U.S. patent application number 12/309293 was filed with the patent office on 2009-09-24 for biocidal compositions.
Invention is credited to David John Duncalf, Alison Jayne Foster, James Long, Steven Paul Rannard, Dong Wang.
Application Number | 20090239749 12/309293 |
Document ID | / |
Family ID | 36955583 |
Filed Date | 2009-09-24 |
United States Patent
Application |
20090239749 |
Kind Code |
A1 |
Duncalf; David John ; et
al. |
September 24, 2009 |
Biocidal compositions
Abstract
The invention provides a solvent-free biocidal composition of
improved efficacy comprising at least one water insoluble biocide
(preferably a herbicide) and a water-soluble carrier material,
wherein the water-insoluble biocide is dispersed through the
carrier material in nano-disperse form having a peak diameter of
the nano-disperse form below 1000 nm. The invention also provides a
process which comprises spray drying a solution of the biocide and
a solution of a water-soluble carrier to obtain a solvent free
dispersion of the biocide in the carrier, which, when dissolved in
water, produces a nano-disperse biocide. The invention also
provides an aqueous dispersion of a water insoluble biocide and a
water-soluble carrier obtained by the dispersion of the composition
of the solvent free composition in water.
Inventors: |
Duncalf; David John;
(Wirral, GB) ; Foster; Alison Jayne; (Wirral,
GB) ; Long; James; (Wirral, GB) ; Rannard;
Steven Paul; (Wirral, GB) ; Wang; Dong;
(Liverpool, GB) |
Correspondence
Address: |
UNILEVER PATENT GROUP
800 SYLVAN AVENUE, AG West S. Wing
ENGLEWOOD CLIFFS
NJ
07632-3100
US
|
Family ID: |
36955583 |
Appl. No.: |
12/309293 |
Filed: |
June 29, 2007 |
PCT Filed: |
June 29, 2007 |
PCT NO: |
PCT/EP2007/056562 |
371 Date: |
January 13, 2009 |
Current U.S.
Class: |
504/116.1 |
Current CPC
Class: |
A61P 1/12 20180101; A61P
1/00 20180101; A61K 9/1635 20130101; A61P 31/10 20180101; A61K 9/10
20130101; A61P 33/00 20180101; A61P 25/06 20180101; A61P 35/00
20180101; A61P 25/04 20180101; Y02A 50/30 20180101; Y02A 50/411
20180101; A61P 29/00 20180101; A61P 43/00 20180101; A61K 9/1652
20130101; A61P 33/06 20180101; A61K 31/167 20130101; A61K 9/1617
20130101; A61P 27/12 20180101; A61P 1/08 20180101; A61P 9/10
20180101; A61P 1/10 20180101; A61P 31/00 20180101; A61P 25/00
20180101; A61P 9/00 20180101; A61P 33/02 20180101; A61K 9/1641
20130101; A01N 25/04 20130101; A61K 9/19 20130101; A61P 1/14
20180101; A61P 25/28 20180101; A61P 9/12 20180101; A01N 25/04
20130101; A01N 43/54 20130101; A01N 53/00 20130101; A01N 31/16
20130101; A01N 37/18 20130101 |
Class at
Publication: |
504/116.1 |
International
Class: |
A01N 25/14 20060101
A01N025/14; A01N 25/08 20060101 A01N025/08; A01P 21/00 20060101
A01P021/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 13, 2006 |
GB |
0613925.7 |
Claims
1. A solvent-free biocidal composition of improved efficacy
comprising at least one water insoluble biocide and a water-soluble
carrier material, wherein the water-insoluble biocide is dispersed
through the carrier material in nano-disperse form having a peak
diameter of the nano-disperse form below 500 nm.
2. A composition according to claim 1 wherein the peak diameter of
the water-insoluble biocide is below 100 nm.
3. A composition according to claim 1 wherein the water insoluble
biocide has solubility in water at ambient temperature of less than
15 mg/L.
4. A composition according to claim 1 wherein the solvent free
dispersion comprises at most 25% wt of biocide.
5. A composition according to claim 1 wherein the biocide is a
herbicide.
6. An aqueous dispersion of a water insoluble biocide and a
water-soluble carrier obtained by the dispersion of the composition
of claim 1 in water.
7. A process for preparing a composition according to claim 1 which
comprises spray drying a solution of the biocide and a solution of
a water-soluble carrier to obtain a solvent free dispersion of the
biocide in the carrier, which, when dissolved in water, produces a
nano-disperse biocide.
8. A process for preparing a composition according to claim 1 which
comprises the steps of: a) providing an emulsion comprising: i) a
solution of the biocide agent in at least one water-immiscible
solvent for the same, and ii) an at least partially aqueous
solution of the carrier, and, b) drying the emulsion to remove
water and the water-immiscible solvent to obtain a nano-dispersion
of the biocide in the carrier
9. A process for preparing a composition according to claim 1 which
comprises the steps of: a) providing a mixture comprising: i) at
least one non-aqueous solvent, ii) optionally, water, iii) a
water-soluble carrier material soluble in the mixture of (i) and
(ii) and iv) a water-insoluble biocide agent which is soluble in
the mixture of (i) and (ii), and, b) drying said mixture to remove
the non-aqueous solvent and any water present to obtain a
nano-dispersion of the biocide in the carrier.
10. A process for the preparation of a biocide composition for use
in the prophylaxis or treatment of infections or infestations which
comprises the step of preparing a composition according to claim
1.
11. A composition obtainable by the process of claim 1.
12. A process for the treatment of a substrate other than a medical
treatment which comprises the step of contacting the substrate with
a composition according to claim 1.
13. A process for the delivery of a water-insoluble biocide which
comprises the steps of: a) dissolving in water a nano-dispersion of
a water-insoluble biocide in a water soluble carrier material,
according to claim 1, b) optionally, adding other components to the
dispersion, and, c) treating a substrate with the aqueous
nano-dispersion of the biocide.
14. A process according to claim 13 wherein step (c) comprises
spraying, dipping or washing the substrate.
15. A process according to claim 13 wherein the substrate is
selected from a plant, soil, an animal, bedding for animals, fodder
or an article manufactured from a plant or an animal.
16. A process comprising using a composition according to claim 1
for the treatment of an infestation.
17. A process according to claim 8 wherein the drying step
comprises spray drying.
Description
FIELD OF THE INVENTION
[0001] The present invention concerns improvements relating to
biocidal compositions.
[0002] In particular it relates to biocidal compositions and
precursors thereof which contains a water-insoluble biocidal
substance.
BACKGROUND OF THE INVENTION
[0003] Biocidal agents are widely used in agriculture, sanitation
and cleaning, wood and paper preservation and various other human,
animal and plant health and industrial applications. The present
invention is believed to be generally applicable to biocidal
compositions but will be described with particular reference to
antimicrobial agents, i.e. anti-bacterial and anti-fungal agents
and also herbicides, although other and broader aspects of the
invention are not intended to be excluded.
[0004] Many effective biocides have poor water solubility and
various proposals have been made for how these materials can be
made more effective. For example, many agricultural formulations
contain water soluble salts of insoluble or poorly soluble
biocides. These salts, such as alkylamine salts, are generally not
as active as their acid equivalents. As an illustration of this,
2,4-Dichlorophenoxyacetic acid (2,4-D acid) is known to be more
herbicidally active than the corresponding dimethylamine salt of
2,4-D. However, the 2,4-D acid is not soluble in water. Solvents
used to formulate, 2,4-D in its acid form are known to be
phytotoxic to plants and enhance herbicide volatility and
subsequent drift to non-target areas.
[0005] Our co-pending international patent application
PCT/GB03/03226 describes the formation of solid, porous beads
comprising a three dimensional open-cell lattice of a water-soluble
polymeric material. These are typically `templated` materials
formed by the removal of both water and a non-aqueous dispersed
phase from a high internal phase emulsion (HIPE) which has a
polymer dissolved in the aqueous phase. The macroscopic beads are
formed by dropping the HIPE emulsion into a low temperature fluid
such as liquid nitrogen, then freeze-drying the particles formed to
remove the bulk of the aqueous phase and the dispersed phase. This
leaves behind the polymer in the form of a `skeletal` structure.
The beads dissolve rapidly in water and have the remarkable
property that a water-insoluble component dispersed in the
dispersed phase of the emulsion prior to freezing and drying can
also be dispersed in water on solution of the polymer skeleton of
the beads.
[0006] WO 2005/011636 discloses a non-emulsion based spray drying
process for forming `solid amorphous dispersions` of drugs in
polymers. In this method a polymer and a low-solubility drug are
dissolved in a solvent and spray-dried to form dispersions in which
the drug is mostly present in an amorphous form rather than in a
crystalline form.
[0007] Our co-pending applications GB 0501835 (filed 28.sup.th Jan.
2005, published 3.sup.rd Aug. 2006) and GB 0613925 (filed 13.sup.th
Jul. 2006) describe how materials which will form a nano-dispersion
in water can be prepared, preferably by a spray-drying process. In
both cases the liquid is dried above ambient temperature (above 20
Celsius), such as by spray drying, to produce particles of the
structuring agent, as a carrier, with the water-insoluble materials
dispersed therein. When these particles are placed in water they
dissolve, forming a nano-dispersion of the water-insoluble material
with particles typically below 300 nm. This size scale is similar
to that of virus particles, and the water-insoluble material
behaves as though it were in solution.
[0008] In the process described in GB 0501835 the water insoluble
material is dissolved in the solvent-phase of an emulsion. This
earlier, prior published application states that the process can be
applied to antimicrobial agents, for example: Triclosan.TM.,
climbazole, octapyrox, ketoconizole, phthalimoperoxyhexanoic acid
(PAP) and quaternary ammonium compounds, or to insecticides,
pesticides and herbicides. Our prior published GB 0501835
application also showed that fluorescer materials prepared by the
method disclosed exhibited better performance than those prepared
by a known freeze-drying method.
[0009] In GB 0613925 the water-insoluble materials are dissolved in
a mixed solvent system and co-exist in the same phase as a
water-soluble structuring agent. Our GB 0613925 application makes
it clear that a Triclosan.TM. nano-dispersion has the additional
benefit that weight for weight it is more effective than is
normally expected of Triclosan.TM. even at very low
concentrations.
[0010] In the present application the term `ambient temperature`
means 20 degrees Celsius and all percentages are percentages by
weight unless otherwise specified.
BRIEF DESCRIPTION OF THE INVENTION
[0011] We have now determined that both the emulsion-based and the
single-phase method can be used to produce a water-soluble form of
biocidal substances which show improved efficacy.
[0012] Accordingly, a first aspect of the present invention
provides a biocidal preparation of improved efficacy comprising at
least one water insoluble biocide and a water-soluble carrier
material, wherein the water-insoluble biocide is dispersed through
the carrier material in nano-disperse form having a peak diameter
of the nano-disperse form below 1000 nm.
[0013] The present invention further provides a process for
improving the efficacy of a water insoluble biocide which comprises
the step of spray drying a solution of the biocide and a solution
of a water-soluble carrier to obtain a solvent free dispersion of
the biocide in the carrier, which, when dissolved in water produces
a nano-disperse biocide with a peak particle diameter of below 1000
nm.
[0014] The preferred method of particle sizing for the dispersed
products of the present invention employs a dynamic light
scattering instrument (Nano S, manufactured by Malvern Instruments
UK). Specifically, the Malvern Instruments Nano S uses a red (633
nm) 4 mW Helium-Neon laser to illuminate a standard optical quality
UV curvette containing a suspension of material. The particle sizes
quoted in this application are those obtained with that apparatus
using the standard protocol.
[0015] Preferably, the peak diameter of the water-insoluble biocide
is below 800 nm. More preferably the peak diameter of the
water-insoluble biocide is below 500 nm. In a particularly
preferred embodiment of the invention the peak diameter of the
water-insoluble biocide is below 200 nm, most preferably below 100
nm.
[0016] We have determined that for smaller particle sizes, in
particular for particle sizes below 40 nm there is a further
significant improvement in the MIC of the water insoluble biocides.
This effect is not well-understood (by comparison, the thickness of
a Gram-negative bacterial cell wall is around 10 nm) and it may
involve some specific interaction of the biocide nano-particles
with the cell wall. This size range is also close to a miscellar
scale and another possible explanation is that only a few molecules
or in some cases a single molecule of certain biocides are needed
to achieve an effect and therefore delivering a very small package
of water-insoluble biocide vastly increases it's efficiency.
[0017] In the context of the present invention, "water insoluble"
as applied to the biocide means that its solubility in water is
less than 10 g/L.
[0018] Preferably, the water insoluble biocide has solubility in
water at ambient temperature (20 Celsius) of less than 5 g/L
preferably of less than 1 g/L, especially preferably less than 120
mg/L, even more preferably less than 15 mg/L and most preferably
less than 5 mg/L. This solubility level provides the intended
interpretation of what is meant by water-insoluble in the present
specification.
[0019] The present invention is applicable to a broad range of
biocides. Preferred water-insoluble biocides for use in the present
invention are antibacterials (for example chlorophenols including
Triclosan), antifungals (for example organochlorines including
Chlorothalonil and imidazoles such as Ketoconazole and
Propiconazole), insecticides (for example pyrethroids, including
.lamda.-cyhalothrin) and/or herbicides (for example phenol-ureas
including Isoproturon). The invention is also envisaged to be
applicable to acaricides, algicides, molluscicides and
nematacides.
[0020] Triclosan (5-chloro-2-(2,4-dichlorophenoxy)-phenol) is an
chlorophenol antibacterial used in soaps, deodorants, toothpastes,
mouthwashes, and cleaning supplies and is infused in an increasing
number of consumer products, such as kitchen utensils, toys,
bedding, socks, and trash bags. It has a poor solubility in water
of 17 mg/L and is a suitable antibacterial biocide for use in the
present invention.
[0021] Ketoconazole (acetyl-dichlorophenyl-imidazole) is a broad
spectrum imidazole antifungal agent that is used in a variety of
formats to treat fungal infections. Creams, lotions and medicated
shampoos are available for topical infections such as dandruff,
whilst an oral tablet is used to treat systemic fungal infections.
Janssen-Cilag Ltd produce a variety of ketoconazole based
formulations under the trade name "Nizoral.RTM.". It has a
solubility of less than 0.1 mg/L.
[0022] Propiconazole
(1-(2-(2,4-dichlorophenyl)-4-propyl-1-1,3-dioxolan-2-ylmethyl)-1H-1,2,4-t-
ri azole) is another broad spectrum antifungal agent. Propiconazole
is predominantly used in antifungal agrochemical formulations such
as "Tilt.RTM." manufactured by Ciba. It has a solubility of around
100 mg/L.
[0023] Azoxystrobin
(methyl(E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacr-
ylate) is a systemic, broad-spectrum strobilurin fungicide with
activity against the four major groups of plant pathogenic fungi
including Ascomcetes (e.g. powdery mildews), Basidiomycetes (e.g.
rusts), Deutoromycetes (e.g. rice blast) and Oomycetes (e.g. downy
mildew). Other strobilurins are azoxystrobin, kresoxim-methyl,
picoxystrobin, fluoxastrobin, oryzastrobin, dimoxystrobin,
pyraclostrobin and trifloxystrobin. Azoxystrobin has a very poor
solubility in water of .about.6 mg/L Chlorothalonil
(2,4,5,6-tetrachloroisophthalonitrile) is a broad-spectrum
organo-chlorine fungicide used to control fungi that threaten
vegetables, trees, small fruits, turf, ornamentals, and other
agricultural crops. It has an exceptionally low solubility in water
of .about.0.6 mg/L.
[0024] Ketoconazole, propiconazole, azoxystrobin and chlorothalonil
are each suitable antifungal biocides for use in the present
invention.
[0025] Isoproturon (3-(4-isopropylphenyl)-1,1-dimethylurea) is a
common herbicide with a low solubility in water (.about.65 mg/L)
and is widely used for the control of broad leaved weeds that grow
in various annual grasses. It is a suitable herbicide for use in
the present invention.
[0026] .lamda.-cyhalothrin, is a suitable insecticide for use in
the present invention and has an aqueous solubility of 0.005
mg/L
[0027] As noted above, it is believed that reduction of the
particle size in the eventual nano-dispersion has significant
advantages in improving the effectiveness of the otherwise
water-insoluble material. This is believed to be particularly
advantageous where an significantly improved bio-availability is
sought, or, in similar applications where high local concentrations
of the material are to be avoided. Moreover it is believed that
nano-dispersions with a small particle size are more stable than
those with a larger particle size.
[0028] Preferred carrier materials are selected from the group
consisting of water-soluble inorganic materials, surfactants,
polymers, sugars and mixtures thereof.
[0029] A further aspect of the present invention provides an
aqueous dispersion of a water insoluble biocide and a water-soluble
carrier material, wherein the biocide is in nano-disperse form
having a peak diameter of the nano-disperse form below 1000 nm,
preferably below 800 nm, more preferably below 500 nm, even more
preferably below 200 nm and especially below 100 nm. As noted
above, it is particularly advantageous when the particle size of
the biocide is below 40 nm. A further aspect of the present
invention provides a method for preparing a biocide composition
comprising a water insoluble biocide and a water-soluble carrier,
which comprises the steps of: [0030] a) forming an emulsion
comprising: [0031] i) a solution of the biocide in at least one
water-immiscible solvent for the same, and [0032] ii) an aqueous
solution of the carrier, and, [0033] b) drying the emulsion to
remove water and the water-immiscible solvent to obtain a
substantially solvent-free nano-dispersion of the biocide in the
carrier
[0034] For convenience, this class of method is referred to herein
as the "emulsion" method.
[0035] A further aspect of the present invention provides a method
for preparing a biocide composition comprising a water insoluble
biocide and a water-soluble carrier which comprises the steps of:
[0036] a) providing a mixture comprising: [0037] i) at least one
non-aqueous solvent, [0038] ii) optionally, water, [0039] iii) a
water-soluble carrier material soluble in the mixture of (i) and
(ii) and [0040] iv) a water-insoluble biocide agent which is
soluble in the mixture of (i) and (ii), and, [0041] b) drying said
mixture to remove the non-aqueous solvent and any water present to
obtain a substantially solvent-free a nano-dispersion of the
biocide in the carrier.
[0042] For convenience, this class of method is referred to herein
as the "single-phase" method.
[0043] In the context of the present invention substantially
solvent free means that the free solvent content of the product is
less than 15% wt, preferably below 10% wt and more preferably below
5% wt.
[0044] In the context of the present invention it is essential that
both the carrier material and the biocide are essentially fully
dissolved in their respective solvents prior to the drying step. It
is not within the ambit of the present specification to teach the
drying of slurries. For the avoidance of any doubt, it is therefore
the case that the solids content of the emulsion or the mixture is
such that over 90% wt, preferably over 95%, and more preferably
over 98% of the soluble materials present is in solution prior to
the drying step.
[0045] In relation to the methods mentioned above, the preferred
biocide and the preferred carrier materials are as described above
and as elaborated on in further detail below.
[0046] Similarly the preferred physical characteristics of the
material are as described above.
[0047] The "single phase" method where both the biocide and the
carrier material are dissolved in a phase comprising at least one
non-aqueous solvent (and optional water) is preferred. This is
believed to give a smaller particle size for the nano-disperse
biocide. Preferably, drying simultaneously removes essentially all
solvents and, more preferably, is accomplished by spray drying at
above ambient temperature.
[0048] A further aspect of the present invention provides a method
for the preparation of a biocide composition for use in the
prophylaxis or treatment of infections or infestations which
comprises the step of preparing a composition according to the
present invention. Preferably, the method is one in which the
particle size of the water-insoluble biocide is reduced to below
100 nm, more preferably below 40 nm. Such compositions are suitable
for use in methods of medical treatment.
[0049] A still further aspect of the present invention provides for
the treatment of a substrate other than a medical treatment which
comprises the step of contacting the substrate with a composition
according to the present invention. Such a method might comprise,
for example, a method for preserving wood or other materials of
natural origin.
DETAILED DESCRIPTION OF THE INVENTION
[0050] Various preferred features and embodiments of the present
invention are described in further detail below.
Biocide:
[0051] As noted above, the present invention is applicable to a
broad range of water-insoluble biocides. Preferred biocides are
non-animal biocides, particularly fungicides, bactericides and
herbicides. Preferably these biocides have solubility in water of
less than 120 mg/L and more preferably less than 15 mg/L.
[0052] In the context of the present invention the term biocide
also includes biostats. For example propiconazole is "fungistatic"
rather than "fungicidal" as its mode of action involves inhibition
of cell mitosis, rather than causing cell death.
[0053] Some known water-insoluble herbicides are listed in U.S.
Pat. No. 6,849,577 and include diuron, linuron, sulfometuron,
chlorsulphuron, metsulfuron, chlorimuron, atrazine, simazine,
quizalofop, butroxydim, nicosulfuron, primsulfuron, bensulfuron,
ametryn, pendimethalin, isoproturon, chlortoluron, diflufenican,
mesotrione, aclonifen, fluorochloridone, oxyfluorfen, isoxaflutole,
imazamox and thifensulfuron.
[0054] Other suitable herbicides include trifluralin, fluoroxypyr,
phenmedipham, fenoxaprop-P-ethyl, acetochlor, alachlor, tri-allate
and propanil.
[0055] The present invention, in its broadest sense, does not
depend critically on the nature of the water-insoluble herbicide.
The invention is suitable for application with the insoluble form
of those herbicides, as mentioned above, which are currently used
in salt form. These include glyphosphate
(N-phosphonomethylglycine), which is commonly used in the form of
its water-soluble salts such as trimethylsulphonium,
isopropylamine, sodium, or ammonium salts, fomesafen which is
commonly used in the form of its water-soluble sodium salt,
glufosinate which is commonly used in the form of its water-soluble
ammonium salt, paraquat dichloride and bentazone which is commonly
used in the form of its water-soluble sodium salt.
[0056] Some known water-insoluble fungicides are disclosed in, for
example, U.S. Pat. Nos. 6,355,675 and 6,113,936 and include
benzimidazole compounds such as benomyl, carbendazim, thiabendazole
and thiophanate-methyl; phenylcarbamate compounds such as
diethofencarb; dicarboxyimide compounds such as procymidone,
iprodione and vinclozolin; azole compounds such as diniconazole,
epoxyconazole, tebuconazole, difenoconazole, cyproconazole,
flusilazole, flutriafol and triadimefon; acylalanine compounds such
as metalaxyl; carboxyamide compounds such as furametpyr, mepronil,
flutolanil and tolyfluanid; organophosphate compounds such as
tolclofos-methyl, fosetyl aluminum and pyrazophos;
anilinopyrimidine compounds such as pyrimethanil, mepanipyrim and
cyprodinil; cyanopyrrrole compounds such as fludioxonil and
fenpiclonil; antibiotics such as blasticidin-S, kasugamycin,
polyoxin and validamycin; methoxyacrylate compounds such as
azoxystrobin, kresoxim-methyl and metominostrobin; chlorothalonil;
manzeb; captan; folpet; tricyclazole; pyroquilon; probenazole;
phthalide; cymoxanil; dimethomorph;
S-methylbenzo[1,2,3]thiadiazol-7-carbothioate; famoxadone; oxolinic
acid; fluaziname; ferimzone; chlobenthiazone; isovaledione;
tetrachloroisophthalonitrile; thiophthalimideoxybisphenoxyarsine;
3-iodo-2-propylbutylcarbamate; parahydroxy benzoic ester. Others
such as fenpropimorph (morpholine based) and thiram
(dithiocarbamate) are also believed suitable.
[0057] Preferred fungicides include those of the polyene, imidazole
and triazole types.
[0058] Particular preferred polyenes include Amphotericin, Nystatin
and mixtures thereof.
[0059] Preferred imidazoles include: Bifonazole, Butoconazole,
Clotrimazole, Econazole, Fenticonazole, Isoconazole, Ketoconazole,
Metronidazole, Oxiconazole, Sertaconazole, Sulconazole,
Tioconazole, Miconazole and mixtures thereof.
[0060] Preferred triazole types include: Fluconazole, Itraconazole,
Posaconazole, propiconazole, Ravuconazole, tebuconazole,
Terconazole, Voriconazole and mixtures thereof.
[0061] Other suitable antifungal biocides for use in the present
invention include: Amorolfine, Anidulafungin, Butenafine,
Naftifine, Caspofungin, Ciclopirox, Flucytosine, Griseofulvin,
Haloprogin, Micafungin, Parabens, Salicylic acid, Terbinafine,
Thiabenazole, Tolnaflate, Undecylenic acid and mixtures
thereof.
[0062] Water insoluble insecticides include cypermethrin,
lambda-cyhalothrin, esfenvalerate, malathion, and chlorpyrifos.
Water-Dispersible Form:
[0063] The present invention provides a method for obtaining a
rapidly dispersible form of an otherwise essentially
water-insoluble material. This is prepared by forming an at least
partially non-aqueous intermediate emulsion or solution in which
both a water-soluble carrier material and the water-insoluble
biocide are dissolved. On removal of solvents the insoluble biocide
is left dispersed through the water-soluble carrier material.
Suitable carrier materials are described in further detail
below.
[0064] The most preferred method for drying of the intermediate
emulsion or solution is one which produces a powder directly, such
as spray drying. Spray drying is particularly effective at removing
both the non-aqueous volatile components and any water present to
leave the carrier and the `payload` material behind in a powder
form. The drying step is described in further detail below.
[0065] The structure of the material obtained after the drying step
is not well understood. It is believed that the resulting dry
powder materials are not encapsulates, as discrete macroscopic
bodies of the water-insoluble materials are not present in the dry
product. Neither are the dry materials `dry emulsions` as little or
none of the volatile solvent comprising the `oil` phase of the
emulsion remains after the drying step. On addition of water to the
dry product the emulsion is not reformed, as it would be with a
`dry emulsion`. It is also believed that the compositions are not
so-called solid solutions, as with the present invention the ratios
of components present can be varied without loss of the benefits.
Also from Xray and DSC studies, it is believed that the
compositions of the invention are not solid solutions, but comprise
nano-scale, phase-separated mixtures.
[0066] Preferably, the compositions produced after the drying step
will comprise the biocide and the carrier in a weight ratio of from
1:500 to 1:1 as biocide:carrier, with 1:100 to 1:1 being preferred.
Typical levels of around 10-30% wt water-insoluble biocide and
90-70% carrier can be obtained by spray drying. Levels of biocide
below 40%, more preferably below 30% wt and most preferably below
25% wt are preferred as they show the improved MIC as discussed
above.
"Emulsion" Preparation Method:
[0067] In one preferred method according to the invention the
solvent for the water-insoluble biocide is not miscible with water.
On admixture with water it therefore can form an emulsion.
[0068] Preferably, the non-aqueous phase comprises from about 10%
to about 95% v/v of the emulsion, more preferably from about 20% to
about 68% v/v.
[0069] The emulsions are typically prepared under conditions which
are well known to those skilled in the art, for example, by using a
magnetic stirring bar, a homogeniser, or a rotational mechanical
stirrer. The emulsions need not be particularly stable, provided
that they do not undergo extensive phase separation prior to
drying.
[0070] Homogenisation using a high-shear mixing device is a
particularly preferred way to make an emulsion in which the aqueous
phase is the continuous phase. It is believed that this avoidance
of coarse emulsion and reduction of the droplet size of the
dispersed phase of the emulsion, results in an improved dispersion
of the biocide in the dry product. In a preferred method according
to the invention a water-continuous emulsion is prepared with an
average dispersed-phase droplet size (using the Malvern peak
intensity) of between 500 nm and 5000 nm. We have found that an
`Ultra-Turrux`T25 type laboratory homogenizer (or equivalent) gives
a suitable emulsion when operated for more than a minute at above
10,000 rpm.
[0071] There is a directional relation between the emulsion droplet
size and the size of the particles of the biocide, which can be
detected after dispersion of the materials of the invention in
aqueous solution. We have determined that an increase in the speed
of homogenization for precursor emulsions can decrease final
particle size after re-dissolution.
[0072] It is believed that the re-dissolved particle size can be
reduced by nearly one half when the homogenization speed increased
from 13,500 rpm to 21,500 rpm. The homogenization time is also
believed to play a role in controlling re-dissolved particle size.
The particle size again decreases with increase in the
homogenization time, and the particle size distribution become
broader at the same time. Such intensive mixing is not an essential
step in the method of the present invention but it is
advantageous.
[0073] Sonication is also a particularly preferred way of reducing
the droplet size for emulsion systems. We have found that a Hert
Systems Sonicator XL operated at level 10 for two minutes is
suitable.
"Single Phase" Preparation Method:
[0074] In an alternative method according to the present invention
both the carrier and the biocide are soluble in either a
non-aqueous solvent or in a mixture of water and a non-aqueous
solvent. Both here and elsewhere in the specification the
non-aqueous solvent can be a mixture of non-aqueous solvents. In
this case the feedstock of the drying step comprises a single phase
material in which both the water-soluble carrier and the
water-insoluble biocide are dissolved. It is also possible for this
feedstock to be an emulsion, provided that both the carrier and the
biocide are dissolved in the same phase.
[0075] The `single-phase` method is generally believed to give a
better nano-dispersion with a smaller particle size than the
emulsion method. As noted above, the smaller particle sizes give
enhanced biocidal effects.
[0076] It is believed that ratios of components which decrease the
relative concentration of the biocide to the solvents and/or the
carrier give a smaller particle size.
Drying:
[0077] Spray drying, the most preferred method of drying the
emulsion or solution, is well known to those versed in the art. In
the case of the present invention some care must be taken due to
the presence of a volatile non-aqueous solvent in the material
being dried. In order to reduce the risk of explosion when a
flammable solvent is being used, an inert gas, for example
nitrogen, can be employed as the drying medium in a so-called
closed spray-drying system. The solvent can be recovered and
re-used.
[0078] We have found that the `Buchi` B-290 type laboratory spray
drying apparatus is suitable for the performance of the present
invention.
[0079] It is preferable that the drying temperature should be at or
above 100 Celsius, preferably above 120 Celsius and most preferably
above 140 Celsius. Elevated drying temperatures have been found to
give smaller particles in the re-dissolved nano-disperse
material.
[0080] Freeze drying can also be used. It is preferred to use a
non-aqueous solvent with a melting point above -120 Celsius,
preferably above -80 Celsius. Chloroform is a particularly
preferred solvent due to it physical characteristics. It a
relatively high melting point (approx. -63.5.degree. C.). Freeze
drying can be employed both with the emulsion method and the single
phase method.
Carrier Material:
[0081] The carrier material is water soluble, which includes the
formation of structured aqueous phases as well as true ionic
solution of molecularly mono-disperse species. The carrier material
preferably comprises an inorganic material, surfactant, a polymer
or may be a mixture of two or more of these.
[0082] It is envisaged that other non-polymeric, organic,
water-soluble materials such as sugars can be used as the carrier.
However the carrier materials specifically mentioned herein are
preferred.
[0083] Suitable carrier materials (referred to herein as `water
soluble carrier materials`) include preferred water-soluble
polymers, preferred water-soluble surfactants and preferred
water-soluble inorganic materials. Particularly preferred materials
are solids, as opposed to soft solids or semi-solids at ambient
temperature such that good powder properties are obtained in the
spray-dried product.
[0084] The particular choice of carrier material will depend on the
proposed end-use of the composition and carriers should be selected
such that they are not detrimentally reactive towards the biocide
and compatible with the proposed use. The carrier can also have an
activity in its own right or contain water soluble materials which
have such an activity. For example, in agricultural applications of
the present invention, the carrier may comprise materials having an
agrochemical activity.
Preferred Polymeric Carrier Materials:
[0085] Examples of suitable water-soluble polymeric carrier
materials include: [0086] (a) natural polymers (for example
naturally occurring gums such as guar gum, alginate, locust bean
gum or a polysaccharide such as dextran; [0087] (b) cellulose
derivatives for example xanthan gum, xyloglucan, cellulose acetate,
methylcellulose, methylethylcellulose, hydroxy-ethylcellulose,
hydroxy-ethylmethyl-cellulose, hydroxy-propylcellulose,
hydroxy-propylmethylcellulose, hydroxy-propylbutylcellulose,
ethylhydroxy-ethylcellulose, carboxy-methylcellulose and its salts
(e.g. the sodium salt--SCMC), or
carboxy-methylhydroxyethylcellulose and its salts (for example the
sodium salt); [0088] (c) homopolymers of or copolymers prepared
from two or more monomers selected from: vinyl alcohol, acrylic
acid, methacrylic acid, acrylamide, methacrylamide, acrylamide
methylpropane sulphonates, aminoalkylacrylates,
aminoalkyl-methacrylates, hydroxyethylacrylate,
hydroxyethylmethylacrylate, vinyl pyrrolidone, vinyl imidazole,
vinyl amines, vinyl pyridine, ethyleneglycol and other alkylene
glycols, ethylene oxide and other alkylene oxides, ethyleneimine,
styrenesulphonates, ethyleneglycolacrylates and ethyleneglycol
methacrylate [0089] (d) cyclodextrins, for example
beta-cyclodextrin [0090] (e) mixtures thereof.
[0091] When the polymeric material is a copolymer it may be a
statistical copolymer (heretofore also known as a random
copolymer), a block copolymer, a graft copolymer or a hyperbranched
copolymer. Co-monomers other than those listed above may also be
included in addition to those listed if their presence does not
destroy the water soluble or water dispersible nature of the
resulting polymeric material.
[0092] Examples of suitable and preferred homopolymers include
poly-vinylalcohol, poly-acrylic acid, poly-methacrylic acid,
poly-acrylamides (such as poly-N-isopropylacrylamide),
poly-methacrylamide; poly-acrylamines, poly-methyl-acrylamines,
(such as polydimethylaminoethylmethacrylate and
poly-N-morpholinoethylmethacrylate), polyvinylpyrrolidone,
poly-styrenesulphonate, polyvinylimidazole, polyvinylpyridine,
poly-2-ethyl-oxazoline poly-ethyleneimine and ethoxylated
derivatives thereof.
[0093] Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),
poly(2-ethyl-2-oxazaline), polyvinyl alcohol (PVA) hydroxypropyl
cellulose and hydroxypropyl-methyl cellulose (HPMC) and alginates
are preferred polymeric carrier materials.
Preferred Surfactant Carrier Materials:
[0094] Where the carrier material is a surfactant, the surfactant
may be non-ionic, anionic, cationic, amphoteric or
zwitterionic.
[0095] Examples of suitable non-ionic surfactants include
ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol
ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty
amine ethoxylates; sorbitan alkanoates; ethylated sorbitan
alkanoates; alkyl ethoxylates; Pluronics.TM.; alkyl polyglucosides;
stearol ethoxylates; alkyl polyglycosides.
[0096] Examples of suitable anionic surfactants include alkylether
sulfates; alkylether carboxylates; alkylbenzene sulfonates;
alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl
sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl
phosphates; paraffin sulfonates; secondary n-alkane sulfonates;
alpha-olefin sulfonates; isethionate sulfonates.
[0097] Examples of suitable cationic surfactants include fatty
amine salts; fatty diamine salts; quaternary ammonium compounds;
phosphonium surfactants; sulfonium surfactants; sulfonxonium
surfactants.
[0098] Examples of suitable zwitterionic surfactants include
N-alkyl derivatives of amino acids (such as glycine, betaine,
aminopropionic acid); imidazoline surfactants; amine oxides;
amidobetaines.
[0099] Mixtures of surfactants may be used. In such mixtures there
may be individual components which are liquid, provided that the
carrier material overall, is a solid.
[0100] Alkoxyayed nonionic's (especially the PEG/PPG e.g.
Pluronic.TM. materials and/or the PEG/alcohol nonionics),
phenol-ethoxylates (especially TRITON.TM. materials), alkyl
sulphonates (especially SDS), ether-sulphates (including SLES),
ester surfactants (preferably sorbitan esters of the Span.TM. and
Tween.TM. types) and cationics (especially cetyltrimethylammonium
bromide--CTAB) are particularly preferred as surfactant carrier
materials.
[0101] Surfactant carrier materials are particularly suitable for
embodiments of the invention in which the re-dispersed particle
size in water is below 100 nm, and particularly below 40 nm.
Preferred Inorganic Carrier Materials:
[0102] The carrier material can also be a water-soluble inorganic
material which is neither a surfactant not a polymer. Simple
organic salts have been found suitable, particularly in admixture
with polymeric and/or surfactant carrier materials as described
above. Suitable salts include carbonate, bicarbonates, halides,
sulphates, nitrates and acetates, particularly soluble salts of
sodium, potassium and magnesium. Preferred materials include,
sodium carbonate, sodium bicarbonate and sodium sulphate. These
materials have the advantage that they are cheap and
physiologically acceptable. They are also relatively inert as well
as compatible with many materials found in household and
pharmaceutical products.
[0103] Mixtures of carrier materials are advantageous. Preferred
mixtures include combinations of inorganic salts and surfactants
and polymers and surfactants.
[0104] Particularly preferred mixtures include combinations of
surfactants and polymers. Which include at least one of: [0105] a)
Polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),
poly(2-ethyl-2-oxazaline), polyvinyl alcohol (PVA) hydroxypropyl
cellulose and hydroxypropyl-methyl cellulose (HPMC) and alginates
and, at least one of; [0106] b) alkoxylated nonionic's (especially
the PEG/PPG Pluronic.TM. materials), phenol-ethoxylates (especially
TRITON.TM. materials), alkyl sulphonates (especially SDS),
ether-sulphates (including SLES), ester surfactants (preferably
sorbitan esters of the Span.TM. and Tween.TM. types) and cationics
(especially cetyltrimethylammonium bromide--CTAB)
[0107] The carrier material can also be a water-soluble small
organic material which is neither a surfactant, a polymer nor an
inorganic carrier material. Simple organic sugars have been found
to be suitable, particularly in admixture with a polymeric and/or
surfactant carrier material as described above. Suitable small
organic materials include mannitol, polydextrose, xylitol and
insulin etc.
[0108] In preferred forms of the invention the level of surfactant
carrier is such that at least 50% of the total carrier is
surfactant. Mixtures having a majority of surfactant present over
the other carriers exhibit better biocidal effects.
Non-Aqueous Solvent:
[0109] The compositions of the invention comprise a volatile,
non-aqueous solvent. As noted above this can be a mixture of
solvents. This may either be miscible with such other solvents
(including water) which may be present in the pre-mix before drying
or, together with those solvents may form an emulsion.
[0110] In one alternative form of the invention a non-aqueous
solvent is employed in which can form a single phase with water in
the presence of the biocide, and the carrier. Preferred solvents
for these embodiments are polar, protic or aprotic solvents.
Generally preferred solvents have a dipole moment greater than 1
and a dielectric constant greater than 4.5.
[0111] Particularly preferred solvents are selected from the group
consisting of haloforms (preferably di-chloromethane, chloroform),
lower (C1-C10) alcohols (preferably methanol, ethanol, isopropanol,
isobutanol), organic acids (preferably formic acid, acetic acid),
amides (preferably formamide, N,N-dimethylformamide), nitrites
(preferably aceto-nitrile), esters (preferably ethyl acetate)
aldehydes and ketones (preferably methyl ethyl ketone, acetone),
and other water miscible species comprising heteroatom bond with a
suitably large dipole (preferably tetrahydrofuran,
dialkylsulphoxide). Mixtures of the aforementioned may also be
employed.
[0112] In another alternative form of the invention the non-aqueous
solvent is not miscible with water and forms an emulsion.
[0113] The non-aqueous phase of the emulsion is preferably selected
from one or more from the following group of volatile organic
solvents: [0114] alkanes, such as heptane, n-hexane, isooctane,
dodecane, decane; [0115] cyclic hydrocarbons, such as toluene,
xylene, cyclohexane; [0116] halogenated alkanes, such as
dichloromethane, dichoroethane, trichloromethane (chloroform),
fluoro-trichloromethane and tetrachloroethane; [0117] esters such
as ethyl acetate; [0118] ketones such as 2-butanone; [0119] ethers
such as diethyl ether; [0120] volatile cyclic silicones such as
either linear or cyclomethicones containing from 4 to 6 silicon
units. Suitable examples include DC245 and DC345, both of which are
available from Dow Corning Inc.
[0121] Preferred solvents include dichloromethane, chloroform,
ethanol, acetone and dimethyl sulphoxide.
[0122] Preferred non-aqueous solvents, whether miscible or not have
a boiling point of less than 150 Celsius and, more preferably, have
a boiling point of less than 100 Celsius, so as to facilitate
drying, particularly spray-drying under practical conditions and
without use of specialised equipment. Preferably they are
non-flammable, or have a flash point above the temperatures
encountered in the method of the invention.
[0123] Preferably, the non-aqueous solvent comprises from about 10%
to about 95% v/v of any emulsion formed, more preferably from about
20% to about 80% v/v. In the single phase method the level of
solvent is preferably 20-100% v/v.
[0124] Particularly preferred solvents are alcohols, particularly
ethanol and halogenated solvents, more preferably
chlorine-containing solvents, most preferably solvents selected
from (di- or tri-chloromethane).
Optional Cosurfactant:
[0125] In addition to the non-aqueous solvent an optional
co-surfactant may be employed in the composition prior to the
drying step. We have determined that the addition of a relatively
small quantity of a volatile cosurfactant reduced the particle
diameter of the material produced. This can have a significant
impact on particle volume. For example, reduction from 297 nm to
252 nm corresponds to a particle size reduction of approximately
40%. Thus, the addition of a small quantity of co-surfactant offers
a simple and inexpensive method for reducing the particle size of
materials according to the present invention without changing the
final product formulation.
[0126] Preferred co-surfactants are short chain alcohols or amine
with a boiling point of <220.degree. C.
[0127] Preferred co-surfactants are linear alcohols. Preferred
co-surfactants are primary alcohols and amines. Particularly
preferred co-surfactants are selected from the group consisting of
the 3-6 carbon alcohols. Suitable alcohol co-surfactants include
n-propanol, n-butanol, n-pentanol, n-hexanol, hexylamine and
mixtures thereof.
[0128] Preferably the co-surfactant is present in a quantity (by
volume) less than the solvent preferably the volume ratio between
the solvent and the co-surfactant falls in the range 100:40 to
100:2, more preferably 100:30 to 100:5.
Preferred Drying Feedstocks:
[0129] The drying feed-stocks used in the present invention are
either emulsions or solutions which preferably do not contain solid
matter and in particular preferably do not contain any undissolved
biocide.
[0130] It is particularly preferable that the level of the biocide
in the composition should be such that the loading in the dried
composition is below 40% wt, and more preferably below 30% wt. Such
compositions have the advantages of a small particle size and high
effectiveness as discussed above.
[0131] Typical spray drying feedstocks comprise: [0132] a) a
surfactant, [0133] b) at least one lower alcohol, [0134] c) more
than 0.1% of at least one water-insoluble biocide dissolved in the
feedstock, [0135] d) a polymer, and, [0136] e) optional water
[0137] Preferred spray-drying feedstocks comprise: [0138] a) at
least one non-aqueous solvent selected from dichloromethane,
chloroform, ethanol, acetone, and mixtures thereof, [0139] b) a
surfactant selected from alkoxylated nonionic's (especially the
PEG/PPG Pluronic.TM. materials), phenol-ethoxylates (especially
TRITON.TM. materials), alkyl sulphonates (especially SDS),
ether-sulphates (including SLES), ester surfactants (preferably
sorbitan esters of the Span.TM. and Tween.TM. types) and cationics
(especially cetyltrimethylammonium bromide--CTAB), and mixtures
thereof, [0140] c) more than 0.1% of at least one water-insoluble
biocidal agent, [0141] d) a polymer selected from Polyethylene
glycol (PEG), Polyvinyl alcohol (PVA), polyvinyl-pyrrolidone (PVP),
hydroxypropyl cellulose and hydroxypropyl-methyl cellulose (HPMC),
alginates and mixtures thereof, and [0142] e) optionally water.
Water Dispersed Form:
[0143] Solid compositions according to the present invention
(preferably those obtained by spray drying) are suitable for use in
the treatment of an infestation. They can be used "as-is" in the
solid form, but it is preferred that they are dissolved in water
prior to use.
[0144] On admixture of the water-soluble carrier material with
water, the carrier dissolves and the water-insoluble biocide is
dispersed through the water in sufficiently fine form that it
behaves like a soluble material in many respects. The particle size
of the water-insoluble materials in the dry product is preferably
such that, on solution in water the water-insoluble materials have
a particle size of less than 1 micron as determined by the Malvern
method described herein. Preferably the determined particle size is
less than 800 nm, more preferably less than 500 nm. In typical
embodiments of the invention the particle size is in the range
250-50 nm and is most preferably in the range 200-75 nm. For
comparative purposes, the broader range is analogous to the size of
a virus particle (which typically range from 450-20 nm). Diameters
of less than 200 nm are most preferred. It is believed that there
is no significant reduction of particle size for the biocidal agent
on dispersion of the solid form in water.
[0145] Very small particle sizes of as low as 4 nm can be obtained
by the method of the invention. In the size range 4-40 nm the
compositions of the invention show a further improvement in
efficacy.
[0146] By applying the present invention significant levels of
`water-insoluble` materials can be brought into a state which is in
many respects equivalent to true solution. When the dry product is
dissolved in water it is also possible to achieve visually clear,
transparent "solutions" comprising more than 0.1%, preferably more
than 0.5% and more preferably more than 1% of the `water-insoluble`
material. For translucent and opaque `solutions` higher levels of
nano-disperse material can be tolerated.
[0147] Advantageously, these "solutions" can be made up using water
and need not contain other solvents. This means that "insoluble"
biocides can be delivered by aqueous spraying, washing or infusion,
without the target of the biocide being exposed to solvents.
[0148] It is envisaged that the solution form will be a form
suitable for use either `as is` or following further dilution or
admixture with other components.
[0149] The present invention therefore also relates to a method for
the delivery of a water-insoluble biocide which comprises the steps
of: [0150] a) dissolving in water a nano-dispersion of a
water-insoluble biocide in a water soluble carrier material,
wherein the water-insoluble biocide is dispersed in the carrier
material in particles having an average particle size below one
micron, [0151] b) optionally, adding other components to the
dispersion, and, [0152] c) treating a substrate with the aqueous
nano-dispersion of the biocide.
[0153] The substrate can be the subject to be treated directly with
the biocide (such as a plant, where the object is the eradication
of, for example, fungi, or a wooden object requiring rot prevention
treatment) or can be associated with the subject (such as bedding
or soil). Preferred substrates are selected from a plant (or part
thereof, including seeds, bulbs, fruits, roots, leaves), soil, an
animal, bedding for animals, fodder or an article manufactured from
a plant or an animal. Preferred treatment methods include spraying,
dipping and washing.
[0154] In order that the present invention may be further
understood and carried forth into practice it is further described
below with reference to non-limiting examples.
EXAMPLES
[0155] A method of particle sizing for the dispersed products of
the present invention used in the following examples employs a
dynamic light scattering instrument (Nano S, manufactured by
Malvern Instruments UK). Specifically, the Malvern Instruments Nano
S uses a red (633 nm) 4 mW Helium-Neon laser to illuminate a
standard optical quality UV curvette containing a suspension of
material.
Example 1
Nano-Dispersions of Chlorothalonil (Water-Insoluble Fungicide) from
a Single Phase Chloroform Solution Stabilised with PVP and
PEG-PPG-PEG
[0156] A solution was prepared of the following:
Composition
TABLE-US-00001 [0157] Chlorothalonil 0.2 g (10 wt. %) PEG-PPG-PEG
0.4 g (20 wt. %) PVP (90 kDa) 1.4 g (70 wt. %) Chloroform 40 ml
[0158] At these concentrations, the solid components were readily
soluble in the chloroform at the measured room temperature
(21.5.degree. C.)
[0159] The solution was spray dried using a Buchi B-290.TM. bench
top spray-dryer, operated in a negative pressure mode. Air drawn
from the lab was used as the drying medium and the operating
conditions were as follows:
TABLE-US-00002 Pump rate 10% (3.6 ml/min) Inlet temperature
105.degree. C. Aspiration 100% N.sub.2 flow (atomisation) Max
(approx. 55 L/hr)
[0160] A dry white powder was obtained. This material was
redispersed in demineralised water at a concentration of 10 mg/ml
(1.0 wt %, 0.1 wt % chlorothalonil). This produced an opaque white
dispersion. At this concentration, the material was relatively slow
to disperse (approx. 5 minutes).
[0161] The resulting solution had the following properties:
TABLE-US-00003 Viscosity 1.95 cP Particle size 437 nm (diameter)
Standard deviation .+-.25.5 nm PdI 0.385
Example 2
Nano-Dispersion of Chlorothalonil (Water-Insoluble Fungicide) from
a Single Phase Chloroform Solution Stabilised with PVP and
PEG-PPG-PEG
Composition
TABLE-US-00004 [0162] Chlorothalonil 0.2 g (10 wt. %) PEG-PPG-PEG
0.4 g (20 wt. %) PVP (55 kDa) 1.4 g (70 wt. %) Chloroform 40 ml
[0163] At these concentrations, the solid components are readily
soluble in chloroform at room temperature (21.5.degree. C.).
Drying
[0164] The solution was spray dried using a Buchi B-290 bench top
spray dryer, operated in a negative pressure mode. Air drawn from
the lab was used as the drying medium.
TABLE-US-00005 Pump rate 15% (5.4 ml/min) Inlet temperature
90.degree. C. Aspiration 100% N.sub.2 flow (atomisation) Max
(approx. 55 L/hr)
Product
[0165] A dry white powder was obtained. This material was
redispersed in demineralised water at a concentration of 1 mg/ml
(0.1 wt %, 0.01 wt % chlorothalonil). This produced an opaque white
dispersion. At this concentration, the material was considerably
quicker (than example 1) to disperse (less than 30 seconds).
TABLE-US-00006 Viscosity 1.0 cP Particle size 452 nm (diameter)
Standard deviation .+-.5.72 nm PdI 0.181
Example 3
Nano-Dispersion of Chlorothalonil (Water-Insoluble Fungicide) from
a Single Phase Chloroform Solution Stabilised with PVP and
PEG-PPG-PEG
Composition
TABLE-US-00007 [0166] Chlorothalonil 0.05 g (10 wt. %) PEG-PPG-PEG
0.1 g (20 wt. %) PVP (55 kDa) 0.35 g (70 wt. %) Chloroform 30
ml
[0167] At these concentrations, the solid components are readily
soluble in chloroform at room temperature (21.5.degree. C.).
Drying
[0168] The solution was spray dried using a Buchi B-290 bench top
spray dryer, operated in a negative pressure mode. Air drawn from
the lab was used as the drying medium.
TABLE-US-00008 Pump rate 15% (5.4 ml/min) Inlet temperature
90.degree. C. Aspiration 100% N.sub.2 flow (atomisation) Max
(approx. 55 L/hr)
Product
[0169] A dry white powder was obtained. This material was
redispersed in demineralised water at a concentration of 1 mg/ml
(0.1 wt %, 0.01 wt % chlorothalonil). This produced an opaque white
dispersion. At this concentration, the material dispersed at a
similar rate to example 2 (less than 30 seconds).
TABLE-US-00009 Viscosity 0.93 cP Particle size 402 nm (diameter)
Standard deviation .+-.15.1 nm PdI 0.228
Example 4-5
Nano-Dispersion of Ketoconazole (Water-Insoluble Fungicide) from a
Single Phase Chloroform Solution Stabilised with PVA/PEG (Single
Phase Method)
[0170] 2 g (10%) Ketoconazole and 18 g (90%) poly(vinyl alcohol)
(10 kDa, Aldrich) were dissolved in 500 ml ethanol and 360 ml
water. The resulting solution was spray dried at an inlet
temperature of 150.degree. C. and a pump rate of approximately 3.6
ml/minute. The recovered dry white powder redispersed in water to
give a clear suspension of average particle size 24.2 nm
(Z-ave).
[0171] 100 mg (10%) Ketoconazole, 500 mg (50%) poly(ethylene
glycol) (10 kDa, Fluka) and 400 mg (40%) sodium lauryl ether
sulfate (SLES) were dissolved in 60 ml ethanol and 60 ml water. The
resulting solution was spray dried at an inlet temperature of
180.degree. C. and a pump rate of approximately 3.6 ml/minute. The
recovered dry white powder redispersed in water to give a clear
suspension of average particle size 16.1 nm (Z-ave).
Example 6
Nano-dispersion of Propiconazole (Water-Insoluble Fungicide) from a
Single Phase Chloroform Solution Stabilised with SLES/PEG (Single
Phase Method)
[0172] Typically between 20 mg and 800 mg (between 1% and 40%)
propiconazole, between 600 mg and 1100 mg (between 32% and 55%)
poly(ethylene glycol) (10 kDa, Fluka), and between 600 mg and 880
mg (between 28% and 44%) sodium lauryl ether sulfate (SLES) were
dissolved in between 30 ml and 80 ml of ethanol and 30 ml of water.
The resulting solutions were spray dried at an inlet temperature of
180.degree. C. and an approximate pump rate of 3.6 ml/minute. The
products were recovered as dry white powders.
Examples 7-9
Biocidal Activity of Ketoconazole and Propiconazole Produced in
Examples 4-6
[0173] These materials produced according to Examples 4-6 were
examined for their biocidal efficacy by following a standardised
Minimum Inhibitory Concentration (MIC) test. The test consisted of
known number of cells of a strain of Candida albicans (CA) in YEME
(yeast extract malt extract media), inoculating concentrations of
the active material and blanks contained in a 96 well plate. The
plates were incubated at 37.degree. C. overnight, and then examined
with a UV plate reader at a wavelength of 550 nm. Concentrations of
biocide that inhibited cell growth resulted in a well with very low
optical density (visually clear), whereas wells in which cells
growth occurred had a very high optical density (visually opaque).
The MIC was defined as the lowest concentration of biocide that
resulted in total inhibition of cell growth, when incubated
overnight.
[0174] Equivalent experiments were also conducted to determine the
MIC for the biocide active dissolved in a water miscible solvent.
In these cases the "blank" reference material was simply a sample
of the solvent containing no active compound.
[0175] All experiments were repeated 4 times. Results are presented
in the tables below.
Example 7
Ketoconazole
TABLE-US-00010 [0176] Particle size Material Initial concentration
(Z-ave, nm) MIC (mg/L) 13/28/20 equivalent to 0.15 mg/ml n/a no
inhibition (SLES/PEG active observed blank matrix) As Example 5
0.15 mg/ml active 16.1 ~14 As Example 4 0.15 mg/ml active 24.2 ~38
DMSO 25% v/v n/a ~9.25% v/v PVA (blank) equivalent to 0.15 mg/ml
n/a no inhibition active observed Ketoconazole 0.15 mg/ml in 25%
v/v n/a 65 in DMSO solvent
[0177] From these results it can be seen that the materials of the
present invention (shown in bold in the table) were more effective
at inhibiting the growth of CA in YEME than an equivalent solution
of the active in DMSO. It was determined that at the concentrations
involved, the MIC recorded was attributable to the active and not
the solvent. It was also shown that the preparation with a smaller
particle size was more active than an equivalent dispersion of
larger particles. In both cases the matrix material was not found
to exhibit any biocidal activity at these concentrations.
Example 8
Propiconazole
[0178] All experiments were conducted in YEME media against a CA
culture.
TABLE-US-00011 Initial concentration Particle Material Ref (mg/ml
of Loading of size MIC (14/22/. . . ) active) active (%) (Z-ave,
nm) (mg/L) 16 0.25 1 6.45 4 17 0.25 3 4.97 11 11 0.25 5 6.08 14 04
0.25 10 4.84 23 12 0.25 15 6.90 27 13 0.25 20 4.66 32 14 0.25 25
6.85 31 15 0.25 30 16.4 38 18 0.25 35 40.8 46 19 0.25 40 245 46
[0179] The MIC of propiconazole dissolved in a water/propylene
glycol cosolvent mixture is for comparison 91.6 mg/L. In all cases
it was shown that the biocidal activity of the preparations
according to the present invention was much greater than that of
the equivalent solution of active in water miscible solvent.
[0180] At the equivalent concentrations, no inhibition of cell
growth was observed for the blank matrix material, with the
exception of the very low loadings of active. In these cases, some
inhibition was attributable to the matrix material, but at orders
of magnitude lower than the active formulation.
[0181] The greatest efficacy was observed with material 14/22/16,
which was more than 20 times more effective than the equivalent
preparation of soluble active.
Example 9
Effect of SLES/PEG Ratio in the Matrix
Fixed Active Loading
TABLE-US-00012 [0182] Initial Material Ref concentration PEG SLES
MIC (14/22/. . . ) (mg/ml of active) (wt. %) (wt. %) (mg/L) 34 0.25
0 90 16 28 0.25 10 80 14 29 0.25 20 70 16 30 0.25 30 60 16 31 0.25
40 50 23 04 0.25 50 40 23 32 0.25 60 30 27 33 0.25 70 20 31 35 0.25
80 10 46
[0183] It has also been demonstrated that biocidal activity of the
materials according to the present invention is influenced by the
composition of its matrix. In this case, the activity of the
formulation (and hence efficacy of the active) increased 3 fold
when the proportion of surfactant is increased from 10 wt. % to 80
wt. %.
Example 10-12
Nano-Dispersion of Triclosan (Water-Insoluble Antibacterial) from a
Single-Phase Mixture of Cosolvents Stabilised by SDS Only
TABLE-US-00013 [0184] Composition Triclosan 2.0 g (20 wt. %) SDS
8.0 g (80 wt. %) Water miscible solvent 125 ml (50/50 v/v
mixture)
[0185] Three different water miscible organic solvents were
employed (ethanol, acetone and isopropyl alcohol). At these
concentrations, the solid components are readily soluble in the
cosolvent mixture at room temperature (21.5.degree. C.).
Drying
[0186] The solution was spray dried using a Buchi B-290 bench top
spray dryer, operated in a negative pressure mode. Air drawn from
the lab was used as the drying medium.
TABLE-US-00014 Pump rate 7% (2.5 ml/min) Inlet temperature
120.degree. C. Aspiration 100% N.sub.2 flow (atomisation) Max
(approx. 55 L/hr)
Products
[0187] For each different cosolvent system, a dry white powder was
obtained. These material was redispersed in demineralised water at
a concentration of 1 mg/ml (0.1 wt %), rapidly producing a crystal
clear dispersion that remained stable for more than 12 hours. All
the dispersions appeared to produce particles of the similar sizes
and distributions.
[0188] Details concerning these experiments and their results are
given in the table below:
TABLE-US-00015 particle size SD Poly Particle size SD Poly Residual
TCN Viscosity peak 1 peak 1 dispersityindex peak 2 peak 2
dispersityindex wt. % Cosolvent (cP) (d nm) (d nm) peak 1 (d nm) (d
nm) peak 2 (UV) Ethanol 0.9 3.5 0.088 0.0674 187 28.2 0.1829 13.6
Acetone 0.9 3.01 0.061 0.0504 127 15.8 0.2605 14.8 IPA 0.9 3.06
0.045 0.0487 179 16.5 0.1957 17
Example 13
Nano-Dispersion of Isoproturon
ISP-Water-Insoluble Herbicide, Emulsion Method
[0189] The formulation consisted of:
TABLE-US-00016 Phase 1: 10% ISP (28) 500 mg in 10 ml Chloroform
Phase 2: 60% PVA (10 kDa) 3000 mg 30% SDS 1500 mg in 75 ml
water
[0190] The two phases were continuously cooled using a water
jacketed beaker whilst being emulsified. Emulsification was
achieved by sonicating for 5 minutes at 50% power, then for a
further 2 minutes at 100% power (using a 1 kW probe type
sonicator).
[0191] The resulting emulsion was spray dried at an inlet
temperature of 150.degree. C. and a pump rate of 5.6 ml/min.
Aspiration and atomisation gas were set to maximum.
[0192] The resulting dry white powder redispersed to give a
slightly cloudy suspension at a concentration of 1 mg/ml. The
particle size was measured as 297+/-8.66 nm
Example 14
Nano-Dispersion of Isoproturon (ISP-Water-Insoluble Herbicide) with
Co-Surfactant
Emulsion Method
[0193] Formulation was as Example 13, but contained a small
quantity of additional volatile cosurfactant (n-butanol).
TABLE-US-00017 Phase 1: 10% ISP (28) 500 mg in 10 ml Chloroform and
2 ml n-butanol Phase 2: 60% PVA (10 kDa) 3000 mg 30% SDS 1500 mg in
75 ml water
[0194] The two phases were continuously cooled using a water
jacketed beaker whilst being emulsified. Emulsification was
achieved by sonicating for 5 minutes at 50% power, then for a
further 2 minutes at 100% power (using a 1 kW probe type
sonicator). The resulting emulsion was spray dried at an inlet
temperature of 150.degree. C. and a pump rate of 5.6 ml/min.
Aspiration and atomisation gas were set to maximum.
[0195] The resulting dry white powder redispersed to give a
slightly cloudy suspension at a concentration of 1 mg/ml, although
noticeably clearer than that of example 13. The particle size was
measured as 252+/-14.0 nm.
Example 15-16
Nano-Dispersion of Azoxystrobin (Water Insoluble Fungicide), Single
Phase Method
Example 15
[0196] 1.10 g Azoxystrobin.TM., 2.00 g Brij.RTM. 58 (Aldrich), and
6.90 g Polyvinylpyrrolidone (Mw 45,000, Aldrich) were all dissolved
into 200 ml DCM. The solution was then spray dried at 70.degree.
C.
[0197] The dry powder was then dispersed into distilled water
giving 1 wt % AzB in dispersion and the nanoparticle size was
measured with Malvern Nano-S. (SG-15)
Example 16
[0198] 5.00 g Azoxystrobin, 10.00 g Poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly (ethylene glycol)
(Mw 8,400, Aldrich), and 35.00 g Polyvinylpyrrolidone (Mw 45,000,
Aldrich) were all dissolved into 1.0 litre DCM. The solution was
then spray dried at 70.degree. C.
[0199] The dry powder was then dispersed into distilled water
giving 1 wt % AzB in dispersion and the nanoparticle size was
measured with Malvern Nano-S. (SG-16)
[0200] Details concerning these experiments and their results are
given in the table below.
TABLE-US-00018 AzB, Surfactant, PVP, Solvent, Spray dry PS, Ex.
mg/ml mg/ml mg/ml ml temp., .degree. C. nm 15 5.5 Brij 58, 10.0
34.5 DCM, 200 70 532 16 5.0 Pluronic, 35.0 DCM, 1000 70 356 10.0
Spray drying conditions: Aspiration rate: 100%; Pump rate: 1.80
ml/min.
Example 17A-L
Nano Dispersion of .lamda.-Cyhalothrin (Water Insoluble
Insecticide), Freeze Drying, Single Phase Method
[0201] A single phase solution of the insecticide
.lamda.-cyhalothrin, PEG and the PEG based surfactants Pluronic.TM.
F68 and Pluronic.TM. F127 was prepared in chloroform. This was
freeze dried using a "Christ alpha 2-4 LSC" freeze dryer in single
batches on a 5 ml per sample scale (i.e. 250 mg solids in each
sample).
[0202] Both the sample and the freeze drying shelf were pre-cooled
in liquid nitrogen, to a final temperature below -140.degree. C.
(operating limit of the freeze dryers temperature probes). Once the
vacuum had been achieved (.about.0.080 mbar) the samples remained
frozen due to the self-cooling effect produced by the sample's own
sublimation. Results and compositions are given in the table
below:
TABLE-US-00019 Example Particle 17 F68 F127 PEG active size A 0.9 0
0 0.1 66.19 B 0 0.9 0 0.1 44.24 C 0 0 0.9 0.1 168.2 D 0.7 0 0 0.3
102 E 0 0.7 0 0.3 80.99 F 0 0 0.7 0.3 240.5 G 0 0.4 0.4 0.2 94.59 H
0.4 0 0.4 0.2 127.5 I 0.3 0.3 0.3 0.1 51.87 J 0.26667 0.26667
0.2667 0.2 90.92 K 0.26667 0.26667 0.2667 0.2 93.54 L 0.26667
0.26667 0.2667 0.2 72.5
* * * * *