeads. Alternatively, the humidity of the environment
or ambient air in which the microbeads are located in can be
increased by entraining air droplets in the air. Thus, the
microbeads can be "re-activiated" by re-hydration, thereby
selectively controlling the release times of the active
material.
[0098] It is contemplated that in the preferred embodiment where
the microbead comprises a secondary layer ionically complexed to
the matrix core surface, swell rates or rehydration effects may
result in a further alteration of the release profile of the
active. This may be due to the secondary layer having a different
absorption rate than that of the hydrophilic matrix core.
Advantageously, this can provide extended release profiles of the
active to a desired environment.
[0099] The microbeads of the invention can be delivered to an
intended substrate by various methods. In the preferred embodiment
where the active material is a pheromone, delivery of the
microbeads will depend on various factors, such as for example, the
size of release coverage desired. For small concentrated areas, the
microbeads can be impregnated into hollow fibres, plastic laminate
flakes or twist-ties and then physically attaching the fibres or
ties to plants to be protected from insect infestation. For larger
areas, spraying (aerially or by back-pack) may be the better
option.
[0100] All patents cited in this specficiation are hereby
incorporated by reference.
[0101] The following examples are provided to illustrate, but not
limit, the scope of the invention. Unless otherwise specified, all
parts and percentages are by weight.
EXAMPLES
[0102] The following list of materials were used in the Examples.
Listed adjacent to each material is the manufacturer and/or
supplier from which the materials were obtained.
1 3M HFE 7100 3M Co. (St. Paul, MN) Carvone Bedoukian (Danbury, CT)
Disponil SUS IC 875 Henkel (Ambler, PA) Drakeol 34 Penreco (Karns
City, PA) E,E-8,10-C12 alcohol Shin-Etsu Chemical Co., Ltd. (Tokyo,
Japan) Igepal C0-630 Rhone-Poulenc (Cranbury, New Jersey) Menthone
Berj (Bloomfield, NJ) Paraffin Wax Aldrich Chemical Co. (Milwaukee,
WI) Sodium alginate SKW (Lannilis, France) Solvent 100 Shell
Chemical Co. (Bayway, NJ) Starch Aldrich Chemical Co. (Milwaukee,
WS) Tixogel EZ100 Sud-Chemie Rheologicals (Louisville, KY) Z11-C14
acetate Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan)
TEST METHODS
[0103] To evaluate the physical performance of microbeads of the
invention, two parameters were measured: (1) air concentrations of
pheromone released from the microbead formulation and (2) the
amount of active remaining (i.e., residual concentration) in the
microbead over time.
[0104] Air Concentration Determination
[0105] A known amount of beads (10 microbeads) were recovered and
placed in a constant airflow chamber of 100 mL/min
(.about.23-24.degree. C. temperature). The effluent air stream from
the chambers was analyzed for active concentration using solid
phase microextraction (SPME) (Supelco, Bellefonte, Pa.) and gas
chromatography (GC) (Varian Chromatography Systems, Walnut Creek,
Calif.) over a period of weeks to evaluate the performance of the
hydrogel microbeads.
[0106] To calculate the Release Rate of an active, the Air
Concentration is multiplied by the Air Flow rate.
[0107] Residual Concentration Determination
[0108] Formulations were filtered using a Buchner type vacuum
funnel, washed with room temperature distilled water and dried in a
fumehood at room temperature for 24 hours. Fifty milligrams of the
dried formulation were put on tinfoil squares as application
substrates. After the required exposure time, the microbeads were
subjected to extraction for at least 24 hours with 4 mL of
dichloromethane to determine the residual level of active still
remaining in the formulation. Each collected sample was then
analyzed by gas chromatography.
Example 1
Formation of Pheromone Entrapped Hydrogel Microbeads
[0109] For each of the Samples A-J (shown in Table 1), a sodium
alginate solution was initially prepared by dissolving a preweighed
amount of alginate into a known volume of distilled water. The
solution was mixed thoroughly to solubilize the polymer and was
deaerated for removal of entrained air bubbles. In a separate 250
mL vessel, the active and surfactant was added and mixed at a speed
of about 2000 RPM using a marine type impeller (3.81 cm diameter).
To the mixture, the alginate solution was gradually added to form
the microemulsion. The emulsion was homogenized for about 30
minutes. The emulsion was then atomized into fine particle droplets
using a coaxial air nozzle sprayer. The size of the particles was
determined by the settings on the atomizing device. This involved
control of the nozzle head diameters, the feed rate of the emulsion
through the nozzle and the airflow which passed along its feed path
(shown in Table 2). For an example, to create fine particles within
the sprayable range (Sample E), the nozzle feed diameter was 0.508
mm, the coaxial air nozzle was 1.4 mm, the feed pressure was about
34.4-110.3 kPa, and the airflow was about 13.8-34.5 kPa. As a
result, discrete spherical microbeads were produced with a particle
size range of 4 to 400 microns.
[0110] Examples A-F demonstrated the ability of this invention to
encapsulate oils or pheromones with function groups of ketones,
alcohols, and acetates. All the formulations resulted in spherical
intact hydrogel microbeads containing the desired active.
[0111] Examples G-I demonstrated the ability of this invention to
absorb oils or pheromones with functional groups of ketones,
alcohols, and acetates within an absorbent material prior to
encapsulation within a hydrogel matrix. All the formulations
resulted in spherical intact hydrogel microbeads containing the
desired active.
2TABLE 1 Hydrogel microbead formulations Sodium alginate Conc.
Active Surfactant Calcium (g/100 Weight Weight Weight conc. Sample
mL) (g) Type (g) Type (g) (mM) A 2.0 50.0 Carvone 20.0 Igepal 2.0
50 CO-630 B 2.0 50.0 Carvone 5.0 Igepal 1.0 50 CO-630 C 2.0 38.6 E,
E-8, 10-C12 1.0 Disponil 1.0 50 alcohol/Solvent SUS IC 100 (1:4 by
wt) 875 D 2.5 250.0 Menthone 50.0 Igepal 5.0 50 CO-630 E 2.5 800.0
Z11-C14 acetate 20.0 Igepal 2.0 1000 CO-630 F 2.0 38.6 Z11-C14
acetate 1.0 Disponil 0.4 50 SUS IC 875 G 2.0 40.0 Z11C14 acetate/
3.0 n/a 50 starch (1:4 by wt) H 2.5 250.0 Menthone/ 56.0 n/a 50
Tixogel EZ100 (8:1 by wt) I 2.5 250.0 Menthone/ 44.0 n/a 50
parrafin wax (10:1 by wt)
[0112] Hydrogel microbeads were formed using coaxial airflow
atomization, using the formulations of Samples A and E. Average
particle diameters were measured by evaluating 30-50 microbeads,
using a stereomicroscope product name STEREOZOOM 7 available from
Bausch & Lomb (Brick, N.J.) and a light microscope product
LEITZ DIAPLAN available from Ernst Leitz (Wetzlar, West Germany).
The nozzle size and settings varied respectively to produce
different size particles, as shown in Table 2.
3 TABLE 2 Feed Nozzle Coaxial air Mean Diameter Pressure Diameter
Pressure Diameter Sample (in.) (psi) (in.) (psi) (mm) A 0.020 10
0.046 0 2.8 0.016 20 0.046 0 1.7 0.020 10 0.046 5 0.9 0.016 20
0.046 5 0.2 E 0.020 5 0.055 5 0.094 0.020 16 0.055 2 0.135 0.020 16
0.055 5 0.126 0.020 14 0.055 4 0.063
Example 2
Ionic Complexation to Form Secondary Layer
Example 2A
2 Step Process
[0113] The procedure outlined in EXAMPLE 1 was adopted, where
Sample E was used, with the variation that a polymer forming
solution was used first to crosslink the emulsion droplet on the
outside peripherial. In a vessel, a solution of chitosan (Seacure
143, Pronova Biopolymer, Washington) containing 5% glacial acetic
acid was prepared by mixing at room temperature. The solution pH
was adjusted to about 5.6 using sodium hydroxide. The method of
microbead preparation utilizing coaxial air atomization was also
adopted using protocol demonstrated in EXAMPLE 1. As an example,
the nozzle feed diameter was 0.020 inches, the coaxial air nozzle
diameter was 0.055 inches, the feed pressure was about 10 psi, and
the airflow was set to 0 psi. After the microbeads were formed,
they were soaked in the forming solution for about 3-4 hours. To
solidify the membrane bound pheromone droplets, 11 g of calcium
chloride crystals were added to the suspension. The microbeads were
then gelled for 3-4 hours, filtered and washed with water. As a
result of the following example, discrete spherical menthone
immobilized hydrogel microbeads were produced with an average
particle size of about 2.5 millimeters.
Example 2B
1 Step Process
[0114] The procedure outlined in EXAMPLE 1 was adopted, where
SAMPLE A was used, in addition to a polymer forming solution along
with the calcium chloride. In a vessel, a solution of chitosan
(Seacure 143, Pronova Biopolymer, Washington) containing 1% glacial
acetic acid and 50 millimolar calcium chloride was prepared by
mixing at room temperature. The solution pH was adjusted to about
5.6 using sodium hydroxide. The method of microbead preparation
utilizing coaxial air atomization was also adopted using protocol
demonstrated in EXAMPLE 1. The nozzle feed diameter was 0.020
inches, the coaxial air nozzle diameter was 0.055 inches, the feed
pressure was about 10 psi, and the airflow was set to 0 psi. As a
result of the following example, discrete spherical carvone
immobilized hydrogel microbeads were produced with an average
particle size of about 3.2 millimeters.
Example 3
In-situ Polymerization
Preparation of the Prepolymer
[0115] A 1 L jacketed reactor set to 71.degree. C. was charged with
326.0 g formaldehyde (Hoechst-Celanese, Rock Hill, S.C.), 121.6 g
urea (Arcadian Corporation, Memphis, Tenn.) and 1.14 g potassium
tetraborate tetrahydrate (Aldrich Chemical Co., Milwaukee, Wis.).
The solution was mixed for 2.5 hours at 350 RPM using a six blade
turbine. Dilution water (552.4 g) was then added and mixed well
before bottling and storing at room temperature.
Example 3A
[0116] The procedure outline in EXAMPLE 1 was adopted, where Sample
E was used to produce discrete menthone immobilized in microbeads
of about 1 millimeter in diameter. Filtered and water washed
microbeads were placed into a 35.degree. C. jacketed reactor
charged with distilled, room temperature water (43.86 g) and the
prepolymer solution (101.54 g). The suspension was then mixed at
about 100 RPM using a six blade turbine for 5 minutes. Gradually,
the pH was was adjusted from an initial 8.5 to a final 2.8 using
concentrated sulfuric acid (1.2N) at an approximate rate of 0.08 pH
units/min. The reaction was stirred at 100 RPM for 30 minutes,
before lowering the pH to 2.1 and temperature to 25.degree. C. The
reaction was stirred for a further 1 hour, then the temperature was
increased to 60.degree. C. over 15 minutes, and the mixture held
for a final 1 hour. The reaction mixture was cooled to room
temperature and neutralized with ammonium hydroxide. The microbeads
were filtered and washed several times with water. The resulting
microbeads were discrete and possessed a rigid, hard coating.
Example 3B
[0117] The procedure outlined in EXAMPLE 3A was adopted and
followed except that the microbeads used were chitosan layered
menthone hydrogel microbeads obtained from EXAMPLE 2A. The
resulting microbeads were discrete and possessed a secondary
layer.
Example 3C
[0118] The procedure outline in EXAMPLE 3A was adopted and followed
except that the microbeads used were carvone hydrogel microbeads
obtained from Sample B. The resulting microbeads were discrete and
possessed a secondary layer.
Example 3D
[0119] The procedure outline in EXAMPLE 3A was adopted and followed
except that the microbeads used were menthone absorbed in clay
(Tixogel EZ 100, Sud-Chemie Rheologicals, Louisville, Ky.) calcium
alginate hydrogels obtained from Sample I. The resulting microbeads
were discrete and possessed a secondary layer.
Example 3E
[0120] The procedure outline in EXAMPLE 3A was adopted and followed
except that the microbeads used were menthone absorbed in wax
(Paraffin Wax, Aldrich) calcium alginate hydrogels obtained from
Sample J. The resulting microbeads were discrete and possessed a
secondary layer.
Example 4
[0121] Following the test methods described above for Air
Concentration, known batches from Sample A and Example 2B were
evaluated over a duration of at least 7 seeks while Sample B and
Example 3C were evaluated for 5 days. Tables 3 provides the release
rate analysis. Air Concentration Determination analysis showed a
burst of active (carvone) in the air during the first day followed
by a gradual decrease with time for all formulations. In the
initial portion of the total release period, the release rate for
the microbeads comprising a secondary layer was observed to be
significantly lower than that of non-layered microbeads.
Subsequently, the longevity of the release is extended
significantly as a result of forming an ionically complexed layer
on hydrogel microbeads. Similarly, lower release rates were
observed for in situ polymerized layers at the initial. This, in
turn, increases the longevity of the release.
4 TABLE 3 Release rate in air (ng/min per mg carvone) Time Sample A
Example 2B Sample B Sample 3C (days) No 2.sup.nd layer w/layer No
2.sup.nd layer w/layer 0 165.9 144.8 601.6 72.2 0.05 556.8 123.0
554.2 25.3 0.08 941.2 126.3 -- -- 0.12 877.5 248.9 -- -- 0.15 854.2
467.8 498.6 15.3 1 -- 141.9 -- -- 2 43.3 118.7 2.1 1.1 5 0.001 36.2
1.0 0.5 8 -- 0.177 -- -- 10 0.001 0.089 -- -- 13 0.001 -- -- -- 15
-- 0.026 -- -- 18 -- 0.016 -- -- 20 -- 0.017 -- -- 25 -- 0.011 --
-- 47 -- 0.007 -- -- 61 -- 0.004 -- --
* * * * *