NZ619224B2 - Polyacrylate-based active compound-comprising particles - Google Patents
Polyacrylate-based active compound-comprising particles Download PDFInfo
- Publication number
- NZ619224B2 NZ619224B2 NZ619224A NZ61922412A NZ619224B2 NZ 619224 B2 NZ619224 B2 NZ 619224B2 NZ 619224 A NZ619224 A NZ 619224A NZ 61922412 A NZ61922412 A NZ 61922412A NZ 619224 B2 NZ619224 B2 NZ 619224B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- particles
- particles according
- active compound
- microparticles
- polyacrylate
- Prior art date
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- 239000002245 particle Substances 0.000 title claims abstract description 183
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- 230000000855 fungicidal Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 238000003197 gene knockdown Methods 0.000 description 1
- 229940052308 general anesthetics Halogenated hydrocarbons Drugs 0.000 description 1
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- 125000005456 glyceride group Chemical group 0.000 description 1
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- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003966 growth inhibitor Substances 0.000 description 1
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- 230000003694 hair properties Effects 0.000 description 1
- 230000003699 hair surface Effects 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001145 hydrido group Chemical group *[H] 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 239000002949 juvenile hormone Substances 0.000 description 1
- 150000003633 juvenile hormone derivatives Chemical class 0.000 description 1
- 229930014550 juvenile hormones Natural products 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing Effects 0.000 description 1
- 238000007561 laser diffraction method Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
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- 239000006193 liquid solution Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229960000453 malathion Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 229960004963 mesalazine Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XGZVLEAZGCUUPH-UHFFFAOYSA-N methylamino(methylimino)methanesulfonic acid Chemical compound CNC(=NC)S(O)(=O)=O XGZVLEAZGCUUPH-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960001952 metrifonate Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
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- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Chemical class 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 239000011164 primary particle Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- ZTHYODDOHIVTJV-UHFFFAOYSA-N propyl 3,4,5-trihydroxybenzoate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 239000002728 pyrethroid Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
- 230000008786 sensory perception of smell Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000004296 sodium metabisulphite Substances 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 238000005507 spraying Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000004763 sulfides Chemical class 0.000 description 1
- 230000000475 sunscreen Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UZNHKBFIBYXPDV-UHFFFAOYSA-N trimethyl-[3-(2-methylprop-2-enoylamino)propyl]azanium;chloride Chemical compound [Cl-].CC(=C)C(=O)NCCC[N+](C)(C)C UZNHKBFIBYXPDV-UHFFFAOYSA-N 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229920003176 water-insoluble polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
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- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
- A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
- A01N47/16—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof the nitrogen atom being part of a heterocyclic ring
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- A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
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- A61K2800/54—Polymers characterized by specific structures/properties
- A61K2800/542—Polymers characterized by specific structures/properties characterized by the charge
- A61K2800/5426—Polymers characterized by specific structures/properties characterized by the charge cationic
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- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
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- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/11—Encapsulated compositions
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
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Abstract
The disclosure relates to novel polyacrylate-based active compound-comprising particles which bind to hair, and to the use of these particles for preparing medicaments, in particular for veterinary medicine. The particles comprise uncharged and cationic polyacrylate and are at most 10 um big.
Description
Polyacrylate—based active compound—comprising particles
The invention relates to novel polyacrylate-based active compound—comprising
particles which bind to hair, and to the use ofthese particles for preparing
medicaments, in particular for veterinary medicine.
In the context of the present invention, the term active compound is to be understood
below as g both the classic pharmaceutical and insecticidally active
compounds and any form ofbeneficial agent in animal husbandry.
The external application of active compounds is an administration form which is
preferred in veterinary medicine and is used in particular for formulations of active
compounds for protection against ectoparasites, but also of ermally effective
active nds and active compounds which moderate the behaviour of the
animals treated, or else that of interacting s. For this purpose, use is frequently
made of n or wipe—on formulations, where the active nd is applied in
liquid form or else as a spray into or onto the coat or the skin of the animals. In most
cases, the duration of action of such formulations is limited to a few days or weeks,
in the case of repellent active compounds in some cases to a few hours. In many
cases, the active compounds, or components of the formulation, may also cause skin
irritation or extensive local inflammation. Accordingly, it is advantageous to provide
administration forms
0 which allow a longer duration of action to be achieved
0 which cause little, if any, skin irritation
0 which are easy to manufacture
o and which have no adverse effect on the flinctional or haptic
properties of animal coat or animal skin.
We have now found that it is possible to achieve this in cationic active compound-
comprising microcapsules of a small size which are applied to the skin or the hair of
the animal treated and which release the active compound in a lled and delayed
11131111611
The delayed release of active compounds from uncharged and charged microparticles
d to hair or the skin is well known in the field of application of cosmetics or
skin care products. In these fields of application, the microparticles themselves are
also capable of influencing the properties of the hairs. However, a relatively long
application in the range of days or weeks has not been described in these fields of
application, and in addition, it is not the object of these applications.
In ceutical ations, the encapsulation of active compounds in cationic
microparticles is also known and described. Here, use is frequently made of
quaternized dimethylaminoethyl methacrylate copolymers (for example rs
from Evonik Industries having the trade name “Eudragit® RS, RL”). However, these
microparticles are mainly used for oral administration forms in pharmacy and having
a size in the order of > 30 um to 1000 um, are too big for application on animal hair.
Moreover, the methods described for the preparation do not yield microparticles
having a size of an order suitable for the application ing to the invention. The
use of quaternized dimethylaminoethyl methacrylate both in hair care products and in
transdermal therapeutic systems is known. r, in these cases the polymers are
not used in combination with microparticles.
Skin tion by active compounds can be avoided in principle by applying the
active compounds in spray form, dissolved in a solvent, to the coat of the animal.
This application, too, is known to the person skilled in the art and described in the
literature. However, in l this does not achieve any prolonged action.
Hereinbelow, the prior art is described in more detail using selected examples.
However, none of the methods and technologies listed can achieve the advantage of
the present invention
0 microparticles for the delayed release of active compounds,
sufficiently small for adhering to hair,
0 ged adhesion to hair by covering the surface of the
microparticles with cationic polymers,
0 no negative effect on the functional and haptic properties of the hair,
0 simple manufacture Via an emulsion process.
Water-insoluble cationic polymers of the quaternized ylaminoethyl
methacrylate copolymer type are used as film-formers in coatings of tablets and
granules to control and delay the decomposition of the tablets and the release of
active compound in a pH—independent manner (Evonik Industries: Eudragit®
Application Guidelines, 10th Edition, Darmstadt, Germany; Evonik Industries AG,
2008).
For the purpose of the present invention, quaternized ylaminoethyl
methacrylate copolymers are preferably understood as meaning a group of water-
insoluble polymers known under the trade name Eudragit® RS or Eudragit® RL from
Evonik (as at 2011). These are copolymers of acrylic acid and methacrylic acid
having a low proportion of nized ammonium groups. (Chemical names:
poly(ethyl te—co-methyl methacrylate-c0-trimethylammonioethyl methacrylate
chloride) having a copolymerization ratio of 122:0.1, CAS number: 33434 — 24 — l,
trade name Eudragit® RS, described in Ph. Eur. as ammonio methacylate copolymer,
type B; and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl
methacrylate chloride) having a copolymerization ratio of 12:02, CAS :
33434 — 24 — 1, trade name Eudragit® RL, described in Ph. Eur. as o
methacyrlate copolymer, type A). They can be employed as aqueous sion
(Eudragit® RS, RL 30D) or as granules (Eudragit® RS, RL PO):
9H. 81
l l
CH2 (‘3 CH2 Ml:
(PiO
l 13:0
c? 092
1 CH
H e—Ne” 3
2 \"CH3
or CH3
R2#CH3,CEH5
General structural formula of copolymers of the “Eudragit® RL, RS” type
The manufacturer states the mean molecular weight of it® type RS, RL as a
weight e value of MW = 30 000 g/mol (Eudragit® RS) and MW = 31 000 g/mol
(Eudragit® RL); the glass tion temperature is stated as 65°C (Eudragit® RS) and
70°C (Eudragit® RL). (Evonik Industries: [1.Sudragit Application Guidelines 10th
Edition, Darmstadt, Germany: Evonik Industries AG, 2008).
It is known that cationic rs adhere well to negatively charged interfaces such
as hair and skin and are capable of forming films thereon. This ple is utilized
for hair setting lotions and haircare products. Eudragit® is also used for this purpose.
EP 1092417, for example, describes the use of cationic Eudragit® as a film-forming
polymer which can be incorporated in finely dispersed form in shampoos and
provides the hair with sed strength and improved hold. Additives mentioned
are hair-cosmetic active compounds, such as Vitamins, but no pharmaceutically
active compounds. WOW/45012 describes the use of film-forming cationic polymers
in formulations comprising ectoparasiticidally active compounds, specifically
pyrethroids, which, by Virtue of their affinity to hair, allow a —lasting
attachment of the active compounds to the hair. Mention is made of cationic
polymers of the polyquaternium type (Polyquat 10,28,11), cationic guar gum
derivatives and also Eudragit RS. For one formulation, an ectoparasiticidal activity of
8 days is described. However, the cationic polymers mentioned in WOW/45012 are
not e of forming suitable microparticles for the purpose of the present
invention. Accordingly, a duration of action of weeks, as can be achieved with the
active compound-comprising microparticles of the present invention, is not
demonstrated. orming acrylate copolymers of the Eudragit® type are also used
in dermal and transdermal therapeutic systems. JP 03-077820 illustrates the use of a
liquid formulation of these polymers in a suitable solvent, preferably ethanol, which
additionally comprises antibacterial or anti-inflammatory agents. Insect repellents as
active compound are likewise mentioned. The formulations are d to the skin as
a liquid or as a spray. W002/0604l 7 claims the cationic methacrylate copolymers as
adhesives or binders for transdermal therapeutic s. The formulations comprise
plasticizers and pharmaceutically active compounds. A further embodiment are
dental applications on the oral mucosa or for the treatment of dental pockets.
US 5438076 and EP 0404558 described the use of Eudragit® L, RL or RS in
alcoholic solution together with antibacterially active compounds and plasticizers. A
longer lasting release of the active compounds from the films adhering to the mucosa
is noticed. The reduced lity of the r materials in water is another
advantage, since l by saliva is delayed, but biological degradation is still
ensured. JP 63—130541 describes a similar process in which the Eudragit® together
with antibacterially active compound and hydrophilic polymers (cellulose ether,
PVP) is dissolved in polyhydric alcohols and the active nd is released longer
from the films formed, compared to preparations t cationic polymer. In such
systems, the term “long-lasting release/application” always refers to a period in the
range from hours to a few days. The time periods required for the application
according to the ion cannot be achieved in this manner.
In principle, microparticles adhering to hair or skin are capable of releasing the
active compounds comprised therein over a relatively long period of time. r,
the problem of ing a relatively long adherence of the articles to the
hairs has to be overcome. Since hairs have a negative surface , it is feasible to
promote adherence by a) making the particles cationic or b) alternatively providing
the hairs with cationic coatings to bind the negatively charged microparticles to hairs
in this manner.
Procedure b) is shown in WOOl/87243. This describes the use of PTFE
microparticles in hair care products whose adherence to hairs was improved by
adding cationic polymers to the preparation. The publication mentions cationized
dialkylmethacrylamides. These PTFE particles improve hair properties. A similar
process is utilized in WOW/38667. articles consisting of polystyrene, PMMA
and other polymers having a diameter of 0.2-1 um are applied to hair. Cationization
of the particles is carried out using cationic polymers or cationic surfactants which
are either used as matrix polymer or mixed into the formulations as an additive. The
particles serve to improve hair gloss. However, a long-lasting adherence for weeks is
not achieved and not described. These systems se do not serve for the
application of active compounds.
atively, anionic microparticles may be coated with cationic rs.
US 5753264 describes the preparation of preemulsions of an oil phase comprising
the active compound (oils which act as a repellent to lice, vitamins) with anionic
surfactants in aqueous solution and the subsequent formation of a polymer coat by
coacervation with chitosan from an acidic aqueous solution by pH shift. uent
crosslinking leads to ically charged, very fine articles < 10 um. These
microparticles can be applied to human hair. In an in vitro test, a repelling action for
one week is demonstrated. However, a longer duration of action of the encapsulated
emulsions compared to the emulsions applied in unencapsulated form is not
demonstrated. US 8 shows that active compounds, preferably perfumes, but
also insect ents, can be introduced into microparticles of urea/melamine
formaldehyde resins by forming an aqueous primary on and subsequent
polycondensation. Mentioned as an alternative are complex coacervates of gelatine
or polyacrylate polymers. In a second step, these microparticles are then coated with
the ic polymer. Cationized starch, guar gum, polysiloxanes can be used for this
purpose, but polyesters are also mentioned. These cationized capsules of a diameter
of 2-15 mm can be applied to hair and release the contents. It is demonstrated that,
compared to non-cationized es, substantially more active compound can be
d, to the hair and released. FR 2801811 describes a similar process where the
charge of microcapsules comprising negatively charged active compounds is
changed by applying a cationic polymer (polyquaternium types), thus ng the
microcapsules to be applied to negatively d textile fibres or hairs. However,
these ations do not mention the use of quaternized dimethylaminoethyl
methacrylate copolymers (Eudragit® RS, RL).
However, the processes mentioned require several process steps to te the
cationic microcapsules, and they are therefore unsuitable for a simple industrial
ation. Moreover, the cationic polymers used have to be water-soluble.
Eudragit® RS/RL are water-insoluble and therefore unsuitable for the techniques
described herein.
The aim of other s developments is to provide the microcapsules themselves
during preparation with a cationic surface charge. WOW/35933 describes the
production of microcapsules where the material to be ulated (for example
vitamins) together with the coating polymer is dissolved in an c solvent which
has to be partially soluble in water (in most cases ethyl acetate). The red
coating polymer is PMMA. This solution is sed in an aqueous phase which
comprises an emulsifier and has been saturated with the organic solvent. From the
emulsion, the solvent is removed by solvent extraction, resulting in the ion of
articles having a size of 3-300 um. However, the microcapsules do not carry
any charge. The application WOOl/35933 therefore describes a s alternative
where the coating polymer used is Eudragit® RS PO, which is applied to the primary
particles in a second step. In this manner, the microparticles are provided with a
cationic surface charge. An advantage which is emphasized is that the process does
not require any chlorinated hydrocarbons as solvent. However, the process described
has a substantial disadvantage in that the solvent extraction s requires a large
excess of aqueous phase. Thus, the dispersions ed comprise, for example, only
0.2% or 0.4% solid, ing concentration or drying steps. In contrast, the
preparation procedure described in the present invention allows a one-pot process.
The proportion by volume of the polymer phase can be adjusted variably such that,
after removal of the organic solvent, a dispersion is formed which can be filled into
containers or applied directly, if appropriate after addition of further formulation
components. The microcapsules of WOW/35933 can be applied according to the
ion to skin or hair; however, having the size mentioned, they are unsuitable for
long-lasting applications on hair. The examples of 5933 describe particle
sizes of a diameter of 40 - 100 um. With hair having a diameter of 50 - 120 um,
depending on the hair type, it is obvious that such les are too big and unsuitable
for long—lasting adherence on animal hair. Moreover, the particles obtained are
visible to the naked eye and thus change the visual appearance of the animal coat. In
contrast, using the preparation process in accordance with the present invention, the
suitable and preferred particle sizes in the range of 0.1 — 3 urn can be ed
easily. Furthermore, to form the preemulsion, an external emulsifier is required in the
outer aqueous phase. The substances dissolved in the oil phase are not capable of
mulsifying action.
EP 1407753 and EP 1407754 describe a process where copolymers of
polyacrylamide and acrylic acid are dispersed together with melamine-formaldehyde
resins in aqueous solution. Perfume oils are introduced into this solution. An increase
in temperature initiates polycondensation around the oil droplets. By addition of
cationic polymer during the reaction phase, this is incorporated into the outer layer of
the microparticles. itly mentioned, is the necessity of the chemical
ibility of the polycondensate with the material of the e wall. These
cationic microparticles can then be applied to textiles or incorporated into shampoos
for use on hair and skin. In a l manner, polyesters are mentioned as es
of cationic polymer groups. However, Eudragit® types are not described.
W002060399 states that cationic hair care products or cationic polymers, for
example polyethyleneimine, are melted together with active compounds and a
hydrophobic matrix polymer. This melt is emulsified in a surfactant-comprising
s solution and cooled. The cationic microparticles have a size of 0.1 — 0.5 um
and are incorporated into shampoos. The particles adhere on hair, the ingredients
being released over a period of several hours. In contrast, EP 0369741 describes
cationized porous microparticles having a diameter of ably 10 — 40 um whose
pores can absorb hair care substances, sunscreens, perfume oils or insect repellents.
A degree of loading of 5 — 65% is stated. The positive charge es adsorption on
keratinic als. The description mentions the possible use of methacrylates as
copolymer. However, the preparation process is complicated. ing
polymerization of the sion, a plurality of washing steps for generating the
porous structure, cationization by protonation of the particle surfaces and loading
with the active compound, at least four steps are required. Moreover, it has not been
demonstrated that the les adhere to the hair for long.
atively, WO98/28399 describes the suspension rization as a suitable
method for generating polymer les having a diameter of 10 — 150 um, the
polymer particles consisting of hydrophobic methacrylic esters, optionally
copolymerized with other rs, such as styrene. For the copolymerization, use
is furthermore made of cationic monomers, preferably cationized (quaternized)
dimethylaminoethyl methacrylates (component of Eudragit®) and crosslinking
monomers. In this manner, the microparticles are provided with their cationic e
charge. The suspension polymerization is carried out in the presence of a
polymerization stabilizer. Preference is given to using polyvinyl alcohol or cellulose
esters. For their part, these hydroxyl group-containing polymers may also have
cationic monomer units. The stabilizer is incorporated into the wall of the
microparticle during particle formation. In this manner, the microparticles are
provided with functional surfaces consisting of quaternary alkylammonium units and
hydroxyl groups. The proportion of this polymer in the microparticles may be from I
to 25%. According to the invention, this firnctionalization enhances adherence to
fibres, even keratinic al (wool fibres). Preferably, these particles are then
loaded with active compounds in the dynamic swelling process. Insecticides, insect
repellents, perfumes, pheromones and other active compounds are mentioned.
However, alternatively the active compound may also be incorporated during
polymerization into the microparticles formed. The dispersions formed are virtually
free of erates and release the active compound on the fibre over a period of
several days. However, this application does not be applications on hair. In any
case, the particles are too large for this purpose. er, this process additionally
requires a complicated polymerization step and optionally subsequent loading with
active compound. Release over a period of several weeks has se not been
demonstrated. The required adical polymerization may have a ve effect
on the stability of many active nds.
In contrast, it is obvious that the embodiment according to the invention represents a
more simple method and leads directly to the active compound-loaded, cationically
charged microparticles of a suitable dimension of 0.1—10 um (preferably
0.1 - 3 um). Moreover, the particles may se various proportions of Eudragit®
types.
In principle, the solvent evaporation process for generating active nd—
sing microparticles of quaternized dimethylaminoethyl methacrylate
copolymers (trade name Eudragit® RS, RL) is part of the prior art and has been
bed sufficiently. However, these processes have been applied and optimized
for developing oral microcapsules with a prolonged release of the active nd.
Here, active compound and Eudragi ® polymers are dissolved in organic solvent and
dispersed into an aqueous phase or an oil phase. The aqueous phase ses
emulsifiers, preferably polyvinyl alcohol or anionic or non-ionic surfactants. If an oil
phase, for example paraffin oil, is used, use is ntly made of stearates. After
removal of the solvent under reduced pressure — it is also possible to employ the
solvent shift s — the microparticles remain in the dispersion. In most cases, the
size is in the range of 10 — 1000 um. As an example of such a process, IL 73597 may
be mentioned. Here, the organic t used is tetrahydrofuran (THF). In
WO92/01443, Eudragit® S 100 and Eudragi ® RS 100 are dissolved together with
ably basic active compound in methylene chloride as solvent, and preferably
dispersed in l oil comprising magnesium stearate. After evaporation of the
solvent, the microparticles are finely divided in the dispersion. The particles have a
size in the order of 0 — 150 um, with < 50 um being preferred. The release of active
compound is delayed and approximately independent of the pH of the environment.
Drug Development and Industrial Pharmacy 16(13), 2057-2075 (1990) describes
how nifedipine is dissolved in methylene chloride together with the polymers
Eudragit® RS and RL. With the aid of a blade agitator, this solution is dispersed in
the aqueous phase (emulsifier nyl alcohol), and the solvent is evaporated. The
size of the particles depends on the stirring speed, the proportion of polymer, the
proportion of emulsifier, the viscosity of the oil phase, etc. There are numerous
publications on this subject. l of lled Release, 16, 311—318 (1991)
investigates the effect of the emulsifiers in the aqueous phase on release of
encapsulated 5-aminosalicylic acid (solid dispersion in the CH2C12 phase). In the
literature references mentioned, in most cases customary stirrer apparatuses are used
to generate the emulsion. These applications and ations state that an emulsifier
dissolved in the aqueous phase is necessary to prepare the emulsion and thus the
microparticles.
Further examples from the extensive literature which may be mentioned are:
- Eudragit® RS and RL (acrylic resin) microcapsules as pH insensitive and sustained
release preparations of Ketoprofen; Goto S. et al.; J. Microencpasulation 3(4), 1986,
293-304
— Evaluation of the sustained release ties of Eudragit® RS, RL and S (acrylic
resins) microcapsules containing Ketoprofen beagle dogs; Goto S. et al.,
J. Microencapsulation 5(4), 1988, 343-360
- A novel method for preparation of Eudragit® RL microcapsules; Satturwar PM. et
al., J. Microencapsulation 19(4), 2002, 407-413
However, all these processes lead to microparticles which are too big for application
to hair. Also, these publications do not demonstrate that these particles bind to
surfaces for long periods. Furthermore, to prepare the emulsions an emulsifier is
required, in the outer aqueous phase. Self—emulsifying effects of the Eudragit®
polymer types are not described and do not come into effect in the processes
ned above.
A totally different method of attaching active compound les to animal hair is
bed in WOO9/056280. Here, functional dies are employed. The
microparticles are functionalized on the surface by yl groups. Through these
groups, the antibodies are, in a multistep process, attached chemically to the
microparticles. These antibodies have le domains capable of specifically
binding to the hairs of various species. However, owing to the requirement to attach
the dies chemically to the surface and to maintain onality for periods of
times required by the applications, this process is likewise to be considered as
complicated and expensive.
According to the invention, functional antibodies for mediating binding of the
microparticles on animal hair are not required.
Thus, none of the methods and technologies listed can achieve the advantage of the
present ion — a) the generation of articles for the delayed release of
active compounds after nce to hair, b) provision of a long-lasting adherence to
hair by covering the surface of the microparticles with cationic polymers, 0)
sufficiently small size of the articles, such that there is no negative effect on
hair properties, and d) simple preparation of the microparticles via an emulsion
process.
Accordingly, it was an object of the invention to develop administration forms for
topical applications in medicine, preferably veterinary medicine, which can meet the
following complex demand profile:
a) being able to release active compounds slowly over a period of several days or
weeks,
b) being able to substantially avoid skin irritation,
c) having no negative effect on functional and haptic properties of coat or skin and
d) at the same time being easy to produce.
This object is achieved according to the invention. The invention relates to:
l. Particles having a particle size d(v,90) of at most 10 um comprising
a) an ged polyacrylate and
b) a cationic polyacrylate which carries positively d filnctional
where the particles
c) comprise one or more active compounds and
d) may optionally comprise further polymers, auxiliaries or additives.
2. Particles according to item 1 having a particle size d(V,90) of 0. 1-3 um.
Particles ing to item 1 or 2 in which the cationic polyacrylate b) is a
quaternized dialkylamino alkyl methacrylate copolymer.
Particles according to item 3 in which the cationic polyacrylate b) is a
copolymer of (methyl, ethyl) tes, (methyl, ethyl) methacrylates and
monochloromethane-quaternized dimethylaminoethyl esters of methacrylic
acid (known under the trade name Eudragit RS or Eudragit RL).
Particles according to any of the preceding items in which the uncharged
polyacrylate a) is poly(methyl methacrylate).
Particles according to any of the preceding items in which the mixing ratio of
the uncharged polyacrylate a) to the cationic polyacrylate b) is from
:95 (w/w) to 95:5 (w/w), preferably from 70:30 (w/w) to 95:5 (w/w),
particularly preferably from 80:20 (w/w) to 90: 10 (w/w).
les according to any of the preceding items comprising, based on the
mass of the particles, 0.1 - 50% by weight, preferably 1 — 20% by weight,
particularly ably 5 — 15% by , of active compound.
Particles according to any of the preceding items where the uncharged
polyacrylate has a weight average molecular weight of from 1000 g/mol to
1 000 000 g/mol, preferably from 20 000 to 600 000 g/mol, particularly
preferably 50 000 — 150 000 g/mol.
Particles according to any of the preceding items comprising 0.1 — 50% by
weight based on the total mass of the particles of one or more further
polymers, ably polystyrene.
10. Particles according to any of the preceding items comprising one or more
plasticizers, surfactants, cosolvents, their sum, based on the total mass of the
microparticles, being 0.1 ~ 40% by , preferably 5 — 30% by ,
particularly preferably 5 — 20% by weight.
ll. Particles according to any of the preceding items sing, as active
compound, flumethrin.
12. Particles according to any of the preceding items comprising, as active
compound, a repellent, ably icaridin or N,N—diethyl-m—toluamide.
13. Particles according to any of the preceding items, comprising, as active
compound, an arylpyrrolidine, ably N-[[4-[3-(3,5-dichlorophenyl)
(trifluoromethyl)- l lidinyl]—2—
(trifluoromethyl)phenyl]methyl]propenamide (CAS No.: 12216929).
14. Process for preparing the particles according to any of the preceding items,
comprising the following steps:
(i) preparing a on of components a) to d) in a solvent or solvent
mixture (1) poorly miscible with water, if at all,
(ii) dispersing the solution (i) in an aqueous phase optionally comprising
additives and solvent or solvent mixture (1) to saturation, to obtain a
fine, stable emulsion,
(iii) removing the solvent or solvent mixture (1) from the emulsion
droplets by
- I) evaporation (solvent evaporation process), to obtain an aqueous
suspension, or
— II) spray drying, to obtain a dry powder.
. Composition comprising particles according to any of items 1 to 13.
16. ition according to item 15, where the particles are sed in a
dispersion medium.
17. Use of the les according to any of items 1 to 13 for preparing
compositions for controlling parasites on animals.
18. Use of the compositions according to item 15 or 16 for repelling arthropods on
animals.
19. Composition according to item 15 or 16 for use for controlling parasites on
animals.
20. Composition according to item 15 or 16 for use for repelling arthropods on
animals.
21. Method for controlling tes on a non-human animal sing applying
to the non-human animal the particles according to any one of items 1 to 13.
The particles according to the invention have a particle size d(v,90) < 10 µm,
preferably d(v,90) < 5 µm, particularly preferably d(v,90) < 3 µm, measured by laser
diffraction using a n Mastersizer 2000. Preferably, the size of the particles
according to the invention is at least d(v,90) > 0.1 µm, ularly ably
d(v,90) > 0.3 µm, particularly preferably ) > 0.5 µm. Unless indicated
otherwise, all particle sizes are d(v,90) values measured by laser diffraction (Malvern
sizer 2000). d(v,90) is to be understood as meaning a volume-based particle
size distribution where 90% of all particles have a dimension smaller than or equal to
this value. The terms d(v,50), d(v,10) etc. are to be understood correspondingly. The
measurement is carried out by the laser diffraction method using the Mastersizer
2000 instrument (dispersing unit Hydro 2000G) from Malvern and the Fraunhofer
diffraction evaluation mode, since the refractive indices of the active compound
particles are not known. Here, a suitable amount of the sample solution is, with
stirring, pre-dispersed in 2-3 ml of a dispersing medium (water or 0.1% aqueous
dioctyl sodium sulphosuccinate solution). With stirring (300 rpm) and g
(900 rpm), the dispersion is then transferred to the dispersing unit of the instrument
and measured. The evaluation software states the particle size as 5), d(v,0.9),
etc., values.
The charged and uncharged polyacrylates form a matrix for the ed active
compound.
Uncharged polymers – in some publications and applications also referred to as
7301726_1 (GHMatters) P95786.NZ KARENM
neutral polymers — or uncharged polyacrylates are to be understood generally as
polymers and specifically as polyacrylates which, in the sense of the Bronsted
acid/base terminology, do not contain any groups which can be protonated or
deprotonated in aqueous systems. In addition, it also refers to all polymers and
specifically polyacrylates which n no permanently anionic or ic groups
and therefore retain their charge state in acidic or basic aqueous solution. As a result,
they are insoluble in water, a further essential property of the ged
polyacrylates used for the purpose of the invention. Accordingly, the articles
formed rom remain intact in water and in the microclimate of the animal coat,
and they are also not swellable to any measurable extent. In this manner only, the
active compounds comprised in the microparticles can be released in a delayed and
controlled manner by ion. For the tion above, it is immaterial whether the
uncharged polyacrylates comprise, for example owing to the production method,
very small proportions of charged, protonatable or deprotonatable groups. In the case
of acrylic or methacrylic esters, for example, it is possible that they may comprise
small proportions of non-esterified carboxyl groups. These can be considered as a
kind of ed “contamination”, and they are not to be taken into account when
assessing whether a polyacrylate is “uncharged” for the purpose of the invention.
Uncharged polyacrylates for the purpose of the invention are not only polymers of
acrylic esters (polyacrylates in the er sense of the word), but also those of
derivatives of the acrylic esters. The esters are preferably alkyl esters, the alkyl group
preferably containing 1 to 4 carbons; very particular preference is given to methyl
. The derivatives are in particular alkyl poly(alkyl)acrylates, where the alkyl
substituent of the crylic acid and the alkyl group of the ester independently of
one another may be alkyl having 1 to 4 carbon atoms; particular preference is in
each case given to the methyl group. The alkyl poly(all<yl)acrylates are used with
particular preference and can be represented by the following general formula:
R1 = alkyl, ably having 1 to 4 carbon atoms, in ular —CH3
= alkyl, preferably having 1 to 4 carbon atoms, in particular ~CH3
A very particularly preferred ged polyacrylate for the matrix is methyl
polymethacrylate (poly(methyl methacrylate), PMMA).
As ged polyacrylates for the matrix, it is also possible to use ged
copolymers of the abovementioned uncharged polyacrylates, or mixtures of different
uncharged rylates.
The molar masses ofthe uncharged rylates ofthe matrix, for example PMMA,
may vary within wide limits. It is expedient to use molecular weights of
MW = 1000 g/mol to l 000 000 g/mol (weight average). However, particularly
suitable is a mean molecular weight range of 20 000 — 600 000 g/mol, and here, in
turn, particularly preferably 50 000 — 150 000 g/mol. Polyacrylate rs having a
low molecular weight are particularly suitable for admixing in order to lower the
glass transition temperature of the microparticles, or to generate particularly small
microparticles of d(v,90) < 2 um (to this end, use is preferably made of molecular
weights MW < 10 000 g/rnol). As already stated above, the microparticles may
optionally also comprise varying proportions of flirther uncharged alkyl polyalkyl
acrylates.
In contrast, anionic polymers, specifically anionic polyacrylates, are not used for the
purpose of the invention. Anionic polymers are to be understood as meaning
polymers containing functional groups which can be deprotonated in the sense of a
Bronsted acid in an aqueous nment and/or contain functional groups which are
permanently negatively charged. A specific example which may be mentioned are
Eudragit® S types. Such polymers are unsuitable, since they , neutralize or
even convert into the negative the positive surface charge of the microparticles,
which would reduce the adherence of the microparticles to the positively charged
hair surfaces.
The cationic polyacrylate s positively charged flinctional groups and is
preferably a polyacrylate in the narrower sense of the word, a polymethacrylate or a
copolymer derived therefrom. The alkyl group of the ester and, if appropriate, the
alkyl tuent of the alkylacrylic acid denote independently of one another alkyl
having 1 to 4 carbon atoms; particular preference is in each case given to the methyl
group. The positively charged group is preferably attached via the ester group to the
polyacrylate skeleton. Usually, an amino or ammonium group is attached via an alkyl
chain having 1 to 4 carbon atoms, preferably an ethylene chain, to the oxygen of the
ester group. The positively charged group is preferably a trialkylated and protonated
or a tetraalkylated amino group, the alkyl groups independently of one another
having 1 to 4 carbon atoms, preferably 1 or 2 carbon atoms. Very particular
ence is given to cationic insoluble copolymers of ylaminoethyl
methacrylate, (ethyl,methyl) acrylate and ,methyl) methacrylate having the
trade name Eudragit® RS or RL (manufacturer and distribution: EVONIK Industries,
as at 2011), in which the tertiary amino group is quaternized with methyl chloride
(CAS No. 33434 — 24 — l; the polymers of the Eudragit® RL and RS types have
already been described in detail . The cationic polyacrylates preferably have a
weight-average molecular weight of from 20 000 to 40 000, ably from 25 000
to 35 000. The cationic polyacrylate is a separate component of the particles
according to the invention; it is not copolymerized with the uncharged polyacrylates
ofthe matrix.
Surprisingly, such cationic rs provide a property profile which, in
combination with the uncharged polyacrylate matrix polymer(s), allows all four of
the complex ements a) to d) for the administration form to be achieved. The
use of ic polymers, in particular Eudragit® RS, RL, allows a simple preparation
process which tes small microparticles having a cationic surface charge and
which, from an aqueous formulation, can adhere efficiently to the vely charged
animal hair and are small enough, so that they don’t effect negatively the optical or
haptic properties of the coat after drying. er, long-lasting adherence of the
particles on the animal hair may also be achieved after drying. By combining various
ratios of the different polymer types (matrix polymer and cationic polyacrylate), it is
possible to modify the particle size and to achieve delayed, continuous and longer—
lasting release of the active compound(s) from the particles. The proportion of
cationic polymer may be varied within wide limits of 5 — 95% by weight, preferably
- 30% by weight, but particularly preferably 10 — 20% by weight, based on the
proportion mer.
The particles according to the invention may also be referred to as microcapsules in
which the active compounds are stored or encapsulated. In the particles, the active
compounds are dissolved in molecularly dispersed form or suspended in disperse
form. Accordingly, the microparticles form an active compound reservoir. The
r matrix may also comprise other polymers and additives. As a further
characteristic of the invention, it may be mentioned that the ic polyacrylate and
also further ves are miscible with the matrix polymer(s). Further additives and
polymers have to be chosen such that there is no phase separation within the polymer
matrix of the particle. The proportion of the additives mentioned, such as, for
example, further polymers or plasticizers, in the microparticles may be up to 40% in
total, based on the total weight of the particles.
The preparation of the particles can take place by various processes. The particle
properties according to the invention can be d by the preparation process.
Thus, the solvent evaporation process is the preferred s to obtain particles of
the size according to the invention and a modified surface. There are many
ptions of this process in the ture, in ent variations. Here, the
components of the les are dissolved in an organic t which is immiscible
with water, and the solvent is then — in most cases with the aid of an emsulifier -
dispersed in an aqueous phase, such that initially an emulsion is formed. By warming
this emulsion, the organic phase is evaporated and the solvent base of the dissolved
components is removed. By adjusting the temperature in a le manner, the
solvents can be removed almost completely from the microparticles. The solids of
the emulsion droplets remain in the form of microparticles. In this manner, the
emulsion is converted into a suspension. If required, further formulation components
may be added to this suspension. After ng, the formulation obtained can be
applied directly. Thus, the formulation can be prepared in one step ot process).
The particles may be purified and isolated by subsequent washing and filtration
steps, if this is advantageous for the application.
In the case according to the invention, a cationic surface charge of the particles is
required for later application. This is achieved by the cationic polyacrylate. Together
with the matrix polymers, the active compound(s) and optionally additives, the
cationic polyacrylate is dissolved in the oil phase. In the present invention, the
volume ratio of the organic solvent with respect to the aqueous phase may be varied
within wide ranges. Thus, volume ratios of from 10:90 to 50:50 (organic t:
aqueous phase) are possible. Preference is given to proportions by volume of c
phase to aqueous phase of from 20:80 to 40:60, whereby, using le dispersing
conditions — for example when using a high—performance dispersing apparatus and/or
a ressure nizer — and variation of energy input the droplet size of the
emulsion and thus ultimately the size of the microparticles may be varied. The
c solvent must be poorly miscible with the aqueous phase, if at all, and has to
evaporate at temperatures below the boiling point of the water. These requirements
can be met in particular by halogenated hydrocarbons and also by ethyl acetate. For
the purpose of the invention, preference is given to dichloromethane,
trichloromethane and ethyl acetate.
ing to the invention, the cationic polyacrylate now acts as emulsifier. For
example, the insoluble cationic it® RL(RS), which is preferably used,
has, in the use ing to the invention, in addition to ibility with the matrix
polymer, also remarkably good emulsifying properties, and it is therefore possible to
generate particularly finely divided oil-in-water emulsion droplets. This is
particularly surprising, since according to conventional teaching a suitable fier
has to be soluble mainly in the aqueous phase in order to generate oil-in-water
emulsions. After removal of the solvent, the active compound-comprising
microparticles are present in the form of an aqueous dispersion. The microparticles
now also have a cationic surface charge. As a consequence, the microparticles,
applied as an aqueous sion formulation, can now be bound preferably on the
negatively charged surfaces of the animal hairs. The properties of the quaternized
dimethylaminoethyl methacrylate copolymer ofthe Eudragit® RS, RL type result in a
particularly good adherence to hair and ensure that the microparticles adhere to the
dry animal hairs even long after the aqueous formulation base has dried off. This
avoids direct contact of the active compounds with the skin, and the skin—irritating
action of some active compounds does not come into effect. In addition, during this
period, the active compound is released from the microcapsules in a delayed manner.
The release properties of the microparticles may additionally and in wide ranges be
varied by further additives (for example cizers, addition of other polymer types,
ratio matrix polymer/Eudragit®).
The high-performance dispersing apparatus used may be, for example, an Ultra
Turrax® T25 from IKA Werke GmbH & Co. KG. A l operating range during
the preparation of the microparticles according to the invention is a number of
revolutions of about 10 000 rpm with a period of application of l — 3 minutes. The
high-pressure nizer used may be, for example, of type MllOY from
Microfluidics. In the context of the present invention, the microparticles were, as
standard, prepared using a re (flow pressure) of 500 bar and an interaction
chamber pore size of 200 and 100 um.
A further, less preferred s for preparing particles according to the invention is
spray drying. To this end, the procedure of the emulsion evaporation method is
adopted, and after dissolution, the particle components are converted into an
emulsion. The latter may be atomized and dried using a uid nozzle.
Less preferred, but also possible, is a subsequent loading of the particles by the
dynamic swelling process. To this end, the placebo particles (i.e. particles according
to the invention not yet comprising any active nds) are sed in a suitable
t. The solvent has to dissolve the active compound and swell the particles.
Owing to this swelling process and driven by the establishment of a distribution
equilibrium in favour of the organic polymer phase, it is possible for the active
compound to diffuse into the particles. By slowly removing the solvent, the swelling
ofthe particles recedes and the active compound remains in the microcapsules.
Preference is given to using active compounds which can be applied externally.
Examples which may be mentioned are active compounds from the group of the
icides, ticides, acaricides, fungicides, the repellents, dermatologically
active compounds or active compounds acting by modifying behaviour. Such active
compounds modifying behaviour include, for e, ones or r
odourous substances associated with uctive behaviour.
There are other systems suitable only for charged active compounds; however, the
particles ing to the invention are also suitable for uncharged active
compounds. Thus, particles according to the invention comprising an uncharged
active compound represent one embodiment of the present invention. “Uncharged
active compounds” are active compounds which do not contain any permanently
positively or negatively charged groups, i.e. which are neutral, and are present in this
neutral uncharged form in the particles. If the compounds may be t in charged
forms depending L
on the pH, ‘uncharged active compounds” are preferably
ered to be those which, at pH 5-9, in particular pH 6-8, are present
predominantly in a neutral uncharged form.
In principle, all active compounds which are suitable for external application and
which the person skilled in the art can think of may be used according to the
invention. Accordingly, the active compounds and active compound groups
mentioned hereinbelow are mentioned only as examples and are not to be considered
as limiting.
Preference is given to using active compounds against ectoparasites on animals and
humans, in particular active compounds having insecticidal and/or acaricidal action.
A preferred group of active nds which may be mentioned are the pyrethrins,
and also the pyrethroids, for example: fenvalerate [a-cyanophenoxybenzyl 0t(p-
Cl—phenyl)isovalerate, rin [(oc-cyanofluorophenoxy)benzyl 3-[2—(4-
chlorophenyl)chlorovinyl]—2,2-dimethylcyclopropanoate] and its enantiomers and
stereoisomers, cyfluthrin [(a-cyanofluorophenoxy)benzyl 2,2,-dimethyl—3-(2,2—
dichorovinyl)cyclopropanecarboxylate], permethrin [3-phenoxybenzyl cis,trans-3—
ichlorovinyl)-2,2-dimethylcyclopropanecarboxylate], cypermethrin [a—cyano-
oxybenzyl 2,2—dimethyl(2,2-dichlorovinyl)cyclopropanecarboxylate],
deltamethrin anophenoxybenzyl cis,trans-3—(2,2,-dibromovinyl)-2,2—
dimethylcyclopropanecarboxylate], fluvalinate [2-cyanophenoxybenzyl 2-(2—
chloro-or,0L,or-trifluoro—p-toluido)-3—methylbutyrate]. Preference is given to using
pyrethroids having acaricidal action. Particularly preferred are or-cyanopyrethroids,
in particular the esters of the or-cyanophenylbenzyl alcohols and the 4-fluoro-or-
cyanophenoxybenzyl alcohols. From among these, cyfluthrin, B-cyfluthrin or in
particular flumethrin are especially preferred.
A further or-cyanopyrethroid which may be mentioned is cyphenothrin. The
pyrethroids also include etofenprox, even though it has a slightly different basic
structure.
A further red group of active compounds are ents. ents are active
compounds which are detected by an organism usually Via the sense of smell, and
which repel this organism without directly killing it. For example, pyrethroids have a
repellent and an insecticidal or acaricidal action. Other repellents have virtually no
relevant icidal or acaricidal action. Preference is given to using repellents
which repel harmful or nuisance insects such as mosquitoes, flies, fleas or acarids
such as ticks or mites from animals and humans. As preferred, examples of the group
of the repellents, the following may be mentioned here: DEET diethylenetoluamide),
icaridin, ethyl butylacetylaminopropionate (IR3535, MERCK). The duration of
action of tional commercial formulations to be applied topically is in most
cases d to a few hours.
In addition, the arylpyrrolidines form a further preferred group of active compounds
which may be encapsulated in the articles according to the invention. Here,
particular mention may be made of N—[[4-[3—(3,5-dichlor0phenyl)—3-
(trifluoromethyl)—1-pyrrolidinyl](triflu0r0methyl)phenyl]methyl]pr0pen—
amide (CAS N0.: 1221692-86—9).
From the group of the insecticides, those used in the field of controlling
rasiticidal arthropods, such as spinosyn, N—phenylpyrazoles, carbamates,
phosphoric and phosphonic esters, growth inhibitors, juvenile hormones and
mixtures of these active compounds with one another may be mentioned as being
preferably used. It is also possible to add further ists. For the purpose of the
present application, synergists are to be tood as meaning compounds which for
their part do not have the desired activity, but which, as mixing rs, increase the
activity of the active compounds.
Carbamates which may be mentioned are substituted phenyl and yl
carbamates.
Phosphoric esters which may preferably be mentioned are the nds having the
common names phoxim, othion, dichlorvos, trichlorfon and malathion.
All active compounds mentioned according to the invention may, if appropriate, be
employed either as mixture of stereoisomers, for example as mixture of
diastereomers or racemate, or else as enriched or substantially pure stereoisomer, for
example enantiomer.
Of course, it is also possible to use combinations of active compounds in the les
according to the invention.
In the particles according to the invention, the active compounds are usually present
in concentrations of 01-50% by weight, preferably 1-20% by , ularly
preferably 5-] 5% by weight, in each case based on the weight of the particles.
Precondition for the incorporation of the active nds into microparticle is the
compatibility with the polymer matrix. Hereinbelow, polymer matrix is to be
understood as meaning the mixture of the matrix polymer polyacrylate (preferably
PMMA) and, the cationic polyacrylate (preferably Eudragit® RL/RS) and any further
polymers optionally added. It is favourable for a long-lasting release of the active
compound from the microparticles if the active compound is present in the particles
dissolved in molecularly dispersed form, or at least in particulate amorphous form,
i.e. not crystalline. Particularly preferred is a larly dispersed distribution of
the active compound in the matrix polymer in the sense of a solid solution. This may
be given, in one case, by a compatibility in principle in the sense of a thermodynamic
ility of active compound and polymer matrix. The advantage of such a
miscibility consists in the fact that a rapid diffusion of the active compounds from
the matrix to the surface of the particles is prevented (principle of phase separation).
A molecularly dispersed distribution may be demonstrated, for example, when no
melting peaks of the active compounds can be found in DSC/DTA diagrams. An
tive method is analysis by X-ray diffractometry. In this method, miscibility is
guished by the absence of ction peaks. However, for the purpose of the
invention, it should not be excluded that at least a certain proportion of the active
compounds may be present crystalline enclosed in the polymer matrix, whereby the
release rates, for example, may be modified further.
However, the use of active compounds for the purpose of the invention is not limited
to active compounds which are miscible with the polymer matrix in a
thermodynamically stable manner. For producing the active compound-comprising
microparticles ing to the invention, use may also be made of all processes
known to the person skilled in the art which se the molecular miscibility 0f
the active compounds with the polymer matrix. As in the case of liquid solutions,
one or more lizers may be used for this purpose. This can be achieved, for
example, by addition of further polymers, of plasticizers, cosolvents, wetting agents
(surfactants) or else further active compounds which prevent demixing, phase
separation or crystallization of the active compound or else other components in the
microparticles. By addition of these substances, it is also possible to te the
release behaviour of the active nds from the microparticles. In general, the
addition of the low-molecular-weight additives mentioned lowers the glass transition
temperature and thus increases the diffusion rate of the active nds in the
matrix, so that, if d, an accelerated release may be achieved.
Optional added polymers are, in general, all types of polymer miscible with the
matrix polymer rylate and the cationic polyacrylate and the active compounds
incorporated into the microparticles. Preference is given to using other polyvinyl
resins such as polyvinylpyrrolidone, polyvinyl chloride,
polyvinylpyrrolidone/polyvinyl acetate copolymers (trade name Luviskol), but in
particular polystyrene. Derivatives of polymeric — at least partially hydrophobic —
carbohydrate compounds, for example cellulose ethers, cellulose esters,
hydrophobized starch, may also be mentioned here, likewise polyethylene glycols
(polyoxyethylene, macrogol, CAS No. 253223). Their proportion may be up to
50% by weight, based on the total mass of the microparticles; preference is given to
using 10-40% by .
The microparticles according to the invention may comprise plasticizers. Suitable for
use as cizers are all pharmaceutically acceptable compounds le with the
matrix polymer and known to the person skilled in the art which have a desired
effect, lower the glass transition temperature and/or increase the miscibility of the
active compound with the matrix polymers. In this manner, it is also le to
increase the rate of release of the active compounds from the apsules.
Examples which may be mentioned are: phthalic and terephthalic , triethyl
citrate, triacetin, lecithins, phosphoric esters, adipic esters, benzyl benzoate, tributyl
acetylcitrate, ascorbyl palmitate, ethyl oleate and fatty acid esters of polyhydric
ls, such as of glycerol and ofpropylene glycol (miglycols). Preference is given
to using benzyl benzoate, tributyl acetylcitrate, triethyl e. The plasticizer is
usually added in the amount required to achieve the intended ng of the glass
transition temperature and increase of the release rate. The amount ed may vary
within wide ranges; however, an upper limit of 40% by weight, based on the total
mass of the particles, has been found to be useful. The amount employed preferably
varies between 10 and 30% by weight.
The microparticles ing to the invention may also comprise pharmaceutically
acceptable cosolvents which are miscible with the polymer material, which act as
solubilizers and also as plasticizers, but which may also have an effect on the
distribution coefficient of the active compound between the particle phase and the
dispersing medium. However, the distribution equilibrium of the cosolvents which
can be used for this purpose has to be predominantly on the side of the
polymer/active compound/solvent phase to avoid diffusion into the outer aqueous
phase during the emulsification s. These cosolvents are usually employed in
proportions of ably 5 to 20% by , based on the proportion of polymer.
Pharmaceutically acceptable, relatively long-chain alcohols, such as n—butanol,
benzyl alcohol, or esters such as tin, ethyl oleate, benzyl benzoate may be
mentioned, for example, as suitable cosolvents. It is also possible to use mixtures of
the solvents mentioned above as cosolvent. Of course, it is also possible to employ
other cosolvents which can be used for this purpose. Particular preference is given to
benzyl benzoate.
The microparticles according to the invention may furthermore also se
pharmaceutically acceptable surface—active compounds (surfactants) miscible with
the r material, which surfactants may se act as solubilizers and
plasticizers, but which may also have an effect on the distribution coefficient of the
active compound between the particle phase and the dispersing medium. However,
here, too, the distribution equilibrium of the surface—active compounds which can
be used for this purpose must be predominantly on the side of the polymer/active
compound/solvent phase to avoid diffusion into the outer aqueous phase during the
emulsification process. It is possible to use mainly hydrophobic surfactants and
wetting agents having an HLB value (hydrophilic-lipophilic balance value,
determined by the Griffin method) of < 8. These tants and wetting agents can
usually be employed in proportions of preferably 5 to 20% by weight, based on the
proportion of polymer. Preference is given to non-ionic surface-active nds.
Examples which may be mentioned are: fatty alkyl polyethylene glycol ethers,
henol polyethylene glycol ethers, polyoxyethylene fatty acid glycerides,
polyoxyethylene fatty acid esters, in each case having a low degree of ethoxylation,
alkyl polyglycosides, fatty acid N—methylglucamides, hobic polysorbates,
sorbitan fatty acid esters, ins and poloxamers having a higher proportion of
polypropylene oxide. It is, of course, also possible to employ further surface-active
compounds (surfactants) known to the person skilled in the art which have the
desired effect, lower the glass transition temperature and/or increase the miscibility
ofthe active nd with the matrix polymers.
If the active compounds are preferably present in the polymeric carrier matrix in
molecularly dispersed form, they can be released by diffusion from the matrix into
the surroundings of the microparticles. This diffusion is ve for the long—lasting
action on the animals. The release duration may be achieved by moderating the rate
of diffusion of the active compounds in the microparticles. Here, too, it is le
to employ, ing to the invention, all methods known to the person skilled in the
art. In the sections above, the addition of plasticizers, cosolvents, surfactants and
other additives which lower the glass temperature of the matrix polymer have already
been mentioned. A ular option of modification which may additionally be
ned here is the use of polymers of different molecular weight. The addition of
polymers having a low molecular weight likewise lowers the glass transition
temperature and can thus modulate the diffusion rate of the active compounds in the
polymer matrix and thus also the release rate (see also example 4).
Of course, the microparticles according to the invention may comprise all further
additives known to the person d in the art which se the stability of the
encapsulated compounds or other active compounds or improve the consistency of
the microparticles, ed they are miscible with the matrix material. Examples
which may be mentioned are: antioxidants, preservatives, fillers.
idants which are particularly suitable for incorporation into the microparticles
are the more hydrophobic representatives. Examples which may be mentioned are:
phenols (tocopherols, such as vitamin E, for example, butylhydroxyanisole,
ydroxytoluene, bile acid esters such as, for example, octyl and dodecyl gallate,
ascorbyl palmitate, and also further suitable esters of organic acids, mercapto
compounds, for example thioglycerol, thiolactic esters. The antioxidants mentioned
may be employed in all concentration ranges sufficient to ensure an antioxidant
protective action; a customary concentration range is 0.01 — 0.1% by weight.
More hydrophobic preservatives would be, for example: benzyl alcohol, n—butanol,
phenol, cresols, chlorobutanol, para-hydroxybenzoic , in particular the propyl
ester. The preservatives ned can be employed in all concentration ranges
sufficient to ensure protective action against microbes; however, a customary
concentration range would be 0.01 — 5% by weight.
The microparticles according to the invention are usually introduced into a suitable
administration form (formulation). They can be applied in the form of a ,
but preferably as a dispersion, more accurately as a suspension, to the animal. From
among the sions, preference is given to aqueous dispersions. The preparation
process described already provides ready-to—use aqueous dispersions as a base for the
formulation. All pharmaceutical auxiliaries and additives known to the person skilled
in the art which have an effect on its shelf—life, stability and applicability can now be
added to this suspension. Of course, the aries and ves should be
compatible with the dispersing medium; i.e. in the case of the preferred aqueous
dispersing , the auxiliaries and additives should be predominantly
hydrophilic and thus miscible with water. Auxiliaries and additives which may be
mentioned are, for example, dispersants, wetting agents (surfactants), spreading
agents, preservatives, antioxidants, pH regulators, antifoams. It is also possible
to employ thickeners and texturizing ingredients to adapt the gical properties
of the dispersion formulations to the requirements. The addition of le organic
solvents to the outer phase may be a further means to moderate the release profiles of
the active compounds from the microparticles in the sense that a certain proportion,
which can be adjusted to a fixed value, of the active compounds is already present in
saturated dissolved form in the outer phase of the dispersion, thus ensuring the
required knock-down effect on the parasites immediately after application of the
formulation.
Suitable dispersing media for the microparticles are, in l, homogeneous
solvents and solvent mixtures with additives which do not dissolve the microparticles
and do not dissolve the active compounds from the mciroparticles. Preference is
given to using water or es of water and water-miscible solvents, where the
mixing ratio of the water to the water-miscible solvent may be varied as desired as
long as the microparticles are not dissolved or swell greatly and the active compound
is not dissolved from the microparticles. To prevent dissolution of the active
compound from the microparticles, the dispersing medium may also comprise the
dissolved active compound, up to the tion limit. Water-containing dispersing
media usually se at least 50% by , preferably from 70 to 95% by
weight, of water. The concentration of the microparticles in this dispersing medium
may vary within wide ranges. Particle concentrations of l — 30% by weight have
been found to be suitable. Preference is given to l —20% by weight, particularly
preferably 5 - 15% by .
Suitable for use as dispersants are all ves known to the person skilled in the art
which adsorb on the surfaces on the microparticles or facilitate a neous
distribution of the microparticles in the dispersion formulation: polyvinylpyrrolidone,
polyvinyl l, cellulose ethers and esters and also poloxamers (polyethylene
glycol/polypropylene glycol/polyethylene glycol three-block copolymers) may be
mentioned as being preferred. The dispersants mentioned are preferably employed in
concentration ranges of 0.05 — 3% by weight.
Possible additives from the group of the wetting agents and tants are
ably more hilic, non-ionic and cationic representatives having an HLB
value of more than 8, such as, for e, fatty alkyl polyethylene glycol ethers,
alkylphenol polyethylene glycol ethers, alkyl polyglycosides, hoxylated fatty
acid glycerides, polyethoxylated fatty acid esters, fatty acid N—methylglucamides,
polysorbates, an fatty acid esters, poloxamers, polyethoxylated castor oil
derivatives. Polyethoxylated sorbitan fatty acid esters and poloxamers are to be
mentioned as being preferred. Anionic surfactants would adsorb on the surface of the
microparticles and reduce the cationic surface charge. For this reason, they are less
suitable. Suitable use concentrations of dispersants and wetting agents and also
surfactants are determined by the particle concentration and the total surface of the
microparticles in the formulation and may vary within wide ranges. The
concentration of micelle-forming wetting agents and surfactants is preferably chosen
such that the critical micelle formation concentration (cmc) is not exceeded.
Preferred for use as spreading agents are water-miscible compounds such as, for
example, non-ionic surfactants and ne surfactants, but in a low concentration,
still miscible with the dispersant, and also oily systems, such as isopropyl myristate,
fatty acid esters, fatty alcohols, adipic esters, triglycerides. Frequently, concentration
ranges of 0.01 — 1% by weight have been found to be suitable for the spreading
agents. r, these concentrations, also those in the sections below, are not to be
understood as ng and may vary depending on auxiliaries and further
formulation components.
Preservatives may also be present in the liquid formulations. By virtue of their
ic charge, quaternary ammonium compounds are particularly suitable since, on
adsorption on the surface of the particle, they do not reduce its positive charge.
Benzalkonium chloride and cetylpyridinium chloride, for example, may be
mentioned here. Examples of further preservatives which may be used are those
mentioned below: aliphatic ls, such as benzyl alcohol, ethanol, butanol,
phenol, cresols, chlorobutanol, para-hydroxybenzoic , in particular the methyl
and propyl esters, salts or the free acids of the carboxylic acids, such as sorbic acid,
c acid, lactic acid, propionic acid. The preservatives are to be added in the
pharmaceutically customary and microbiologically effective amounts. tration
ranges which are used are, for example, 0.01 — 5% by weight. They may be added
either individually or in combination with synergists. Synergists which may be
employed are, for example: citric acid, tartaric acid, ic acid, or the sodium salt
of editic acid.
The addition of idants may be useful if the active compound or other
auxiliaries dissolved in the continuous aqueous phase is sensitive to oxidation.
Antioxidants which may be used are, for e: sulphites (sodium sulphite,
sodium metabisulphite), organic sulphides (cystine, cysteine, cysteamine,
methionine, thioglycerol, thioglycolic acid, thiolactic acid), phenols, tocopherols
such as vitamin E, butylhydroxyanisole, butylhydroxytoluene, bile acid esters, for
example octyl and dodecyl gallate, organic acids (ascorbic acid, citric acid, tartaric
acid, lactic acid) and their salts and esters. Antioxidants are usually added in amounts
0f0.01 - 1% by weight.
Thickeners and texturizing ingredients are inorganic thickeners such as bentonites,
dal silicic acid, ium stearates, and organic thickeners such as cellulose
derivatives, for example methylcellulose, carboxymethylcellulose and salts thereof,
hydroxyethylcellulose, hydroxypropylmethylcellulose 4000, polyvinyl alcohols and
their copolymers, polyacrylic acids (carbopols), polyacrylates such as polyethyl and
methacrylates, mixtures of ized cellulose and sodium carboxymethylcellulose,
polymeric hydrocarbons such as, for example, xanthan gum, alginates, gum Arabic,
polypeptides such as gelatine, polyvinylpyrrolidones, polyvinyl alcohols, starch
derivatives, copolymers of methyl vinyl ether and maleic anhydride. Mixtures of
these substance s may be particularly advantageous. In most cases, amounts of
0.01 — 5% by weight are sufficient in order to achieve the required thickening effect.
pH regulators are pharmaceutically customary acids or bases. The bases include
alkali metal or alkaline earth metal hydroxides (for example NaOH, KOH), basic
salts such as, for example, ammonium chloride, basic amino acids such as, for
example, arginine, choline, meglumine, ethanolamines, or else buffers such as, for
example, tris(hydroxymethyl)aminomethane, citric acid buffers or phosphate buffers.
The acids e, for example, hydrochloric acid, acetic acid, tartaric acid, citric
acid, lactic acid, succinic acid, adipic acid, methanesulphonic acid, octanoic acid,
linolenic acid, gluconolactone, and, also acidic amino acids such as, for example,
ic acid.
Antifoams are preferably those based on silicone, for example dimeticone or
simeticone. Here, frequently, even very small amounts of 0.001 — 0.01% by weight
are effective.
The use of water—miscible solvents in the aqueous phase of the dispersion
formulation may be useful, for example in order to adjust the saturation
tration of the active nd in the continuous phase to a required value.
However, the additives have to be chosen carefully, and their concentration has to be
limited, since solvents and cosolvents must not compromise the ity of the
microparticles and dissolve relatively large s of the active compounds from
the microparticles. If water-miscible solvents are added, the amounts ed are
preferably 5 — 30% by weight. Suitable solvents are, for example: physiologically
acceptable solvents such as ls, such as, for example, monohydric alkanols (for
example ethanol or n—butanol), polyhydric ls, such as glycols (for example
ethylene glycol, propylene glycol, tetraglycol/glycofiirol), polyethylene glycols,
polypropylene glycols, ol; aromatically substituted alcohols such as benzyl
alcohol, phenylethanol, phenoxyethanol; esters, such as ethyl acetate, butyl acetate,
ethers such as alkylene glycol alkyl ethers (for example dipropylene glycol
thyl ether, lene glycol monoethyl ether); ketones such as acetone,
methyl ethyl ketone; glycerol formal, solketal (2,2—dimethylhydroxymethyl-l,3-
dioxolane), N—methylpyrrolidone, 2-pyrrolidone, N,N—dimethylacetamide, dimethyl
isosorbite, lauroglycol, propylene carbonate, dimethylformamide, and also mixtures
ofthe solvents mentioned.
To prepare the liquid formulations according to the invention, appropriate amounts
of the desired components are mixed with one r, for example using
conventional stirring tanks or other le apparatus. If required for the ingredients,
the operations can be carried out under a protective atmosphere or using other
methods of excluding oxygen.
By virtue of their positive surface charge, the microparticles according to the
invention, applied as an aqueous dispersion formulation, adsorb rapidly and
preferably on the negatively charged surfaces of the animal hairs and, e of the
particular properties of the cationic polyacrylates used according to the ion,
remain adhered on the coat ofthe animal for days and weeks. Over this entire period,
the active nd can be released from the microparticles, thus displaying its
treating or protecting action over a prolonged period of time. Owing to the nce
of the microparticles on the animal hair, direct contact with the skin is substantially
avoided and the skin-irritating action of many active compounds does not come into
effect. Furthermore, by virtue of the small size of the articles, the visual and
haptic properties of the coat are not negatively affected. A further advantage of the
invention is the fact that microparticles comprising different active compounds can
be mixed in a dispersion ation, so that active compounds which are ise
chemically incompatible can be applied jointly in one formulation.
The application of the particles to the coat is carried out from an aqueous suspension,
for example as spray, spot-on, pour-on, pump spray, aerosol spray or wipe-on
formulation. A wipe-on formulation is an administration form where the
ation— advantageously using a suitable applicator~ is spread on the coat of
the animal or incorporated into the coat of the animal. Here, ence is given to a
pour-on and a wipe-on formulation or a pump spray administration. The Wipe-on
application may be mentioned as being particularly preferred. To this end, using the
active compound content of the microparticles, the required amount of particles is
determined. The ed application volume is calculated using the solids
concentration in the microparticle suspension. For easier application, a surfactant (for
example Tween 20, 0.01%) is added to the aqueous dispersion. This allows better
wettability of the coat. The formulation is either sprayed on or rubbed into the coat.
To this end, suitable applicators are used.
The formulations ing to the invention are ably suitable for external use
on animals, preferably warm-blooded animals, such as, for example, birds or in
particular mammals. These may be domestic animals and useful animals, and also
200 s, laboratory s, test animals and pets.
The useful and breeding animals include mammals such as, for example, goats,
camels, water buffalo, donkeys, s, fallow deer, reindeer, fur-bearing animals
such as, for example, mink, chinchilla, raccoon, and also, in particular, cattle, horses,
sheep, pigs.
The laboratory animals and test animals include mice, rats, guinea pigs, golden
hamsters, dogs and cats.
The pets include dogs, cats and horses.
Particular emphasis is given to application on cat, dog or horse.
According to the invention, application to animals es the application to
humans.
Application can take place both prophylactically and therapeutically.
Ultimately, the use and the active spectrum of the particles according to the invention
and the compositions comprising them depends on the active compound comprised
therein or the active compounds comprised therein; the respective activity spectra
and fields of use are known in principle to the person skilled in the art. The particles
according to the invention and their formulations are preferably used for controlling
tes, in particular ectoparasites, on animals. Parasites which may be mentioned
are s such as, for example, fleas, lice, mosquitoes, flies, etc., and s such
as, for example, ticks and mites. Particular emphasis is given to the use against fleas
and ticks.
The examples below are meant to illustrate the invention:
Example 1
The particles are prepared using the emulsion evaporation process. The composition
ofthe particles can be seen from the table below.
Table 1 Feed materials
Feed materials
Demin. Water
Dichloromethane 40 ml
PMMA 3.70 g
Eudragit® RS 100 0.74 g
Flumethrin 0.88 g I
Flumethrin, PMMA (Terez® PMMA 5003, Ter Hell Plastics GmbH,
MW = 94 000 g/mol) and Eudragit® RS 100 (Mw = ~ 30 000 g/mol; Evonik
Industries AG) are dissolved in the organic phase (dichloromethane). Using the Ultra
Turrax® (T25, IKA® Werke GmbH & Co. KG), the organic phase is dispersed in the
aqueous phase by slow addition (9500 rpm, 2 min). This gives a stable emulsion
which is then homogenized more intensively using a ressure homogenizer
(Microfluidizer MllOY, microfluidics, at a flow pressure of 500 bar). The organic
phase is removed by gentle heating (max. 60°C) with stirring using a magnetic
stirrer. The dissolved components harden, giving a particle sion. This is then
filtered using a stirred cell (Millipore Solvent-resistant Stirred Cell, for 47 mm
nes, Cat No XFUF04701; Millipore GmbH) and suitable filters (Pall Ultipor
N66 / 0.2 um, Cat No. NRG047100; Pall Corporation) and purified in uent
wash steps using water. The particles are then terized:
a) Particle size is by laser diffraction (Mastersizer® 2000, Malvern
Instruments Ltd.) and scanning electron microscopy (Sirion 100T, FEI
Company). For the results, see Table 2, Fig. l and Fig. 2.
Table 2 Particle sizes and analytically determined active compound content
Active
compound
content [%]
l 2-PMMA
b) Active compound content
The active compound content is determined by HPLC analysis. This gives an
active compound content of 15.0% for the particles.
Release
The formulation is applied to the coat of the dog, where the particles adhere
and release the active compound. These special release conditions are
difficult to reproduce in vitro. Accordingly, a release model was chosen
which affords reliable reproducible results, but which only allows a
comparison of different formulations as it cannot reflect the complex release
parameters in vitro. A ol/water e of a ratio of 70/30 was found
to be suitable. This release medium does not dissolve the particles, and they
don’t swell.
For the release experiment, the particles are dispersed in 5 ml of release
medium and, at room temperature, continuously shaken over a period of
7 days (stage 7, horizontal sample ement; Multi Wrist® Shaker, Lab-
Line Instruments).
The release starts with a burst effect of ~ 10%. uently, the active
compound is released in a steady manner. The logarithmic representation
gives a straight line having a coefficient of determination of R2 = 0.9557. The
release curve shows that about 45% of the active compound present are
released after 7 days (168 h) (Fig. 3).
60 Glass transition temperature
Using DSC analysis, it is le to demonstrate how homogeneous the
structure of the particles is. In the case of an inhomogeneity, a plurality of
thermal ons would be visible. If the le components are of
sufficient compatibility, only one endothermic reaction should be observed.
In this case, there is a glass transition. er, the emulsifier Eudragit®
RS 100 (first curve, Tgonset= 41°C) and the active compound (not shown,
since Tg not measurable) have been found to be plasticizers, as they lower the
glass transition of the active compound-loaded les (fourth curve,
Tgonset = 65°C) compared to the placebo particles (third curve, Tgonset = 92°C)
and to the pure polymer (second curve, Tgonset = 105°C) (Fig. 4).
The measurement was carried out using an open 40 ul aluminium crucible (DSC
822°, STAR° SW 9.20, Mettler Toledo GmbH). To this end, the sample is heated in
temperature steps of 10 K/min from 20°C to 200°C. In the same manner, the sample
is cooled from 200°C to 20°C and then reheated.
Example 2
A further option for zation or modification consists in the selection of the
matrix polymer employed. A further polymer may be added to the PMMA used.
Thus, the preparation procedure of Example 1 is ed, but polystyrene
(MW: ~ 265 800 g/mol; PS 158, BASF) is added to the matrix polymer. In this
manner, it is possible to e mixtures of 90/10, 80/20 or else 60/40 of PMMA
and polystyrene (see Table 3). To demonstrate miscibility of the two polymers,
placebo particles are prepared. One of these formulations is repeated with addition of
the active compound flumethrin. The active compound can be incorporated without
any problems.
Table 3 Feed materials
Amount Amount Amount Amount
Feed materials a) 90/10 b) 80/20 0) 60/40 (1) 80/20
with active
compound
Demin. water
Dichloromethane
PMMA
Polystyrene (PS 1 5 8; BASF)
Eudragit® RS 100
The particles resulting from the formulations are examined for their size distribution
and glass transition temperature. For comparison, the glass tion temperatures of
the pure polymers are also measured (Table 4).
Table 4 Particle sizes and glass transition temperature
Sample
PMMA/PS 90/10
PMMA/PS 80/20
PMMA/PS 60/40
S 80/20
with flumethrin
Fig. 5 shows a scanning electron microscope e of the placebo particles with the
mixture PMMA/PS 60/40.
The preparation of the particles is carried out as described in e 1, only the
organic t dichloromethane is replaced by a different solvent. In this example,
for dissolving the components of the particles, ethyl acetate is used. Data for the
formulation with and without active compound (AC) are shown.
Table 5 Feed materials
Amount Amount
Feed materials
a) without AC b) with AC
Demin. water 80 ml
Ethyl acetate 20 ml
PMMA 1.85 g
Eudragit® RS 100 0.33 g
Flumethrin — I 0.38 g
For the further course of the experiment, the same procedure is adopted; however, in
order to evaporate the solvent, the emulsion has to be heated to 75°C. The particle
size distribution is shown in Table 6.
Table 6 Particle size distribution
Formulation D(V’ 10) D0550) ) D(V990)
[um] [um] [um] [mm]
1.31
b) with AC 1.26
A scanning electron microscope picture is shown in Fig. 6.
Example 4
The microparticles are prepared using the preparation procedure of Example 1. The
composition is shown in Table 7. The matrix polymers used are thyl
methacrylates of various molecular weights (Mw = 2000 to 600 000 Da). Also, the
active compound flumethrin is ed by an arylpyrrolidine derivative N—[[4-[3-
(3 ,5 orophenyl)-3 -(trif1uoromethyl)- l -pyrro l] —2-(trifluoromethyl
)phenyl]methyl]propenamide (CAS No.: 12216929). This active
compound, too, can be incorporated into the microparticles without any problems.
Table 7 Feed materials
Feed materials Amount
Demin. water 160 m1
Dichloromethane 40 ml
PMMA (Mw = 2000 — 600 000 Da) 3.70 g
Eudragit® RS 100 0.65 g
Arylpyrrolidine derivative 0.77 g
Table 8 shows the particle size distributions and glass transition temperatures
obtained.
Table 8 Particle size distribution and glass tion temperature
Formulation with Tg Active D(v,80) D(v,90)
matrix polymer compound [um] A [um] [um]
content
[0/0]
PMMA Mw 2000 14.9 0.84
PMMA Mw 12 000 14.6 0.73
PMMA Mw 80 000 15.5 0.18 0.67
PMMA MW 600 000 13.0 1.09 2.23
The DSC analyses are shown in Fig. 7 (method as described in Example 1).
With increasing molecular weight, an increase in glass transition temperature is
observed.
Example 5
The use of cizers may also be utilized to modify the properties of the les.
Here, the preparation is carried out as described, in Example 1. The plasticizer is co-
dissolved in the organic phase. The composition of formulations having an
increasing content of plasticizers is shown in the table below. In this case, the
cizer is benzyl benzoate, which is also used as a solvent for parenteral injection
formulations in veterinary medicine.
Table 9 Feed als of formulations having different plasticizer
concentrations
Feed materials Amount
b) 20%
Dichloromethane
PMMA
Eudragit® RS 100
Benzyl benzoate
The plasticizer may be mixed into the formulation at various concentrations. In this
manner, it is possible to vary the glass transition temperature. The glass tion
temperatures resulting from the plasticizer concentration are shown in Table 10, as is
the particle size distribution.
Table 10 Particle size distribution and glass transition atures
Proportion of
plasticizer [%]
26 I 0.96
The following nces are likewise suitable for use as cizer: tributyl
acetylcitrate, triethyl e, Hexamoll® (BASF). These, too, reduce the glass
transition temperature with increasing concentration.
Example 6
In addition to the encapsulation of insecticides, it is also possible to encapsulate
repellents such as the active compound icaridin. However, the solubility of the active
nd in water has to be taken into account. Thus, the procedure of Example 1 is
adopted, but in addition the aqueous phase is saturated with active compound. The
composition is shown in the table below.
Table 11 Feed materials
Demin. water 160 ml
Dichloromethane 40 ml
PMMA 3.70 g
Gafquat® 755N 0.74 g
Icaridin (to saturate the
aqueous phase)
The particle components are dissolved in the organic phase. The aqueous phase is
saturated with the active compound. The organic phase is dispersed in the aqueous
phase using the Ultra Turrax® (9500 rpm, 2 min). The solvent is removed, by heating
(450C) and stirring with a magnetic stirrer, and the particle suspension is then
washed with water, filtered off and dried. The particle size distribution is shown in
Table 12.
Table 12 le size distribution
) ) D(v,80) D(v,90)
Sample
[um] [um] [um] [mm]
The particles obtained are shown in Fig. 8
Example 7
As a further repellent, it is possible to encapsulate DEET (N,N—diethyl-m—toluamide).
The solubility of the active compound in water has to be taken into account to ensure
successful encapsulation. The preparation is carried out as described in Example 6,
and here, too, the s phase is saturated with active compound. The particle size
distribution is shown in Table 13.
Table 13 Particle size distribution
Sample
PMMA/DEET
The ratio of c to aqueous phase was varied and optimized in favour of the
organic phase. Thus, with the same amount of PMMA based on the non-aqueous
phase, it is possible to increase the amount of particles obtained. The preparation of
the particles is carried out as described under Example 1. In addition to various
placebo formulations, verum particles are also generated. The composition of the
individual formulations is shown in Table 14.
Table 14 Feed materials
Feed materials Formulation
1 2 3 4 5 6 7
Demin. water 80 ml 70 ml 60 ml 70 ml 60 ml 80 ml 60 ml
Dichloromethane 20 ml 20 ml 20 ml 30 ml 40 ml 20 ml 40 ml
PMMA 1.86 g 1.86 g 1.86 g 2.79 g 3.72 g 1.86 g 3.72 g
Eudragit® RS 100 0.37 g 0.37 g 0.37 g 0.56 g 0.74 g 0.37 g 0.74 g
flumethrin — — — - — 0.39 g 0.79 g
For the active compound-comprising formulations, the following size distributions
were found for the particle size (Table 15).
Table 15 Particle size distribution
Example 9 rative e)
Polyguaternium-l 1
The microparticles are ed according to the preparation procedure of
Example 6. Instead of the copolymer Eudragit® RS 100, the water-soluble cationic
polymer atemium—ll (Gafquat® 755N, ISP, Cas No.: 536338, quaternized
copolymer of vinylpyrrolidone and dimethylaminoethyl methacrylate, cf.
012) is used.
{CHf—(EHjjn—fCngéa-a
N 5'0
l ; (5:0 CH
x(CH;)yN: 3’
when ,K=D. y=z
when X; N, 3133
General structural formula for mers of the “Gafquat® 755N” type
The composition is shown in Table 16.
Table 16 Feed materials
Feed materials '
Demin. water
Dichloromethane
Gafquat® 75SN
lcaridin
lcaridin (to saturate the
aqueous phase)
It is not possible to prepare a stable emulsion having a homogeneous particle size
distribution. After evaporation of the solvent, the polymer forms an aggregate and
hardly any te microcapsules can be identified. A light-microscopic photo taken
afier the microfluidizer had been allowed to act on the emulsion is shown in Fig. 9,
the resulting suspension is shown in Fig. 10.
In contrast to the water-insoluble Eudragit® RS 100, the water—soluble Gafquat®
755N is not suitable for preparing a stable suspension.
Example 10 (comparative e):
aternium—ZS
The microparticles are prepared according to the ation procedure of
Example 6. Instead of the mer Eudragit® RS 100, the water-soluble cationic
polymer polyquaternium-28 (Gafquat® HS-lOO, ISP, CAS No.: 1319548,
copolymer of Vinylpyrrolidone and methacrylamidopropyl trimethylammonium
chloride, cf. WOW/45012) is used.
General structural formula for copolymers of the “Gafquat® HS—lOO” type
The composition is shown in Table 17.
Table 17 Feed materials
Feed materials
Demin. water
Dichloromethane
Gafquat® HS- 1 00
Icaridin
aqueous phase) I I
It is not possible to prepare a stable emulsion having a homogeneous particle size
distribution. After evaporation of the solvent, the polymer forms an aggregate and
hardly any separate microcapsules can be identified. A light-microscopic photo taken
after the microfluidizer had been allowed to act on the emulsion is shown in Fig. l l,
the resulting suspension is shown in Fig. 12.
In contrast to the water-insoluble Eudragit® RS 100, the water—soluble Gafquat®
HS-lOO is not suitable for preparing a stable suspension.
Example 11 (comparative example):
PMMA
Only PMMA is used, Eudragit is not employed.
The articles are prepared by the ation procedure of Example 6.
However, the experiment is carried out t using the copolymer Eudragit®
RS 100. The composition is shown in Table 18.
Table 18 Feed materials
Demin. water
Dichloromethane
PMMA
aqueous phase)
It is not possible to e a stable emulsion, there is phase tion. A light-
microscopic photo is shown in Fig. 13.
Example 12 (comparative example):
Eudragit® RS 100
Only Eudragit® RS 100 is used as polymer phase, but no uncharged polymer PMMA.
The microparticles are prepared by the procedure of Example 6. Instead of the
polymer PMMA, only i ® RS 100 is used. The composition is shown in
Table 19.
Table 19 Feed materials
Demin. water
Dichloromethane
Eudragit® RS100
lcaridin 0.88 g
in (to saturate the 2 g
aqueous phase)
In this case, microparticles are formed, however, most of these are present in the
dispersion as agglomerates which can no longer be re-dispersed, even after
prolonged treatment with ultrasound. The particle size distribution was measured
using a Mastersizer 3000 from Malvern. (Evaluation: ofer diffraction,
refractive index of the articles 1.59; refractive index of the solvent 1.33,
ultrasound treatment at 100%).
The particle size distribution is shown in Table 20.
Table 20 Particle size distribution
ound,
Sample treatment [min]
Eudragit® RS
1 00/icaridin 0
The particle size distribution of the sion without ultrasound, treatment is shown
in Fig. 14, Fig. 15 shows the particle size distribution of the dispersion after 16 min
of treatment with ultrasound.
In the electron-microscopy image, alter the dispersion has dried, it is no longer
possible to identify any individual particles (Fig. 16).
Thus, active nd-comprising microparticle dispersions prepared exclusively
with cationic film-forming polymer Eudragi® RS 100 cannot be used for the
purposes ofthe invention for achieving the object at hand.
Biological example
The laboratory formulation (Example 1) is tested in an in vivo experiment. For this
purpose, in each case three beagle dogs are available for the formulation and the
control group. The microparticles are tested in a spray formulation sing 66 mg
of an encapsulated active compound in 30 ml of aqueous dispersion, which is
d onto the dog.
Fluorescent particles having the same composition as the verum particles, only with
the active compound being replaced by a fluorescent dye (Uvitex® OB) are added to
the experimental formulation. These fluorescent particles are inactive and serve only
for a more rapid and easier visualization of the particles on the coat. Thus, with the
aid of a fluorescent microscope it can be Checked whether there are still particles on
the coat.
The in vitro experiment carried out comprises nine beagle dogs, both female and
male. The animals are 21 —30 month old and weigh between 8.8 and 15.5 kg.
Identification is by ear tattoo numbers. The dogs are without any al signs,
healthy and used to the conditions under which they are kept during the experiment.
If there are unexpected reactions to the experimental formulations, or if an animal
becomes ill for any other reason, it is removed from the study. The dogs are kept in
dual cages to avoid cross reactions. According to a fixed ol, the dogs are
populated with in each case 25 female and 25 male ticks of the genus cephalus
sanguiineus (brown dog tick). To ensure better biting of the ticks, the dogs are
anaesthetized for this purpose. The schedule of the study is shown in the table below.
Table 21 Schedule of the ol in the animal experiment
Week Study day Activity
— physical examination for acceptance
- weighing ofthe dogs
— infestation with ticks
- counting of ticks prior to the treatment
- grouping ofthe dogs into treatment and control group
- treatment
- clin. examination (before, 2 and 4 h after treatment)
- clin. ation
— clin. ation
— counting of ticks
— infestation with ticks
- detailed general health monitoring
- counting of ticks
- infestation with ticks
— detailed general health monitoring
- counting of ticks
- infestation with ticks
— detailed general health monitoring
— counting of ticks
- infestation with ticks
— detailed general health monitoring
- counting of ticks
- infestation with ticks
- detailed l health monitoring
— counting of ticks
- infestation with ticks
9 63 — detailed general health monitoring
- counting of ticks
24 h prior to the treatment (study day = SD -l), the ticks are placed onto the dogs.
Shortly before the start of the experiment (SD 0), the ticks which remain on the dogs
are counted and the number is noted. The animals are grouped into ent and
control group depending on the number of ticks present on the dogs. At the start of
the experiment, roughly the same number of ticks should be present in each group so
that the starting conditions are as equal as possible. The dogs in the treatment group
are sprayed evenly over the entire body with the experimental formulation. The
control group is not treated. For safety reasons, 2 and 4 h after the ation the
dogs are examined for their state of health. Counting and removal of any live ticks
still present on the dog is carried out 48 h after application of the formulation. The
efficacy is checked on SD 2, 7, 23, 50, 63. On study days SD 2, 7, l4 and 42, hair
samples (about 100 mg/sample) are removed from the dogs and examined
analytically for the active compound flumethrin. To be able to make representative
statements concerning the persistence of flumethrin particles on the dog, the coat
samples are d from different regions of the body. Individual hairs are
examined microscopically. Under a fluorescent microscope, the placebo les
loaded with the fluorescent dye Uvitex® OB become visible. During the course ofthe
experiment, the number of les on the dog hair which adhere to the coat via
electrostatic interaction falls. The fluorescent particles only have an indicator
on. In this presentation, it is not possible to visualize the verum particles.
The microscopic pictures allow an illustrative presentation and rapid and simple
checking of particles on the hair. In addition, the samples are worked up analytically.
To this end, the coat samples are d with 5 ml of acetonitrile. In this manner,
the active compound rin is extracted from the particles remaining on the coat
overnight. Part of the acetonitrile is filtered and worked up by HPLC analysis. The
s are shown in Fig. 17.
From the number of ticks on the dog, the geometrical mean and the efficiency are
calculated as follows.
(Eq- 1)
N — N
E1?zcacJI % =#-100
N (Eq_ 2)
N1 Geometrical mean of the number of ticks in the verum group
N2 Geometrical mean of the number of ticks in the control group
The number of ticks counted on the respective study days on the individual dogs
(dog ID = dog identification number; the last four numbers of the ear ) is shown
in Table 22.
Table 22 Results of the animal experiment
Study Group Number ofticks
0 6
lZ-PMMA
.0 %
flumethrin
Efficacy
623 1 L
Control
group
untreated Geom. 15.9 9.8 10.1 8.7 11.9
mean
SD 0 is the day on which the dogs are sprayed with the particle formulation. On
SD 2, the ticks remaining on the dog are counted. During the further course of the
experiment, there are further infestations of the dogs with ticks, and the ticks are
counted alter 48 h. There is no onal spraying of the dogs with the experimental
formulation. The vely high variations in efficacy between the study days can be
explained by the number of experimental animals used and the known high variance
of biological experiments. In spite of this, Table 22 shows clearly that good ty
against ticks can be noticed up to SD 50. Only between SD 50 and 63, is there a
marked loss of activity. Thus, using the formulation of Example 1 ing to the
invention, it is le to e a duration of action of 7 weeks against ticks.
List of figures:
Fig. 1 Particle size analysis in water, evaluation by Fraunhofer diffraction
Fig. 2 Scanning electron microscopic photo of the particles lZ-PMMA
Fig. 3 Release of flumethrin from PMMA particles
Fig. 4 DSC analysis
Fig. 5 PMMA/PS 60/40
Fig. 6 Placebo particles prepared from ethyl acetate
Fig. 7 DSC analysis
Fig. 8 PMMA particles loaded with icaridin
Fig. 9 Emulsion with polyquaternium—l 1
Fig. 10 Suspension with polyquaternium—l 1
Fig. l l Emulsion with polyquatemium—ZS
Fig. 12 Suspension with polyquaternium—28
Fig. 13 le emulsion with PMMA (coalescing droplets/phase separation)
Fig. 14 Particle size distribution of the dispersion after 0 min of ultrasound treatment
Fig. 15 Particle size distribution of the sion after 16 min of ultrasound
treatment
Fig. 16 SEM picture of the film-coated Eudragit® RS 100 particles
Fig. 17 s of the flumethrin content on the coat during the course of the
experiment
Patent
Claims (27)
1. Particles having a particle size d(v,90) of at most 10 µm comprising a) an uncharged polyacrylate and 5 b) a cationic polyacrylate which carries positively charged functional groups, where the particles c) comprise one or more active compounds and d) may optionally comprise further polymers, auxiliaries or additives.
2. Particles ing to Claim 1 having a le size d(v,90) of 0.1-3 µm.
3. Particles according to Claim 1 or 2 in which the cationic polyacrylate b) is a quaternized dialkylaminoalkyl methacrylate mer.
4. Particles according to Claim 3 in which the cationic polyacrylate b) is a copolymer of (methyl, ethyl) acrylates, (methyl, ethyl) methacrylates and monochloromethane-quaternized dimethylaminoethyl esters of methacrylic acid (known under the trade name Eudragit RS or Eudragit RL).
5. Particles ing to any one of the preceding claims in which the uncharged polyacrylate a) is poly(methyl methacrylate).
6. Particles according to any one of the preceding claims in which the mixing ratio 25 of the uncharged polyacrylate a) to the cationic polyacrylate b) is from 5:95 (w/w) to 95:5 (w/w).
7. les ing to Claim 6 in which the mixing ratio of the uncharged rylate a) to the cationic polyacrylate b) is from 70:30 (w/w) to 95:5 (w/w).
8. Particles according to Claim 7 in which the mixing ratio of the uncharged polyacrylate a) to the cationic polyacrylate b) is from 80:20 (w/w) to 90:10 (w/w). 35
9. Particles according to any one of the ing claims comprising, based on the mass of the particles, 0.1 - 50% by weight of active compound. 7301726_1 (GHMatters) P95786.NZ KARENM
10. Particles according to Claim 9 sing, based on the mass of the particles, 1 - 20% by weight of active compound.
11. Particles according to Claim 10 comprising, based on the mass of the particles, 5 5 - 15% by weight of active compound.
12. Particles according to any one of the preceding claims where the uncharged polyacrylate has a weight average molecular weight of from 1000 g/mol up to 1 000 000 g/mol.
13. Particles according to Claim 12 where the uncharged rylate has a weight average molecular weight of from 20 000 to 600 000 g/mol.
14. Particles according to Claim 13 where the uncharged polyacrylate has a weight 15 average molecular weight of from 50 000 - 150 000 g/mol.
15. Particles according to any one of the preceding claims comprising 0.1 - 50% by weight based on the total mass of the particles of one or more r polymers. 20
16. Particles according to Claim 15 wherein the one or more further polymers is polystyrene.
17. Particles ing to any one of the preceding claims comprising one or more cizers, surfactants, cosolvents, their sum, based on the total mass of the 25 articles, being 0.1 - 40% by weight.
18. Particles according to Claim 17 comprising one or more plasticizers, surfactants, ents, their sum, based on the total mass of the microparticles, being 5 - 30% by weight.
19. Particles according to Claim 18 comprising one or more plasticizers, surfactants, cosolvents, their sum, based on the total mass of the microparticles, being 5 - 20% by weight. 35
20. Particles according to any one of the preceding claims comprising, as active compound, flumethrin. 7301726_1 (GHMatters) P95786.NZ KARENM
21. Particles according to any one of the preceding claims comprising, as active compound, a repellent.
22. Particles according to Claim 21 wherein the repellent is icaridin or N,N-diethyl- 5 m-toluamide.
23. Process for preparing the particles according to any one of the preceding claims, comprising the ing steps: (i) preparing a solution of components a) to d) in a solvent or solvent 10 mixture (1) poorly miscible with water, if at all, (ii) dispersing the solution (i) in an aqueous phase optionally comprising additives and solvent or solvent mixture (1) to saturation, to obtain a fine, stable emulsion, (iii) removing the solvent or solvent mixture (1) from the emulsion droplets 15 by - I) evaporation (solvent evaporation s), to obtain an aqueous suspension, or - II) spray drying, to obtain a dry powder. 20
24. Composition comprising particles ing to any one of Claims 1 to 22.
25. Use of the particles according to any one of Claims 1 to 22 for preparing compositions for controlling tes on animals. 25
26. Method for controlling parasites on a non-human animal comprising applying to the non-human animal the les ing to any one of Claims 1 to 22.
27. The particles according to Claim 1, the process ing to Claim 23, the composition ing to Claim 24, the use according to Claim 25, or the 30 method according to Claim 26, substantially as herein described with reference to the Examples (excluding the comparative examples) and/or the
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11175537A EP2550863A1 (en) | 2011-07-27 | 2011-07-27 | Particles on a polyacrylate basis containing active materials |
EP11175537.7 | 2011-07-27 | ||
PCT/EP2012/064424 WO2013014127A1 (en) | 2011-07-27 | 2012-07-23 | Polyacrylate-based active compound-comprising particles |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ619224A NZ619224A (en) | 2016-02-26 |
NZ619224B2 true NZ619224B2 (en) | 2016-05-27 |
Family
ID=
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