HK1075013B - Crystal modification of a cyclic depsipeptide having improved strength - Google Patents

Description

Crystal forms of cyclodepsipeptides with improved activity

The invention relates to the use of a crystalline modification I of a cyclodepsipeptide of formula (I) for producing a medicament, in particular for controlling endoparasites.

Cyclic depsipeptides of the formula (I) are known from EP-A0634408 (WO 93/19053).

It is also known that the active compounds exist in four different crystal forms, as described in EP-A-1031565 (WO 99/24412). Wherein the crystalline form described as crystal (V) has been disclosed in EP-A-0872481 (WO 97/02256) together with ｃA novel preparation process.

The following designations are used in this application to refer to the various crystalline forms.

Form I is referred to as "crystal (III)" in EP-A-1031565 and has ｃA melting point of 191.9 ℃.

Form II is referred to as "crystalline (II)" in EP-A-1031565 and has ｃA melting point of 182.4 DEG C

Form III is referred to as "crystalline (I)" in EP-A-1031565 and has ｃA melting point of 157.8 DEG C

Form IV is referred to as "crystalline (V)" in EP-A-1031565 and has ｃA melting point of 145.0 deg.C

This crystalline form is already known from EP-A-0872481, according to the teaching in EP-A-1031565.

Of these four forms, form I is the most thermodynamically stable, form II is the second thermodynamically stable, form III is the third thermodynamically stable, and form IV is the fourth thermodynamically stable.

Surprisingly, it has now been found that the most thermodynamically stable form I in the above-described forms has the greatest bioavailability and thus the greatest activity. This cannot be expected by the person skilled in the art: in the case of such active substances which are very poorly water-soluble, the solubility and bioavailability should decrease with increasing thermodynamic stability.

The invention relates to a medicament containing depsipeptides of the formula (I) in the form of crystalline solid I

Due to the superior bioavailability of form I, the drug should contain as high a content of this form as possible. That is to say that the active substance of the formula (I) should preferably be present in the pharmaceutical in the form of the crystalline modification I in at least 50%, particularly preferably in at least 80%, very particularly preferably in at least 90%. It is desirable that substantially all (i.e., greater than 99%) of the depsipeptide be present in the pharmaceutical agent in crystalline form I.

According to the invention, medicaments containing the compounds of the formula (I) in the form of crystalline modification I are used for controlling endoparasites of pathogens. Such endoparasites are encountered in humans and animal husbandry and productive livestock, farm animals, zoo animals, laboratory animals, test animals and pets. They are active against all or some stages of growth of the pests and against resistant and often sensitive species. By controlling pathogenic endoparasites, the diseases, mortality and productivity losses (for example in the production of meat, milk, wool, hides, eggs, honey, etc.) can be reduced, so that simpler and more economical animal feeding is possible by applying the active compounds. Preferably, the medicaments are used in warm-blooded animals for controlling endoparasites of pathogens. Endoparasites belonging to the etiology are cestodes, trematodes, nematodes, echinocandins, in particular:

dummy pages, for example: genus Schistosoma, Echinococcus, Schistosoma, Hematospora, Diphyllophora, Diphenoporous spp.

From the order of the orbicularis, for example: genus Zoacy, genus Eucephalia, genus Paragymncephalia, genus Mennitz tapeworm, genus Onaglia, genus Onagelia, genus Trigonella, genus Ovearia, genus Ohathia, genus Stellaria, genus Taenia, genus Andriella, genus Borter tapeworm, genus Taenia, genus Echinococcus, genus Onagelia, genus Deltaenia, genus Rickettsia, genus Membristylis, genus Echinococcus, genus Dipterenia, genus Echinochloa, genus Diphyllia, genus Chondrichta, genus Choriotaenia, and genus Diphyllum.

The subclasses Monozoea, for example: third-generation Suppers, Dactylogyrus spp, Polysiphonia (Polystoma spp.)

Subclasses of the reproductively, for example: genus Strongopus, genus Diploculus, genus Split, genus Trichophyton, genus Torulopsis, genus Obliga, genus Meretricis, genus Leuconostoc (Leucochloridium spp.), genus Brachylaena (Brachylaema spp.), genus Echinochloa, genus Echinopanaxaphytes (Echinopayphium spp.), genus interstitial Diploculus, genus Loxophaga, genus pleomorphus (Fasciolides spp.), genus Spongopus, genus Helicoverpa, genus cyclophora, genus caecum, genus anteroposterium, genus Calcilobula, genus Strongopus, genus Meretrix, genus Strongopus, genus Phillidium, genus Philippinophora, genus Abelmoschus (Gastraylacus spp.), genus Aphanoticus, subphyloma, genus Strongopus, genus Paragonia, genus Paragonina, genus Strongopus, genus Paragonia, genus Spongopus, genus Paragonia, genus Spodopteropilus, genus Spongopus, Sulfoma, Sulforum, Sulforhodorona, later reproduction of the genus schistosoma.

Stingers, for example: trichuris, capillaris, Trichomossoides spp.

Rod-shaped mesh (rhabditis), for example: micronematoda, strongyloides.

Round mesh, for example: strongyloides (Stronylus spp.), trichloteles (trichontophorus spp.), odontodes, trichinella, trichloteles, colubrium, strongyloides, cycloocervis spp., cuprocinia, oraria, rabbitoltera, strongyloides, columbiostomum, columbioplopendra, columbiostomum, columbiopyrata, columbiostomum, dictyodinum, dictyotidea, mulleinchoblongus, mullerodera, euglenopteres, neologyne, colubriella, strongyloides (episcaulobulus spp.), euglenoptertagia, parapleydia, odontophaga, paracoloma spp, angiostrongyloides, catorostachydis, columbiostomus, strongyloides, ostertas, strongyloides, strong, Camphoid, Sclerodera, Pantoea.

From the order of the pointeda (Oxyurida), for example: ostertagia, Ostertagia.

From the order of avian ascariales, for example: ascaris, toxocara, ascaris suum, anisakia, and ascaris avium.

The order of the gyrodacty, for example: orthoenchus, Ostertagia, Acidovorax, Strongyloides, Lithodias, Paralewisia, Derashi, and Dracocephalides.

From the order of filariales, for example: cyrtotrachelus, Parathrips, celiac filaria, Rodia, Dirofilaria, Gomphrena, Brugia, Wuchereria, and Dictyocaulus.

Megakiss, for example: echinocandis tenuis (Filicolis spp.), echinocandis megakiss, and epididymis.

Domestic and farm animals include mammals, such as cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, cattle,Deer, prairie deer, fur-bearing beasts, e.g. mink, chinchilla or racoon, birds, e.g. chickens, geese, turkeys, ducks, freshwater and marine fish, e.g. trout, carp, eel, reptiles and insects, e.g. bees and silkworms.

Laboratory and experimental animals include rats, mice, guinea pigs, hamsters, dogs, and cats.

Pets include dogs and cats.

Can be administered prophylactically and therapeutically.

Of course, suitable pharmaceutical preparations according to the invention are generally those in which the active substance is present only as a solid of crystalline form I. The advantages are not observed with formulations in which the active substance is present only in dissolved or amorphous form.

The application of the active substances can be carried out enterally, parenterally, transdermally, nasally, directly or in the form of suitable preparations, by treating their habitat or with active substance-containing mouldings, such as strips, tablets, bands, collars, ear ornaments, limb loops (straps), decorative devices, etc.

Enteral application of the active substances is carried out by oral administration, for example in the form of powders, tablets, capsules, pastes, drinks, granules, suspensions, boluses, medicated feeds or drinking water. Transdermal application is carried out by dipping, spraying or pouring and dripping. Parenteral application is carried out, for example, by injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implantation.

Suitable formulations are:

pouring preparation and gel;

suspensions for oral or transdermal application and for injection; a semi-solid formulation;

formulations in which the active ingredient of the medicament is contained in an ointment base or in an oil-in-water or water-in-oil emulsion base;

solid preparations, such as powders, premixes or concentrates, granules, pills, tablets, boluses, capsules; aerosols and inhalants, shaped bodies containing active substances.

Pour-on and drip-off formulations are applied or sprayed onto localized areas of the skin where the active substance penetrates the skin and acts systemically.

Pour-on and drip-off formulations were prepared as follows: the active substance is suspended in a suitable skin-tolerable liquid adjuvant or mixture, optionally with the addition of further adjuvants, such as colorants, absorption promoters, antioxidants, light stabilizers or adhesives.

Suitable liquid auxiliaries which may be mentioned include water, alkanols, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerol, sorbitol, phenoxyethanol, esters, such as ethyl acetate, ethers, such as alkylene glycol alkyl ethers, for example dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, 2-dimethyl-4-oxymethylene-1, 3-dioxolane.

Mention may additionally be made of: paraffin oil, silicone oil, natural vegetable oil such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic/capric acid diglyceride, vegetable fatty acid with chain length of 8-12 carbon atoms or triglyceride mixture of other specifically selected natural fatty acids, and optionally mixture of partial glyceride of saturated or unsaturated fatty acid containing hydroxyl group, C₈/C₁₀Mono-and diglycerides of fatty acids.

Fatty acid esters, such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of medium-chain branched fatty acids with saturated fatty alcohols having a chain length of 16 to 18 carbon atoms, isopropyl myristate, isopropyl palmitate, caprylate/caprate esters of saturated fatty alcohols having a chain length of 12 to 18 carbon atoms, isopropyl stearate, oleyl oleate, decyl oleate, ethyl lactate, waxy fatty acid esters, such as artificial duck tail fat, dibutyl phthalate, diisopropyl adipate, mixtures of esters related to the latter, and the like.

Fatty alcohols, such as isotridecanol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as oleic acid and mixtures thereof.

Colorants include all colorants approved for use in animals, which may be dissolved or suspended.

The absorption enhancer is dimethyl sulfoxide (DMSO), spreading oil, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oil, fatty acid ester, triglyceride, and fatty alcohol.

Antioxidants include sulfites or metabisulfites, such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, propyl gallate.

The light stabilizer is, for example, Novantisols ure.

Examples of binders are cellulose derivatives, starch derivatives, polyacrylates, natural polymers, such as alginates, gelatin.

Other suitable auxiliaries which may be mentioned are: viscosity-increasing and suspension-stabilizing substances, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether with maleic anhydride, polyethylene glycols, waxes, colloidal silica, or mixtures of the substances mentioned.

Suspensions can be used orally, transdermally or as injections. They are prepared by suspending the active ingredient in a liquid carrier, optionally together with other auxiliaries, such as wetting agents, colorants, absorption promoters, preservatives, antioxidants, light stabilizers.

Wetting agents (dispersants) which may be mentioned are:

nonionic surfactants, such as polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycols;

amphoteric surfactants, such as disodium N-dodecyl- β -iminodipropionate or lecithin;

anionic surfactants, such as sodium lauryl sulfate, fatty alcohol ether sulfates, monoalkyl/dialkyl polyglycol ether orthophosphate monoethanolamine salts.

Suitable other adjuvants include those mentioned further above.

The semisolid formulations can be administered orally or transdermally. They differ from the above-mentioned suspensions and emulsions only by their relatively high viscosity.

To prepare solid preparations, the active substances are mixed with suitable carrier substances, optionally with the addition of auxiliaries, and brought into a suitable form, as desired.

Carriers which may be mentioned are all physiologically acceptable inert solid substances. For this purpose, inorganic and organic substances are used as carriers. Examples of inorganic substances include sodium chloride, carbonates such as calcium carbonate, hydrogen carbonate, alumina, silica, alumina, precipitated or colloidal silicon dioxide, phosphates.

Examples of organic substances include sugars, cellulose, foodstuffs and animal feeds, such as milk powder, animal meal, cereal flour and meal, starch.

The auxiliary agents include the preservatives, antioxidants, colorants already mentioned hereinbefore.

Other suitable auxiliaries include lubricants and glidants, such as magnesium stearate, stearic acid, talc, bentonite, disintegrants, for example starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.

In the formulations, the active substances may also be present in admixture with synergists or other active substances having a combative activity against pathogenic endoparasites. Examples of such active substances are L-2, 3, 5, 6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates, praziquantel, pyrantel or phenylthionocarbamate.

Ready-to-use preparations contain the active substance in a concentration of 10ppm to 20% by weight, preferably 0.1 to 10% by weight.

The preparations to be diluted before use contain 0.5 to 90% by weight, preferably 5 to 50% by weight, of active substance.

It has proven advantageous in general to administer about 0.1 to about 100mg of active substance per kg of animal body weight per day in order to achieve effective results.

Examples

Example 1 Activity of depsipeptide forms I-IV of formula (I) on Haemonchus contortus (Haemonchus contortus) at various oral doses

Sheep (merino or blackhead sheep, 25-35kg body weight) were experimentally infected with 5000 haemonchus contortus L3 larvae and treated with the formulated test substance at the end of the pre-stage of development of parasitic symptoms. The test compounds were administered orally (gelatin capsules). The insect repellent activity of the test substance was determined by the reduction in the number of eggs per gram of feces. For this, new faeces from experimental animals were processed and the number of eggs was determined according to the Wetzel modified McMaster method. The number of eggs was determined periodically before and after treatment. The insect repellent activity is defined as follows: the number of 3 ═ eggs decreased by > 95%, the number of 2 ═ eggs decreased by 75-95%, the number of 1 ═ eggs decreased by 50-75% and the number of 0 ═ eggs decreased by < 50% (see g.von samson-himmelsturna, a.harder, t.schnieder, j.kalbe, n.mencke (2000), the in vivo activity of the novel anthelmintic depsipeptide PF1022A, parasitol.res.86: 194-.

Nematode (nematode)	Crystal form	Dosage (mg/kg)	Activity of
				Haemonchus contortus	I	1.0	3(1 sheep, EPG)
Haemonchus contortus	I	0.5	3(1 sheep, EPG)
				Haemonchus contortus	I	0.1	3(1 sheep, EPG)
Haemonchus contortus	II	1.0	3(1 sheep, EPG)
				Haemonchus contortus	II	0.5	0(1 sheep, EPG)
Haemonchus contortus	II	0.1	0(1 sheep, EPG)
				Haemonchus contortus	III	1.0	3(1 sheep, EPG)
Haemonchus contortus	III	0.5	1(1 sheep, EPG)
				Haemonchus contortus	III	0.1	1(1 sheep, EPG)
Haemonchus contortus	IV	1.0	3(1 sheep, EPG)
				Haemonchus contortus	IV	0.5	0(1 sheep, EPG)
Haemonchus contortus	IV	0.1	0(1 sheep, EPG)

Activity > 95%; activity 75-95%; 50-75% of 1 ═ activity and 50% of 0 ═ activity; EPG ═ number of eggs per gram of stool in the egg reduction test.

Example 2: activity of depsipeptide forms I and IV of formula (I) on Cooperia oncophora at different oral doses

Cattle (variety: Hostein Friesean, species: cattle (Bos taurus), calves or young cattle under about 200 kg) were experimentally infected with 15000 larvae of Cupressus spp.L 3. The number of eggs per gram of faeces was measured 3 times a week after successful infection (latency period about 18-21 days). The formulated test compound is then administered orally (gelatin capsule) or by subcutaneous injection (on day 0 ═ the day of treatment). Animals were slaughtered (after 10 days of treatment) and the anthelmintic activity of the test substances (expressed as a percentage of untreated controls) was determined by reduction of the number of worms in the small intestine (see g. von Samson-Himmelstjerna, a. harder, t. schnieder, j. kalbe, n. mencke (2000), in vivo activity of the novel anthelmintic depsipeptide PF1022A, parasitol. res.86: 194-.

Nematode (nematode)	Crystal form	Dosage (mg/kg)	Activity of
				Trichosanthes gigantea of Cooperia spp	I	1.0	93.81% (3 cattle, slaughter test)
Trichosanthes gigantea of Cooperia spp	IV	2.0	99.15% (3 cattle, slaughter test)
				Trichosanthes gigantea of Cooperia spp	IV	1.0	43.09% (3 cattle, slaughter test)

The activity in the slaughter test is given as% reduction of worms compared to untreated controls.

Claims (3)

1. Depsipeptides of formula (I) in solid form in crystalline form I

Use for the preparation of a medicament containing depsipeptides of the formula (I) in crystalline form I and having improved bioavailability for controlling pathogenic endoparasites.

2. Use according to claim 1 for the preparation of a medicament for oral administration to an animal.

3. Use according to claim 1 or 2 for the control of cestodes, trematodes, nematodes, echinococci in animals.