NZ625817B2 - Preparations containing amorphous emodepside - Google Patents
Preparations containing amorphous emodepside Download PDFInfo
- Publication number
- NZ625817B2 NZ625817B2 NZ625817A NZ62581712A NZ625817B2 NZ 625817 B2 NZ625817 B2 NZ 625817B2 NZ 625817 A NZ625817 A NZ 625817A NZ 62581712 A NZ62581712 A NZ 62581712A NZ 625817 B2 NZ625817 B2 NZ 625817B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- spp
- emodepside
- polyvinylpyrrolidone
- preparations
- pharmaceutical
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 108010056417 emodepside Proteins 0.000 title abstract description 39
- ZMQMTKVVAMWKNY-YSXLEBCMSA-N Emodepside Chemical compound C([C@@H]1C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@H](C(O[C@H](CC=2C=CC(=CC=2)N2CCOCC2)C(=O)N(C)[C@@H](CC(C)C)C(=O)O[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)O1)=O)CC(C)C)C(C=C1)=CC=C1N1CCOCC1 ZMQMTKVVAMWKNY-YSXLEBCMSA-N 0.000 title abstract description 38
- 229960001575 emodepside Drugs 0.000 title abstract description 38
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 43
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- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical class [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910001884 aluminium oxide Inorganic materials 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000507 anthelmentic Effects 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229950008597 drug INN Drugs 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 235000021307 wheat Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/15—Depsipeptides; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
Abstract
Provided are preparations comprising amorphous emodepside in a polyvinylpyrrolidone matrix. The preparation may be a coprecipitate or a melt extrudate. The preparations may be useful against endoparasites in animals or humans.
Description
Preparations containing amorphous emodepside
The invention relates to preparations comprising amorphous emodepside in a polyvinylpyrrolidone
, pharmaceuticals comprising such preparations, and their use against endoparasites in animals
or humans.
The cyclic depsipeptide emodepside, which has anthelmintic activity, is known from WO 93/19053. A
variety of application forms have already been described, for example starch-based extrudates
(WO 02/00202), or a solid dosage form with delayed release ( A2).
Kachi et al. (Jpn. J. Pharmacol. 77 (1998) 235-245) bes the amorphous and polymorphous
crystalline forms of the ctadepsipeptide PF1022A.
Schütte (PhD thesis, Bonn 2004) describes “Untersuchungen zur Komplexierbarkeit von
pharmazeutischen Wirkstoffen mit e durch Extrusion mit Hochamylosestärken” [Studies on the
complexability of pharmaceutical active substances with amylose by extrusion with high-amylose
starches]. Also described therein are emodepside extrudates in which starch was used as the base.
Emodepside is a sparingly soluble drug substance with poor permeability. The solubility in water in the
range of pH 4 – 10 is 5 – 7 mg/l.
Said active substances frequently have poor ilability. There is therefore a need for emodepside
ations with improved bioavailability.
It has now been found that amorphous emodepside in specific matrices has a better solubility in water
and very good bioavailability in comparison with crystalline emodepside.
The invention relates to preparations comprising emodepside in amorphous form in a
polyvinylpyrrolidone .
The invention furthermore relates to pharmaceuticals comprising such preparations.
The invention furthermore s to the use of the preparations according to the invention or of the
pharmaceuticals comprising the preparations according to the invention for lling endoparasites
in humans or s.
The invention furthermore relates to the use of the preparations according to the invention in the
cture of a pharmaceutical composition. Preferably the composition is for controlling
endoparasites in humans or animals.
- 2 —
The INN emodepside represents the compound with the atic name: cyclo[(R)—lactoyl-N—
methyl-l-leucyl-(R)(p-morpholinophenyl)lactoyl-N-methyl-l-lcucyl-(R)-lactoy1—N-methyl-l-
leucyl-(R)-3—(p-m0rpholin0phenyl)lactoyl-N-methyl-l-leucyl. Emodepside is described in
W0 93/19053 and has the following formula:
In principle, the ations according to the invention may comprise further active substances.
Depending on the structure, active substances can be t in stereoisomeric forms or as
stereoisomer mixtures, for example as enantiomers or as a racemat. The active substance emodepside
has a total of 8 chiral C atoms — 41 leucine units, 2 D—lactic acid units and 2 D-polylactic acid units.
However, the synthesis is anenatioselective, so that the tation process only generates the one
enantiomer of PF1022A.
In the preparations ing to the invention, the emodepside is present in the amorphous state.
Amorphous means that the atoms are present in an unordered structure. In the case of a crystalline
substance, or in crystalline zones, the atoms have both a short-range order and a long-range order.
Amorphous material, in contrast, only has a short—range order. The degree of llization of the
active substance can be determined for example with the aid of dynamic differential calorimetry or
x-ray diffractometry.
In the case of a metric measurement, it is the melting enthalpy, in other words the energy
required for melting the crystals, that is measured. If the active substance is present in a tely
ous state, no change in the endothermal enthalpy can be measured upon heating.
When using x-ray diffraction as the measuring method, it is the distances between the molecular
chains which are measured. In the amorphous state, no regular distances exiSt, which results in a
broad distribution and no clear peaks in the diffractogram.
Other possibilities of checking the amorphous state are density ement, x-ray diffraction,
infrared spectroscopy and nuclear-resonance spectroscopy.
In the preparations according to the invention, a proportion of at least 50% by weight, preferably at
least 70% by weight, especially preferably at least 80% by , very specially ably at least
90% by weight, of the emodepside is present in the amorphous state, the percentages being based
on the total amount of emodepside.
In case of doubt, the ous emodepside content is determined by dynamic differential
calorimetry.
The side is present in a polyvinylpyrrolidone matrix. Suitable “polyvinylpyrrolidones” are
not only pure polyvinylpyrrolidones, but also their derivatives or mixtures of polyvinylpyrrolidones
and polyvinylpyrrolidone derivatives.
Polyvinylpyrrolidones (povidones, PVPs) are commercially available hydrophilic polymers.
Various types of PVPs are able. PVPs with a relatively low molecular weight are
conventionally employed as binders for tablets. In an aqueous medium, PVPs will swell and erode.
The polyvinylpyrrolidones or polyvinylpyrrolidone derivatives employed are preferably water—
soluble. As a rule, they are linear, osslinked polyvinylpyrrolidones or polyvinylpyrrolidone
derivatives.
The pure polyvinylpyrrolidones or polyvinylpyrrolidone derivatives employed in accordance with
the ion y have a K value in the range of from 12 to 90, preferably 12 to 30.
The K value of the polyvinylpyrrolidones or polyvinylpyrrolidone derivatives is in a relationship
with the viscosity and the molecular weight and can be determined by methods known per se. In
case of doubt, the information on the K value found in the European Pharrnacopeia (Ph. Eur.) will
be used.
Preferably, the pure polyvinylpyrrolidones have a K value of from 12 to 90, especially preferably
from 12 to 25, very especially preferably from 12 to 17.
The polyvinylpyrrolidone derivatives are usually polyvinylpyrrolidone mers. In the case of
the polyvinylpyrrolidone copolymers, polymers with a K value of 25-30 will preferably be used.
- 4 —
A preferred polyvinylpyrrolidone derivative is copovidone (for e Kollidon VA 64 from
BASF). This is a vinylpyrrolidone/vinyl acetate copolymer in the ratio of 6:4 with a K value of
approximately 30.
The preparation usually comprises at least 50% by weight, preferably at least 66% by weight,
especially preferably 75% by , of polyvinylpyrrolidone.
Details on the abovementioned polyvinylpyrrolidones, polyvinylpyrrolidone derivatives and certain
mixtures can be found in the ing book: V. Biihler, “Kollidon, Polyvinylpyrrolidone for the
pharmaceutical industry”, 9th revised edition, BASF Pharma Ingredients, Germany, 2008.
At least two methods which are known per se exist for preparing the preparations according to the
invention: solvent coprecipitation and melt extrusion.
In the case of t ipitation, emodepside together with the polymer is dissolved in the
solvent, and the solvent is subsequently removed again, for example with reduced pressure and,
optionally, elevated temperature. Suitable are solvents and solvent mixtures in which both the
active substance and the polymer will dissolve. nces which are le for the preparations
according to the invention are, for example, ethanol, acetonitrile, methanol, acetone and
isopropanol or their es. The polymers employed in solvent coprecipitation are preferably
polyvinylpyrrolidones with a K value of between 12 and 30, preferably 12 and 17, since it is easier
to remove the solvent from those than from polyvinylpyrrolidones with a greater K value.
In the case of melt extrusion, the active substance is mixed with the polymer and transferred into an
extruder. The extrusion temperature is below the melting point of the active substance. In the case
of emodepside, the extrusion may take place between 80 and 190°C, preferably between 140 and
l 80°C.
The melting point of the dynamically most stable emodepside ation is 192°C.
During the extrusion, emodepside ves in the polymer, and upon cooling it precipitates in the
amorphous state. In general, preferred polyvinylpyrrolidones are those with a low glass transition
temperature so as not to pose a risk to the stability of the active substance. In on, it must not
be too low so as to ensure a certain degree of storage stability. Polymers which can be
recommended are those with a glass transition temperature of at least 80°C, but markedly below
the g point of emodepside, that is 80°C to 160°C, preferably 80°C to 140°C. The glass
transition temperature of polyvinylpyrrolidone with a K value of 12 is approximately 90°C and
with a K value of 25 approximately 155°C.
In the case of melt extrusion, it is possible to additionally add surfactants to the system. Surfactants
which are suitable in principle are customary pharmaceutically acceptable pulverulent or liquid
surfactants. Examples which may be mentioned are: polyoxyethylene glycerol ricinoleate 35,
macrogol glycerol hydroxystearate 40, but also bile salts, lecithins and non-ionic surfactants such
as sodium dodecyl sulphate. Other examples which may be mentioned are the polysorbate 20, 60 or
80 and poloxamers.
The preparations ing to the ion may be used directly per se, or else they are processed
with addition of other adjuvants. In this context, they are present in the form of granules or in the
form of a powder, preferably following a grinding step, both for direct use and for processing.
“Pharmaceuticals” for the purpose of the present invention may be the preparations themselves or
else compositions which, in addition to the preparations, also comprise pharmaceutically
acceptable adjuvants.
Oral pharmaceutical forms which are suitable are s, granules, suspensions, capsules or
tablets, with tablets being preferred.
Possible adjuvants which may be mentioned are: , ts, lubricants, disintegrants,
surfactants and the like.
Fillers which are suitable are fillers which are conventionally used for solid preparations (for
example tablets), such as, for example, pharmaceutically employed starches, for example potato,
wheat, maize and rice starch, various mono- and disaccharides, for example glucose, e and
sucrose, and the sugar alcohols mannitol and sorbitol. Colloidal carbonates such as calcium
carbonates, hydrogencarbonates, sodium chloride, aluminium oxides, silicas, clays and ates
(especially calcium phosphates) may also be employed, it also being possible for ent fillers to
be ed with each other. Fillers having additional dry-binding properties which are used are
celluloses, ably microcrystalline ose. The total amount of filler(s) is usually 5-80%
3O (In/m), preferably 10 to 70% (In/m), especially preferably 20 to 50% .
Furthermore, the solid pharmaceutical preparations according to the invention may, besides the
active substance(s) and other abovementioned constituents, additionally se further
adjuvants. Glidants which are used are, for example, colloidal silica, hydrogenated vegetable oils,
stearic acid, talc or their mixtures, optionally in amounts of from usually 0.1 to 2%, preferably
0.5-1.5% (m/m). ants, such as, for example, magnesium stearate, are optionally t in
amounts of from usually 0.3-2% (m/m), preferably 0.5 to 1.5 (m/m). In addition, it is possible to
add, to the formula, egrants such as, for example, croscarmellose sodium in s of
usually 1-10% (m/m). However, higher concentrations such as 10-40% may also be used.
tants, for example sodium dodecylsulphate, usually 0.1-1% (In/m), preferably 0.5-l% (m/m),
be incorporated are the non-ionic
may be added to improve wetting. Further tants which may
surfactants polyoxyethylene glycerol ricinoleate 35, macrogol glycerol hydroxystearate 40,
ylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate,
polyoxyethyl stearate and alkylphenol propyl glycol ether, the ampholytic surfactants disodium N-
lauryl-B-iminodipropionate and lecithin, and the anionic surfactants sodium lauryl sulphate, fatty
alcohol ether sulphate and mono/dialkyl polyglycol ether orthophosphoric ester monoethanolamine
salts.
To improve the palatability, aromas and/or flavourings may furthermore be added to the formula.
The preparations according to the invention can be prepared for example by mixing or granulating
the components and then compressing the product to give tablets. Preferred in this context is the
direct tableting of the starting materials, that is to say that all starting materials are mixed and that
the mixture is directly compressed to give tablets, without further s steps such as granulation
or the like.
The preparations according to the invention, or the pharmaceuticals according to the invention, are
suitable for lling pathogenic endoparasites which are found in humans and in animal keeping
and animal ng in ock, breeding stock, 200 animals, laboratory animals, experimental
animals and pets, while having favourable toxicity to warm-blooded species. They can be employed
against all or individual developmental stages of the pests and against resistant and normally-sensitive
rasite isolates. By controlling the pathogenic rasites, it is intended to reduce disease,
deaths and reduced performance (for example in the production of meat, milk, wool, hides, eggs,
honey and the like), so that more economical, simpler and healthier animal keeping is made possible
by employing the active substances. The pathogenic endoparasites e helrninths such as
Platyhelmintha (in particular Monogenea, a and Trematoda), Nematoda, Pentastoma and
ocephala. Examples which may be mentioned are:
Monogenea: for e: Gyrodactylus spp., Dactylogyrus spp., Polystoma spp..
Cestoda: From the order Pseudophyllidea, for e: Diphyllobothrium spp., Spirometra spp.,
Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp..
From the order Cyclophyllida, for example: Mesocestoides spp., cephala spp., Paranoplo-
cephala Stilesia spp., Moniezia spp., Thysanosoma spp., Thysaniezia spp., Avitellina spp., spp.,
Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp.,
Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis
spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp..
PCT/EP2012/O75909
Trematoda: from the class Digenea, for example: Diplostomum spp., Posthodiplostomum spp.,
Schistosoma spp., bilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilhar-
Zia spp., Leucochloridium spp., Brachylaima spp., stoma spp., Echinoparyphium spp., Echi-
nochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoe-
lum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp., Cotylophoron spp., Gi-
gantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp., Catatropis spp., Pla-
is spp., Prosthogonimus spp., oelium spp., Eurytrema spp., Troglotrema spp., -
nimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis
spp., Heterophyes spp., Metagonimus spp..
Nematoda: From the order Trichinellida, for example: Trichuris spp., Capillaria spp., Tri-
chomosoides spp., Trichinella spp..
From the order hida, for example: Micronema spp., Strongyloides spp..
From the order Rhabditina, for example: Strongylus spp., Triodontophorus spp., Oesophagodontus
ostomum spp., Cycloco-
spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp.,
cercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., An-
cylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathosto-
ma spp., rongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus
spp., Cystocaulus Parela—
spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp.,
ongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus
spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp.,
Marshallagia spp., Cooperia spp., dirus spp., Hyostrongylus spp., Obeliscoides spp.,
Amidostomum spp., Ollulanus spp..
From the order Spirurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia
spp., Aspiculuris spp., Heterakis spp.; Ascan's spp., Toxascaris spp., Toxocara spp., Baylisascaris
spp., Parascaris spp., Anisakis spp., Ascaridia spp.; Gnathostoma spp., Physaloptera spp., Thelazia
spp., onema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.;
Stephanofilaria spp., Parafilaria spp., Setan'a spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia
spp., Wuchereria spp., Onchocerca spp..
Acanthocephala: From the order Oligacanthorhynchida, for example: Macracanthorhynchus spp.,
Prosthenorchjs spp.; from the order Polymorphida, for example: Filicollis spp.; from the order
Monilifonnida, for example: formis spp..
From the order Echinorhynchida, for e: Acanthocephalus spp., Echinorhynchus spp.,
Leptorhynchoides spp..
Pentastoma: From the order Porocephalida, for e: Linguatula spp..
- 8 —
In ance with a preferred embodiment, the preparations according to the invention, or the
pharmaceuticals according to the invention, are employed for controlling heart worm, Dirofilaria
immitis.
Animals may be fish, reptiles, birds or in particular mammals.
The livestock and breeding stock include mammals such as, for example, cattle, horses, sheep, pigs,
goats, camels, water buffalo, monkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as, for
e, mink, chinchilla, racoon, birds such as, for example, ns, geese, turkeys, ducks,
ostriches, fish such as trout, salmon, carp, perch, pikes, eels.
Laboratory animals and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs
and cats.
The pets include dogs and cats.
Preferred in accordance with the invention is the use in animals, but the use in humans is also possible
in ple.
The application may be either prophylactic or else therapeutic.
The preparations according to the invention with ous emodepside have good bioavailability.
They show a high plasma level concentration and good data as s the area under the
concentration-time curve of emodepside in the blood.
Examples
1. Coprecipitate prepared by solvent method
When preparing a solvent coprecipitate, side and polyvinylpyrrolidone with a K value of 12,
17 or 25 are mixed and ved in ethanol or in a solvent mixture of acetone and isopropanol. After
everything has dissolved, the solution is transferred to a sheet, and the solvent is stripped off at
elevated temperature and reduced pressure in a vacuum drying oven. Thereafter, the ipitate thus
obtained is scrapped off the sheet and ground. The powder thus ed may now be administered
either directly, for example filled into capsules, or, after processing, in the form of tablets.
Coprecipitates ofthe following compositions were prepared, where the compositions were in each case
converted to a theoretical total weight of 100 g of the coprecipitate. In each case three compositions
with polyvinylpyrrolidone-12, -17 and -25 were ed for each example:
Example 1:
g Emodepside
75 g Polyvinylpyrrolidone-12, -17 or -25
Isopropanol/acetone 1:1 (until everything has dissolved)
Example 2:
50 g side
50 g nylpyrrolidone—l2, -17 or -25
Isopropanol/acetone 1:1 (until everything has dissolved)
Example 3:
9.09 g Emodepside
90.91 g Polyvinylpyrrolidone-12, -17 or -25
Isopropanol/acetone 1:1 (until everything has dissolved)
Example 4:
25 g Emodepside
75 g nylpyrrolidone—IZ, -17 or -25
Ethanol (until everything has dissolved)
Example 5:
2O 33.33 g Emodepside
66.67 g nylpyrrolidone—12, -17 or -25
Ethanol (until everything has dissolved)
Example 6:
9.09 g Emodepside
90.91 g Polyvinylpyrrolidone-IZ, -17 or -25
Ethanol (until everything has dissolved)
2. Tablet formulation:
When the coprecipitate is processed to give tablets, it is mixed with the tableting aids microcrystalline
cellulose, croscarmellose sodium, highly-dispersed silica, sodium dodecyl sulphate and magnesium
stearate and the mixture is compressed to give tablets.
The following tablet formulation may be ned by way of example:
Example 7: (a 100 g batch is composed of)
21.3 g Solvent coprecipitate as per Example 1 with polyvinylpyrrolidone-12
32 g Microcrystalline ose
42.6 g Croscarmellose sodium
PCT/EP2012/O75909
0.8 g Sodium dodecyl sulphate
1.6 g Highly-dispersed silica
1.6 g Magnesium te.
3. Cowpitatiprepired bmelt extrusion
In the case of the preparation which is ed by melt extrusion (extruded coprecipitate),
emodepside and the polyvinylpyrrolidone copolyrner idone, for example Kollidon VA 64 from
BASF) are mixed and transferred into the extruder. If required, a surfactant, for example,
polyoxyethylene glycerol ricinoleate 35, can be introduced via liquid metering. This mixture is
extruded at 160°C. Extrusion at 180°C is also possible. The ing
emodepside/polyvinylpyrrolidone extrudates are cooled and ground. Again, here the powder may
be administered as such or processed to give tablets.
Extruded coprecipitates of the following compositions were prepared, while the compositions were in
each case converted to a theoretical total weight of 100 g of the extruded coprecipitate:
Example 8:
g Emodepside
70 g Copovidone
10 g yethylene glycerol ricinoleate 35
Example 9:
9.09 g Emodepside
80.91 g Copovidone
10 g Polyoxyethylene glycerol ricinoleate 35
Example 10:
g Emodepside
80 g Copovidone
4. Tablet formulation
The preparation which is obtained by melt extrusion, too, can be processed in the same manner to
give tablets. An example which may be mentioned is the following tablet e:
Example 11 (a 100 g batch is ed of):
.3 g Extruded coprecipitate according to Example 8
.4 g Microcrystalline cellulose
40.5 g Croscarmellose sodium
0.8 g Sodium dodecyl sulphate
1.5 g Highly-dispersed silica
1.5 g ium stearate.
Biological example
A. Study into the pharmacokinetics:
The tablets of Example 7 (with 10 mg emodepside and a total weight of 187.5 mg) were administered
to 10 dogs and the tablets of e 11 (with 10 mg emodepside and a total weight of 197.5 mg)
were administered to 4 dogs, in each case orally. By way of comparison, an emodepside solketal
solution (10% m/m) was administered to 4 dogs, in each case orally. For all ations, the dosage
was 1 mg/kg body weight. Thereafter, blood was taken from the dogs at regular intervals up to 72 h
after the application. The values of the maximum plasma level concentration Cmax were improved
ly by using the active substance in the amorphous state: from 93 ug/l in the case of the
emodepside solketal solution to 187 pg/l for tablets of Example 11 and 246 ug/l for tablets of
Example 7. The AUC(0-24 h) values were d of 508 ug/l in the case of the solution 825 ug/l for
the tablets of Example 11 and 1129 ug/l for the tablets of Example 7, respectively.
Patent
Claims (15)
1. Preparation comprising side in amorphous form in a polyvinylpyrrolidone matrix.
2. Preparation according to Claim 1, additionally comprising a surfactant.
3. Preparation according to Claim 1, characterized in that it is a melt extrudate.
4. ation according to Claim 1, characterized in that it is a coprecipitate.
5. Pharmaceutical, comprising a preparation according to one of the ing claims and pharmaceutically acceptable adjuvants.
6. Preparation according to one of Claims 1 to 4 for use in the control of endoparasites in humans or animals.
7. Preparation according to Claim 6 for use in the control of Dirofilaria s.
8. Use of a preparation according to one of Claims 1 to 4 for the manufacture of a pharmaceutical.
9. Use according to Claim 8 for the manufacture of a pharmaceutical for controlling endoparasites in humans or animals.
10. Use of a preparation according to any one of claims 1 to 4, or a pharmaceutical according to claim 5 for lling tes in non-human animals.
11. Use according to Claim 9 or 10, where the endoparasites are Dirofilaria immitis.
12. A preparation according to claim 1, substantially as herein described or exemplified.
13. A pharmaceutical according to claim 5, substantially as herein described or exemplified.
14. A use according to claim 8, ntially as herein described or exemplified.
15. A use according to claim 10, substantially as herein described or exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11194878.2 | 2011-12-21 | ||
EP11194878 | 2011-12-21 | ||
PCT/EP2012/075909 WO2013092558A1 (en) | 2011-12-21 | 2012-12-18 | Preparations containing amorphous emodepside |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625817A NZ625817A (en) | 2016-08-26 |
NZ625817B2 true NZ625817B2 (en) | 2016-11-29 |
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