U.S. patent application number 16/711616 was filed with the patent office on 2020-04-16 for microcapsules comprising active ingredients and a metal oxide shell, a method for their preparation and uses thereof.
This patent application is currently assigned to Sol-Gel Technologies Ltd.. The applicant listed for this patent is Sol-Gel Technologies Ltd.. Invention is credited to Raed Abu-Reziq, Natalia Loboda, Ofer TOLEDANO Olfer TOLEDANO, Hanan Sertchook.
Application Number | 20200114327 16/711616 |
Document ID | / |
Family ID | 41467117 |
Filed Date | 2020-04-16 |
![](/patent/app/20200114327/US20200114327A1-20200416-P00001.png)
United States Patent
Application |
20200114327 |
Kind Code |
A1 |
Olfer TOLEDANO; Ofer TOLEDANO ;
et al. |
April 16, 2020 |
MICROCAPSULES COMPRISING ACTIVE INGREDIENTS AND A METAL OXIDE
SHELL, A METHOD FOR THEIR PREPARATION AND USES THEREOF
Abstract
The present invention provides a process for preparing
microcapsules comprising a core material encapsulated by a metal
oxide shell, microcapsules obtained therewith and uses thereof.
Inventors: |
Olfer TOLEDANO; Ofer TOLEDANO;
(Kfar Saba, IL) ; Sertchook; Hanan; (Gedera,
IL) ; Loboda; Natalia; (Jerusalem, IL) ;
Abu-Reziq; Raed; (Jatt Hamesholash, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sol-Gel Technologies Ltd. |
Ness Ziona |
|
IL |
|
|
Assignee: |
Sol-Gel Technologies Ltd.
Ness Ziona
IL
|
Family ID: |
41467117 |
Appl. No.: |
16/711616 |
Filed: |
December 12, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13056952 |
Apr 6, 2011 |
|
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PCT/IL2009/000751 |
Aug 2, 2009 |
|
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16711616 |
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61085255 |
Jul 31, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/27 20130101; A61P
31/04 20180101; A61P 31/10 20180101; B01J 13/14 20130101; A61P
29/00 20180101; A61P 17/00 20180101; A61P 17/10 20180101; A01N
25/28 20130101; A61P 17/04 20180101; A61P 17/08 20180101; A61K 8/28
20130101; A61Q 19/00 20130101; A61K 8/25 20130101; A61P 17/06
20180101; A61K 2800/412 20130101; A61K 8/29 20130101; A61K 8/11
20130101; A01N 25/28 20130101; A01N 37/16 20130101; A01N 37/22
20130101; A01N 43/80 20130101; A01N 47/24 20130101 |
International
Class: |
B01J 13/14 20060101
B01J013/14; A61Q 19/00 20060101 A61Q019/00; A61K 8/11 20060101
A61K008/11; A61K 8/29 20060101 A61K008/29; A01N 25/28 20060101
A01N025/28; A61K 8/27 20060101 A61K008/27; A61K 8/25 20060101
A61K008/25; A61K 8/28 20060101 A61K008/28 |
Claims
1. Microcapsules comprising a core material encapsulated by a metal
oxide shell, wherein the microcapsules are prepared by a process
comprising: (a) preparing an oil-in-water emulsion by
emulsification of an oily phase that comprises a core material, in
an aqueous phase, wherein one or both of the oily phase and the
aqueous phase comprise a sol-gel precursor; (b) adding metal oxide
nanoparticles to said aqueous phase prior to the preparation of the
emulsion of step (a), or adding the metal oxide nanoparticles
during the preparation of the emulsion of step (a) or adding the
metal oxide nanoparticles after the preparation of the emulsion of
step (a); and thereby obtaining a stable emulsion; and (c) applying
conditions to obtain microcapsules; wherein said core material
comprises a pharmaceutically, cosmetically, or agrochemically
active ingredient, wherein the active ingredient is in a solid form
and dispersed in the core, and wherein said metal oxide is selected
from silica, titania, zirconia, ZnO, and mixtures thereof.
2. The microcapsules of claim 1, wherein said core material is a
dispersion of the solid active ingredient; wherein the thickness of
said metal oxide shell is in the range of 0.1-10 microns, and
wherein said shell is obtained from (a) metal oxide nanoparticles,
and (b) a hydrolyzed and polymerized sol gel precursor.
3. The microcapsules of claim 1, wherein said core material
comprises a dermatologically active agent selected from antifungal
agents, antibacterial agents, anti-inflammatory agents,
antipruritic agents, anti psoriatic agents, anti acne agents, anti
rosacea agents, and combinations of any of the above.
4. The microcapsules of claim 1, wherein said core material
comprises an anti acne agent selected form benzoyl peroxide,
retinoid, and mixtures thereof.
5. A composition comprising microcapsules according to claim 1 and
a carrier.
6. A method for treating a surface condition in a subject,
comprising topically administering onto the surface a composition
according to claim 5, wherein core material comprises a topically
acting active agent.
7. The method of claim 6, wherein said surface is skin or mucosal
membrane.
8. The method of claim 6, wherein said surface condition is a skin
disease or disorder selected from acne, infection, inflammation,
pruritis, psoriasis, seborrhea, contact dermatitis, rosacea, and a
combination thereof.
9. A composition comprising microcapsules according to claim 1,
wherein the core material comprises a topically acting active
agent, for treatment of a disease or disorder selected from acne,
infection, inflammation, pruritis, psoriasis, seborrhea, contact
dermatitis, rosacea, and combination thereof.
10. A composition for pest control comprising microcapsules
according to claim 1, wherein said core material comprises a
pesticide.
11. The composition of claim 10 for crop protection or noncrop pest
control.
12. The composition of claim 10, wherein said pesticide is selected
from a herbicide, an insecticide, a fungicide, and mixtures
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation Application of
United-States application Ser. No. 13/056,952, filed Apr. 6, 2011,
which is National Phase Application of PCT International
Application No. PCT/IL2009/000751, International Filing Date Aug.
2, 2009, claiming priority from United-States Provisional
Application No. 61/085,255, filed Jul. 31, 2008, which are
incorporated in their entirety herein by reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to process for
preparing microcapsules, compositions comprising microcapsules and
uses thereof.
BACKGROUND OF THE INVENTION
[0003] The following publications are considered pertinent for
describing the state of the art in the field of the invention.
U.S. Pat. No. 5,500,223 U.S. Pat. No. 6,303,149 U.S. Pat. No.
6,238,650 U.S. Pat. No. 6,468,509 U.S. Pat. No. 6,436,375 U.S. Pat.
No. 6,337,089
US 2005037087
US 2002064541
[0004] U.S. Pat. No. 6,251,313 U.S. Pat. No. 4,931,362 U.S. Pat.
No. 6,855,335
WO 00/09652
WO 00/72806
WO 01/80823
WO 03/03497
WO 03/039510
WO 00/71084
WO 05/009604
WO 04/81222
WO 03/066209
GB 2416524
EP 0 934 773
EP 0 941 761
S. A. F. Bon et al., Pickering Stabilization as a Tool in the
Fabrication of Complex Nanopattemed Silica Microcapsules, Langmir,
23: 9527-9530, 2007.
[0005] C. A. Prestidge et al. Nanoparticle encapsulation of
emulsion droplets, International Journal of Pharmaceutics
324:92-100. 2006.
SUMMARY OF THE INVENTION
[0006] The present invention relates to a process for preparing
microcapsules comprising a core material encapsulated by a metal
oxide shell, said process comprising:
[0007] preparing an oil-in-water emulsion by emulsification of an
oily phase that comprises a core material, in an aqueous phase,
wherein one or both of the oily phase, and the aqueous phase
comprises a sol-gel precursor;
[0008] including metal oxide nanoparticles in said aqueous phase
either prior, during or after (a); and
[0009] applying conditions to obtain microcapsules.
[0010] The invention further relates to microcapsules obtainable by
the process as described in the present invention.
[0011] The invention additionally relates to microcapsules
comprising a core material encapsulated by a metal oxide shell,
wherein said core material is (i) a liquid or (ii) a dispersion in
liquid; wherein the thickness of said shell is in the range 0.1-10
micron; and wherein said shell is obtained from (a) metal oxide
nanoparticles, and (b) a hydrolyzed and polymerized sol gel
precursor.
[0012] Moreover, the invention relates to a composition comprising
microcapsules as described in the present invention; and a
carrier.
[0013] The invention additionally relates to a method for treating
a surface condition in a subject, comprising topically
administering onto the surface a composition as described in the
invention, wherein the core material comprises a topically acting
active agent.
[0014] The invention further relates to a composition comprising
microcapsules as described in the present invention, wherein the
core material comprises a topically acting active agent, for
treatment of a disease or disorder selected from acne, infection,
inflammation, pruritis, psoriasis, seborrhea, contact dermatitis,
rosacea, and a combination thereof.
[0015] Moreover, the invention relates to use of microcapsules as
described in the present invention, wherein the core material
comprises a topically acting active agent for the preparation of a
medicament for topical administration on the skin or mucosal
membrane.
[0016] Additionally, the invention relates to compositions for pest
control comprising micro capsules as described in the present
invention, wherein said core material comprises a pesticide.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention is based on the finding of a manner of
obtaining a thick and dense coating on a liquid water insoluble
core or a dispersion in a liquid water insoluble core, using metal
oxide nanoparticles in combination with a sol-gel precursor.
[0018] Thus, in one aspect of the present invention, there is
provided a process for preparing microcapsules comprising a core
material encapsulated by a metal oxide shell, said process
comprising:
[0019] preparing an oil-in-water emulsion by emulsification of an
oily phase that comprises a core material, in an aqueous phase,
wherein one or both of the oily phase, and the aqueous phase
comprises a sol-gel precursor;
[0020] including metal oxide nanoparticles in said aqueous phase
either prior, during or after (a); and applying conditions to
obtain microcapsules.
[0021] In the present invention the term "core material" refers to
the inside part of the microcapsules comprising an active
ingredient that is surrounded by the metal oxide shell of the
microcapsules. This term refers to any material present in the
core, both the active ingredient and the excipients such as the
liquid carrier.
[0022] The core material which may be a water insoluble liquid or a
dispersion in water-insoluble liquid comprises an active ingredient
(e.g. a pesticide, dermatological active ingredient). The core
material may be constituted by a water-insoluble liquid active
ingredient; may comprise a first, water-insoluble liquid active
ingredient dissolved and/or dispersed in a second, water insoluble
liquid being another active ingredient or serving as a carrier
medium; may comprise a solid active ingredient dissolved and/or
dispersed in a water-insoluble liquid being another active
ingredient or serving as a carrier medium. The active ingredient
may be a single type of active ingredient or may be a combination
of two or more active ingredients.
[0023] The term "water insoluble liquid" or "dispersion in
water-insoluble liquid" refers to a solubility of the liquid
(including the ingredients included therein, dissolved and/or
dispersed) in water of about less than 1% w/w at room temperature
(20-25.degree. C.). In one embodiment a solubility of the liquid
(including the ingredients included therein, dissolved and/or
dispersed) in water of about 0.5% w/w at room temperature
(20-25.degree. C.). In another embodiment a solubility of the
liquid (including the ingredients included therein, dissolved
and/or dispersed) in water of about less than 1% w/w at room
temperature (20-25.degree. C.). In one embodiment a solubility of
the liquid (including the ingredients included therein, dissolved
and/or dispersed) in water of about 0.15% w/w at room temperature
(20-25.degree. C.).
[0024] Accordingly, the constituents included in the core material
whether solid or liquid ingredients have a solubility of about less
than 1% w/w at room temperature (20-25.degree. C.). In one
embodiment the constituents included in the core material whether
solid or liquid ingredients have a solubility of about 0.5% w/w at
room temperature (20-25.degree. C.). In another embodiment, the
constituents included in the core material whether solid or liquid
ingredients have a solubility of about 0.15% w/w at room
temperature (20-25.degree. C.).
[0025] A water insoluble liquid may be selected from the following
non-limiting list: squalane oil, polydimethylsiloxane, mineral oil,
castor oil, aromatic 200, and mixtures thereof.
[0026] In the present invention, the term "sol-gel precursor"
refers to any metal or semi-metal organo-metallic monomer, or a
prepolymer (which means several monomers polymerized together)
thereof, which allows to obtain a glass or ceramic material by
in-situ polymerization (an inorganic sol-gel polymerization
process). In one embodiment a sol-gel precursor is a metal or
semi-metal organo-metallic monomer (e.g. a metal or semi-metal
alkoxide monomer.
[0027] In the present invention, the term "active ingredient"
refers to any molecule or substance that can be used in medicine,
cosmetics, agriculture and which grants the final product
(cosmetics, pesticide, drug, etc.) at least one desired
property.
[0028] As used herein the term "metal oxide nanoparticles" refers
to substantially pure metal oxide nanoparticles consisting
essentially of or comprised wholly of metal oxide. In one
embodiment a metal oxide nanoparticles do not include organic
material, in particular not polystyrene.
[0029] According to an embodiment of the present invention said
core material comprises a pharmaceutically, cosmetically, or
agrochemically active ingredient.
[0030] Additionally according to another embodiment of the present
invention said core material comprises a dermatologically active
agent.
[0031] Further according to another embodiment of the present
invention said dermatologically active agent is selected from
antifungal agents, antibacterial agents, anti inflammatory agents,
antipruritic agents, anti psoriatic agent, anti acne agents, anti
rosacea agents, and combinations of any of the above.
[0032] In one embodiment, said anti acne agent is selected from
benzoyl peroxide, retinoid, and mixtures thereof.
[0033] The retinoid may be for example tretinoin (all trans
retinoic acid), tazarotene, iso-tretinoin, adapalene or mixtures
thereof.
[0034] According to another embodiment of the present invention
said agrochemical active ingredient is a pesticide.
[0035] Pesticides which may be employed in the practice of this
invention include a wide range of herbicides, nematocides,
insecticides, acaricides, fungicides, plant growth promoting or
controlling chemicals and other crop treating products which may be
solid or liquid at ambient temperatures. One of ordinary skill in
the art can find a listing of suitable pesticides by consulting
references such as the Ashgate Handbook of Pesticides and
Agricultural Chemicals, G. W. A. Milne (ed.), Wiley Publishers
(2000). Combinations of two or more pesticides may also be
employed.
[0036] The pesticide may be selected from herbicides, insecticides,
fungicides, and mixtures thereof.
[0037] Non limiting examples of herbicides are triazines,
dinitroanilines, phenoxy esters, benzamides, chloroacetamides,
isoxazolidinone, pyridine carboxamides, quinolinecarboxylates,
thiocarbamates, triazolinones, triazolopyrimidines, triketones,
ureas, and mixtures thereof.
[0038] Non limiting examples of insecticides are mectins, benzoyl
ureas, carbamates, diacylhydrazines, isoxazoles, neonicitonoids,
organophosphates, oxadiazines, phenylpyrazoles, pyrethroids,
semicarbazones, strobilurons, tetronic acids, and mixtures
thereof.
[0039] Non limiting examples of fungicides are benzimidazoles,
carboxamides, azoles, mandelamide, morpholine, phenyl amides, and
mixtures thereof.
The agrochemical active ingredient may also be pheromones,
synergists, plant growth regulators.
[0040] Non limiting examples of pesticide active ingredients
are:
[0041] 2,4-D-2-ethylhexyl, abamectin, acetochlor, aclonifen,
alachlor, aldrin, alpha-cypermethrin, ametryn, atrazine,
azadirachtin, azinphos-ethyl, azinphos-methyl, azoxystrobin,
benalaxyl, benalaxyl-M, bendiocarb, benfluralin, benomyl,
bentazone, beta-cyfluthrin, beta-cypermethrin, bifenthrin,
binapacryl, bioresmethrin, boscalid, bromophos, bromophos-ethyl,
bromoxynil, butachlor, butylate, cadusafos, captafol, captan,
carbaryl, carbendazim, carbofuran, carbosulfan, carboxin,
carfentrazone-ethyl, chlorfenvinphos, chlorfluazuron,
chlorothalonil, chlorphoxim, chlorpyrifos, chromafenozide,
clodinafop-propargyl, clomazone, cloquintocet-mexyl,
cloransulam-methyl, clothianidin, cyanazine, cyazofamid,
cyfluthrin, cyhalofop-butyl, cyhalothrin, cypermethrin,
cyproconazole, deltamethrin, diazinon, diclofop-methyl,
diclofop-P-methyl, dimethomorph, dimethylvinphos, dimoxystrobin,
disulfoton, dithianon, dithiopyr, diuron, dodemorph acetate,
dodemorph, emamectin benzoate, endosulfan, epoxiconazole,
esfenvalerate, etaconazole, ethalfluralin, ethofumesate,
etofenprox, fenamiphos, fenbuconazole, fenoxaprop-ethyl,
fenpropimorph, fenvalerate, fipronil, fluazifop-butyl,
fluazifop-P-butyl, fluazinam, flucythrinate, flufenacet,
flufenoxuron, flumetsulam, fluotrimazole, fluoxastrobin,
fluquinconazole, flusilazole, flutolanil, flutriafol, fluvalinate,
folpet, fomesafen, fosmethilan, gamma-cyhalothrin, halofenozide,
haloxyfop-P-methyl, hexaconazole, hydramethylnon, imidacloprid,
indoxacarb, ioxynil octanoate, ipconazole, isazofos, isofenphos,
isoproturon, isoxaflutole, isoxathion, karbutilate,
kresoxim-methyl, lactofen, lambda-cyhalothrin, linuron, lufenuron,
malathion, mancozeb, mandipropamid, MCPA-2-ethylhexyl,
metaflumizone, metazachlor, metconazole, methoxyfenozide,
metofluthrin, metominostrobin, metoxuron, metrafenone, metribuzin,
milbemectin, myclobutanil, napropamide, nicosulfuron, nitralin,
nitrofen, norflurazon, novaluron, oryzalin, oxyfluorfen,
paclobutrazol, penconazole, pencycuron, pendimethalin, permethrin,
petroleum oils, phenthoate, phorate, phosalone, phosdiphen,
phosmet, phoxim, picloram, picolinafen, picoxystrobin, pinoxaden,
piperonyl butoxide, pirimiphos-ethyl, pirimiphos-methyl,
prallethrin, prochloraz, prodiamine, prometryn, propachlor,
propanil, propaphos, propargite, propiconazole, pymetrozine,
pyraclostrobin, pyrazophos, pyrethrins (chrysanthemates),
pyridalyl, pyridate, quinclorac, quinmerac, quizalofop-ethyl,
quizalofop-P-ethyl, quizalofop-P-tefuryl, resmethrin, simazine,
simeconazole, S-metolachlor, spinosad, spirodiclofen, spiromesifen,
spiroxamine, sulcotrione, sulfentrazone, sulprofos,
tau-fluvalinate, tebuconazole, tebufenozide, tebufenpyrad,
tebupirimfos, teflubenzuron, tefluthrin, temephos, terallethrin,
terbacil, terbufos, tetraconazole, tetramethrin, thiacloprid,
thidiazuron, thiram, tralomethrin, transfluthrin, tri-allate,
triazamate, trifloxystrobin, trifluralin, triticonazole,
zeta-cypermethrin, ziram, zoxamide, pheromones, sulfur, and
mixtures of any of the above.
[0042] According to an embodiment of the present invention said
metal oxide is selected from Silica, Titania, Zirconia, ZnO, and
mixtures thereof.
[0043] According to one embodiment of the present invention said
metal oxide nanoparticles have a particle size diameter (d50) in
the range of 1-100 nanometer. In another embodiment, said metal
oxide nanoparticles have a particle size diameter (d50) in the
range of 1-50 nm. In yet a further embodiment, said metal oxide
nanoparticles have a particle size diameter (d50) in the range of
5-30 nm.
[0044] By the term "particle size diameter (d50) in the range of
1-100 nanometer" is meant that 50% by volume of the particles may
be less than or equal to a value in the range of 1-100
nanometer.
[0045] Unless otherwise indicated referring to size of particles
will be through their D90 meaning that 90% of the particles have
the stated dimension or less (measured by volume). Thus, for
examples, for nanoparticles stated to have a diameter of 10
nanometer, this means that the nanoparticles have a D90 of 10
nanometer. The D90 may be measured by laser diffraction.
[0046] According to one embodiment of the present invention the
weight ratio of said metal oxide nanoparticles to said core
material is in the range of 1:99 to 3:2. In one embodiment the
weight ratio of said metal oxide nanoparticles to said core
material is in the range of 1:50 to 1:1. In another embodiment the
weight ratio of said metal oxide nanoparticles to said core
material is in the range of 1:20 to 1:5.
[0047] According to one embodiment of the present invention the
mole ratio between the metal oxide produced from said sol-gel
precursor and said metal oxide nanoparticles is in the range 1:99
to 1:1. In one embodiment the mole ratio between the metal oxide
produced from said sol-gel precursor and said metal oxide
nanoparticles is in the range 1:50 to 1:2. In another embodiment
the mole ratio between the metal oxide produced from said sol-gel
precursor and said metal oxide nanoparticles is in the range 1:25
to 1:4.
[0048] According to an embodiment the process of the present
invention further comprising adding a salt of a metal oxide to said
aqueous phase either prior, during or after (a).
[0049] In one embodiment, said salt of metal oxide is selected from
sodium silicate, potassium silicate, sodium titanate, potassium
titanate, sodium zirconate, potassium zirconate, and mixtures
thereof.
[0050] In one embodiment, the weight ratio of said metal oxide
nanoparticles to said metal oxide salt is in the range 99:1 to 1:2.
In another embodiment the weight ratio of said metal oxide
nanoparticles to said metal oxide salt is in the range of 50:1 to
2:1. In a further embodiment the weight ratio of said metal oxide
nanoparticles to said metal oxide salt is in the range of 50:1 to
10:1.
[0051] According to an embodiment the process of the present
invention further comprising adding a binding or cross-linking
additive selected from a polymeric agent, a di- or trivalent metal
salt, a polyelectrolyte, and mixtures thereof, to said aqueous
phase either prior, during or after (a).
[0052] In one embodiment, said polymeric agent is selected from
sodium alginate, polyvinyl alcohol, carboxymethyl cellulose,
polyvinyl pyrrolidone, and mixtures thereof.
[0053] In another embodiment, said di- or trivalent metal salt is
selected from aluminum sulfate, sodium aluminate, sodium borate,
calcium chloride, and mixtures thereof.
[0054] The purpose of using the following ingredients was to make
capsules more cross-linked and strengthen the shell.
[0055] Without being bound to theory the ingredients below may act
as follows:
[0056] Aluminum sulfate--the positively charged aluminum cations
may be attracted to the negatively charged metal oxide
nanoparticles and as such may work as cross-linkers between the
metal oxide nanoparticles which are adsorbed on the oil
droplet-water interface
[0057] Sodium aluminate--sodium aluminate may react with the
silanol groups on the metal oxide nanoparticles surface, and as
such may work as cross-linkers between the metal oxide
nanoparticles which are adsorbed on the oil droplet-water
interface.
[0058] PVA (polyvinyl alcohol) may adsorb onto the metal oxide
shell via hydrogen bonds and also can be cross-linked by sodium
borate.
[0059] Sodium borate--sodium borate may cross link the PVA with the
metal oxide shell of the micro capsules.
[0060] Sodium alginate--sodium alginate may adsorb onto the metal
oxide shell (produced from adsorption of metal oxide nanoparticles)
and may be cross-linked by addition of calcium chloride.
[0061] PDAC 7 (polyquatemium 7)--PDAC 7 may be used for coating of
the metal oxide shell. PDAC 7 which is positively charged may
adsorb onto the negatively charged metal oxide shell and as such
decrease the "gaps" between the metal oxide nanoparticles and thus
strengthen the shell.
[0062] CMC (carboxymethyl cellulose)--CMC may be used for
additional coating of the metal oxide shell. It can be used after
coatings with PDAC 7.
[0063] PDAC 7 and CMC when used in combination may be added for
coating and strengthening the metal oxide shell.
[0064] In one embodiment, said polyelectrolyte is selected from
Polyquatemium-7 (Dimethyldiallylammonium chloride acrylamide
copolymer), Polyquatemium-1
[Poly[(dimethyliminio)-2-butene-1,4-diyl
chloride],a-[4-[tris(2-hydroxyethyl)ammonio]-2-butenyl]-a>-[tris(2-hyd-
roxyethyl)ammonio]-, dichloride], Polyquatemium-10 [Cellulose
2-hydroxyethyl 2-(2-hydroxy-3
(trimethylammonio)propoxy)ethyl-2-hydroxy-3-(trimethylammonio)propyl
ether, chloride], Chitosan, Poly lysine, and mixtures thereof.
[0065] According to an embodiment of the present invention said
oily phase comprises a sol-gel precursor.
[0066] According to an embodiment of the present invention said
sol-gel precursors are selected from metal alkoxide monomers,
semi-metal alkoxide monomers, metal ester monomers, semi-metal
ester monomers and from monomers of the formula M(R) n (P) m,
wherein M is a metallic or semi metallic element, R is a
hydrolysable substituent, n is an integer from 2 to 6, P is a non
polymerizable substituent and m is and integer from 0 to 6, a
partially hydrolyzed and partially condensed polymer of any of the
above, and mixtures of any of the above.
[0067] In one embodiment, said metallic or semi metallic element is
selected from Si, Ti, Zr, Al, and Zn.
[0068] In another embodiment, said sol-gel precursors are selected
from silicon alkoxide monomers, silicon ester monomers, monomers of
the formula Si(R)n(P)m, where R is a hydrolysable substituent, n is
an integer from 2 to 4, P is a non polymerizable substituent and m
is and integer from 0 to 4, a partially hydrolyzed and partially
condensed polymer of any of the above, and mixtures of any of the
above.
[0069] In a further embodiment, said silicon alkoxide monomer is
selected from tetramethoxy silane, tetraethoxy silane, and mixtures
thereof.
[0070] In yet a further embodiment, said monomers of the formula
Si(R)n(P)m are selected from methyl trimethoxysilane, dimethyl
dimethoxysilane, and mixtures thereof.
[0071] In one embodiment, the sol-gel precursor is a monomer (e.g.
a metal alkoxide monomer, a semi-metal alkoxide monomer) as
described hereinbefore. In one embodiment the sol-gel precursor is
not a polymerized monomer, which can undergo a sol-gel process.
[0072] According to an embodiment of the present invention the pH
of said aqueous phase is in the range 2-9. In one embodiment, the
pH of said aqueous phase is in the range 2-7. In a further
embodiment, the pH of said aqueous phase is in the range 3-5.
[0073] According to an embodiment of the present invention said
conditions comprising isolating the microcapsules through
procedures selected from at least one of: separation by centrifuge,
filtration, evaporation, re-suspension in aqueous medium, and
dialysis.
[0074] According to an embodiment of the present invention said
conditions comprising pH in the range 2-9. In a further embodiment
the pH is in the range 3-5.
[0075] According to one embodiment of the present invention said
conditions comprising stirring. The stirring may be for example by
mechanical stirrer at 200-500 rpm.
[0076] According to another embodiment of the present invention
said conditions comprising drying the obtained microcapsules in
suspension.
[0077] According to one embodiment the product obtained in the
process of the present invention is a suspension of said
microcapsules.
[0078] According to another embodiment of the present invention the
product obtained in the process of the present invention is a
powder of said microcapsules.
[0079] In another aspect of the present invention there is provided
microcapsules obtainable by the process of the present
invention.
[0080] Yet in another aspect of the present invention there is
provided microcapsules comprising a core material encapsulated by a
metal oxide shell, wherein said core material is (i) a liquid or
(ii) a dispersion in liquid; wherein the thickness of said metal
oxide shell is in the range 0.1-10 micron; and wherein said shell
is obtained from (a) metal oxide nanoparticles, and (b) a
hydrolyzed and polymerized sol gel precursor.
[0081] Further according to another embodiment of the present
invention the metal oxide shell has a width (thickness) of about
0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 1, 1.5, 2 or 5 micron or
above. In one embodiment the metal oxide shell has a width
(thickness) of about up to 10 micron.
[0082] The core material, shell, etc. constituents may be as
described in the present invention.
It is appreciated that the final form of the dispersion in a liquid
may be liquid or semisolid depending on the ratio between the solid
ingredients and the liquid ingredients.
[0083] The width of the metal oxide layer may be determined for
example by a Transmission Electron Microscope or Confocal
Microscope such that in a circular cross sectional area of the
microcapsules the smallest width is at least e.g. 0.1 micron (the
width is determined as the smallest distance from the outer surface
of the microcapsules (i.e. metal oxide surface) to the core-metal
oxide interface).
[0084] The mole ratio between the metal oxide produced from said
sol-gel precursor and said metal oxide nanoparticles is in the
range 1:99 to 1:1. In one embodiment mole ratio between the metal
oxide produced from said sol-gel precursor and said metal oxide
nanoparticles is in the range 1:50 to 1:2. In a further embodiment
mole ratio between the metal oxide produced from said sol-gel
precursor and said metal oxide nanoparticles is in the range 1:25
to 1:4.
[0085] According to another embodiment of the present invention
said core material comprises a pharmaceutically, cosmetically, or
agrochemically active ingredient.
[0086] Additionally according to one embodiment of the present
invention said core material comprises a dermatologically active
agent.
[0087] In one embodiment, said dermatologically active agent is
selected from antifungal agents, antibacterial agents,
antiinflammatory agents, antipruritic agents, anti psoriatic agent,
anti acne agents, anti rosacea agents, and combinations of any of
the above.
[0088] In another embodiment, said anti acne agent is selected from
benzoyl peroxide, retinoid, and mixtures thereof
[0089] In another aspect of the present invention there is provided
a composition comprising a carrier and the microcapsules of the
present invention.
[0090] Further in another aspect of the present invention there is
provided a method for treating a surface condition in a subject,
comprising topically administering onto the surface a composition
of the present invention, wherein the core material comprises a
topically acting active agent.
[0091] The term "treating" or "treatment" as used herein includes
any treatment of a condition (disease or disorder) associated with
a patient's body surface such as the skin or mucosal membrane, and
includes inhibiting the disease or disorder (i.e. arresting its
development), relieving the disease or disorder (i.e. causing
regression of the disease or disorder), or relieving the conditions
caused by the disease (i.e. symptoms of the disease). The
concentrations of the dermatological agents that can be used for
treatment of a specific disease or disorder may be as described in
The Merck index an encyclopedia of chemical drugs, and biologicals,
Rahway, N.J.; Merck & Co; 1989, incorporated herein by
reference in its entirety.
[0092] Although individual needs may vary, determination of optimal
ranges for effective amounts of the compositions is within the
skill of the art. Generally, the dosage required to provide an
effective amount of a pharmaceutical composition, which can be
adjusted by one skilled in the art, will vary depending on the age,
health, physical condition, weight, type and extent of the disease
or disorder of the recipient, frequency of treatment, the nature of
concurrent therapy (if any) and the nature and scope of the desired
effect(s).
[0093] According to an embodiment of the present invention said
surface is skin or mucosal membrane.
[0094] According to another embodiment of the present invention
said surface condition is a skin disease or disorder selected from
acne, infection, inflammation, pruritis, psoriasis, seborrhea,
contact dermatitis, rosacea, and a combination thereof.
[0095] Additionally, in another aspect of the present invention
there is provided a composition comprising microcapsules as
described in the present invention, wherein the core material
comprises a topically acting active agent, for treatment of a
disease or disorder selected from acne, infection, inflammation,
pruritis, psoriasis, seborrhea, contact dermatitis, rosacea, and a
combination thereof.
[0096] Yet, in another aspect there is provided a use of the
microcapsules of the present invention, wherein said core material
comprises a topically acting active agent for the preparation of a
medicament for topical administration on the skin or mucosal
membrane.
[0097] According to another embodiment of the invention said
topical administration is for treating a disease or disorder
selected from acne, psoriasis, seborrhea, contact dermatitis,
infection, rosacea, inflammation, and a combination thereof.
[0098] In another aspect of the present invention there is provided
a composition for pest control comprising the microcapsules of the
invention, wherein said core material comprises a pesticide.
[0099] According to another embodiment of the present invention
said composition is for use in crop protection or non-crop pest
control.
[0100] Further according to an embodiment of the present invention
said pesticide is selected from a herbicide, an insecticide, a
fungicide, and mixtures thereof.
Pesticide Compositions and Uses
Composition
[0101] In one aspect, the present invention is directed to
pesticidal compositions comprising the coated pesticides described
above. Typically, such compositions are comprised of the coated
pesticide and an agriculturally acceptable carrier. Such carriers
are well know in the art and may be solids or liquids.
Other Components
[0102] To the extent that the compositions contain other
components, these components make up minor portions of the
composition. Minor components may also include free pesticide,
which has not been incorporated into the coated pesticide
(microcapsules). In addition to the other components listed herein,
compositions of this invention may also contain carriers, such as
for example water or other solvents in amounts equal to or greater
than the major components.
[0103] The coated pesticides of this invention may be formulated
and/or applied with one or more second compounds. Such combinations
may provide certain advantages, such as, without limitation,
exhibiting synergistic effects for greater control of pests,
reducing rates of application of pesticide thereby minimizing any
impact to the environment and to worker safety, controlling a
broader spectrum of pests, resistance of crop plants to
phytotoxicity, and improving tolerance by non-pest species, such as
mammals and fish.
[0104] Second compounds include, without limitation, other
pesticides, fertilizers, soil conditioners, or other agricultural
chemicals. The compositions of the present invention may also
contain additional surface active compounds as dispersants. Typical
wetting, dispersing or emulsifying agents used in agricultural
formulations include, but are not limited to, the alkyl and
alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl
polyether alcohols; sulfated higher alcohols; polyethylene oxides;
sulfonated animal and vegetable oils; sulfonated petroleum oils;
fatty acid esters of polyhydric alcohols and the ethylene oxide
addition products of such esters; and the addition product of
long-chain mercaptans and ethylene oxide. Many other types of
useful surface-active agents are available in commerce.
Surface-active agents, when used, normally comprise 1 to 20% weight
of the composition.
[0105] One skilled in the art will, of course, recognize that the
formulation and mode of application of a pesticide may affect the
activity of the material in a given application. Thus, for
agricultural use, the present coated pesticides may be formulated
as a granular of relatively large particle size (for example, 8/16
or 4/8 US Mesh), (e.g. agglomerates of coated pesticide that may
redisperse in water to the primary coated pesticide), as
water-dispersible granules, as powdery dusts, as wettable powders,
as suspension concentrates, as capsule suspension (coated
pesticide, in suspension), or as any other known types of
agriculturally-useful formulations, depending on the desired mode
of application. They may be applied in the dry state (e.g., as
granules, powders, or tablets) or they may be formulated as
concentrates (e.g., solid, liquid, gel) that may be diluted to form
stable dispersions (suspensions).
Concentrates
[0106] The compositions may be formulated as concentrates by
techniques known to one of ordinary skill in the art. If the
composition is to be formulated as a solid, a filler such as
Attaclay may be added to improve the rigidity of the granule.
[0107] The coated pesticides and pesticidal formulations may be
stored and handled as solids which are dispersible into stable
aqueous emulsions or dispersions prior to application. The
dispersions allow uniform application from water. This is
particularly advantageous at the field point of use, where normal
admixing in water is all that is required before application.
[0108] The compositions of the present invention may also be in the
form of wettable powders. Wettable powders are finely divided
particles that disperse readily in water or other dispersant. The
wettable powder is ultimately applied to the locus where pest
control is needed either as a dry dust or as a dispersion in water
or other liquid. Typical carriers for wettable powders include
Fuller's earth, kaolin clays, silicas, and other highly absorbent,
readily wet inorganic diluents. Wettable powders normally are
prepared to contain about 5-80% of pesticide, depending on the
absorbency of the carrier, and usually also contain a small amount
of a wetting, dispersing or emulsifying agent to facilitate
dispersion. For example, a useful wettable powder formulation
contains 80.0 parts of the pesticidal compound, 17.9 parts of clay
and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated
aliphatic polyester as wetting agents. Additional wetting agent
and/or oil will frequently be added to a tank mix to facilitate
dispersion on the foliage of the plant.
[0109] Water-Dispersible Granules (WDG or DG) are dry compositions
of the coated pesticide that will disperse in water yielding a
dispersion of primary particles. Pesticide contents may range from
10-70% w/w. Polymers are used as dispersants (polyacrylate salts
and lignosulfonate salts) and as binders to hold the granule
together. Advantages of the dry product are that less potential for
hydrolysis exists and high pesticide content may be achievable.
Disadvantages are a more complex process involving milling blending
extrusion and drying. Usually excipients are solids in this
formulation.
Other useful formulations for the pesticidal compositions of the
invention include suspo-emulsions, flowable formulations, and
suspension concentrates.
[0110] Flowable formulations consist of particles of the coated
pesticide suspended in a liquid carrier, generally water.
Flowables, may include a small amount of a surfactant as a wetting
agent and dispersants that are generally anionic or nonionic, and
will typically contain pesticides in the range of 5% to 95%,
frequently from 10 to 50%, by weight of the composition. For
application, flowables may be diluted in water or other liquid
vehicle, and are normally applied as a spray to the area to be
treated.
[0111] Suspension concentrates (SC) are dispersions of finely
particles (e.g. 2-15 micron) of coated pesticide in water.
Pesticide contents range from 8-50% w/w. They are pourable, easily
dispersible in water and should be stable to settling in the
package. Polymers such as xanthan gum are used to prevent settling
by increasing the yield stress of the suspension. Some polymeric
dispersants, such as polyacrylic acid salts, are used. The
dispersions may be stabilized against flocculation by use of
polymers such as methacrylate grafted with polyethylene glycol
(Atlox). Ethylene oxide/propylene oxide copolymers may be used to
provide some stabilization after dilution.
[0112] Suspo-emulsions (SE) are dispersions of water immiscible
liquids and fine particles (e.g. 2-15 micron) of coated pesticide
in water. Pesticide contents range from 8-50% w/w. They are
pourable, easily dispersible in water and should be stable to
settling in the package. They contain several surfactants, in order
to both stabilize the particles and emulsify the liquids. Some
polymeric dispersants, such as polyacrylic acid salts, are used.
SEs, like SCs, may be stabilized against flocculation by use of
polymers such as methacrylate grafted with polyethylene glycol
(Atlox). Ethylene oxide/propylene oxide copolymers may be used to
provide some stabilization after dilution.
[0113] Useful formulations include suspensions of the coated
pesticide in a relatively non-volatile solvent such as water, com
oil, kerosene, propylene glycol, or other suitable solvents.
Granular formulations, wherein the coated pesticide is carried on
relative coarse particles, are of particular utility for aerial
distribution or for penetration of cover crop canopy. Pressurized
sprays, typically aerosols wherein the coated pesticide is
dispersed in finely divided form as a result of vaporization of a
low-boiling dispersant solvent carrier may also be used.
Water-dispersible granules are free flowing, non-dusty, and readily
water-miscible. In use by the farmer on the field, the granular
formulations, suspo-emulsions, flowable concentrates, aqueous
emulsions, solutions, etc., may be diluted with water to give a
concentration of pesticide in the range of e.g., 0.2-2%.
Method of Controlling Pests
[0114] In a further aspect, this invention is directed to a method
of controlling pests comprising applying to the locus of such pests
a pesticidally effective amount of the pesticidal compositions
described herein. Such locus may be where pests are present or are
likely to become present.
[0115] In applying the compositions of this invention, whether
formulated alone or with other agricultural chemicals, an effective
amount and concentration of the active compound is employed; the
amount may vary in the range of, e.g. about 0.001 to about 3 kg/ha,
or in some embodiments about 0.03 to about 2 kg/ha. For field use,
where there are losses of pesticide, higher application rates
(e.g., four times the rates mentioned above) may be employed.
[0116] The pesticidal compositions of this invention may be applied
either as water-diluted sprays, or dusts, or granules to the areas
in which suppression of pests is desired. These formulations may
contain as little as 0.1% to as much as 35% or more by weight of
pesticide. Dusts are free flowing admixtures of the pesticide
compositions of the invention with finely divided solids such as
talc, natural clays, kieselguhr, flours such as walnut shell and
cottonseed flours, and other organic and inorganic solids which act
as dispersants and carriers for the pesticide. These finely divided
solids have an average particle size of less than about 50 microns.
A typical dust formulation useful herein is one containing 1.0 part
or less of the pesticidal composition and 99.0 parts of talc.
[0117] Different application methods are used for the pesticide
formulations depending on the target pest, e.g., weed, fungus, or
insect, and on the type of crop being treated. Application of
pesticide may be by spraying for example solutions, emulsions or
dispersions including coated pesticide to achieve accurate and even
concentration over the entire treated area or target. Usually, the
water used to dilute the pesticide composition in the spray mixture
amounts to approximately 5-80 gallons per acre and the active
ingredient amount may range approximately from 20 to 1000 grams per
acre.
[0118] Pesticides may also be applied by broadcast spreading of
granular formulations using machinery to achieve even distribution
over the entire target. The coated pesticide may be incorporated
into granular formulations by using a sticker (additional
surfactant, polymer solution, or latex) to attach the pesticide to
an inert support. Other granules are prepared by extrusion of
powdered coated pesticide with inert powdered ingredients, water,
binders, and dispersants to form granules that are subsequently
dried. Pre-formed granular supports are often used to absorb liquid
pesticide or solutions of the pesticide.
[0119] Formulations of these types are normally used to deliver
pesticides to the soil before emergence of the crop. The target may
be weed seeds or insects residing at different depths in the soil.
There are two types of water used in the formulation and
application of the compositions of the invention. The first is the
water used to dilute the concentrates for application. The second
type of water is the water that interacts with the coated pesticide
after application. This water includes water from the environment
such as rain water or water from irrigation systems. Movement of
the pesticide through the soil is generally affected and controlled
by rainfall. Generally, the pesticide composition is dissolved or
dispersed in water originating from a spray solution or from a
spray solution or from rainfall, after application.
EXAMPLES
[0120] In the examples below:
[0121] Unless otherwise indicated "%" refers to weight per weight
(w/w) %.
[0122] "BPO (75%)" refers to 75% w/w BPO (Benzoyl peroxide) with
25% w/w water. "Ludox TM 50 (50%)" refers to a dispersion of silica
nanoparticles (average particle size diameter of about 20-30 nm) in
water (50% w/w in water). Ludox TM 50 was obtained from
Sigma-Aldrich, Israel.
[0123] "Ludox AM-30" refers to colloidal silica stabilized with
sodium aluminate and dispersed in water (30% w/w in water). Ludox
AM-30 was obtained from Sigma-Aldrich, Israel.
[0124] "CTAC (29%)" refers to a solution of cetyl trimethyl
ammonium chloride 29% w/w in water.
[0125] "PVA (10%)" refers to a solution of polyvinyl alcohol 10%
w/w in water. "sodium silicate (25%)" refers to a solution of
sodium silicate 25% w/w in water. "GMIS" refers to glyceryl
monoisostearate. GMIS was obtained from Scher Chemicals, USA.
"aluminum sulfate solution (50%)" or "aluminum sulfate (50%)"
refers to a solution of aluminum sulfate decaoctahydrate 50% w/w in
water.
[0126] "PDAC 7 (5%)" refers to a solution of polyquatemium 7
(Diallyldimethylammonium chloride/acrylamide copolymer), 5% w/w in
water.
[0127] "CMC (10%)" refers to a solution of sodium salt of
carboxymethyl cellulose 10% w/w in water. [0128] "sodium aluminate
(50%)" refers to solution of sodium aluminate 50% w/w in water.
"sodium borate (5%)" refers to solution of sodium borate 5% w/w in
water.
[0129] "sodium alginate (5%)" refers to solution of sodium alginate
5% w/w in water.
[0130] "PVP K30 (40%)" refers to solution of PVP K30
(Polyvinylpyrrolidone K-30) 40% w/w in water.
Example 1
Encapsulation of BPO (Benzoyl Peroxide) (BPO Dispersed in
DC-246)
[0131] Preparing the oil phase: A mixture of 67.68 g BPO (75%),
132.04 g DC-246 (cyclohexasiloxane, Dow Comig, USA) and 10.06 g
Span 65 as dispersant agent and 45.6 g of TEOS (tetraethoxy silane)
were milled first by high shear at 4000 rpm for 2 minutes and then
by microfluidizer for 15 minutes.
[0132] Preparing the water phase: An aqueous phase including 6.06 g
of Myrj 45 (polyoxyethylene (8) stearate), 2.68 g CT AC (29%),
64.54 g PVA (10%) and 328.13 g of water was prepared.
[0133] The oil phase (a) was added to the water phase (b) under
shearing at 6000 rpm for 2 minutes. Then, 49.93 g of Ludox TM 50
(50%) and 5 ml of sodium silicate (25%) were added, and then the pH
was adjusted to 3. The mixture was transferred to reactor and
stirred for 20 h.
Example 2
Encapsulation of BPO (BPO Dispersed in DC-350)
[0134] a) Preparing the oil phase: A mixture of 67.49 g BPO (75%),
130.92 g DC-350 (polydimethylsiloxane, obtained from Dow coming,
USA) and 10.16 g cetyl alcohol as dispersant agent and 45.42 g of
TEOS were milled first by high shear at 4000 rpm for 2 minutes and
then by microfluidizer for 15 minutes.
[0135] b) Preparing the water phase: A water phase including 5.69 g
of Myrj 45 (polyoxyethylene (8) stearate), 2.25 g CTAC (29%), 65.05
g PVA (10%) and 327.24 g of water, was prepared.
[0136] The two phases were preheated at 50.degree. C. and then the
oil phase (a) was added to the water phase (b) under shearing at
5000 rpm for 2 minutes. Then, 50.09 g of Ludox TM 50 (50%) were
added and the solution became viscous. Then, 5 ml of sodium
silicate (25%) was diluted up to 100.09 g with water and the
resulted solution was added to the viscous mixture under shearing
of 5000 rpm for 1 minute. The pH was adjusted to 3 and then the
mixture was transferred to reactor and stirred for 20 h.
Example 3
Encapsulation of BPO (BPO Dispersed in Squalane)
[0137] Preparing the oil phase: A mixture of 68.64 g BPO (75%),
129.58 g squalane (obtained iron from Lake Oil, Spain) and 5.08 g
GMIS as dispersant agent and 89.85 g of TEOS were milled first by
high shear at 10000 rpm for 2 minutes and then by microfluidizer
for 15 minutes.
[0138] Preparing the water phase: A water phase including 1.18 g
CTAC (29%), 65.10 g PVA (10%) and 329.93 g of water, was
prepared.
[0139] The oil phase (a) was added to the water phase (b) under
shearing at 5000 rpm for 30 seconds. Then, 49.64 g of Ludox TM 50
(50%) was added and shearing continued further 30 seconds. Then,
20.72 g of aluminum sulfate solution (50%) were added and the
obtained pH was 3. The mixture was transferred to reactor preheated
at 40.degree. C. and the mixture was stirred at 118 rpm for 4
hours. Then, the temperature was decreased to room temperature and
stirring continued for 20 h.
Example 4
Encapsulation of BPO (BPO Dispersed in Squalane)
[0140] Preparing the oil phase: A mixture of 80.63 g BPO (75%),
108.15 g squalane (obtained fron from Lake Oil, Spain) and 5.71 g
GMIS as dispersant agent and 27.97 g of TEOS were milled first by
high shear at 10000 rpm for 1 minute and then by microfluidizer for
15 minutes.
[0141] Preparing the water phase: A water phase including 1.02 g
CTAC (29%), 60.27 g PVA (10%) and 290.09 g of water, was
prepared.
[0142] The oil phase (a) was added to the water phase (b) under
shearing at 5000 rpm for 30 seconds. Then, 30.58 g of Ludox TM 50
(50%) was added and shearing continued further 30 seconds. Then,
20.09 g of aluminum sulfate solution (50%) were added under
shearing for 30 seconds and the obtained pH was 3.2. The mixture
was transferred to reactor preheated at 40.degree. C. and the
mixture was stirred at 100 rpm for 4 hours. Then, the temperature
was decreased to room temperature and stirring continued for 20
h.
Example 5
Encapsulation of BPO (BPO Dispersed in Squalane)
[0143] Preparing the oil phase: A mixture of 53.19 g BPO (75%),
75.21 g squalane and 5.12 g GMIS as dispersant agent and 80.68 g of
TEOS were milled first by high shear at 10000 rpm for 1 minute and
then by microfluidizer for 15 minutes.
[0144] Preparing the water phase: A water phase including 4.16 g
CTAC (29%), 6.5 g PVA (10%) and 280.45 g of water, was
prepared.
[0145] The oil phase (a) was added to the water phase (b) under
shearing at 5000 rpm for 30 seconds. Then, 90.11 g of Ludox TM 50
(50%) was added and shearing continued further 30 seconds. Then,
9.96 g of aluminum sulfate dissolved in 15.19 g water were added
and the resulted mixture was milled at 6100 rpm for 1 minute. The
mixture was then transferred to reactor preheated at 38.8.degree.
C. and it was stirred at 118 rpm for 4 hours. Then, the temperature
was decreased to room temperature and stirring continued for 20
h.
Example 6
Encapsulation of BPO (BPO Dispersed in Squalane)
[0146] Preparing the oil phase: A mixture of 106.35 g BPO (75%),
88.09 g squalane and 4.91 g GMIS as dispersant agent and 41.05 g of
TEOS were milled first by high shear at 10000 rpm for 1 minute. A
thick mixture was obtained and it could not be milled by
microfluidizer.
[0147] Preparing the water phase: A water phase including 1.31 g
CTAC (29%), 6.3 g PVA (10%) and 283.1 g of water, was prepared.
[0148] The oil phase (a) was added to the water phase (b) under
shearing at 5000 rpm for 30 seconds. Then, 60.66 g of Ludox TM 50
(50%) was added and shearing continued further 30 seconds. Then,
50.18 g of aluminum sulfate (50%) were added and the resulted
mixture was milled at 6000 rpm for 1 minute. The mixture was then
transferred to reactor preheated at 41.8.degree. C. and it was
stirred at 100 rpm for 4 hours.
[0149] Then, the temperature was cooled down to room temperature
and stirring continued for 20 h.
Example 7
Encapsulation of BPO (BPO Dispersed in Squalane)
[0150] Preparing the oil phase: A mixture of 106.24 g BPO (75%),
61.12 g squalane and 5.65 g cetyl alcohol as dispersant agent and
60.49 g of TEOS were milled first by high shear at 10000 rpm for
1.5 minutes. A thick mixture was obtained and it could not be
milled by microfluidizer.
[0151] Preparing the water phase: A water phase including 1.09 g
CTAC (29%), 61.52 g PVA (10%) and 269.45 g of water, was
prepared.
[0152] The oil phase (a) was added to the water phase (b) under
shearing at 5000 rpm for 30 seconds. Then, 59.87 g of Ludox TM 50
(50%) was added and shearing continued further 1 minute. Then,
21.87 g of aluminum sulfate (50%) were added and the resulted
mixture was milled at 6000 rpm for 1 minute. The mixture was then
transferred to reactor preheated at 40.degree. C. and stirred for 4
hours. Then, the temperature was cooled down to room temperature
and stirring continued for 20 h.
Example 8
Encapsulation of BPO (BPO Dispersed in Squalane)
[0153] Preparing the oil phase: A mixture of 105.28 g BPO (75%),
130.13 g squalane and 5.48 g Span and 32.51 g of TEOS were milled
first by high shear at 10000 rpm for 1 minute. A thick mixture was
obtained and it could not be milled by microfluidizer.
[0154] Preparing the water phase: An aqueous phase including 4.31 g
CTAC (29%), 6.5 g PVA (10%) and 279.8 g of water, was prepared.
[0155] The oil phase (a) was added to the water phase (b) under
shearing at 4000 rpm and then 90.41 g of Ludox TM 50 (50%) was
added and shearing continued 1 minute. Then, 20.88 g of aluminum
sulfate (50%) were added and the resulted mixture was milled at
5000 rpm for 1 minute. The mixture was then transferred to reactor
preheated at 39.2.degree. C. and stirred at 103 rpm for 4 hours.
Then, the temperature was cooled down to room temperature and
stirring continued for 60 h.
Example 9
Encapsulation of BPO (BPO Dispersed in Squalane)
[0156] a) Preparing the oil phase: A mixture of 80.25 g BPO (75%),
107.04 g squalane and 5.01 g cetyl alcohol and 30.40 g of TEOS were
milled first by high shear at 10000 rpm for 1 minute. A thick
mixture was obtained and it could not be milled by
microfluidizer.
[0157] b) Preparing the water phase: A water phase including 4.33 g
CTAC (29%), 6.16 g PVA (10%) and 279.59 g of water, was
prepared.
[0158] The oil phase (a) was added to the water phase (b) under
shearing at 4000 rpm and then 59.43 g of Ludox TM 50 (50%) was
added, and then the resulted mixture was homogenized at 8000 rpm
for 1 minute since the mixture was very thick. Then, 49.45 g of
aluminum sulfate (50%) were added and the resulted mixture was
milled at 8000 rpm for 30 seconds. The mixture was then transferred
to reactor preheated at 41.2.degree. C. and stirred at 103 rpm for
4 hours. Then, the temperature was cooled down to room temperature
and stirring continued for 20 h.
Example 10
Encapsulation of BPO (BPO Dispersed in Squalane)
[0159] Preparing the oil phase: A mixture of 80.2 g BPO (75%), 93.5
g squalane (obtained from Lake Oil, Spain) and 5.38 g Span 20 and
42.07 g of TEOS were milled first by high shear at 10000 rpm for 1
minute and then by microfluidizer for 15 minutes.
[0160] Preparing the water phase: A water phase including 4.05 g
CTAC (29%), 61.51 g PVA (10%) and 257.74 g of water, was
prepared.
[0161] The oil phase (a) was added to the water phase (b) under
shearing at 4000 rpm and then 61.42 g of Ludox TM 50 (50%) was
added and shearing at 5000 rpm continued for 1 minute. Then, 21.1 g
of aluminum sulfate (50%) were added and the resulted mixture was
milled at 5000 rpm for 1 minute. The mixture was then transferred
to reactor preheated at 41.2.degree. C. and stirred at 103 rpm for
4 hours. Then, the temperature was cooled down to room temperature
and stirring continued for 20 h.
[0162] Examples 11-21 relate to encapsulation of active ingredients
with modifications in the process. The procedures are suitable for
any active ingredient which is a liquid, or which can be dissolved
or dispersed in a hydrophobic liquid" or solids that can melt and
become liquid at low temperatures (30-60.degree. C.).
Example 11
Procedure 1 for Encapsulation of General Al (Active Ingredient)
[0163] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 150
g of the oil phase [including an Al and a sol-gel precursor e.g.,
TEOS, TMOS] is added and milling is continued for 1 minute. Then,
50 g of Ludox TM 50 (50%) is added and the resulted mixture is
milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 5 by adding HC1 (5 N) and then 50 g of PVA
(10%) and 5 g of sodium silicate (25%) are added and then the pH of
the mixture is adjusted to 4. The mixture is then stirred for 20
hours.
Example 12
Procedure 2 for Encapsulation of General Al
[0164] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 150
g of the oil phase (including an Al and a sol-gel precursor e.g.,
TEOS, TMOS) is added and milling is continued for 1 minute. Then,
50 g of Ludox TM 50 (50%) is added and the resulted mixture is
milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 5 by adding HC1 (5 N) and then 50 g of PVA
(10%) and 5 g of sodium silicate (25%) are added and then the pH of
the mixture is adjusted to 4. The mixture is then stirred for 20
hours.
[0165] Then, 40 g of PDAC 7 (5%) is added till the zeta-potential
is +20 mv. After that, a solution of CMC(10%) (25 g) is added
gradually till obtaining negative zeta-potential (of -20 mv).
During the additions the mixture was kept under milling of 7000
rpm.
Example 13
Procedure 3 for Encapsulation of General Al
[0166] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 150
g of the oil phase (including an Al and a sol-gel precursor e.g.,
TEOS, TMOS) is directly added and milling is continued for 1
minute. Then, 50 g of Ludox TM 50 (50%) is added and the resulted
mixture is milled for 1 minute by high shear at 8000 rpm. The pH of
the mixture is adjusted to 5 by adding HC1 (5 N) and then 50 g of
PVA (10%) and 10 g of sodium aluminate (50%) are added and then the
pH of the mixture is adjusted to 4. The mixture is then stirred for
20 hours.
Example 14
Procedure 4 for Encapsulation of General Al
[0167] A water phase containing 8.6 g of CT AC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 150
g of the oil phase (including an Al and a sol-gel precursor e.g.,
TEOS, TMOS) is added and milling is continued for 1 minute. Then,
50 g of Ludox TM 50 (50%) is added and the resulted mixture is
milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 5 by adding HC1 (5 N) and then 50 g of PVA
(10%) and 50 g of sodium borate (5%) are added and then the pH of
the mixture is adjusted to 4. The mixture is then stirred for 20
hours.
Example 15
Procedure 5 for Encapsulation of General Al
[0168] A water phase containing 8.6 g of CT AC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al) and 20 g of dimethyl
dimethoxysilane are added and milling is continued for 1 minute.
Then, 50 g of Ludox TM 50 (50%) is added and the resulted mixture
is milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 3 by adding HC1 (5 N) and the mixture is
then stirred for 20 hours.
Example 16
Procedure 6 for Encapsulation of General Al
[0169] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al) and 20 g of dimethyl
dimethoxysilane are added and milling is continued for 1 minute.
Then, 50 g of Ludox TM 50 (50%) is added and the resulted mixture
is milled for 1 minute by high shear at 8000 rpm. Then, 25 g of
aluminum sulfate (50%) and 50 g of PVA (10%) are added and the
resulted mixture is stirred for 24 hours.
Example 17
Procedure 7 for Encapsulation of General Al
[0170] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al) and 20 g of Al(O'Pr)3 (1Pr
stands for isopropyl) are added and milling is continued for 1
minute. Then, 50 g of Ludox TM 50 (50%) is added and the resulted
mixture is milled for 1 minute by high shear at 8000 rpm. The pH of
the mixture is adjusted to 3 by adding HC1 (5 N) and the mixture is
then stirred for 20 hours.
Example 18
Procedure 8 for Encapsulation of General Al
[0171] A water phase containing 8.6 g of CT AC (29%) diluted, with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al) and 20 g of Ti(O'Pr)4
(1Pr=isopropyl) are added and milling is continued for 1 minute.
Then, 50 g of Ludox TM 50 (50%) is added and the resulted mixture
is milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 3 by adding HC1 (5 N) and the mixture is
then stirred for 20 hours.
Example 19
Procedure 9 for Encapsulation of General Al
[0172] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al), 20 g of TEOS and 5 g of
dimethyl dimethoxysilane are added and milling is continued for 1
minute. Then, 50 g of Ludox TM 50 (50%) is added and the resulted
mixture is milled for 1 minute by high shear at 8000 rpm. The pH of
the mixture is adjusted to 3 by adding HC1 (5 N) and the mixture is
then stirred for 20 hours.
Example 20
Procedure 10 for Encapsulation of General Al
[0173] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 130
g of the oil phase (including an Al) and 20 g of TEOS are added
under milling for 1 minute at 6000 rpm. Then, 50 g of Ludox TM 50
(50%) is added and the resulted mixture is milled for 1 minute by
high shear at 8000 rpm. The pH of the mixture is adjusted to 5 by
adding HC1 (5 N) and then 50 g of PVA (10%) and 10 g of calcium
chloride are added and then the pH of the mixture is adjusted to 4.
The mixture is then stirred for 20 hours.
Example 21
Procedure 11 for Encapsulation of General Al
[0174] A water phase containing 8.6 g of CTAC (29%) diluted with
water up to 150 g, is milled by high shear at 6000 rpm and then 150
g of the oil phase (including an Al and a sol-gel precursor e.g.,
TEOS, TMOS)) is added and milling is continued for 1 minute. Then,
50 g of Ludox TM 50 (50%) is added and the resulted mixture is
milled for 1 minute by high shear at 8000 rpm. The pH of the
mixture is adjusted to 5 by adding HC1 (5 N). Then, 40 g of PDAC
5%) ) is added till the zeta-potential is +20 mv. After that, a
solution of sodium alginate (5%) (35 g) is added gradually till
obtaining negative zeta-potential (of -20 mv). During the additions
the mixture was kept under milling of 7000 rpm. Then, 5 g of
calcium chloride is added and the resulted mixture is stirred for 2
hours.
Examples 22-24 relate to oil-dispersed encapsulation of ATRA
(all-trans retinoic acid).
Example 22
Encapsulation Using an Oil Phase Comprising Squalane Oil and
Tretinoin
[0175] Preparing the oil phase: 10 g of Tretinoin 4 g of BHT (butyl
hydroxytoluene) (40% of Tretinoin weight), 100 g of squalane oil,
and 2 g of GMIS were mixed under stirring at room temperature. Then
the mixture was milled by high shear homogenizer at 12000 rpm for 2
min to obtain particle size of about 30 micron. The resulted
suspension was milled in a microfluidizer for 30 min to obtain
particles of 3-7 micron in size. 49.7 g of TEOS (TEOS/oil weight
ratio 30/70 was added to the suspension under stirring.
[0176] Preparing the water phase: 285.5 g of TDW (tridistilled
water), 1 g of CTAC (cetyl trimethyl ammonium chloride) (29%) w/w
in water and 100 g of
[0177] 10% --.sup.-PVA- were mixed
under-stirring.-Oil-phase/water-phase (OP/WP) weight ratio was
30/70.
[0178] Emulsion was prepared at 4000 rpm for 1 min. Immediately
after emulsification 20 g of Ludox AM-30 was added at 3500 rpm,
mixing time 30 sec. Then 30 g of aluminum sulfate was added at 3000
rpm, mixing time 2 min. The reaction mixture was kept at 40.degree.
C. for 4 hr (aging) under stirring.
[0179] Optionally the capsules were coated with polymers as
follows. To the emulsion HOg of 5% PDAC-7 was added at 3500-4000
rpm.sup.- Z potential was +3 mV. Then 120 g of 5% CMC was added at
3500-4000 rpm, Z potential was -2 mV.
[0180] Coating of capsules with polymers strengthens the capsules
and should be, in some embodiment, be made within Z potential
limits from +3 mV to +5 mV for PDAC-7 and within Z potential limits
from -3 mV to -5 mV for CMC.
Example 23
Encapsulation Using an Oil Phase Comprising Castor Oil and
Tretinoin
[0181] Preparing the oil phase: 10 g of Tretinoin, 4 g of BHT, 100
g of castor oil) and 2 g of GMIS were mixed and stirred at
40.degree. C. 49.7 g of TEOS was added (TEOS/oil weight ratio
30/70) Then the mixture was milled by high shear homogenizer at
12000 rpm for 2 min to obtain particle size of about micron. The
resulted suspension was milled in a microfluidizer for 30 min.
[0182] Preparing the water phase: 285.6 g of tridistilled water, 1
g of CTAC (29%) and 40 g of PVA (10%) were mixed under stirring and
heated to 40.degree. C. Oil phase/water phase (OP/WP) weight ratio
was 30/70.
[0183] Emulsion was prepared at 5000 rpm for 1 min. Immediately
after emulsification 60 g of Ludox AM-30 was added at 3500-4000
rpm. Then, 150 g of aluminum sulfate solution (50%) was added. The
reaction mixture was kept at 40.degree. C. for 4 hr under
stirring.
[0184] Optionally the capsules were coated with polymers as
follows. To the emulsion 105 g of 5% PDAC-7 was added at 4000 rpm,
Z potential was +3.5 mV. Then 275 g of 10% CMC was added at 4000
rpm, Z potential was -1.5 mV.
[0185] Coating of capsules with polymers should be within Z
potential limits from +3 mV to +5 mV for PDAC-7 and within Z
potential limits from -3 mV to -5 mV for CMC.
Example 24
Encapsulation Using an Oil Phase Comprising Cyclomethicone DC-246
Oil and Tretinoin
[0186] Tretinoin crystals dispersed in DC-246 were milled in
Dyno-mill MutiLab KD 0.3 L for 10 min at 27.degree. C. Tretinoin
particles were obtained with d(0.9)<3 micron, (which were
smaller than those milled in microfluidizer), and thus facilitated
inclusion of Tretinoin crystals into emulsion drops. Milling
proceeded successfully without dispersant addition.
[0187] Oil phase preparation: 50 g of TEOS was added to 114 g of
the milled material containing 10 g of Tretinoin, 4 g of BHT and
100 g of DC-246, the mixture was stirred.
[0188] Water phase preparation: 285.6 g of tridistilled water, 5 g
of CT AC (29%) and 80 g of PVA were mixed.
[0189] Emulsion was prepared by addition of oil phase to water
phase at 5000 rpm for 1 min. Immediately after emulsification 50 g
of Ludox AM-30 was added at 40001 pm, mixing time was 1 min. Then
47 g of aluminum sulfate solution (50%) was added at
[0190] I 4000 rpm, mixing time was 1 min.
[0191] To the emulsion 85 g of PDAC-7 (5%) was added at 4000 rpm, Z
potential was +5.8 mV. Then 254 g of CMC (10%) was added at 4000
rpm, Z potential was -4.5 mV.
[0192] Coating of capsules with polymers should be within Z
potential limits from +3 mV to +5 mV for PDAC-7 and within Z
potential limits from -3 mV to -5 mV for CMC.
Example 25
Encapsulation of Carbosulfan
[0193] 75 g Water (deionized) and 25 g Agrimer AL -10LC (1-butene
vinyl pyrrolidone polymer, International Specialty Products (ISP),
USA) 5% solution in water, were charged to a 1000-mL Blender
(Waring, variable speed). 70 g Carbosulfan (88.8%, FMC, USA)
homogeneously mixed with 6 g tetramethoxysilane (Aldrich, USA) in a
separate vessel was charged. The two phases were combined and the
mixture was blended at 9000 RPM for 2 min. 20 g Ludox TM-50
(colloidal silica suspension, 50% in water, Aldrich, USA) was added
and homogenized 40 sec at 8000 RPM. 30 g Ludox TMA (colloidal
silica suspension, 34% in water, Aldrich, USA) was added--and
further homogenized 40 sec at 8000 RPM. The particle size was
determined using a Horiba LA910 particle size analyzer (D90<10
pm).
[0194] The dispersion was poured to a jacketed reaction vessel
equipped with a paddle-type Teflon stirrer blade, and stirred
gently at room temperature. The pH was adjusted to pH 3.0 using 6 N
HC1. The reaction vessel was purged with a gentle stream of
nitrogen to remove formed MeOH, and stirring was continued for 24
hr.
Suspension pH was adjusted to 7.5 by addition of saturated
NaHCO.sub.3 (ca. 5 g). Suspension (21.3 wt. % assay) was bottled
and stored.
Example 26
Encapsulation of Metolachlor with TMOS
[0195] 90 g 5% Na2SO4 solution (J.T. Baiker, USA) and 22 g Agrimer
DA 102W (2% solution in water, ISP (International Specialty
Products, ISP, USA)) were charged to a 1000-mL Blender (Waring,
variable speed). 52.0 g Metolachlor 98.8%, (Agan Chemical
Manufacturers, Israel) homogeneously mixed with 6.0 g aromatic 200
(ExxonMobile--USA), 5.2 g tetramethoxysilane (Aldrich, USA) and 1.0
g epoxidized soyabean oil in a separate vessel was charged. The two
phases were combined and the mixture was blended at 9000 RPM for 2
min. 20 g Ludox TM-50 (colloidal silica suspension, 50% in water,
Aldrich, USA) was added and homogenized 40 sec at 9000 RPM. 20 g
Ludox TMA (colloidal silica suspension, 34% in water, Aldrich, USA)
was added and further homogenized 40 sec at 8000 RPM. The particle
size diameter was determined using a Horiba LA910 particle size
analyzer (D90<10 pm).
[0196] The dispersion was poured to a jacketed reaction vessel
equipped with a paddle-type Teflon stirrer blade, and stirred
gently at room temperature. The pH was adjusted to pH 2.0 using 6 N
HC1. The reaction vessel was purged with a gentle stream of
nitrogen to remove formed MeOH, and stirring was continued for 24
hr. Suspension pH was adjusted to 4.1 by addition of saturated
NaHCO3 (ca. 1 g). 40 g of water and 10 g PVP K30 (40%) was added,
and the mixture was sheared at 3500 RPM for 3 min. The encapsulated
metolachlor with 22 wt. % assay was bottled.
Example 27
Encapsulation of Clomazone
[0197] 150 ml water (deionized) was mixed with 25 g Agrimer -10LC
(5% aqueous solution) in a stainless steel beaker. 20 g Ludox TM 50
(50%) was added while mixing. The solution was neutralized to pH 7
using 1 N HC1.
[0198] In a separate bottle, 120 g clomazone (91% assay) was mixed
with 30 g tetramethoxysilane (99% purity, TMOS) until a homogeneous
solution was obtained.
[0199] While mixing the aqueous solution using a Silverson L4R
homogenizer the clomazone/TMOS solution was added and the mixture
homogenized at 5000 rpm for 1 minute. The resulting emulsion was
transferred to a jacketed resin flask equipped with a propeller
stirrer and 2 g aluminum sulfate (A12(SO4)3 18 hydrate in 50 ml
H2O) was added in portions to the stirring slurry.
[0200] Sample was stirred at 250 rpm overnight at 30.degree. C.
[0201] While this invention has been shown and described with
reference to preferred embodiments thereof, it will be understood
by those skilled in the art that many alternatives, modifications
and variations may be made thereto without departing from the
spirit and scope of the invention. Accordingly, it is intended to
embrace all such alternatives, modifications and variations that
fall within the spirit and broad scope of the appended claims.
[0202] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference.
* * * * *