U.S. patent application number 17/002266 was filed with the patent office on 2020-12-10 for method for preparing particles comprising metal oxide coating and particles with metal oxide coating.
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, Haim BAR-SIMANTOV, Nissim BILMAN, Hanan SERTCHOOK, Leora SHAPIRO, Ofer TOLEDANO.
Application Number | 20200383927 17/002266 |
Document ID | / |
Family ID | 1000005046960 |
Filed Date | 2020-12-10 |
![](/patent/app/20200383927/US20200383927A1-20201210-D00001.png)
United States Patent
Application |
20200383927 |
Kind Code |
A1 |
TOLEDANO; Ofer ; et
al. |
December 10, 2020 |
METHOD FOR PREPARING PARTICLES COMPRISING METAL OXIDE COATING AND
PARTICLES WITH METAL OXIDE COATING
Abstract
The invention relates to a process for coating a solid,
water-insoluble particulate matter, with a metal oxide comprising:
(a) contacting the solid, water-insoluble particulate matter with
an ionic additive and an aqueous medium to obtain a dispersion of
said particulate matter having positive charges on its surface; (b)
subjecting the particulate matter to a coating procedure comprising
precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide layer thereon to thereby
obtain particulate matter coated by a metal oxide coating layer;
(c) repeating step (b) at least 4 more times; and (d) aging said
coating layer. The invention further relates to particles
comprising a particulate matter coated by a metal oxide layer, to a
use of the particles for topical administration, and to a method
for preventing, reducing, or eliminating pests at a locus, using
the particles.
Inventors: |
TOLEDANO; Ofer; (Kfar Saba,
IL) ; BAR-SIMANTOV; Haim; (Netanya, IL) ;
BILMAN; Nissim; (Rehovot, IL) ; SHAPIRO; Leora;
(Jerusalem, IL) ; ABU-REZIQ; Raed; (Jatt
Hamesholash, IL) ; SERTCHOOK; Hanan; (Gedera,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SOL-GEL TECHNOLOGIES LTD. |
Ness Ziona |
|
IL |
|
|
Assignee: |
SOL-GEL TECHNOLOGIES LTD.
Ness Ziona
IL
|
Family ID: |
1000005046960 |
Appl. No.: |
17/002266 |
Filed: |
August 25, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12525331 |
Oct 6, 2009 |
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PCT/IL08/00141 |
Feb 3, 2008 |
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17002266 |
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60898700 |
Feb 1, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 8/671 20130101;
B01J 13/22 20130101; A61K 8/25 20130101; A61K 9/501 20130101; A61K
9/5021 20130101; A01N 53/00 20130101; A01N 25/26 20130101; A61K
9/5073 20130101; C09C 3/063 20130101; A61K 9/5026 20130101; A61K
8/11 20130101; A61K 8/38 20130101; A61K 2800/412 20130101; B01J
13/02 20130101; Y10T 428/2991 20150115; A61Q 19/00 20130101 |
International
Class: |
A61K 9/50 20060101
A61K009/50; A01N 53/00 20060101 A01N053/00; A61K 8/25 20060101
A61K008/25; C09C 3/06 20060101 C09C003/06; B01J 13/02 20060101
B01J013/02; A61K 8/67 20060101 A61K008/67; A61K 8/11 20060101
A61K008/11; A61K 8/38 20060101 A61K008/38; A61Q 19/00 20060101
A61Q019/00; A01N 25/26 20060101 A01N025/26; B01J 13/22 20060101
B01J013/22 |
Claims
1. A method for treating a surface condition in a subject,
comprising topically administering onto the surface a composition
comprising an effective amount of dispersed particles comprising
solid benzoyl peroxide particulate matter encapsulated by a metal
oxide coating, wherein the metal oxide coating comprises four or
more layers, wherein the outermost portion of the metal oxide
coating being substantially free of benzoyl peroxide; wherein, (i)
the coated particles having leaching of less than 5% w/w, of the
benzoyl peroxide in the composition until administered to the skin;
(ii) the coated particles release an effective amount of benzoyl
peroxide when the composition is in contact with the surface; (iii)
the time for releasing 50% w/w of the benzoyl peroxide being at
least two-fold longer when in coated form than the time to
dissolution of benzoyl peroxide particles of the same particle size
diameter when in free form under identical conditions.
2. The method of claim 1, wherein said surface is skin or mucosal
membrane.
3. The method of claim 1, wherein said surface condition is a
disease or disorder selected from the group consisting of acne,
infection, inflammation, pruritus, psoriasis, seborrhea, contact
dermatitis, rosacea, and a combination thereof.
4. The method of claim 1, wherein said metal oxide is selected from
Silica, Titania, Alumina, Zirconia, ZnO, and mixtures thereof.
5. The method of claim 4, wherein the metal oxide is silica.
6. The method of claim 1, wherein the weight ratio of the metal
oxide to said particulate matter is in the range of 1:99 to
40:60.
7. The method of claim 1, wherein the four or more layers of said
metal oxide has a thickness of 0.1-10 micron.
8. The method of claim 1, wherein the metal oxide coating comprises
between 4 to 1000 layers, more preferably 4 to 300 layers, more
preferably 4 to 100 layers.
9. The method of claim 1, wherein the solid benzoyl peroxide
particles encapsulated by a metal oxide coating have a diameter of
between 0.5-100 micron.
10. Particles comprising solid benzoyl peroxide particulate matter
encapsulated by a metal oxide coating, wherein the metal oxide
coating comprises four or more layers; wherein the outermost
portion of the metal oxide coating being substantially free of
benzoyl peroxide the coated particles having teaching of less than
5% w/w, of the benzoyl peroxide in the composition until
administered to the skin; the coated particles release an effective
amount of benzoyl peroxide when the composition is in contact with
the surface; and the time for releasing 50% w/w of the benzoyl
peroxide being at least two-fold longer when in coated form than
the time to dissolution of benzoyl peroxide particles of the same
particle size diameter when in free form under identical
conditions.
11. The particles of claim 10, wherein said metal oxide coating has
a thickness of 0.1-10 micron.
12. Particles comprising solid benzoyl peroxide particulate matter
encapsulated by a metal oxide coating, wherein the metal oxide
coating comprises four or more layers, wherein the outermost
portion of the metal oxide coating being substantially free of
benzoyl peroxide; wherein the particles are prepared by the
following steps: a) contacting in a medium consisting of an aqueous
medium, the solid benzoyl peroxide particulate matter, with a first
cationic additive being a cationic surfactant, to obtain a
dispersion of said benzoyl peroxide particulate matter in said
aqueous medium, said benzoyl peroxide particulate matter having
positive charges on its surface; b) adding an aqueous solution of a
metal oxide salt to said dispersion of said benzoyl peroxide
particulate matter, under conditions wherein said metal oxide salt
precipitates onto the surface of said benzoyl peroxide particulate
matter, and acidifying to thereby form a solid, water-insoluble
benzoyl peroxide particulate matter that has a metal oxide layer
coated thereon; b1) contacting, in a medium consisting of an
aqueous medium, said benzoyl peroxide particulate matter coated
with a metal oxide layer of the preceding step with a surface
adhering additive being one or both of (i) a second cationic
additive being a cationic polymer and (ii) a non-ionic additive, to
obtain a dispersion of said coated benzoyl peroxide particulate
matter having an adhering additive on the surface thereof in said
aqueous medium; b2) bringing the dispersion obtained in step (b1)
into contact with an aqueous solution of a metal oxide salt, under
conditions wherein said metal oxide salt precipitates onto the
surface of said coated benzoyl peroxide particulate matter, and
acidifying to thereby form a solid, water-insoluble benzoyl
peroxide particulate matter that has a further metal oxide layer
coated thereon; c) repeating steps (b1) and (b2) at least 3 more
times; and d) after completion of step (c), aging the metal oxide
layer to form an aged, coated, solid, water-insoluble benzoyl
peroxide particulate matter having a coating thickness in the range
of 0.1-10 micron.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional Application from U.S.
patent application Ser. No. 12/525,331, filed Oct. 6, 2009, which
is a US National Phase of PCT International Application No.
PCT/IL2008/000141, filed Feb. 3, 2008, claiming priority from U.S.
Provisional Patent Application No. 60/898,700, filed Feb. 1, 2007,
which are all incorporated in their entirety herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention generally relates to method for
preparation of particles comprising metal oxide coating layer and
to compositions comprising particles with metal oxide coating.
BACKGROUND OF THE INVENTION
[0003] Metal oxides have been used as encapsulating materials and
as matrices for various applications such as cosmetics,
biomaterials, optics, laser, florescence, etc. using a variety of
methods.
[0004] Shells consisting of hybrid inorganic-organic structures
with bulk and surface properties that are compositionally
controlled have been described in Hall, Simon, R., et al.,
Cocondensation of Organosilica Hybrid Shells on Nanoparticle,
Templates: A Direct Synthetic Route to Functionalized Core--Shell
Colloids, Langmuir, 16:1454-1456, 2000.
[0005] The formation of silica shells on core silver particles by a
modified Stober process is reported by Matijevi et al in Journal of
Colloid and Interface Science, Volume 221, Issue 1, 1 Jan. 2000,
Pages 133-136. They also report on the formation of spherical
particles of Cu(II) basic carbonate coated with amorphous titania
by hydrolysis of Ti(IV) butoxide in Colloids and Surfaces A:
Physicochemical and Engineering Aspects, Volume 81, 13 Dec. 1993,
Pages 153-159. In this report they show how the thickness of the
shell could be varied by altering the experimental conditions.
White pigments (whiteners) were prepared by coating monodispersed
silica particles with titania. The hiding power of this powder was
evaluated as a function of the particle diameter, the thickness of
the titania shell, and the calcination temperature. Matijevi et al,
Journal of Colloid and Interface Science, Volume 156, Issue 1, 1
Mar. 1993, Pages 56-65.
[0006] Colloidal boehmite (A1OOH) rods were used as cores for the
preparation of rods with a silica shell as described in van
Bruggen, M. P. B., Preparation and Properties of Colloidal
Core--Shell Rods with Adjustable Aspect Ratios, Langmuir,
14:2245-2255. 1998.
[0007] A method for the encapsulation of fluorescent molecule into
silica "nanobubbles" has been reported in Makarova, Olga V., et
al., Adsorption and Encapsulation of Fluorescent Probes in
Nanoparticles, J. Phys. Chem. B, 103:9080-9084, 1999. Bugnon,
Philippe, (Bugnon, Philippe, Surface treatment of pigments.
Treatment with inorganic materials, Progress in Organic Coatings
29: 39-43, 1996) has reported novel treatments of pigments with
inorganic materials. Mikrajuddin, et al., (Mikrajuddin, et al.,
Stable pho to luminescence of zinc oxide quantum dots in silica
nanoparticles matrix prepared by the combined sol-gel and spray
drying method, Journal of Applied Physics, 89:11. 2001) reported a
ZnO/SiO2 nanocomposite with improved photoluminescence stability
over ZnO colloids.
[0008] A spray drying approach has been used to apply 15-nm-thick
SiCb continuous coatings onto ZnS:Ag phosphor particles as
described in Villalobos, Guillermo, R., et al., Protective Silica
Coatings on Zinc-Sulfide-Based Phosphor Particles, J. Am. Ceram.
Soc., 85(8):2128-2130, 2002.
[0009] Iskandar et al. have reported the preparation of
microencapsulated powders by an aerosol spray method. The powders
prepared by mixing two type of sols or sol-aqueous mixture
precursor solution (Iskandar, Ferry, et al., Preparation of
microencapsulated powders by an aerosol spray method and their
optical properties, Advanced Powder Technol. 14(31:349-367. 2003).
Iskandar et al. (Control of the morphology of nano structured
particles prepared by the spray drying of a nanoparticle sol. J
Colloid Interface Sci., 265(21:296-303. 2003) additionally
described the parameters influencing particles morphology by spray
drying of silica nanoparticle sol.
[0010] Silica coating using layer by layer technique has been
described in Dun, Huijuan, et al., Eayer-by-Layer Self-Assembly of
Multilayer Zirconia Nanoparticles on Silica Spheres for HPLC
Packings, Anal, Chem., 76:5016-5023, 2004; Yuan, Junjie, et al.,
Organic Pigment Particles Coated with Colloidal Nano-Silica
Particles via Layer-by-Layer Assembly, Chem. Mater.,
17(41:3587-3594. 2005; Chung, Chau-Chyun, et al., Aqueous Synthesis
of Y2O2S:Eu/Silica Core-Shell Particles, J. Am. Ceram. Soc., 88(5):
1341-1344, 2005.
[0011] Y2O2:Eu red phosphor Powders coated with silica using
sol-gel and heterocoagulation techniques were described in Jean,
Jau-Ho, et al., Y2025: Eu Red Phosphor Powders Coated with Silica,
J. Am. Ceram. Soc., 83(8): 1928-1934, 2000.
[0012] Wilhelm, P., et al., (Wilhelm, P., et al, On-line tracking
of the coating of nanoscaled silica with titania nanoparticles via
zeta-potential measurements, Journal of Colloid and Interface
Science, 293:88-92, 2006) reported nanoscaled spherical particles
which were directly coated with titania nanoparticles by means of
heterogenic coagulation.
[0013] The interaction between colloidal silica particles and the
surface of ZnS-type phosphors has been studied in Merikhi, J., et
al., Adhesion of Colloidal SiCb Particles on ZnS-Type Phosphor
Surfaces, Journal of Colloid and Interface Science, 228:121-126,
2000.
[0014] Sodium Silicate utilized to obtain a SiCb coating on
particles has been described in Wang, Hongzhi, et al., Effect of
Polyelectrolyte Dispersants on the Preparation of Silica-Coated
Zinc Oxide Particles in Aqueous Media, J. Am. Ceram. Soc.,
85(81:1937-1940, 2002; U.S. Pat. Nos. 2,885,366; 3,826,670.
[0015] The sources of silica gels and factors controlling gel
characteristics were described in Iler Ralph K., The Chemistry of
Silica, Wiley-Interscience publication, 1979, pp. 510-533. U.S.
Pat. No. 6,303,290 describes the encapsulation of biomaterials in
porous glass-like matrices prepared via an aqueous colloidal
sol-gel process. This process includes entrapment of the
biomaterial in silica cages forms by controlling the gel
characteristics.
[0016] JP02-002867 and JP 02-251240 disclose spherical particles
made principally of silica, prepared by coprecipitation on of
silica and UV filters such as benzophenone derivatives or
dibenzoylmethane derivative, prepared in a water-in-oil
emulsion.
[0017] U.S. Pat. No. 6,875,264 discloses a multilayer effect
pigment including a transparent substrate, a layer of high
refractive index material on the substrate, and alternating layers
of low refractive index and high refractive index materials on the
first layer. The high refractive index material may be titanium
dioxide and the low refractive index material may be silicon
dioxide.
[0018] U.S. Pat. No. 6,090,399 discloses a controlled release
composition comprising one or more biologically active compounds
incorporated into a metal oxide glass having a porous matrix
[0019] U.S. Pat. Nos. 7,001,592 and 7,037,513 disclose a
composition for topical application, e.g., a body-wash, where the
additive contains a sol-gel encapsulated active either a sunscreen
or a non-sunscreen. U.S. Pat. No. 7,052,913 discloses a
biocompatible matrices, such as sol-gels encapsulating a reaction
center, which may be administered to a subject for conversion of
prodrugs into biologically active agents.
[0020] U.S. Pat. Nos. 6,303,149, 6,238,650, 6,468,509, 6,436,375,
US2005037087, US2002064541, and International publication Nos. WO
00/09652, WO00/72806, WO 01/80823, WO 03/03497, WO 03/039510,
WO00/71084, WO05/009604, and WO04/81222, disclose sol-gel
microcapsules and methods for their preparation. EP 0 934 773 and
U.S. Pat. No. 6,337,089 teach microcapsules containing core
material and a capsule wall made of organopolysiloxane, and their
production. EP 0 941 761 and U.S. Pat. No. 6,251,313 also teach the
preparation of microcapsules having shell walls of
organopolysiloxane. U.S. Pat. No. 4,931,362 describes a method of
forming microcapsules or micromatrix bodies having an interior
water-immiscible liquid phase containing an active,
water-immiscible ingredient. Microcapsules prepared by a sol-gel
process are also disclosed in GB2416524, U.S. Pat. No. 6,855,335,
WO03/066209.
[0021] Another media, which can be utilized to protect sensitive
ingredients, is doping within sol-gel matrices. In this method,
monoliths, particles or other forms (such as thin films) are
prepared, and the active ingredient is immobilized in the pores of
the sol-gel matrix. The sol-gel matrix is doped with small amounts
of the active ingredient. This method was utilized in WO98/31333,
U.S. Pat. Nos. 6,495,352, and 5,292,801.
[0022] Thus there is a widely recognized need and will be highly
advantageous to have a new process for metal oxide coating of a
solid water insoluble particulate matter, enabling the growth of a
metal oxide layer on said solid water insoluble particulate matter
to the desired thickness and having the advantage of controlling
and tuning of the thickness of the metal oxide layer. There is
additionally a need for compositions especially for dermatological
or agricultural use, characterized by the ability to isolate the
active agent from the surrounding (by reducing its leaching through
the metal oxide coating layer) thus lowering the side effects and
toxicity associated with the active agent, and yet which are
efficient at controlling the release of the active agent to the
loci to be treated.
SUMMARY OF THE INVENTION
[0023] The present invention is based on the finding of a manner of
obtaining a thick and dense coating of metal oxide on a solid
water-insoluble particulate matter. The formation of the metal
oxide layer by the new method is irreversible, i.e. it does not
erode or disintegrate upon dispersion in water. The new method
further enables to obtain a more dense layer and is capable of fine
tuning of the width of the metal oxide layer, thus allowing better
control of the release of the active ingredient from the
microparticles upon application on a surface (such as skin or
mucosal membrane, or pest-infested surface). The new method
comprises treating the solid water-insoluble particulate matter
with an ionic additive, e.g. a first cationic additive in an
aqueous medium to obtain a dispersion of said particulate matter
having positive charges on its surface; coating the particulate
matter by precipitation of a metal oxide salt; and aging the
coating layer. The coating is repeated at least 4 more times,
preferably 4 to about 1000 more times, more preferably 4 to about
300 times, even more preferably 4 to about 100 times. The aging
step is conducted at the end of the process. Thus, the aging is not
conducted between repeated coating steps (i.e. repeated coating
steps of at least 4 more times), but only at the end of the
process. The process includes additional steps as will be detailed
below such as treating the so formed coating with a surface
adhering second cationic additive to obtain positive charges on the
coating, in order to modify the surface charge of the metal oxide
layer to make it reactive for further coating by an additional
metal oxide layer in a similar manner to that described above.
Alternatively, or in addition to said cationic additive, a
non-ionic, surface adhering additive (e.g. a non-ionic polymer) may
be used. Without being bound to theory such non-ionic additive may
function as an adhesive material allowing precipitation of a
further metal oxide layer on the coated metal oxide layer. The
process may further include for example a step of separating the
coated particulate matter such as by filtration, centrifugation or
decantation; and optionally a step of washing and re-dispersing the
obtained coated particulate matter in an aqueous medium.
[0024] The new method of preparation enables the formation and
growth of a thick layer or layers of a metal oxide coating on the
particulate matter, with the ability of fine control of the width
of the obtained layer. This is particularly advantageous for
certain uses where the active ingredient should be isolated, from
its surroundings with an ability to be gradually released through
the metal oxide layer. Exemplary uses are dermatological or
cosmetic uses as well as in the case of pesticides for home,
horticultural or agricultural use. The new method enables fine
tuning and control of the thickness of the metal oxide layer.
[0025] Preferred is coating intended to achieve substantially the
same or a larger therapeutic effect of the active agent and reduced
side effects compared to an uncoated composition of the active
agent.
[0026] According to one aspect of the present invention there is
provided a process for coating a solid, water-insoluble particulate
matter, with a metal oxide comprising:
[0027] (a) contacting the solid, water-insoluble particulate matter
with an ionic additive and an aqueous medium to obtain a dispersion
of said particulate matter having positive charges on its
surface;
[0028] (b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide layer thereon to thereby
obtain particulate matter coated by a metal oxide coating
layer;
[0029] (c) repeating step (b) at least 4 more times; and
[0030] (d) aging said coating layer.
[0031] According to another aspect of the present invention there
is provided coated particulate matter obtained by the process as
described in the present invention.
[0032] According to yet 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 comprising coated particulate matter as described in
the present invention, the particular matter being a topically
dermatologically active agent.
[0033] According to additional aspect of the present invention
there is provided use of coated particular matter as described in
the present invention, the particular matter being a topically
dermatologically active agent, for topical administration on the
skin or mucosal membrane.
[0034] According to a further aspect of the present invention there
is provided a method for preventing, reducing, or eliminating pests
at a locus, comprising applying to the locus of said pest a
pesticidaly effective amount of a pesticidal composition comprising
a coated particulate matter as described in the present invention,
the particulate matter being a pesticide.
[0035] Also provided by the invention are particles comprising a
particular matter coated by a metal oxide layer wherein: (i) said
metal oxide layer has a width of 0.1-10 micron, and (ii) said
particles are characterized in that when tested in Dissolution
Tester using Paddle Method in a medium, typically organic-based
solvent such as acetonitrile, iso propyl miristate, ethanol, or
methanol, in which said particulate matter is soluble, and a
dissolution volume in which the concentration of the particular
matter is lower than the solubility of the particular matter, the
time for releasing 50% w/w of the particulate matter from said
particulars is at least two-fold higher, preferably three-fold
higher, more preferably five-fold higher and most preferably
ten-fold higher as compared to the dissolution of the free form of
the particulate matter having substantially the same particle size
diameter as the particulate matter in said particles.
[0036] Further provided by the invention are particles comprising a
core composed of a solid, water insoluble particulate matter; said
core is coated by a metal oxide layer; wherein said metal oxide
layer is substantially not in an amorphous and/or not in a
crystalline form. The term "said metal oxide layer is substantially
not in an amorphous and/or not in a crystalline form" is meant to
denote that distinct regions of amorphous metal oxide (in case the
metal oxide in its pure form is amorphous) or crystalline metal
oxide (in case the metal oxide in its pure form contains
crystalline material, or is purely crystalline) cannot be detected
by methods such as X-Ray diffraction. The non-amorphous and/or
non-crystalline metal oxide layer refers to a co-structured
composite of metal oxide and an adhering additive. Such adhering
additive may be for example a polymer which interrupts the
formation of continues regions of the metal oxide, thereby leading
to the non-amorphous and non crystalline metal oxide form. The non
amorphous and non crystalline metal oxide form is characterized by
not having any X-ray diffraction peak specific to the metal oxide
in its pure form. For example, if the metal oxide in its pure form
is amorphous, a characteristic X-ray diffraction peak or peaks may
be detected. This may be the case, for example, in case of a
particle with a pure metal oxide coating. In the case of the
particles according to this aspect of the disclosure, the
characteristic X-ray diffraction peak(s), specific to the amorphous
form is absent, shifted, or flattened. An example are particles
with a silica-based coating, which will have a different
peak--namely absent, shifted, or flattened--as compared to
particles with an amorphous silica coating. In the case of a metal
oxide which in its pure form contains crystalline regions, or is
purely crystalline, in the case of a composite coating a peak
specific to the crystalline form is absent, shifted, or flattened.
Thus, X-ray diffraction may serve to distinguish particles of this
aspect of the disclosure over others.
BRIEF DESCRIPTION TO DRAWINGS
[0037] FIG. 1 shows the release rate of BPO for sample SGT025,
prepared according the coating procedure in Example 1, using step
2b: coating option #2. Number of repeating coating was 20, 30, 40.
Aging was conducted for 96 hours at 25 C. The release rate is
compared to free BPO.
[0038] FIG. 2 shows the release rate of BPO for sample SGT010,
prepared according |the coating procedure in Example 1, using step
2a: coating option #1. Number of repeating coating was 20, 35.
Aging was conducted for 72 hours at 25 C. The release rate is
compared to free BPO.
DETAILED DESCRIPTION OF THE INVENTION
[0039] The present invention relates to a process for coating a
solid, water-insoluble particulate matter, with a metal oxide
comprising:
[0040] (a) contacting the solid, water-insoluble particulate matter
with an ionic additive and an aqueous medium to obtain a dispersion
of said particulate matter having positive charges on its
surface;
[0041] (b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide layer thereon thereby to
obtain particulate matter coated by a metal oxide coating
layer;
[0042] (c) repeating step (b) at least 4 more times; and
[0043] (d) aging said coating layer.
[0044] As used herein the term "solid, water-insoluble particulate
matter" refers to a solid material having solubility in water of
less than 1% w/w, typically less than 0.5% and at times less than
0.1% w/w at room temperature (20.degree. C.).
[0045] The "solid, water-insoluble particulate matter" constitutes
the "core" of the particles obtained by the process. The solid,
water-insoluble particulate matter, is preferably in such a state
of subdivision that it can be suspended in water, e.g. in the form
of a finely-divided powder having a D90 (see definition below),
preferably in the range of 0.3-50 micron. Such a particulate matter
can readily be suspended in an aqueous systems by stirring, with or
without the aid of a surfactant. The "solid, water-insoluble
particulate matter" may be comprised of the active ingredient per
se or may be comprised of the active ingredient and excipients
(e.g. solid carrier).
[0046] The terms "solid, water-insoluble particulate matter" and
"particulate matter" will be used interchangeably.
[0047] In the present invention the terms "layer", "coating" and
similar terms, refer to a layer of metal oxide formed around a
particle or particulate matter. The layer or coating may not always
be complete or uniform and may not necessarily lead to complete
coverage of the particulate matter or particle surface. It is
appreciated that upon repetition of the coating steps as the
coating process proceeds a more uniform coating and more complete
coverage of the particulate matter is obtained.
[0048] The term "dispersion" as used herein in step (a) of the
process refers to a solid dispersion of the particulate matter in
the aqueous medium.
[0049] Step (a) of the process may further comprise reducing the
particle size of the particulate matter to the desired particle
size for example by milling or homogenization.
[0050] The core (i.e. solid, water insoluble particulate matter)
may be of any shape for example rod-like, plate-like, ellipsoidal,
cubic, or spherical shape.
[0051] 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 spherical particles
stated to have a diameter of 10 micrometer {"microns"), this means
that the particles have a D90 of 10 microns. The D90 may be
measured by laser diffraction. For particles having a shape other
than spheres, the D90 refers to the mean average of the diameter of
a plurality of particles.
[0052] In the case of cores having a spherical shape, the diameter
(D90) may be in the range of 0.3 to 90 microns, preferably 0.3 to
50 microns, more preferably 1 to 50, even more preferably 5 to 30
microns.
[0053] By the term "D90 may be in the range of 0.3 to 90 microns"
is meant that 90% by volume of the particles (in this case the
particle's core) may be less than or equal to a value in the range
of 0.3 to 90 microns.
[0054] For generally cubic-shaped cores or cores having a shape
resembling that of a cube, the mean size of a side may be in the
range 0.3 to 80 microns, preferably 0.3 to 40 microns, more
preferably 0.8 to 40, even more preferably 4 to 15 microns.
[0055] For rod-like shaped, ellipsoidal-shaped and plate-like
shaped cores, the largest dimension (that of the longest axis) is
typically in the range 10 to 100 microns, preferably 15 to 50
microns; and the smallest dimension is typically in the range 0.5
to 20 microns, and more preferably 2 to 10 microns.
[0056] As used herein, unless otherwise indicated, the term
"particle" refers to the metal oxide coated particulate matter.
[0057] It is appreciated that some of the particles obtained by the
process may at times be formed from two or more original particles
of the solid, water-insoluble particulate matter and may
accordingly include at times more than one core, such cores being
separated from each other by a metal oxide region.
[0058] The core may be an organic or inorganic material. Preferably
the core is composed of a material other than a metal oxide.
[0059] The weight of the solid, water-insoluble particulate matter
(core material) based on the total weight of the particle may be in
the range 99%-50% w/w, more preferably in the range 97%-50% w/w.
The core material may be in a crystalline form, amorphous form, or
combination thereof. The core material may be a cosmetically,
pharmaceutically or an agrochemical active ingredient.
[0060] Preferably step (c) of the process described above is
repeated 4 to about 1000 times. This means that preferably step (b)
of the process described above is repeated 4 to about 1000
times.
[0061] Preferably the process comprising repeating step (c) 4 to
about 300 times, and more preferably 4 to about 100 times. Even
more preferably step (c) of the process described above is repeated
5-80 times and most preferably 5-50 times. This means that
preferably step (b) is repeated as indicated above with respect to
step (c).
[0062] By the term "repeated 4 to about 1000 times" is meant that
the process may be repeated 4, 5, 6, 7, 8, 9 . . . , etc. times up
to and including about 1000 times.
[0063] According to a preferred embodiment of the present invention
step (d) further comprising after aging, separating the coated
particulate matter from the dispersing aqueous medium, such as by
filtration, centrifugation or decantation and optionally rinsing
and redispersing the obtained coated particulate matter in an
aqueous medium.
[0064] During the coating process it is preferred that at least 50%
of the content the particulate matter (active agent) in the aqueous
medium is in a solid state during the coating process.
[0065] According to a preferred embodiment of the present invention
the process comprising:
[0066] (a) contacting the solid, water-insoluble particulate
matter, with a first cationic additive and an aqueous medium to
obtain a dispersion of said particulate matter having positive
charges on its surface;
[0067] (b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide coating layer on the
particulate matter;
[0068] (b1) in an aqueous medium, contacting the coated particulate
matter with a surface adhering additive being one or both of (i) a
second cationic additive, and (ii) a non-ionic additive;
[0069] (b2) subjecting the particulate matter obtained in step (b1)
to a coating procedure as in step (b);
[0070] (c) repeating steps (b1) and (b2) at least 3 more times;
and
[0071] (d) aging the metal oxide coating layer.
[0072] Preferably the process comprising repeating step (c) 3 to
about 1000 times.
[0073] Preferably the process comprising repeating step (c) 3 to
about 300 times, and more preferably 3 to about 100 times.
[0074] As used herein by the term "repeating step (c) 3 to about
1000 times" is meant that the process may be repeated 3, 4, 5, 6,
7, 8, 9, . . . etc. times up to and including about 1000 times.
[0075] This means that preferably steps (b1) and (b2) are repeated
as indicted above with respect to step (c).
[0076] Additionally according to a preferred embodiment of the
present invention the process comprising:
[0077] (a) contacting the solid, water-insoluble particulate
matter, with an anionic additive, a first cationic additive and an
aqueous medium to obtain a dispersion of said particulate matter
having positive charges on its surface;
[0078] (b) subjecting the particulate matter to a coating procedure
comprising precipitating a metal oxide salt onto the surface of the
particulate matter to form a metal oxide coating layer on the
particulate matter;
[0079] (b1) in an aqueous medium, contacting the coated particulate
matter with a surface adhering additive being one or both of (i) a
second cationic additive, and (ii) a non-ionic additive;
[0080] (b2) subjecting the particulate matter obtained in step (b1)
to a coating procedure as in step (b);
[0081] (c) repeating steps (b1) and (b2) at least 3 more times;
and
[0082] (d) aging the metal oxide coating layer.
[0083] When an anionic additive and first cationic additive are
used in step (a) of the process, preferably the anionic additive is
added before the first cationic additive.
[0084] Step (c) may be repeated 3 to about 1000 times. Preferably
step (c) is repeated 3 to about 300 times, and more preferably 3 to
about 100 times. This means that preferably steps (b1) and (b2) are
repeated as indicted above with respect to step (c).
[0085] The ionic additive (such as first cationic additive) used in
step (a) of the process have a dual effect: to form positive
charges on the surface of the particulate matter as will be
described below, and also to serve as a wetting agent, thus
allowing dispersion of the particulate matter as discrete core
particles, where each core particle is individually suspended in
the aqueous medium.
[0086] Step (a) of the process may be conducted for example by (i)
contacting the particulate matter with dry ionic additives and then
suspending both in an aqueous medium to obtain a dispersion of said
particulate matter having positive charges on its surface, or
alternatively by (ii) suspending the solid, water-insoluble
particulate matter in an aqueous medium comprising ionic additives
to obtain a dispersion of said particulate matter having positive
charges on its surface.
[0087] According to another preferred embodiment of the process may
comprise (a) contacting the solid, water-insoluble particulate
matter, with an ionic additive selected from (i) an anionic
additive; (ii) a first cationic additive, and a combination
thereof, and an aqueous medium to obtain a dispersion of said
particulate matter having positive charges on its surface; (b),
(b1), (b2), (c), (d) are as described herein.
[0088] The concentration of the ionic additives in the dispersion
can be about 0.001% to about 30%, preferably about 0.01% to about
10% w/w and most preferably about 0.1% up to about 5% w/w. The
solid content of the water dispersion can be about 0.1% to about
80% w/w, preferably about 1% to about 60% w/w most preferably about
3% to about 50% w/w.
[0089] The purpose of step (a) is to modify the electrical charge
of the particulate matter by using ionic additives such that it
will be made reactive to the attachment of the metal oxide
layer.
[0090] For preparing the core material of the particles, the
particulate matter ought to be suitably coated with an ionic
additive (e.g. cationic additive), such that it can be attached to
the precipitated metal oxide salt.
[0091] Preferably the ionic additive is selected from a cationic
additive, an anionic additive, and a combination thereof. The
cationic additive may be a cationic surfactant and/or cationic
polymer. The anionic additive may be an anionic surfactant and/or
anionic polymer.
[0092] The particulate matter is contacted with an ionic additive,
for example by mixing it with a solution of a cationic surfactant
and/or cationic polymer or an anionic surfactant and a cationic
additive (e.g. cationic surfactant and/or cationic polymer).
Cationic and anionic surfactants are particularly effective in
being adsorbed upon the surface of the particulate matter. The
ionic additive may also be anionic polymers used in combination
with a cationic additive. The cationic surfactant and/or the
cationic polymer and optionally further the anionic surfactant (or
anionic polymer) need to be used in sufficient amount to provide
positive charges on the surface of the particulate matter. A
monolayer of the ionic additive is preferred, but the coating need
not be continuous. It is sufficient that there are at least spots
of cationic additive. These spots will then serve as anchors for
the attachment of the metal oxide layer. It is preferred that there
are fairly uniform distribution of these anchoring points on the
core surface so that as the metal oxide layer builds up it will
bridge over and be firmly attached to the core.
[0093] According to one preferred embodiment said first and said
second cationic additive are the same.
[0094] According to another preferred embodiment said first and
said second cationic additive are different.
[0095] More preferably the first ionic additive is an anionic
surfactant and the second ionic additive is a cationic polymer
[0096] Most preferably the first cationic additive is a cationic
surfactant and the second cationic additive is a cationic
polymer.
[0097] According to another preferred embodiment, the first
cationic additive is a cationic surfactant and the additive in step
(b1) is a non-ionic additive (e.g. a non-ionic polymer).
[0098] Preferably the coated particulate matter and the second
cationic additive are mixed, and most preferable said mixing is
under vigorous stirring (e.g. mixer speed above 1000 rpm).
[0099] According to a preferred embodiment of the present invention
the process further comprising following step (d): (e) separating
the coated particulate matter from the aqueous medium and
optionally rinsing and redispersing the coated particulate matter
in an aqueous medium.
[0100] Preferably the separation of the coated particulate matter
is conducted by a method such as filtration, centrifugation,
decantation, dialysis, or by evaporation of the aqueous medium.
[0101] Additionally, according to a preferred embodiment of the
present invention, step (b) comprises adding a metal oxide salt to
the aqueous medium; and optionally acidifying the aqueous
medium.
[0102] Further according to a preferred embodiment of the present
invention, step (b2) comprises adding a metal oxide salt to the
aqueous medium; and optionally acidifying the aqueous medium.
[0103] Preferably step (b1) further comprising adjusting the pH of
the dispersion obtained in (b) to a value higher than the
isoelectric point of the metal oxide before adding the second
cationic additive, more preferably to a pH value of at least about
1 unit higher than the isoelectric point of the metal oxide, before
adding the second cationic additive.
[0104] Preferably step (b1) further comprising adjusting the pH of
the dispersion obtained in (b) to a value higher than the
isoelectric point of the metal oxide before adding one or both of
(i) a second cationic additive, and (ii) a non-ionic additive, more
preferably to a pH value of at least about 1 unit higher than the
isoelectric point of the metal oxide, before adding one or both of
(i) a second cationic additive, and (ii) a nonionic additive.
[0105] For example, in case the metal oxide is silica (e.g. having
an isoelectric point in the range 1.7-2.5) the preferred pH may be
at least in the range of about 2.5-6.5.
[0106] The purpose of the pH adjustment of the dispersion to a
value higher than the isoelectric point of the metal oxide is to
form negatively charged metal oxide on the particulate matter
surface that will be bound to the positive charges of the second
cationic additive thus enabling the attachment of the second
cationic additive to the surface of the particulate matter.
[0107] The non-ionic additive is of a kind that adheres to the
surface ("surfaceadherent"). An example is a non-ionic polymer. The
non-ionic additive may be used alone or in addition to the second
cationic surfactant. Without wishing to be bound by theory, the
surface-adherent property may be through hydrogen-binding groups
such as hydroxyl or amine groups. This allows adhesion of a further
layer of metal oxide on the preceding precipitated metal oxide
layer.
[0108] Preferably the particulate matter/metal oxide salt weight
ratio, in each of the steps (b) or (b2) is about 5,000/1 to about
20/1, preferably about 5,000/1 to about 30/1, or about 5,000/1 to
about 40/1, more preferably about 1,000/1 to about 40/1, and most
preferably about 500/1 to about 80/1.
[0109] Preferably the particulate matter/cationic additive ratio,
in step (b1) is about 25,000/1 to about 50/1, preferably about
5,000/1 to about 100/1, and most preferably about 2000/1 to about
200/1.
[0110] According to preferred embodiment the particulate
matter/metal oxide salt weight ratio, in each of the steps (b) or
(b2) is about 5,000/1 to about 65/1, and more preferably about
1000/1 to about 100/1.
[0111] Preferably the particulate matter/cationic additive weight
ratio, in step (b1) is about 10,000/1 to about 100/1, and more
preferably about 5000/1 to about 200/1.
[0112] The aging in step (d) is crucial for obtaining a
strengthened and dense layer of metal oxide.
[0113] Preferably step (d) comprises raising the pH to a value in
the range 3-9 and mixing the suspension in this pH.
[0114] According to a preferred embodiment of the present invention
step (d) comprises raising the pH to a value in the range 3-9 and
mixing the suspension in this pH for a period of at least 2 h.
[0115] According to a preferred embodiment of the present invention
step (d) comprises raising the pH to a value in the range 3-9,
preferably to a range of 5-7, and mixing, e.g. by stirring, the
suspension (dispersion) in this pH range e.g. for a period of at
least 2 h (two hours). Preferably stirring is for 2-96 h, more
specifically 2-72 h, more preferably at least 10 h (for example
10-72 h). The stirring is preferably a gentle stirring, preferably
in the range 200-500 rpm.
[0116] Upon completion of aging, the separation (e.g. filtration,
centrifugation or decantation) will be easy to perform (due to the
hard metal oxide layer formed) and the obtained cake or
concentrated dispersion will be easily re-dispersed in an aqueous
medium to form a dispersion of particles.
[0117] The purpose of aging in step (d) is to obtain a strengthened
and denser layer of metal oxide.
[0118] In the absence of the aging step a thinner and softer layer
of metal oxide would be obtained since the metal oxide salt upon
precipitation forms a gel layer of metal oxide which may
disintegrate or erode upon separation and washing or by mechanical
stirring.
[0119] The aging may be conducted at a temp of 4-90.degree. C.,
preferably at 15-60.degree. C. and most preferably the aging is
conducted at a temperature 20.degree. C.-40.degree. C.
[0120] Thus the repeated steps of coating and aging at the end of
the process also enable the growth of thicker and stronger layer of
metal oxide. The aging is not conducted between the repeated
coating steps (i.e. between the repeated coating step (b)), but
only at the end of the process. Thus the aging is conducted only at
the end of the process described herein.
[0121] According to certain embodiments, the process may further
comprise adding a colloidal metal oxide suspension, preferably
aqueous-based suspension (comprising nanometric metal oxide
(nanoparticles of metal oxide)) during the coating procedure.
Preferably the colloidal metal oxide suspension is selected from
colloidal silica suspension, colloidal titania suspension,
colloidal alumina suspension, colloidal zirconia suspension,
colloidal ZnO suspension, and mixtures thereof. The colloidal metal
oxide suspension may be added during the coating process (e.g. in
step (b) in one or more of its repeated steps). Preferably the size
of the nanometric metal oxide in diameter is in the range between
5-1OO nm (average particle size diameter). The weight ratio of the
nanometric metal oxide to the metal oxide salt may be in the range
95:5 to 1:99 preferably 80:20 to 5:95 more preferably 70:30 to
10:90, most preferably about 60:40 to 20:80. The weight ratio of
the nanometric metal oxide to the metal oxide salt may be about
50:50.
[0122] According to other embodiments, the process does not include
addition of colloidal metal oxide suspension during the coating
process. According to this embodiment nanometric metal oxide
particles (nanoparticles of metal oxide) are not added during the
coating process.
[0123] As used herein, the term "metal oxide coating layer" or
"metal oxide layer" encompasses the product of both a single
processing step as well as a product of the process in which the
initially coated particles are further processed, by the repeated
processing steps of step (c), described above.
[0124] The solid, water insoluble particulate matter may be a
pharmaceutically, cosmetically, or agrochemical active
ingredient.
[0125] Preferably the solid, water insoluble particulate matter is
a dermatological active agent.
[0126] Preferably the dermatological active agent is selected from
antifungal agents, antibacterial agents, antiinflammatory agents,
antipruritic agents, anti psoriatic agent, and anti acne agents.
The dermatological agent may also be combinations of any of the
above agents.
[0127] The antibacterial agents may be a bacteriostatic or
bacteriocidal drug.
[0128] The dermatological active agent may be for example
antifungal agents such as ketoconazole, bacteriostatic drugs such
as metronidazole or erythromycin, bactericidal drugs such as
bacitracin, corticosteroids such as mometasone furoate,
methylprednisolone aceponate, prednicarbate, triamcinolone
acetonide, fluocinonide, desoximetasone, bethasone valerate or
mometasone furoate, antipruritic agent such as doxepin
hydrochloride, and anti acne agents such as benzoyl peroxide,
azelaic acid, retinoids such as tretinoin (all trans retinoic
acid), tazarotene, iso-tretinoin or adapalene.
[0129] More preferably the active agent (e.g. anti-acne agent) is
selected from benzoyl peroxide, retinoid, and mixtures thereof.
[0130] Most preferably the active agent (e.g. anti-acne agent) is
benzoyl peroxide.
[0131] The agrochemical agent may be a pesticide.
[0132] Pesticides which may be employed include a wide range of
herbicides, nematocides, insecticides, acaricides, fungicides,
plant growth promoting or controlling chemicals and other crop
treating products which are solids 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.
[0133] Illustrative examples of the pesticides which may be
employed are Azoxystrobin, Carbendazim, Chlorothalonil,
Copper-oxychloride, Cyazofamid, Cymoxanil, Cyproconazole,
Dimethomorph, Epoxiconazole, Fluazinam, Flusilazole, Flutolanil,
Folutriafol, Kresoxim-methyl, Mancozeb, Maneb, Pencycuron,
Pyraclostrobin, Tebuconazole, Thiophanate-methyl, Trifloxystrobin,
Ziram, Aclonifen, Ametryn, Amicarbazone, Atrazine, Bentazone,
Chlorimuron-ethyl, Cyhalofop-butyl, Ethalfluralin, Ethofumasate,
Florasulam, Flufenacet, Flumetsulam, Fomesafen,
Halosulfuron-methyl, Imazamox, Imazapic, Imazethapyr, Imazapyr,
Imazaquin, Isoproturon, Isoxaflutole, Lactofen, Linuron,
Mesotrione, Metamitron, Metazachlor, Metoxuron, Metribuzin,
Metsulfuron-methyl, Oxyfluorfen, Pendimethalin, Prometryn,
Propanil, Quinclorac, Quinmerac, Quizalofop-ethyl,
Quizalofop-P-ethyl, Rimsulfuron, Simazine, Sulcotrione,
Sulfentrazone, Sulfometuron-methyl, Sulfo sulfuron, Tebuthiuron,
Thifensulfuron-methyl, Tralkoxydim, Triasulfuron, Triclopyr,
Trifluralin, Abamectin, Acetamiprid, Aldicarb, Alphacypermethrin,
Betacyfluthrin, Bifenthrin, Carbofuran, Chlorfenapyr,
Chlorfluazuron, Chlorpyrifos, Cypermethrin, Deltamethrin,
Endosulfan, Esfenvalerate, Fipronil, Imidacloprid, Indoxacarb,
Lambda-cyhalothrin, Lufenuron, Methoxyfenozide, Novaluron, Oxamyl,
Pirimicarb, Spinosad, Teflubenzuron, Thiacloprid, Thiamethoxam,
Fenamiphos, Thidiazuron, Sulphur, and mixtures of any of the
above.
[0134] Preferably the metal oxide is selected from Silica, Titania,
Alumina, Zirconia, ZnO, and mixtures thereof. Most preferably the
metal oxide is silica. The metal oxide salt is preferably an alkali
metal oxide salt, e.g. a sodium or potassium salt.
[0135] According to a preferred embodiment the metal oxide salt is
selected from sodium silicate, potassium silicate, sodium
aluminate, potassium aluminate, sodium titanate, potassium
titanate, sodium zirconate, potassium zirconate, and mixtures
thereof. Most preferably the metal oxide salt is a silicate
salt.
[0136] Further according to a preferred embodiment of the present
invention the ionic additive is selected from a cationic
surfactant, anionic surfactant, a cationic polymer, and mixtures
thereof. When an anionic surfactant is used, preferably a cationic
additive is further added such as a cationic surfactant and/or a
cationic polymer.
[0137] Preferably the cationic additive is selected from a cationic
surfactant, a cationic polymer, and mixtures thereof
[0138] According to a preferred embodiment the first cationic
additive is a cationic surfactant, and the second cationic additive
is a cationic polymer.
[0139] The first cationic additive is preferably a cationic
surfactant.
[0140] Preferably the cationic surfactant is selected from
monoalkylquaternary ammonium salts, dialkyl quaternary ammonium
salts, and mixtures thereof.
[0141] Preferably the monoalkylquaternary ammonium salts are
selected from benzethonium chloride, benzalkonium chloride,
cetyltrimethylammonium chloride (CTAC), cetyltrimethylammonium
bromide (CTAB), lauryltrimethylammonium chloride,
stearyltrimethylammonium chloride, cetylpyridinium chloride, and
mixtures thereof.
[0142] Most preferably the monoalkylquaternary ammonium salt is
cetyltrimethylammonium chloride.
[0143] Preferably the dialkyl quaternary ammonium salt is
distearyldimethylammonium chloride.
[0144] Additional cationic surfactants which can be used are
described in: John A. Wenninger et al. (Editors) International
Cosmetic Ingredient Dictionary and Handbook (Eighth Edition 2000),
Vol. 2 pp. 1140-1147, Published by The cosmetic, Toiletry, and
Fragrance Association.
[0145] The ionic additive may be an anionic surfactant.
[0146] Preferably the anionic surfactant is selected from alkyl
benzene sulphonic acids and salts, alkyl ether carboxylic acids and
salts, alkyl sulpho succinamates, alkyl sulphossucinates, alpha
olefin sulphonates, aromatic hydrocarbon sulphonic acids and salts,
fatty alcohol ethoxy sulphates, fatty alcohol sulphates, phosphate
esters, and mixtures thereof.
[0147] Preferably the alkyl benzene sulphonic acid salt is sodium
dodecyl benzene sulphonate, the fatty alcohol sulphate is sodium
lauryl sulphate, the alkyl sulphossucinates is sodium dioctyl
sulphossucinate, and mixtures thereof. The anionic surfactant may
be mixtures of any of the above.
[0148] Additional anionic surfactants which can be used are
described in: John A. Wenninger et al. (Editors) International
Cosmetic Ingredient Dictionary and Handbook (Eighth Edition 2000),
Vol. 2 pp. 1140-1147, Published by The cosmetic, Toiletry, and
Fragrance Association incorporated herein by reference in its
entirety.
[0149] Preferably the weight ratio of the ionic additive to the
water-insoluble particulate matter is in the range 1:1000-1:10,
more preferably in the range 1:200-1:50, most preferably about
1:100. The ratios indicated above refer to an ionic additive such
as the first cationic additive or to the combination of a first
cationic additive and an anionic additive. The second cationic
additive may be a cationic polymer, a cationic surfactant, or
mixtures thereof. The cationic surfactant may be as described
above.
[0150] According to a preferred embodiment of the present invention
the second cationic additive is a cationic polymer.
[0151] Preferably the weight ratio of the first coated particulate
matter (i.e. in step (b1)) to the second cationic additive is in
the range of about 25,000/1 to about 50/1, more preferably about
5,000/1 to about 100/1 most preferably about 2000/1 to about
200/1.
[0152] Preferably the weight ratio of the further processed coated
particulate matter (e.g. in the repeated steps described in step
(c)) to the second cationic additive is in the range of about
25,000/1 to about 50/1, more preferably about 5,000/1 to about
100/1 most preferably about 2000/1 to about 200/1.
[0153] Preferably the particulate matter/cationic additive weight
ratio, in step (b1) is about 10,000/1 to about 100/1, and more
preferably about 5000/1 to about 200/1.
[0154] Preferably the weight ratio of the further processed coated
particulate matter (e.g. in the repeated steps described in step
(c)) to the second cationic additive is in the range of about
10,000/1 to about 100/1, and more preferably about 5000/1 to about
200/1.
[0155] In case a non-ionic additive (e.g. non-ionic polymer) is
used alone or in addition to the second cationic additive, the
weight ratios of the of the first coated particulate matter to the
(i) non-ionic additive or (ii) a combination of a non-ionic
additive and second cationic additive, and the weight ratios of the
further processed coated particulate matter to the (i) non-ionic
additive or (ii) the combination of the non-ionic additive and
second cationic additive, may be as indicated above with respect to
the second cationic additive.
[0156] Preferably the cationic polymer (of the first cationic
additive or second cationic additive) is selected from
poly(ethyleneimine) (PEI), poly(dimethyldiallylammonium chloride)
(PDAC), poly(acrylamide-co-diallyl-dimethylammonium chloride)
(polyquaternium-7), poly(allylamine hydrochloride) (PAH), Chitosan,
polylysine, and mixtures thereof.
[0157] The second cationic polymer may also be a copolymer of
non-ionic and ionic monomers such as pyrrolidone/dimethylaminoethyl
methacylate copolymer.
[0158] According to another preferred embodiment of the present
invention the second cationic additive is selected from colloidal
alumina, colloidal ceria (CeO2), colloidal alumina coated silica
(such as Ludox CL, Sigma-Aldrich), and mixtures thereof.
[0159] The second cationic additive may be a colloidal metal oxide
bearing a positive charge such as described above (e.g. colloidal
alumina, colloidal ceria (CeO2), colloidal alumina coated silica,
or mixtures thereof).
[0160] The non-ionic additive used in the process is preferably a
non-ionic polymer. The non-ionic polymer may be for example
polyvinylalcohol, polyvinylpyrrolidone, and mixtures thereof.
[0161] Further according to a preferred embodiment of the present
invention, the process further comprises drying the obtained coated
particulate matter.
[0162] Still further according to a preferred embodiment of the
present invention, the drying is by a method selected from spray
drying, lyophilization, oven drying, vacuum drying, and fluidized
bed.
[0163] Additionally, according to a preferred embodiment of the
present invention, the process further comprises chemically
modifying the surface of the coated particulate matter.
[0164] The surface chemical modification preferably comprises
modifying the metal oxide surface with organic groups, preferably
hydrophobic groups.
[0165] Preferably process comprising attaching hydrophobic groups
to the surface of the metal oxide layer.
[0166] The purpose of attaching hydrophobic groups to the surface
of the metal oxide layer is to control the water penetration rate
into the particles and consequently to control the release of the
active agent from the particles. Modifying the surface of the metal
oxide layer by hydrophobic groups enables to further control the
release of the active agent from the particles, according to the
desired rate.
[0167] The hydrophobic groups may be for example an alkyl silane,
dialkyl silane, trialkyl silane, (such alkyl groups may be further
substituted with one ore more flouro atoms), aryl silane (such as
benzyl silane, or phenyl silane), diaryl silane, or triaryl
silane.
[0168] Moreover according to a preferred embodiment of the present
invention, the chemical surface modification comprises reacting
silanol groups on the surface of the metal oxide layer with
precursors selected from monohalotrialkyl silane such as
chlortrimethylsilane, dihalodialkyl silane such as dichloro
dimethyl silane, trihaloalkyl silane such as trichloromethylsilane,
monoalkoxytrialkyl silane such as methoxy tri methyl silane,
dialkoxydialkyl silane such as dimethoxydimethylsilane,
trialkoxyalkyl silane such as trimethoxymethylsilane, aryltrihalo
silane such as phenyltrichlorosilane, diaryldihalo silane such as
diphenyldichloro silane, triarylhalo silane such as triphenylchloro
silane, aryltrialkoxy silane such as phenyltrimethoxysilane,
diaryldialkoxysilane such as diphenyldimethoxysilane,
triarylalkoxysilane such as triphenylmethoxysilane, and mixtures
thereof.
[0169] Preferably the alkyl group includes 1-18 carbon atoms, more
preferably 1-6 carbon atoms. Most preferably the alkyl is methyl.
The alkyl groups may be substituted by one or more flouro atoms.
Preferably the alkoxy group includes 1-6 carbon atoms and more
preferably 1-2 carbon atoms.
[0170] The halo group may be for example chloro, bromo, iodo,
fluoro. Most preferably the halo groups are chloro and bromo.
[0171] The aryl is preferably phenyl or benzyl.
[0172] The precursors react with the silanol groups on the surface
of the metal oxide layer to form a siloxane bond.
[0173] The attachment of the hydrophobic groups to the surface of
the metal oxide layer can be performed by reacting the dried coated
particulate matter with the above precursors. The procedure for
attaching hydrophobic groups to the metal oxide can be conducted as
follows: a dried powder of coated particulate matter is suspended
in an organic solvent such as toluene. A precursor
(hydrophobization reagent) from the list above such as
dimethyldichloro silane is added to the organic phase (mixture),
optionally in the presence of a halogen scavenger such as trialkyl
amine or triethanol amine. The organic mixture is refluxed for at
least about 24 hours to obtain coverage of the metal oxide layer
with the hydrophobic groups via attachment of the hydrophobic
groups to the silanol groups on the surface of the metal oxide
layer.
[0174] Further according to a preferred embodiment of the present
invention the obtained metal oxide coating layer has a width
(thickness) of about 0.1, 0.2, 0.3, 0.5, 0.7, 1, 1.5, 2 or 5 micron
or above, preferably up to 10 micron.
[0175] 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
particle the smallest width is at least e.g. 0.1 micron (the width
is determined as the smallest distance from the surface of the
particle (i.e. metal oxide surface) to the core-metal oxide
interface).
[0176] The invention additionally relates to the coated particulate
matter obtained by the processes as described in the present
invention.
[0177] According to a preferred embodiment of the present
invention, the weight ratio of the metal oxide to the solid,
water-insoluble particulate matter, is in the range of 1:99 to
40:60. The weight ratio may also be in the range 1:99 to 50:50.
Preferably the weight ratio of the metal oxide to the solid,
water-insoluble particulate matter, is in the range of 10:90 to
about 20:80. The weight ratio may also be as described in the
present invention.
[0178] According to a preferred embodiment of the present invention
the particles (coated particulate matter) have a diameter of
0.5-100 micron. More preferably the diameter of the particles is in
the range 1-50 micron and most preferably in the range 2-30
micron.
[0179] The particles may be useful for cosmetic or medical
applications.
[0180] The particles may also be used in agricultural or polymeric
industry.
[0181] The particles may be useful for any application wherein the
active ingredient should be isolated, temporally or permanently
from the ambient surroundings.
[0182] It is appreciated that the particles of the present
invention are composed of distinct regions of the metal oxide layer
and the core material (i.e. the solid water insoluble particulate
matter). The core material in newly prepared particles is
preferably substantially free of the metal oxide and further the
metal oxide layer is preferably substantially free of said core
material, e.g. either as particle dispersion (in the nanometric
range of below 0.1 micron) of the water insoluble particulate
matter or as molecular dispersion of said water insoluble
particulate matter. Thus, according to a preferred embodiment of
the present invention the metal oxide layer in newly prepared
particles, is substantially free of core material (either as
molecules or as nanometric particles). The term "substantially
free" in this context denotes that the concentration of the
molecules of the core material or the concentration of the
nanometric particles of the core material is negligible as compared
to the metal oxide. Similarly, by the term "the core material is
substantially free of the metal oxide" is meant that the
concentration of the metal oxide in the core, is negligible as
compared to the core material.
[0183] Th invention further relates to a pharmaceutical, cosmetic
or cosmeceutical composition for topical administration comprising
a carrier; and a plurality of coated particulate matter obtained by
the process described in the present invention, each of said
particles comprising a solid, water insoluble dermatologically
active agent, coated by a metal oxide layer.
[0184] The carrier may be a cosmetic or pharmaceutically acceptable
carrier. The coated dermatologically active agent is preferably
dispersed in the carrier.
[0185] The coated dermatological active agent may be easily
dispersed or suspended in a carrier or diluent.
[0186] Simple mixing with any suitable mixer or carrier is
sufficient to achieve an effective dispersion. If necessary, high
shear forces may be applied to facilitate fast and efficient mixing
of the coated particles in the carrier.
[0187] The particles are preferably non-leaching when dispersed in
a carrier, and most preferably non-leaching in an aqueous-based
carrier.
[0188] By the term "non-leaching" it is meant that the leaching of
the particulate matter (active agent) from the particles into an
aqueous-based liquid is less than 5% w/w, preferably less than 1%
w/w and most preferably less than 0.5% w/w at room temperature
(20.degree. C.), under gentle agitation for 1 hour or until a
steady state concentration is achieved. Typically, said
aqueous-based liquid is water. The values indicated above refer to
the percentage of the active agent leached into an aqueous medium
relative to the initial amount of the active agent in the
particles. The leaching values indicated above refer preferably to
a dispersion having a concentration of the particulate matter in
the aqueous medium higher than 0.1% w/w, more preferably higher
than 1% w/w, and most preferably higher than 10% w/w.
[0189] The metal oxide coating obtained by the present invention is
highly advantageous since it is capable of isolating the solid,
water insoluble particulate matter from its surrounding medium, and
yet enables the release the particulate matter upon application to
the surface to be treated.
[0190] Preferably the dermatological active agent is selected from
antifungal agents, antibacterial agents, antiinflammatory agents,
antipruritic agents, anti psoriatic agent, anti acne agents, and
mixtures thereof.
[0191] Preferably the anti-acne agent is selected from benzoyl
peroxide, a retinoid, and mixtures thereof.
[0192] Preferably the retinoid is all trans retinoic acid (ATRA),
iso-tretinoin, tazarotene or adapalene.
[0193] Most preferably the anti-acne agents are benzoyl peroxide
(BPO) and all trans retinoic acid (ATRA).
[0194] BPO and ATRA are particularly preferred compounds for
coating with a metal oxide in accordance with the invention. The
purpose of the BPO and ATRA coating is to provide at least one of
the following benefits: a) to reduce the skin irritation of the BPO
and ATRA crystals, b) to significantly reduce side effects caused
by BPO and ATRA in topical formulations, c) to increase the
dispersability of BPO and ATRA crystals in aqueous solutions in the
absence of surfactant, d) to prevent direct contact of the BPO and
ATRA crystals from the skin, e) prevent additional crystal growth
processes of BPO and ATRA after grinding, f) to increase the
stability of the BPO and ATRA, g) to have good compatibility with
other ingredients in the formulation, h) to produce a sustained
release mechanism of BPO and ATRA onto the skin.
[0195] According to a preferred embodiment of the present
invention, the metal oxide is selected from Silica, Titania,
Alumina, Zirconia, ZnO, and mixtures thereof. Most preferably the
metal oxide is silica.
[0196] Further according to a preferred embodiment of the present
invention, the weight ratio of said metal oxide to said solid,
water-insoluble particulate matter, is in the range 1:99 to 40:60.
The weight ratio may be in the range 3:97 to 50:50. The weight
ratio of the metal oxide layer to the solid, water-insoluble
particulate matter, may be also in the range 5:95 to 40:60, 10:90
to 40:60, 5:95 to 30:70, or 10:90 to 30:70.
[0197] Still further according to a preferred embodiment of the
present invention, the weight ratio of said metal oxide to said
solid, water-insoluble particulate matter, is in the range 10:90 to
20:80.
[0198] Moreover, according to a preferred embodiment of the present
invention, the particles (coated particulate matter) have a
diameter of 0.5-100 micron.
The thickness of said metal oxide layer may be as described
above.
[0199] Additionally, according to a preferred embodiment of the
present invention, the thickness of said metal oxide layer is in
the range 0.1-10 micron.
[0200] Further according to another preferred embodiment of the
present invention, the thickness of said metal oxide layer is in
the range 0.3-10 micron.
[0201] The carrier may be in the form of ointment, a cream, a
lotion, an oil, an emulsion, a gel, a paste, a milk, an aerosol, a
powder, a foam, a wash. Most preferably the carrier is in the form
of a gel or a cream more preferably oil-in-water cream. Most
preferably the dispersing phase (i.e. the carrier) is aqueous based
and comprises water as dispersing medium.
[0202] As disclosed herein the composition may be for the treatment
of a disease or condition selected from acne, infection,
inflammation, pruritis, psoriasis, seborrhea, contact dermatitis,
rosacea, and a combination thereof.
[0203] Further according to a preferred embodiment of the present
invention, the dermatological agent is selected from antifungal
agents, antibacterial agents, antiinflammatory agents, antipruritic
agents, anti psoriatic agent, and anti acne agents.
[0204] The antifungal agents, antibacterial agents,
antiinflammatory agents, antipruritic agents, anti psoriatic agent,
and anti acne agents may be as described in the present invention
above.
[0205] Most preferably the dermatological active agent is an
anti-acne agent.
[0206] Moreover according to a preferred embodiment of the present
invention, the anti acne agent is selected from benzoyl peroxide,
retinoid, and mixture thereof.
[0207] Most preferably the anti-acne agent is selected from benzoyl
peroxide, tretinoin (ATRA), and mixtures thereof.
[0208] According to a preferred embodiment of the present invention
the metal oxide is selected from Silica, Titania, Alumina,
Zirconia, ZnO, and mixtures thereof. Additionally according to a
preferred embodiment of the present invention, the weight ratio of
said metal oxide to said solid, water-insoluble dermatological
active agent, is in the range 1:99 to 40:60. The weight ratio of
the metal oxide layer to the solid, water-insoluble particulate
matter, may be also in the range 1:99 to 40:60, 5:95 to 40:60, 5:95
to 30:70, or 10:90 to 30:70.
[0209] Further according to a preferred embodiment of the present
invention, the weight ratio of said metal oxide to the solid,
water-insoluble particulate matter, is in the range 10:90 to 20:80.
The weight ratios may also be as detailed above with respect to the
weight ratio of the metal oxide to the solid, water-insoluble
particulate matter.
[0210] Moreover, according to a preferred embodiment of the present
invention, the particles have a diameter of 0.5-100 micron.
Preferably the particles have a diameter of 0.8-100 micron, more
preferably 1-50 micron and most preferably 5-30 micron.
[0211] Additionally, according to a preferred embodiment of the
present invention, the thickness of said metal oxide layer is in
the range 0.1-10 micron. The thickness may be as defined above in
relation to the process. Typical thickness is about 0.1-3 micron,
preferably about 0.1-1 micron. The thickness of the metal oxide
layer may also be in the range about 0.3 to 3 micron, and most
preferably about 0.3 to 2 micron.
[0212] According to a preferred embodiment of the present
invention, the carrier is in the form of an ointment, a cream, a
lotion, an oil, an emulsion, a gel, a paste, a milk, an aerosol, a
powder, a foam, or a wash.
[0213] Also disclosed is a method for treating a surface condition
in a subject, comprising topically administering onto the surface a
composition comprising a coated particulate matter as described in
the present invention, the particulate matter being a topically
dermatologically active agent.
[0214] The coated particulate matter may be obtained by the process
of the present invention.
[0215] It is appreciated that the compositions may comprise a
plurality of coated particulate matter.
[0216] Preferably the subject is a mammal, and most preferably the
mammal is a human.
[0217] 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/The Merck index an encyclopedia of chemical, drugs, and
biologicals. Rahway, N.J.; Merck & Co; 1989., incorporated
herein by reference in its entirety.
[0218] 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).
[0219] According to a preferred embodiment of the present
disclosure, the surface of a subject body is skin or mucosal
membrane.
[0220] The surface condition may be a disease or disorder selected
from acne, infection, inflammation, pruritis, psoriasis, seborrhea,
contact dermatitis, rosacea, and a combination thereof.
[0221] According to a preferred embodiment of the present
disclosure, the metal oxide layer releases the particulate matter
following topical application (administration). Preferably the
solid, water insoluble particulate matter is a dermatological
active agent as described above, more preferably an anti-acne
agent, and most preferably the dermatological active agent (e.g.
anti acne agent) is benzoyl peroxide.
[0222] According to another preferred embodiment the dermatological
active agent (e.g. anti acne agent) is a retinoid (preferably
tretinoin).
[0223] Without being bound to theory it is assumed that benzoyl
peroxide is released from the particles through the metal oxide
coating layer by extraction by lipids available on the skin. Upon
application on the skin, it is assumed that the skin lipids diffuse
through the metal oxide layer and extract the benzoyl peroxide
present in the core. Other dermatological agents may be similarly
released from the particles.
[0224] The invention further relates to the use of coated
particulate matter as described herein, the particulate matter
being a topically dermatologically active agent, for the
preparation of a medicament for topical administration on the skin
or mucosal membrane.
[0225] The topical administration is preferably for treating a
disease or disorder selected from acne, psoriasis, seborrhea,
rosacea contact dermatitis, infection, inflammation, pruritis, and
any combination thereof.
[0226] According to a preferred embodiment of the present
disclosure, the surface of the metal oxide later of the coated
particulate matter may be chemically modified by organic groups,
preferably hydrophobic groups, attached to its surface.
[0227] The hydrophobic groups may be for example an alkyl groups
(such alkyl groups may be further substituted with one ore more
flouro atoms), aryl groups (such as benzyl or phenyl), and
combinations thereof. The groups may be as described above with
respect to the process.
[0228] Also disclosed are particles comprising a particular matter
coated by a metal oxide layer wherein: (i) said metal oxide layer
has a width of 0.1-10 micron, and (ii) said particles are
characterized in that when tested in Dissolution Tester using
Paddle Method in a medium, typically organic-based solvent such as
acetonitrile, iso propyl miristate, ethanol, or methanol, in which
said particulate matter is soluble, and a dissolution volume in
which the concentration of the particular matter is lower than the
solubility of the particular matter, the time for releasing 50% w/w
of the particulate matter from said particulars is at least
two-fold higher, preferably at least three-fold higher, preferably
at least four-fold, more preferably at least five-fold higher and
most preferably at least ten-fold higher as compared to the
dissolution of the free form of the particulate matter having
substantially the same particle size diameter as the particulate
matter in said particles.
[0229] The dissolution of the free form of the particulate matter
is measured under the same conditions as the coated particulate
matter. The time for releasing 50% w/w of the particulate matter
(active agent) from the particles is compared to the time of 50%
w/w dissolution of the free form. Preferably the dissolution volume
is such that the concentration of the particulate matter is lower
than at least half of the solubility of the particulate matter. The
"solubility" relates to the solubility of the particulate matter
(active ingredient) in the dissolution medium (e.g. an
organic-based solvent such as acetonitrile, iso propyl miristate,
ethanol or methanol). It is appreciated that the dissolution volume
will also depend on the detection level of the analytical method.
The dissolution may be conducted at a temperature of 20 C-40 C. The
dissolution may be conducted at a paddle rate of 50-200 rpm.
Pesticide Compositions and Uses
[0230] In one aspect, the present disclosure 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 known in the art and may be solids or liquids.
Other Components
[0231] 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. In
addition to the other components listed herein, the compositions
may also contain carriers, such as water or other solvents in
amounts for example equal to or greater than the major
components.
[0232] The coated pesticides 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.
[0233] Second compounds include, without limitation, other
pesticides, fertilizers, soil conditioners, or other agricultural
chemicals. The compositions 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.
[0234] 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 particulate matter of
the pesticide that may redisperse in water to the primary coated
particulate matter), as water-dispersible granules, as powdery
dusts, as wettable powders, as suspension concentrates, as capsule
suspension (coated particulate matter, 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
[0235] 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.
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.
[0236] The compositions 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.
[0237] 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.
[0238] Other useful formulations for the pesticidal compositions
include suspo-emulsions, flowable formulations, and suspension
concentrates.
[0239] Flowable formulations consist of particles of the pesticide
complex (coated particulate matter of the 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.
[0240] Suspension concentrates (SC) are dispersions of finely
divided (2-15 micron) water-insoluble solid particles of the
pesticide complex 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.
[0241] Suspo-emulsions (SE) are dispersions of water immiscible
liquids and finely divided (2-15 micron) water-insoluble solid
particles of the pesticide complex (coated particulate matter of
the 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.
[0242] Useful formulations include suspensions of the coated
pesticide in a relatively non-volatile solvent such as water, corn
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 dispersible. In use by the farmer on the field, the granular
formulations, suspo-emulsions, flowable concentrates, 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
[0243] In a further aspect, this disclosure 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.
[0244] Thus the disclosure additionally relates to a method for
preventing, reducing, or eliminating pests at a locus, comprising
applying to the locus of said pest a pesticidaly effective amount
of a pesticidal composition comprising a coated particulate matter
as described herein the particulate matter being a pesticide.
[0245] According to preferred embodiment the method is for
preventing pest infestation at a locus, comprising introducing said
coated particulate matter onto a surface or into a substrate prone
to pest attack.
[0246] The locus may be any location where pests are found or are
expected to be found for example foliage, soil or porous surfaces
such as cement, wood, ceramics and similar surfaces.
[0247] The pesticide may be as described herein. Preferably the
pesticide is selected from carbofuran, imidacloprid, thiamethoxam,
tebuconazole, indoxacarb and pyrethroids including bifenthrin,
cypermethrin, alphacypermethrin, deltamethrin, and
lambda-cyhalothrin.
[0248] In applying the compositions, whether formulated alone or
with other agricultural chemicals, an effective amount and
concentration of the active compound is of course employed; the
amount may vary in the range of, e.g. about 0.001 to about 3 kg/ha,
preferably 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.
[0249] The pesticidal compositions 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
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.
[0250] 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 solutions, emulsions or dispersions of
finely divided pesticide complex 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.
[0251] 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 pesticide complex 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.
[0252] It is appreciated that the coated particulate matter,
coating metal oxide layer, particulate matter, etc. described in a
particular aspect may be characterized by the various features,
properties, etc. as described in the other aspects.
EXAMPLES
[0253] In the examples below, all % values referring to a solution
are in (w/w). All % values, referring to dispersions are in
(w/w).
[0254] All solutions used in the examples below unless otherwise
stated refer to an aqueous solution of the indicated
ingredient.
Example #1: Silica Coating of BPO
[0255] Step 1: Milling:
[0256] 110 g. of hydrous BPO 75% (USP grade from Sigma) were
suspended in 152 g. of 0.4% CTAC solution containing 0.001% silicon
antifoam. The BPO was milled using a stator rotor mixer (Kinematika
polytron 6100 operated at 15,000 rpm/25 m/s). The milling was
stopped when the particle size distribution (PSD) of the suspension
was d(0.9)<35|im or the temperature has reached 50 C. The final
suspension was cooled to room temperature.
[0257] Step 2a: Coating Option #1:
[0258] During the coating procedure the suspension was stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled BPO suspension was corrected to 8 using NaOH 5N
solution. A portion of 1 g of 15% sodium silicate solution (15% w/w
as SiO2) was added and the suspension was stirred for 5 min. A
portion of 1 g of 3% Polyquaternium 7 was added and the suspension
was stirred for 5 min. pH was adjusted to 6-7 using 5N HCl
solution.
[0259] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0260] Step 2b:
[0261] coating option #2: During the coating procedure the
suspension was stirred with a mechanical dissolver, 80 mm, at 500
RPM at all times. The pH of the milled BPO suspension was corrected
to 8 using NaOH 5N solution. A portion of 2.5 g of 15% sodium
silicate solution (15% w/w as SiO2) was added and the suspension
was stirred for 5 min. A portion of 2.5 g of 3% Polyquaternium 7
was added and the suspension was stirred for 5 min. pH was adjusted
to 6-7 using 5N HCl solution.
[0262] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0263] The aging step: The coated BPO suspension at pH 6.5 was kept
for aging at room temperature (25 C+/-2) under gentle agitation for
24 hrs.
Example #2: Analytical Evaluation of the BPO Release
[0264] The release profile of BPO out of the silica shell was done
in a water/Acetonitrile solution, which is capable of dissolving
BPO. The method is based on the strong oxidation properties of BPO.
BPO reacts with potassium iodine (KI) ions to form 12, which gives
a color reaction. 12 is than reduces back to T using sodium
thiosulfate (ST S) to eliminate the color. Each 12.11 mg of
oxidizing BPO was reduced by 1 ml of 0.1M STS.
[0265] Solution A is composed of deionized water, acetone, 0.1M STS
solution and KI. The following table includes the ratios between
the components in order to distinguish a certain % of released
BPO.
TABLE-US-00001 % released % % 0.IM % % dionized BPO acetone STS
soln. KI water 10 60 3.67 4.5 31.83 20 60 7.34 4.5 28.16 30 60
11.01 4.5 24.49 50 60 18.35 4.5 17.15 70 60 25.69 4.5 9.81 90 60
33.03 4.5 2.47
[0266] Suspension B, preparation of BPO: weigh 200 mg of BPO as
100% (1 gas 20% suspension) into 5 ml measuring bottle and fill
with deionized water up to 5 ml.
[0267] Procedure: Into 50 ml glass beaker add 40 ml of solution A
and the 5 ml of suspension B and measure the time for yellow color
appearance.
[0268] The following table summarizes the results obtained for
encapsulated (coated) BPO as described in example #1.
TABLE-US-00002 Sample CS #oEC ATm ATp *10 *20 *30 *50 *70 *90 Free
BPO -- 0 0 -- 0.5 1 SGT010 2a 20 72 25 1.2 3 4 7 7.5 7.66 SGT010 2a
35 72 25 2.2 5 11 17 24 26 SGT025 2b 20 96 25 3 7 10.3 19.3 28 29.5
SGT025 2b 30 96 25 4.6 12.3 23 40 60 68 SGT025 2b 40 96 25 7 25 32
69 113 123 SGT025 2b 40 96 40 7 21 47 80 140 170 #oEC--number of
repeating coating as described in example #1 CS--coating step as
described in example #1 ATm--aging time in hours ATp--aging
temperature in Celsius. *(10, 20 . . .) - time (in min.) for (10,
20 . . .) % of BPO released from the capsule (coated BPO).
[0269] The release rates of BPO of Samples SGT 025 and SGT 010 are
shown in FIGS. 1 and 2.
Discussion:
[0270] It is clearly shown that the higher the amount of silica
added per encapsulation (coating) cycle and/or the higher the
number of coating cycles, the longer the time for BPO release.
Example #3: Silica Coating of Tretinoin (ATRA
[0271] Step 1: Milling:
[0272] 75 g. of all trans Retinoic acid (ATRA) (USP grade from
Rhodia) are suspended in 250 g. of 0.3% CT AC solution containing
0.001% silicon antifoam. The ATRA is milled using a M-110Y micro
fluidizer processor (Microfluidics) at 15,000 psi. The milling is
stopped when the particle size distribution (PSD) of the suspension
is d(0.9)<20|im. The temperature is kept below 30 C at all
times.
[0273] Step 2: Coating:
[0274] During the coating procedure the suspension is stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled ATRA suspension is corrected to about 4 using HCl 5N
solution. A portion of 0.5 g of 15% sodium silicate solution (15%
w/w as SiCh) is added and the suspension is stirred for 5 min. A
portion of 0.5 g of 3% Polyquaternium 7 is added and the suspension
is stirred for 5 min. pH is readjusted to about 4 using 5N HCl
solution.
[0275] This procedure is repeated for 5-100 times in order to
create a series of silica layers around ATRA having different
thicknesses.
[0276] The Aging Step:
[0277] The coated ATRA suspension at pH 4.5 is kept for aging at
room temperature under gentle agitation for 24 hrs.
Example #4: Silica Coating Using Anionic Surfactant
[0278] Step 1: Milling:
[0279] 110 g. of hydrous BPO 75% (USP grade from Sigma) were
suspended in 152 g. of 0.4% sodium dodecyl sulphonate (SDS)
solution containing 0.005% silicon antifoam. The BPO was milled
using a stator rotor mixer (Kinematika polytron 6100 operated at
15,000 rpm/25 m/s). The milling was stopped when the particle size
distribution (PSD) of the suspension was d(0.9)<35|im or the
temperature has reached 50 C. The final suspension was cooled to
room temperature and a portion of 1-2.5 g of 3% Polyquaternium 7
was added and the suspension was stirred for 5 min.
[0280] Step 2a: Coating Option #1:
[0281] During the coating procedure the suspension was stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled BPO suspension was corrected to 8 using NaOH 5N
solution. A portion of 1 g of 15% sodium silicate solution (15% w/w
as SiO2) was added and the suspension was stirred for 5 min. A
portion of 1 g of 3% Polyquaternium 7 was added and the suspension
was stirred for 5 min. pH was adjusted to 6-7 using 5N HCl
solution.
[0282] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0283] Step 2b: Coating Option #2:
[0284] During the coating procedure the suspension was stirred with
a mechanical dissolver, 80 mm, at 500 RPM at all times. The pH of
the milled BPO suspension was corrected to 8 using NaOH 5N
solution. A portion of 2.5 g of 15% sodium silicate solution (15%
w/w as SiO2) was added and the suspension was stirred for 5 min. A
portion of 2.5 g of 3% Polyquaternium 7 was added and the
suspension was stirred for 5 min. pH was adjusted to 6-7 using 5N
HCl solution.
[0285] This procedure was repeated for 5-100 times in order to
create a series of silica layers around BPO having different
thickness.
[0286] The Aging Step:
[0287] The coated BPO suspension at pH 6.5 was kept for aging at
room temperature (25 C+/-2) under gentle agitation for 24 hrs.
Example #5: Silica Coating of Tretinoin (ATRA), Using Non-Ionic
Polymer
[0288] Step 1: Milling:
[0289] 12.5 g. of tretinoin were suspended in 250 g. of 0.3% CTAC
solution containing 7.5 g BHT. The tretinoin was milled using a
M-110Y microfluidizer processor (Microfluidics) at 15,000 psi. The
milling was stopped when the particle size distribution (PSD) of
the suspension was d(0.9)<13|im. The temperature has kept below
30 C at all times.
[0290] Step 2: Coating:
[0291] During the coating procedure the suspension was stirred with
a mechanical stirrer at all times. The pH of the milled ATRA
suspension was about 3.5. A portion of 1 g of 15% sodium silicate
solution (15% w/w as SiCb) was added and the suspension was stirred
for 5 min. HCl 1 M was added until the pH of the solution was about
3. A portion of 1 g of 1% polyvinyl alcohol water solution was
added and the suspension was stirred for 5 min.
[0292] This procedure was repeated 50 times in order to create
silica layers around ATRA.
[0293] The Aging Step:
[0294] The coated tretinoin suspension was kept for aging at room
temperature at pH 3 under gentle agitation for 24 hrs.
Example #6: Silica Coating of Bifenthrin Using Cationic Polymer
[0295] 3.58 grams of cetyltrimethylammonium chloride (CTAC) (29%
w/w aqueous solution) were added to 196.5 grams of deionized water
in a 1 liter flask. 50.5 grams of dry milled bifenthrin technical
(having an average particle size of about 15 microns) were added,
and the mixture was homogenized using a Polytron PT 6100
Homogenizer. 216 grams of the resulting dispersion were transferred
to a Mettler Toledo LabMax Automatic Lab Reactor.
[0296] 1.8 grams of sodium silicate (25% w/w aqueous solution) were
added and the mixture was stirred for 5 minutes. The pH was
adjusted to 7.0 by the addition of 5 M HCl. The mixture was stirred
for an additional 2 minutes, and 3 grams of
poly(acrylamide-co-diallyldimethylammonium chloride (3% w/w aqueous
solution)(PDAC) were added. The mixture was stirred for 5
minutes.
[0297] The process in the above paragraph (commencing with the
addition of the sodium silicate) was repeated 49 times. Then, after
5 minutes of additional stirring, 1.8 grams of sodium silicate (25%
w/w aqueous solution) was added. The pH was adjusted to 7.0 (using
5 M HCl) to produce a final dispersion which was kept stirred at 20
C for 12 hours. An assay indicated that the dispersion comprised
7.7% active ingredient.
Example #7: Silica Coating of Bifenthrin Using Non Ionic
Polymer
[0298] 2.1 grams of CT AC (29% w/w aqueous solution) were added to
125 grams of deionized water in a 1 liter flask. 125 grams of a 20%
w/w aqueous dispersion of bifenthrin (also containing 0.5% w/w
CTAC) were added. The mixture was homogenized using a Polytron PT
6100 Homogenizer and the resulting dispersion transferred to a
Mettler Toledo LabMax Automatic Lab Reactor.
[0299] 1.8 grams of sodium silicate (25% w/w aqueous solution) were
added and the mixture was stirred for 5 minutes. The pH was
adjusted to 3.0 by the addition of 5 M HCl. The mixture was stirred
for an additional 2 minutes, and 3 grams of Celluol 24203 (a 3% w/w
polyvinyl alcohol) added. The mixture was stirred for 5
minutes.
[0300] The process in the above paragraph (commencing with the
addition of the sodium silicate) was repeated 49 times. Then, after
5 minutes of additional stirring, 1.8 grams of sodium silicate (25%
w/w aqueous solution) was added. The pH was adjusted to 3.0 (using
5 M HCl) to produce a final dispersion which was kept stirred at 20
C (20.degree. C.) for 12 hours. An assay indicated that the
dispersion comprised 4.2% active ingredient.
Example #8: Silica Coating of Bifenthrin Using a Copolymer
[0301] 2.1 grams of CTAC (29% w/w aqueous solution) were added to
125 grams of deionized water in a 1 liter flask. 125 grams of a 20%
w/w aqueous dispersion of bifenthrin (also containing 0.5% CTAC)
were added. The mixture was homogenized using a Polytron PT 6100
Homogenizer. An additional 75 grams of deionized water were added
and the resulting dispersion transferred to a Mettler Toledo LabMax
Automatic Lab Reactor.
[0302] 1.8 grams of sodium silicate (25% w/w aqueous solution) were
added and the mixture was stirred for 5 minutes. The pH was
adjusted to 5.0 by the addition of 5 M HCl. The mixture was stirred
for an additional 2 minutes, and 3 grams of Agrimer DA 102W (a 3%
w/w aqueous suspension of vinyl pyrrolidone/dimethylaminoethyl
methacylate copolymer) added. The mixture was stirred for 5
minutes.
[0303] The process in the above paragraph (commencing with the
addition of the sodium silicate) was repeated 49 times. Then, after
5 minutes of additional stirring, 1.8 grams of sodium silicate (25%
w/w aqueous solution) was added. The pH was adjusted to 5.0 (using
5 M HCl) to produce a final dispersion which was kept stirred at 20
C for 12 hours. An assay indicated that the dispersion comprised
4.0% active ingredient.
Comparative Experiment A
[0304] Employing a sol-gel process of the type disclosed in U.S.
Pat. No. 6,303,149, a core/shell composition of bifenthrin was
prepared employing an aqueous phase comprising
cetyltrimethylammonium chloride and an organic phase comprising
tetraethoxysilane (TEOS) and bifenthrin technical in an aromatic
organic solvent. The composition comprised 8.4% w/w of 96%
bifenthrin technical.
Biological Testing
[0305] The residual activity of the above formulations on a porous
surface (cement) against German Roaches was evaluated as
follows:
[0306] Poured cement tiles were produced by mixing 1 part water
with 3 parts dry cement mix powder (Quikrete or Sakrete). Once
thoroughly mixed, the wet cement was poured directly into the "lid"
side of plastic Petri dishes (100.times.20 mm). Enough wet cement
was added to form a thin layer of cement 5-10 mm thick. The lids
were agitated slightly to flatten out the cement and to prevent it
from drying unevenly. The wet dishes were allowed to cure for 24
hours. The walls of the bottom of each Petri dish were coated with
a 50/50 mixture of mineral oil and petroleum jelly to prevent the
roaches from climbing up onto the untreated plastic portion of the
Petri dishes, thereby escaping the treated cement surface.
[0307] The initial compositions above were diluted with distilled
water to an application rate of 0.5 oz/gallon. A DeVilbis hand
sprayer was used to spray the tiles, with treatments being applied
at a rate ca. 0.005 mL/cm2. The tiles were moved into a drying hood
and held for 1-2 hours until completely dry. They were then used
for initial (day 0) testing, or stored (at ambient humidity and at
68-75.degree. F.) for residual evaluation.
[0308] German roaches were knocked down with carbon dioxide and
transferred with featherweight forceps directly on to the treated
surface. Ten roaches were added to each treated surface and the
mineral oil/petroleum jelly coated Petri dish bottom was used as a
cover. The percentage of roaches that were "knocked down" (which
includes insects that were moribund i.e, showed movement but failed
to right themselves when turned over--or dead) was recorded at
various time intervals.
[0309] The formulation of Comparative Experiment A showed no
activity after 24 hours exposure after a 2 day residual treatment.
In contrast, after a 28 day residual treatment, the formulations of
Examples 6, 7 and 8 exhibited the following activity after 24 hour
exposure:
TABLE-US-00003 Laver % Knockdown Example Coating After 24 Hour
Exposure Control None 0 6 PDAC 90 7 PVA 100 8 Agrimer 100
[0310] The above results show that the compositions prepared by the
method of this invention exhibit unexpectedly prolonged activity of
cement surfaces relative to the prior art process which also coats
the bifenthrin with a silica shell.
[0311] 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, modification
and variations may be made hereto 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.
[0312] 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.
* * * * *