HK1162936B - Solid pharmaceutical formulation with delayed release - Google Patents
Solid pharmaceutical formulation with delayed release Download PDFInfo
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- HK1162936B HK1162936B HK12103484.3A HK12103484A HK1162936B HK 1162936 B HK1162936 B HK 1162936B HK 12103484 A HK12103484 A HK 12103484A HK 1162936 B HK1162936 B HK 1162936B
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Description
The present invention relates to solid pharmaceutical formulations with delayed release of active ingredients, which are particularly suitable for use in animals.
Although many sustained release drugs based on various technologies are available for use in humans, it is not uncommon in veterinary medicine, particularly for cats and dogs, to have a delayed release (controlled release, sustained release). One of the main reasons for this is that: the residence time of the gastrointestinal tract (gastrointestinal transit time GITT), the influence of food, the influence of the habit of food intake, the kind, size, pH of the stomach, enzymes in the intestine, permeability of the gastrointestinal tract and the region in which the active ingredient is absorbed, animal, in particular cat and dog, are different from humans [ s.c. sutton, adv.drug delivery reviews, 56(2004) 1383-. Physiological differences between dogs and humans have been described in detail in the literature [ Dressman, Pharm res, 3(1986) 123-; schneider et al, J.Med.chem., 42(1999)5072 ]. If the animal chews or otherwise comminutes a conventional sustained release tablet upon oral administration, the active ingredient is released very rapidly and the true purpose of the sustained release tablet is not achieved. The absorption of the active ingredient or- "in other words" -the pharmacokinetic properties of which can be considerably altered by animal chewing of the tablet. The object of the present invention is to develop a formulation which has as little influence as possible on the absorption of the active ingredient during the comminution in this case. Therefore, the development of such formulations for animals presents technical difficulties for the skilled person. In this connection it must also be taken into account that the mechanical stresses in the canine stomach are significantly greater than in the human stomach, for example.
WO 2004/014346 describes a tablet of carprofen with delayed release in which the hydrophilic polymers methylcellulose (Methocel) (hydroxypropyl methylcellulose "HPMC"), Polyox and carbopol are used. The tablets are based on the principle that they comprise microparticles with controlled release properties themselves. Such formulations are expensive to produce and it is not clear whether a suitable release profile can be obtained in the gastrointestinal tract of an animal without loss of bioavailability.
Another difficulty for the pharmaceutical technician (Galeniker) is that the residence time in the stomach and digestive tract can fluctuate considerably. There was considerable variation in the residence time in the gastrointestinal tract of fasted and fed beagle dogs [ see, e.g., figures 7 and 8 in Sutton, supra ]. Sutton states that about 80% of the tablets have a high residence time in the digestive tract of more than 24 hours. He therefore concludes that: sustained release formulations having an in vitro release time of less than 24 hours may generally be absorbed by the dog in its full dose without premature excretion. In addition, the residence time in the stomach depends on the size of the drug and the type and breed of the animal concerned [ see, e.g., Fix et al, pharm. Res., 10(1993)1087-1089 ]. The object of the present invention is to develop a preparation which is suitable for a wide variety of animal species and breeds.
Another difficulty for the pharmaceutical skilled person arises from the fact that the active ingredient is generally only completely absorbed in certain limited regions of the gastrointestinal tract. If, for example, the active ingredient is absorbed exclusively in the small intestine, the formulation should also release the active ingredient as completely as possible in the small intestine. Fluctuations in the residence time of the formulation in the gastrointestinal tract can affect bioavailability. In the case of dogs, for example, peristaltic activity travels through the alimentary tract at specific time intervals, also known as "sweeping waves"; this sweeping wave has an effect on the residence time of the formulation in the gastrointestinal tract, as residence time depends on whether the sweeping wave has just started or has only started thereafter. The residence time in the stomach also depends considerably on the nature and quantity of food eaten, and even on the size of the pyloric opening.
To our knowledge, these difficulties may be due to the fact that there is no controlled release oral drug on the market for dogs. In any case, the development of controlled release formulations suitable for, for example, cats and/or dogs is a difficult task, the solution of which cannot be inferred directly from the literature.
Many possible methods for obtaining delayed release are known. Matrix tablets comprising hydrophilic gel-forming polymers such as, for example, cellulose ethers (hydroxypropyl cellulose or hydroxypropylmethyl cellulose) are generally preferred by the person skilled in the art, since such tablets can be prepared by machines customary in the pharmaceutical industry, which are also insensitive to the preparation conditions. For example, even if a dog chews such a tablet, the pieces swell due to the gel-forming polymer, thereby delaying immediate rapid release of the active ingredient.
Animals such as, for example, dogs, may vary in size and weight, depending on the type. Therefore, accurate metering suitable for the respective dimensions is hardly available from the market, since it is too difficult to produce and sell. Because of this, tablets designed for use in smaller animals are also typically administered to larger animals. In this case, two or more tablets must be administered to the larger animal. If hydrophilic matrix tablets comprising gel-forming polymers such as cellulose ethers of the conventional art as described above are used, the tablets swell in the aqueous medium of the gastrointestinal tract to form a gel envelope (gelhulle). In our studies, we found that the gel layers of such tablets stick to each other, forming larger lumps in the gastrointestinal tract. The surface area of such agglomerates is significantly smaller than the sum of the surface areas of the individual swollen tablets. This results in a release rate of the agglomerates that is substantially lower than that of a single tablet. Thus, the in vivo release of the active ingredient from the gel matrix is no longer reproducible.
According to prior art recommendations, a release time of up to 24 hours is believed to be acceptable for sustained release tablets for dogs, as about 80% of the tablet residence time (GITT) in the gastrointestinal tract is at least 24 hours. However, we have surprisingly found the following facts: even when cellulose ether-based tablets that release > 80% of the active ingredient during about 12 hours in vitro were administered to fasted dogs, tablets that were only partially swollen and had a dry core were found in the feces. This can cause a reduction in bioavailability. This problem is further exacerbated when multiple tablets are administered in order to obtain the correct dosage, as is common in practice for larger animals. In this case, caking of the adhesive tablet was also found in the feces.
McInnes et al, (Pharm res, 10 months 2007) studied two different matrix tablets, which had different in vitro release rates for fed and fasted dogs. In their studies, no simple correlation between the in vitro and in vivo release of these two matrix tablets was found. This highlights the fact that: it is not easy to develop tablets with delayed release, which on the one hand release all the active ingredient before excreting the faeces, and on the other hand allow the administration of more than one tablet without disadvantages.
The present invention therefore aims to develop a tablet with delayed release which dissolves as completely as possible in the gastrointestinal tract and releases the active ingredient as completely as possible within a specific time and independently of whether the animal is fed or fasted. This is also important because if the owner of the animal or veterinarian finds an insoluble tablet fraction in the faeces, he may lose confidence in the product. Said object is in particular to find a Matrix (Matrix) system which, if two or more tablets are administered, releases preferably at least 80% of the total active ingredient within 1 to 6 hours without the presence of lumps in the aqueous medium of the gastrointestinal tract. Finally, it should be readily preparable, if possible, by conventional machines of the pharmaceutical industry.
The present invention relates to a solid pharmaceutical formulation with delayed release comprising:
a. at least one pharmaceutically active ingredient
Polyvinylpyrrolidone with b.K value of at least 17
c. At least one filler.
Suitable pharmaceutically active ingredients in principle all suitable pharmaceutically active compounds can be considered.
In a preferred embodiment, these are anthelmintic active ingredients.
One preferred group of active ingredients of anthelmintic drugs that may be mentioned are depsipeptides (depsipeptides):
depsipeptides are similar to peptides, but differ from the latter in that one or more of the alpha-amino acid building blocks are replaced by alpha hydroxy carboxylic acid building blocks. Cyclic depsipeptides having from 18 to 24 ring atoms, in particular 24 ring atoms, are preferably used according to the invention.
Depsipeptides having 18 ring atoms include compounds of the general formula (I):
wherein
R1、R3And R5Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl-alkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can optionally be substituted by one or two benzyloxycarbonyl residues or one, two, three or four alkyl residues, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl (where halogen, hydroxy, alkyl and alkoxy may be mentioned as substituents),
R2、R4and R6Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, aryl-alkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or arylalkyl (where halogen, hydroxyl, alkyl, alkoxy may be mentioned as substituents), and also photopheres thereofChemical isomers and racemates.
Preferred are compounds of formula (I)
Wherein
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, in particular hydroxymethyl, 1-hydroxyethyl, C1-C4-alkanoyloxy-C1-C6Alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl is in particular benzyloxymethyl, 1-benzyloxyethyl, mercapto-C1-C6Alkyl, especially mercaptomethyl, C1-C4-alkylthio-C1-C6Alkyl, especially methylthioethyl, C1-C4-alkylsulfinyl-C1-C6Alkyl, especially methylsulfinylethyl, C1-C4-alkylsulfonyl-C1-C6Alkyl, especially methylsulfonylethyl, carboxy-C1-C6Alkyl, in particular carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, C1-C4-aryl-alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C1-C6Alkyl, in particular carbamoylmethyl, aminoFormylethyl, amino-C1-C6Alkyl, in particular aminopropyl, aminobutyl, C1-C4-alkylamino-C1-C6Alkyl, in particular methylaminopropyl, methylaminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, guanidino C1-C6Alkyl, especially guanidinopropyl, C1-C4-alkoxycarbonylamino-C1-C6Alkyl is in particular tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxycarbonyl (Fmoc) amino-C1-C6Alkyl is in particular 9-fluorenylmethoxycarbonyl (Fmoc) aminopropyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminobutyl, C2-C8Alkenyl, in particular vinyl, allyl, butenyl, C3-C7Cycloalkyl is in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4-an alkyl group, in particular a benzyl group which can be optionally substituted by a group chosen from the following series: halogen, especially fluorine, chlorine, bromine or iodine, hydroxy, C1-C4Alkoxy, especially methoxy or ethoxy, C1-C4-an alkyl group, in particular a methyl group,
R2、R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, in particular hydroxymethyl, 1-hydroxyethyl, C1-C4-alkanoyloxy-C1-C6Alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, especially methoxyYlmethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl is in particular benzyloxymethyl, 1-benzyloxyethyl, mercapto-C1-C6Alkyl, especially mercaptomethyl, C1-C4-alkylthio-C1-C6Alkyl, especially methylthioethyl, C1-C4-alkylsulfinyl-C1-C6Alkyl, especially methylsulfinylethyl, C1-C4-alkylsulfonyl-C1-C6Alkyl, especially methylsulfonylethyl, carboxy-C1-C6Alkyl, in particular carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, C1-C4-aryl-alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C1-C6Alkyl, in particular carbamoylmethyl, carbamoylethyl, amino-C1-C6Alkyl, in particular aminopropyl, aminobutyl, C1-C4-alkylamino-C1-C6Alkyl, in particular methylaminopropyl, methylaminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C2-C8Alkenyl, in particular vinyl, allyl, butenyl, C3-C7Cycloalkyl is in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl is especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4-alkyl is in particular benzyl which can be optionally substituted by a group chosen from the following series: halogen, especially fluorine, chlorine, bromine or iodine, hydroxy, C1-C4Alkoxy, especially methoxy or ethoxy, C1-C4Alkyl, in particular methyl, and the optical isomers and racemates thereof.
Particularly preferred are compounds of the formula (I), in which
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, in particular hydroxymethyl, 1-hydroxyethyl, C1-C4-alkanoyloxy-C1-C6Alkyl, in particular acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, in particular methoxymethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl is in particular benzyloxymethyl, 1-benzyloxyethyl, C1-C4-alkoxycarbonylamino-C1-C6Alkyl is especially tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, C2-C8Alkenyl, especially vinyl, allyl, C3-C7Cycloalkyl is in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4Alkyl is in particular benzyl which can optionally be substituted by one or more identical or different radicals such as those mentioned above,
R2、R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, especially hydroxymethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl, especially benzyloxymethyl1-benzyloxyethyl, carboxy-C1-C6Alkyl, in particular carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, in particular methoxycarbonylmethyl, ethoxycarbonylethyl, C1-C4-aryl-alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, C1-C4-alkylamino-C1-C6Alkyl, in particular methylaminopropyl, methylaminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, in particular dimethylaminopropyl, dimethylaminobutyl, C2-C8Alkenyl, in particular vinyl, allyl, butenyl, C3-C7Cycloalkyl is in particular cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4Alkyl is in particular benzyl which can optionally be substituted by one or more identical or different radicals such as those mentioned above, and also optical isomers and racemates thereof.
Very particular preference is given to compounds of the formula (I) in which
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl is in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C1-C8Alkenyl, especially allyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclohexylmethyl, phenyl-C1-C4-an alkyl group, in particular a benzyl group,
R2、R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl is especially methyl, ethyl, propyl, isopropyl, butyl,Isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C2-C8Alkenyl, especially vinyl, allyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclohexylmethyl, phenyl-C1-C4Alkyl is in particular benzyl which can optionally be substituted by one or more identical or different radicals such as those mentioned above, and also optical isomers and racemates thereof.
In particular, mention is made of the radicals R1To R6The following compounds of the general formula (I) having the following meanings:
| R1 | R2 | R3 | R4 | R5 | R6 |
| -CHMeCH2Me | -cyclohexyl radical | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -cyclohexyl radical | -CHMeCH2Me | -Me | -CHMeCH2Me | -cyclohexyl radical |
| -CHMeCH2Me | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -CH2-Phe |
| -CHMeCH2Me | -(CH2)3-Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -(CH2)3-Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)3-Me |
| -CHMe2 | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CH2-Phe | -CHMe2 | -CH2-Phe | -CHMe2 | -CHMeCH2Me | -CHMe2 |
| -CH2CHMe2 | -CH2-Phe | -CH2CHMe2 | -Me | -CH2CHMe2 | -CH2-Phe |
| -(CH2)3-Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMe2 | -Me | -CHMe2 | -Me | -CHMe2 | -Me |
| -CH2-Me | -Me | -CH2-Me | -Me | -CH2-Me | -Me |
| -(CH2)2-Me | -Me | -(CH2)2-Me | -Me | -(CH2)2-Me | -Me |
| -(CH2)3-Me | -Me | -(CH2)3-Me | -Me | -(CH2)3-Me | -Me |
| -CH2-CH＝CH2 | -Me | -CH2-CH＝CH2 | -Me | -(CH2)-CH＝CH2 | -Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -CH2-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)2-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)3-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CH2Me | -Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -(CH2)2-Me | -Me |
| -cyclohexyl radical | -Me | -cyclohexyl radical | -Me | -cyclohexyl radical | -Me |
| -CH2CHMe2 | -cyclohexyl radical | -CH2CHMe2 | -Me | -CH2CHMe2 | -cyclohexyl radical |
| -CH2CHMe2 | -cyclohexyl radical | -CH2CHMe2 | -Me | -CH2CHMe2 | -Me |
| -CHMeCH2Me | -CHMe2 | -CHMeCH2Me | -CHMe2 | -CHMeCH2Me | -Me |
| -CH2-Phe | -Me | -CH2-Phe | -Me | -CH2-Phe | -Me |
| -cyclohexyl radical | -Me | -cyclohexyl radical | -Me | -cyclohexyl radical | -Me |
| -CHMe2 | -CHMe2 | -CHMe | -Me | -CHMe2 | -Me |
| -CHMe2 | -CHMe2 | -CHMe2 | -CHMe2 | -CHMe2 | -Me |
| -CH2-Me | -CHMe2 | -CH2Me | -Me | -CH2-Me | -Me |
| -CH2-Me | -CHMe2 | -CHMe2 | -CHMe2 | -CH2-Me | -Me |
| -(CH2)2-Me | -CHMe2 | -(CH2)2-Me | -Me | -(CH2)2-Me | -Me |
| -(CH2)2-Me | -CHMe2 | -(CH2)2-Me | -CHMe2 | -(CH2)2-Me | -Me |
| -(CH2)3-Me | -CHMe2 | -(CH2)3-Me | -Me | -(CH2)3-Me | -Me |
| -(CH2)3-Me | -CHMe2 | -(CH2)3-Me | -CHMe2 | -(CH2)3-Me | -Me |
| -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -Me | -CH2-CH＝CH2 | -Me |
| -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -Me |
| -Me | -Me | -CHMeCH2Me | -Me | -CH2-Me | -Me |
| -Me | -Me | -CHMeCH2Me | -Me | -(CH2)3-Me | -Me |
Me ═ methyl; phe ═ phenyl group
Furthermore, the compound PF1022 of the following formula (IIa), known from EP 0382173, is mentioned as depsipeptide:
furthermore, as depsipeptides, the compounds known from PCT application WO93/19053 are mentioned.
Mention may in particular be made of the compounds of formula (IIb) from WO 93/19053:
wherein
Z is N-morpholinyl, amino, mono-or dimethylamino.
Mention may furthermore be made of compounds of the formula (IIc):
wherein
R1、R2、R3、R4Independently of one another are hydrogen, C1-C10Alkyl or aryl, in particular phenyl, optionally substituted by hydroxy, C1-C10-alkoxy or halogen substitution.
Compounds of the general formulae (I) and (IIｃA), (IIb) and (IIc) are known and can be obtained by the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498, EP-A-903347 or analogously thereto.
Cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (IId)
Wherein
R1a、R2a、R11aAnd R12aIndependently of one another are C1-8Alkyl radical, C1-8-haloalkyl group, C3-6-cycloalkyl, aralkyl, aryl,
R3a、R5a、R7a、R9aindependently of one another, hydrogen or C, straight-chain or branched1-8-alkyl, which can optionally be substituted by hydroxy, C1-4-alkoxy, carboxyl,Amide groups (Carboxamid),Imidazolyl, indolyl, guanidino, -SH or C1-4Alkylthio, which is additionally capable of being substituted by halogen, hydroxy, C1-4Alkyl radical, C1-4-an alkoxy-substituted aryl-or aralkyl group,
R4a、R6a、R8a、R10aindependently of one another, hydrogen, straight chain C1-5Alkyl radical, C2-6-alkenyl, C3-7-cycloalkyl, each of which can be optionally substituted with: hydroxy, C1-4Alkoxy, carboxyl, amidoImidazolyl, indolyl, guanidino, SH or C1-4An alkylthio radical and is optionally substituted by halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy-substituted aryl or aralkyl groups, and optical isomers and racemates thereof.
Preference is given to using compounds of the formula (IId) in which
R1a、R2a、R11aAnd R12aIndependently of one another, methyl, ethyl, propyl, isopropyl, n-, i-, t-butyl or optionally substituted by halogen, C1-4Alkyl, OH, C1-4-phenyl substituted by alkoxy, and is benzyl or phenethyl which can optionally be substituted by the groups indicated for phenyl;
R3ato R10aHave the meaning as described above.
Particularly preferred are compounds of the formula (IId), in which
R1a、R2a R11aAnd R12aIndependently of one another, methyl, ethyl, propyl, isopropyl or n-, i-, t-butyl,
R3a、R5a、R7a、R9ais hydrogen, straight-chain or branched C1-8-alkyl groups, in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl, each of which can be optionally substituted by: c1-4Alkoxy, in particular methoxy, ethoxy, imidazolyl, indolyl or C1-4Alkylthio is in particular methylthio, ethylthio and additionally phenyl, benzyl or phenethyl, each of which can optionally be substituted by halogen, in particular chlorine.
R4a、R6a、R8a、R10aIndependently of one another, hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, each of which can optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and is isopropyl, sec-butyl, and additionally optionally halogen-substituted phenyl, methyl, ethyl, propyl, hexyl, and also,Benzyl or phenylethyl.
The compounds of the formulｃA (IId) can also be obtained by the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498, EP-A-903347.
Very particularly preferred depsipeptides according to the invention are PF 1022A (cf. formula (IIa)) and Emodepside (PF 1022-221), compounds of the formula (IIb) in which the two radicals Z are morpholino groups. INN Emodepside represents a compound with the following system name: cyclo [ (R) -lactoyl-N-methyl-L-leucyl- (R) -3- (p-morpholinophenyl) lactoyl-N-methyl-L-leucyl- (R) -3- (p-morpholinophenyl) lactoyl-N-methyl-L-leucyl.
Praziquantel or epsiprantel can be considered as further anthelmintic active ingredients. Both have long been known as active ingredients against endoparasites (for epsiprantel see e.g. US 4661489 and for praziquantel see e.g. US 4001411). Products containing Praziquantel are, for example, under the name DroncitCommercially available. Within the scope of the present invention, the use of praziquantel is preferred.
In a particularly preferred embodiment, depsipeptides may be used in combination with praziquantel or epsiprantel, with praziquantel being preferred as a combination partner.
The preferred depsipeptides mentioned above are also correspondingly preferred or particularly preferred in combination.
In a very particularly preferred embodiment, the solid pharmaceutical formulation of the invention comprises a combination of praziquantel and PF 1022A.
In a further very particularly preferred embodiment, the solid pharmaceutical formulation of the invention comprises a combination of praziquantel and Emodepside.
Macrolides, in particular avermectins, dihydroavermectins (ivermectin) or milbemycins, can be mentioned as further active ingredients. These have anthelmintic effects and show more or less pronounced effects on ectoparasites, such as insects or mites.
The avermectins in the narrow sense are in particular eight avermectin components A1a、A1b、A2a、A2b、B1a、B1b、B2aAnd B2b. In practice, for example, the use of a compound mainly comprising avermectin B, known as avermectin1A mixture of (a). In addition, among the avermectins, there are included, for example, doramectin and avermectins.
The hydrogenation product of abamectin, called ivermectin, corresponds to 22, 23-dihydroavermectin B1。
Mention may be made, as milbemycins, of milbemycins B41D, nemadectin, moxidectin.
In a further very particularly preferred embodiment, the solid pharmaceutical formulation of the invention comprises praziquantel, Emodepside and a combination of one of the aforementioned macrolides. Among these, ivermectin is very particularly preferred in these embodiments.
Analgesics such as non-opioid analgesics or opioid analgesics may be considered as a group of further active ingredients. Mention may be made, as non-opioid analgesics, for example, of meloxicam, carprofen and analgin. Mention may be made, as opioid analgesics, for example, of buprenorphine and fentanyl.
Analgin (N-methyl-N- (2, 3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl) aminomethane sulfonic acid, also known as Dipyrone), which is commonly used in the form of its sodium salt, is mentioned as a preferred example. Other pharmaceutically acceptable salts may also be used. More precisely, analgin is considered a prodrug with four major metabolites. Two of these are effective, in particular 4-N-methylaminoantipyrine (4-MAA) and aminoantipyrine (4-AA).
Further active pharmaceutical ingredients which can be employed are pharmacologically acceptable phosphonic acid derivatives, these being generally organic compounds which are suitable as metabolic stimulators and tonics, in particular for useful animals (Nutztier) and domestic animals. Mention may be made, as preferred examples, of the long-known compound tolidine, in particular butafosinate (Butaphosphan) (for example, as product CatosalUsed), which in particular acts as a mineral supplement (phosphorus).
The active ingredients may, depending on the structure, be present in stereoisomeric form or as a mixture of stereoisomers, for example as enantiomers or racemates. According to the invention, both stereoisomeric mixtures and pure stereoisomers can be used.
Optionally, it is further possible to use: salts of the active ingredient with pharmaceutically acceptable acids or bases and solvates, especially hydrates, of the active ingredient or a salt thereof.
In a preferred embodiment, the formulation of the invention is a tablet.
The formulation includes a slow release polymer that is a water swellable polymer. Because the water-swellable polymers form gels in the presence of water, they may also be referred to as "gel-forming polymers". Examples which may be mentioned are: chitosan, guar gum and polyvinyl acetate. The water-swellable polymer preferably used according to the invention is polyvinylpyrrolidone or a derivative thereof, but it is also contemplated to use a mixture of polyvinylpyrrolidone and polyvinylpyrrolidone derivatives. However, the use of polyvinylpyrrolidone is particularly preferred.
It is also conceivable to use polyvinylpyrrolidone in combination with other suitable polymers, mention being made of Kollidon from BASFSR is an example. These include mixtures containing spray-dried polyvinyl acetate (weight average molecular weight of about 450000) and soluble polyvinylpyrrolidone (povidone K30) in a ratio of 8: 2.
One example of a suitable polyvinylpyrrolidone derivative that may be mentioned is copovidone (e.g., Kollidon VA 64 from BASF). It is a copolymer of vinylpyrrolidone and vinyl acetate in a ratio of 6: 4.
Polyvinylpyrrolidone (povidone, PVP) is a commercially available hydrophilic polymer suitable for solid pharmaceutical formulations with delayed release. Various types of PVP are commercially available. PVP of relatively low molecular weight is commonly used as a binder for tablets. PVP swells and erodes in aqueous media (oleoderen). However, it was shown that tablets comprising PVP do not form a sticky gel layer, such as cellulose ether. According to our in vitro tests, tablets comprising PVP did not become sticky even in aqueous media. When administering a plurality of tablets, the risk of forming lumps in the gastrointestinal tract is low. The release kinetics can be varied within a defined range by using PVP with different molecular weights.
The polyvinylpyrrolidone or polyvinylpyrrolidone derivative used is preferably water-soluble. In this case, it is generally a linear, uncrosslinked polyvinylpyrrolidone or polyvinylpyrrolidone derivative.
The polyvinylpyrrolidone or polyvinylpyrrolidone derivative typically has a K-value of at least 17.
The K value of the polyvinylpyrrolidone or polyvinylpyrrolidone derivative is related to viscosity and molecular weight and can be determined by methods known per se. In case of doubt, K-value data from european pharmacopoeia (ph.
Preference is given to using polyvinylpyrrolidone and/or polyvinylpyrrolidone derivatives having a K value of from 17 to 90, particularly preferably from 25 to 90.
The final formulation generally comprises from 10 to 50% by weight, preferably from 15 to 40% by weight, particularly preferably from 25 to 35% by weight, of polyvinylpyrrolidone or polyvinylpyrrolidone derivatives or mixtures thereof.
In a preferred embodiment, a polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative having a smaller chain length and a polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative having a longer chain length are used. The release profile can be adjusted particularly well in this way, since a relatively fast release is obtained with short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives, whereas a slower release is caused by longer-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives. The ratio of longer chain to short chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives may generally vary from 1: 10 parts by weight to the use of longer chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives alone. The exact ratio will be adjusted according to the diffusion characteristics of the active ingredient used. Readily water soluble active ingredients such as, for example, analgin, readily diffuse out of the gel. In this case, suitable release kinetics can be achieved without short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives or with relatively small amounts thereof. Thus, in a preferred embodiment, the weight ratio of long-chain to short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is at least 5: 1 to the weight ratio of long-chain polyvinylpyrrolidone used alone, which is preferably at least 10: 1.
The less readily (weniger gut) active ingredient dissolved in water, such as Emodepside or praziquantel, diffuses more slowly out of the gel and is only substantially released when the gel erodes. In this case, therefore, a higher proportion of short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives is recommended in order to achieve the desired release kinetics. Thus, in a further preferred embodiment, the weight ratio of long-chain to short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is from 1: 1 to 5: 1, preferably from 2: 1 to 4: 1.
The short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives generally have a K value of from 17 to 40, preferably from 17 to 30, particularly preferably about 25.
The longer-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives generally have a K value of greater than 40, preferably from 60 to 120, particularly preferably about 90.
Details regarding the aforementioned polyvinylpyrrolidone, polyvinylpyrrolidone derivatives and specific mixtures can be found in the following books: v. buhler, "Kollidon, polyvinypyrrolone for the pharmaceutical industry," 9 th revision, BASF pharmaceuticals, Germany, 2008.
The release rate of the formulation of the invention can be adjusted by using the following water-soluble adjuvants (Hilfsstoffe): such as, for example, polyethylene glycol, lactose (in particular lactose monohydrate) or polyols, for example mannitol, sorbitol, xylitol or mixtures of the aforementioned auxiliaries; optionally, these auxiliaries are generally present in an amount of from 1 to 20% (m/m), preferably from 5 to 15% (m/m).
The release profile of the formulation of the invention may preferably be further modified by the addition of a disintegrant as follows: such as, for example, starch, croscarmellose sodium (croscarmellose sodium), sodium starch glycolate, crospovidone (crospovidone, such as, for exampleKollidon CL). In such a case, then, the use of the aforementioned water-soluble auxiliary is not absolutely necessary. A preferred disintegrant is croscarmellose sodium, and a further preferred disintegrant is crospovidone. When disintegrants are used, they are generally present in an amount of up to 5% (m/m), preferably from 0.1 to 3% (m/m), particularly preferably from 0.5 to 1.5% (m/m).
Overall, a very well reproducible bioavailability can be adjusted by the measures described above, the risk of finding non-or partially decomposed tablets in the faeces being very low.
Conventional fillers, such as, for example, carbonates, such as calcium carbonate, hydrogen carbonate, salt, aluminum oxide, silica, alumina, phosphates (in particular calcium phosphate) or organic fillers, such as lactose or microcrystalline cellulose, come into consideration as fillers for solid preparations (e.g. tablets). Anhydrous dibasic calcium phosphate is preferably used. Microcrystalline cellulose is also preferred. It is also possible to mix different fillers together. The total amount of fillers is generally from 5 to 80% (m/m), preferably from 10 to 70% (m/m), particularly preferably from 20 to 60% (m/m).
The solid pharmaceutical formulation of the present invention may further comprise, in addition to the one or more active ingredients and other aforementioned ingredients, adjuvants such as, for example: slip agents (Gleitmitel), e.g. colloidal silicas such as AerosilHydrogenated vegetable oil, stearic acid, talc or mixtures thereof, optionally present in an amount generally of from 0.1 to 2% (m/m), preferably from 0.5 to 1% (m/m). Optionally, a lubricant (Schmiermittel) such as, for example, magnesium stearate, is typically present in an amount of 0.3 to 2% (m/m), preferably 0.5 to 1.5% (m/m).
To improve palatability, in a preferred embodiment, flavoring agents and/or flavoring agents are added.
Suitable as meat flavoring agents are dry liver powders from cattle, poultry, sheep or pigs, preferably from poultry and pigs, and other preparations of aromas. In a preferred embodiment, suitable flavourings and aromas are mixtures of specially post-treated proteins, fats and carbohydrates; mention may in particular be made of the Artificial Beef Flavor from Pharma Chemie (Syracuse, Nebraska, USA)。Artificial Beef FlavorIs a pork liver extract to which other proteins are added. In a further preferred embodiment, dry liver powder may be used. The flavoring or aromatizing agents are used in the pharmaceutical preparations according to the invention in amounts of 1 to 40% by weight, preferably 5 to 30% by weight, in particular 10 to 25% by weight, based on the final preparation. The percentage data in this case are the weight percentages of the final formulation.
The formulations of the invention may be prepared, for example, by mixing or granulating the ingredients, followed by compression into tablets. Wet granulation is preferred. After granulation, the flavoring or flavouring agent, disintegrant, glidant and lubricant are preferably mixed and the mixture is then tableted.
The in vitro release of the formulations of the invention can be determined with conventional release devices, in particular with the "paddle test" of the United States Pharmacopeia (USP) in a Sink-Sink state (Sink-belling). "sink state" is a term commonly used in pharmacy and means the nature and amount of the release medium used are selected such that three times the amount of the relevant active ingredient is dissolved therein. The maximum amount of release medium was 900 ml. The medium includes water as a main component, and optionally, a surfactant is added thereto to improve solubility. Conventional buffers are used to adjust the pH at which the relevant active ingredient is most stable. The aim of the formulation of the invention is to achieve an in vitro release of at least 80%, preferably at least 85%, in particular at least 90%, of the active ingredient within 1 to 6 hours, preferably 1 to 5 hours, in particular 1.5 to 5 hours. The measurements were carried out at 37 ℃ and 75 rpm. In the case of the depsipeptide release from depsipeptide-containing formulations analogous to Emodepsid, the release medium has a pH of 3.0 (disodium phosphate dihydrate/citric acid monohydrate buffer), 0.5% sodium lauryl sulfate is added. The volume containing up to 10mg emodepsid per unit of formulation was 500 ml. The sink conditions must be such that units (e.g., tablets) containing higher Emodepsid contents are met. Thus, for a 30mg unit, 900ml of medium is required.
In the case of the analgin-containing formulation, the conditions for in vitro release were determined as follows: pH 6.8 (phosphate buffer, USP standard release medium), 900 ml.
The formulations of the invention are suitable for use in humans and in animal breeding for useful animals (Nutztier), breeding animals (Zuchttier), zoo animals, laboratory animals and companion animals.
Useful animals and breeding animals include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, buffalos, donkeys, rabbits, elk, reindeer, fur-bearing animals such as, for example, mink, chinchilla, racoon and birds such as, for example, chickens, geese, turkeys, ducks, ostriches.
Companion animals include dog-cats. Preferably applied to cats and in particular dogs.
In a preferred embodiment, the formulation includes an anthelmintic active ingredient as described above. They are therefore suitable for controlling pathogenic endoparasites present in humans and in animal breeding and animal breeding in the case of useful animals (Nutztier), breeding animals (Zuchttier), zoo animals, laboratory animals and companion animals. Depending on the active ingredients used, in this respect they are effective against all or some stages of development of the pests and against resistant and generally sensitive species. The aim of controlling pathogenic endoparasites is to reduce disease, mortality and loss of productivity (for example in the production of meat, milk, wool, hides, eggs, honey etc.), so that the use of the active ingredients makes possible a more economical and simpler livestock management. The pathogenic endoparasites include cestodes, trematodes, nematodes, echinoderms:
from the order of the Ruscus aculeatus, for example: schizophyllum spp, stenotropha spp, glossoplastic spp, phyllopodium spp.
From the order of the orbicularis, for example, the genus Mesothecoides spp, the genus Onaeocephala spp, the genus Paranaeocephala spp, the genus Meniere tapeworm (Paratopocephala spp), the genus Meniere tapeworm (Moniezia spp), the genus Thysanospora, the genus Triplophyta (Thysaniezia spp), the genus Annularia tapeworm (Avitellina spp), the genus Stellite tapeworm (Stileria spp), the genus Cittomenia spp, the genus Andella (Andyra spp), the genus Bertella spp, the genus Lateochella spp (Mesothecia spp), the genus Ectoinophthalmia spp, the genus Ectoinophyllum (Ectoides spp), the genus Ectolerotheca spp (Ectoides spp), the genus Echinococcus spp, the genus Echinococcus spp (Echinococcus spp), the genus Echinococcus spp, About Youkesella (Joyeuxiella spp.) and Diplophora (Diplylideum spp.).
The subclasses Monozoea, for example: the genus Dactylicaria (Gyrodactylus spp.), the genus Dactylogyrus spp, and the genus Polysiphonia (Polystoma spp.).
Subclasses of the reproductively, for example: the genus Fasciolopsis (dipterolimus spp.), the genus stemfluke (posthoplusitum spp.), the genus schizothorax (Schistosoma spp.), the genus pilifera (trichotillus spp.), the genus avicularis (Ornithobium spp.), the genus Australia (Australitum spp.), the genus Gigantolitoria (Gigantelopa spp.), the genus cercaria (Leuchteridium spp.), the genus Brachylous (Brachylaima spp.), the genus Echinopodium, the genus echinochytrium (histostospop), the genus echinodesmus (Echinopsis spp.), the genus Echinopodium (Echinosporium spp.), the genus Echinopodium (Hypocrea spp.), the genus Echinochloa (Hypocrea spp.), the genus Echinospora (Hypocrea spp.), the genus Echinochloa (Hypocrea spp.), the genus Echinospora (Buchthyospora spp.), the genus Echinospora (Buchthys (Buchthyospora spp.), the genus Echinospora (Buchthys spp.), the genus Echinochloa (Buchthys), the genus Echinochloa (Buchthys), the genus Echinochloa (Buchthys (Buchthysans), the genus Echinochytea (Buchthys (Buchthy, Genus Fezeculus (Fischoederus spp.), genus Abdominal pouch (Gastrophyllus spp.), genus Orthosiphon (Notocotylus spp.), genus lower reproduction (Catatropis spp.), genus Clonorchis (Plagiorchis spp.), genus Protozoa (Prosthonium spp.), genus Biterglenophora (Dicocolium spp.), genus Diabrospira (Eurytrema spp.), genus Cryptospira (Cryptotrema spp.), genus Paragonimus (Paragonimus spp.), genus Onyulus spp.), genus Acerospira (Colosporium spp.), genus Nanophytulus spp.), genus Nanophyticus (Phaeopterus spp.), genus posterodendron (Ophiopterus spp.), genus Heteropterus (Heteropteropistphalus spp.).
Stingers, for example: trichuris (Trichuris spp.), capillaris (Capillaria spp.), trichinosides spp.
Rod-shaped mesh (rhabditis), for example: micronematia (Micronema spp.), Strongyloides (Strongyloides spp.).
Round mesh, for example: nematoda spp, trichlophora spp, nematoda spp, rhabdomina spp, thyophele spp, cylindrographa spp, cupola spp, Cycloocerus spp, Cyllocysticercus spp, Cyllophytylogodonta spp, Bullophora spp, Bullotrella spp, Charcot nematode spp, Cycotiana spp, and Uncaria spp
Stropharia globosa (Globoesophagus spp.), Stropharia biglensis (Syngamus spp.), Stropharia cupreum (Cyathostoma spp.), Stropharia postcois (Metastrophylus spp.), Stropharia reticulalis (Dictyocaulus spp.), Stropharia muller (Mueller spp.), Stropharia prototheca (Protostrongylus spp.), Stropharia neostrongoides (Neostrophylaxis spp.), Stropharia capsulata (Cystocaulus spp.), Stropharia pulalis (Stropharia spp.), Stropharia pulata (Stropharia spp.), Stropharia cois (Stropharia spp.), Stropharia spp (Stropharia spp.), Stropharia stylosa (Stropharia spp.), Stropharia styles spp.), Stropharia stylosa (Stropharia spp.), Stropharia styles spp.), and Stropharia styles recited, Marshland (marshallia spp.), Cooperia (Cooperia spp.), Cooperia spp, necator cervid (Nematodirus spp.), strongyloides suis (hysstrongylous spp.), catodera (obeliscosticoides spp.), mitsunobus (Amidostomum spp.), and entomophilus capitis (ullulanus spp.).
From the order of the pointeda (Oxyurida), for example: ostertagia spp, Enterobacter spp, Strongyloides spp, Cytodyloides spp, Trichostrongylus spp, Aspiculus spp, and Heterostrongyloides spp.
From the order of avian ascariales, for example: ascaris (Ascaris spp.), Toxocara nematoda (Toxascaris spp.), Toxocara (Toxocara spp.), Ascaris parapascaris (Parascaris spp.), anisaki (Anisakis spp.), and Ascaris avium (Ascaris spp.).
The order of the gyrodacty, for example: orthostomia (Gnathostoma spp.), Heterodera (Physalopetera spp.), Heterodera (Thelazia spp.), Cylindrocarpus (Gongylonema spp.), Heterodera (Habronema spp.), Paralexoma (Parabronema spp.), Drechira (Draschia spp.), and Cologynia (Dracunulus spp.).
From the order of filariales, for example: coronary filaria (Stephanofilaria spp.), Parafilaria (Parafilaria spp.), celiac filaria (Setaria spp.), Rodia (Loa spp.), Dirofilaria (Dirofilaria spp.), Gomopsis (LitomoSophora spp.), Brugia spp, Wuchereria (Wuchereria spp.), and Strongyloides fascicularis (Onchocerca spp.).
Megakiss, for example: echinocandis tenuis spp, echinocandis spp, and epididymis spp.
The compositions of the invention are particularly preferably used for Toxocara cati, Toxocara litori, Toxocara vesiculosa leonina, Ancylostoma tubulosa, canine pyelothecium caninum, Taenia megajuga and Echinococcus multocida.
In principle, the formulations are also suitable for the treatment of indications for which the corresponding active ingredients are known per se to be suitable for treatment, together with other active ingredients.
Analgesics such as analgin may be used, for example, in the treatment of mild and moderate to severe pain states such as, for example: post-traumatic pain (e.g. blunt trauma, sprain (detontation)), perioperative pain, post-operative pain, tumour pain, osteoarthritic pain, tendonitis (tendonithien), abdominal soft tissue pain, elderly dental pain.
Both prophylactic and therapeutic uses are possible.
Examples
A.Formulation examples
The following example is prepared by mixing anhydrous dibasic calcium phosphate, povidone 90 (and optionally copovidone 64) and a portion of the total amount of povidone 25 and microcrystalline cellulose, followed by mixing Emodepsid and praziquantel. Granulating the mixture with a second portion of an aqueous solution of povidone 25, and drying in a fluid bed granulator at a temperature below 110 deg.C. The granules were sieved and mixed with artifiacial Beef flavour, croscarmellose sodium, anhydrous colloidal silicon dioxide and magnesium stearate.
The mass thus obtained can be compressed into tablets.
Example 1
3.00mg Emodepside
15.00mg Praziquantel
19.20mg of anhydrous calcium hydrogen phosphate
37.80mg microcrystalline cellulose
31.50mg Artificial beef seasoning (PC 0125, Pharma Chemie Inc., Syracuse/USA)
36.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
12.90mg Povidone 25 (polyvinylpyrrolidone with K value of 25)
0.90mg of anhydrous colloidal silica
1.20mg croscarmellose sodium (croscarmellose sodium)
1.50mg magnesium stearate
Example 2
10.00mg Emodepside
50.00mg Praziquantel
64.00mg of anhydrous calcium hydrogen phosphate
126.00mg microcrystalline cellulose
105.00mg artificial beef seasoning (PC 0125, Pharma Chemie Inc., Syracuse/USA)
120.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
43.00mg Povidone 25 (polyvinylpyrrolidone with K value of 25)
3.00mg of anhydrous colloidal silica
4.00mg croscarmellose sodium (croscarmellose sodium)
5.00mg magnesium stearate
Example 3
10.00mg Emodepside
50.00mg Praziquantel
64.00mg of anhydrous calcium hydrogen phosphate
126.00mg microcrystalline cellulose
37.50mg artificial beef seasoning (PC 0125, Pharma Chemie Inc., Syracuse/USA)
40.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
42.00mg Povidone 25 (polyvinylpyrrolidone with K value of 25)
2.00mg of anhydrous colloidal silica
4.00mg croscarmellose sodium (croscarmellose sodium))
3.75mg magnesium stearate
Example 4
500.00mg analgin
300.00mg microcrystalline cellulose
300.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
10.00mg of anhydrous colloidal silica
10.00mg magnesium stearate
Example 5
1000.00mg analgin
600.00mg microcrystalline cellulose
600.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
20.00mg of anhydrous colloidal silica
20.00mg magnesium stearate
278.00mg anhydrous liver powder
Example 6
10.00mg Emodepside
50.00mg Praziquantel
64.00mg of anhydrous calcium hydrogen phosphate
126.00mg microcrystalline cellulose
105.00mg artificial beef seasoning (PC 0125, Pharma Chemie Inc., Syracuse/USA)
90.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
30.00mg of copovidone 64 (Kollidon from BASF)VA 64 copolymer of vinylpyrrolidone and vinyl acetate in a ratio of 6: 4)
43.00mg Povidone 25 (polyvinylpyrrolidone with K value of 25)
3.00mg of anhydrous colloidal silica
4.00mg croscarmellose sodium (croscarmellose sodium)
5.00mg magnesium stearate
Example 7
10.00mg Emodepside
50.00mg Praziquantel
64.00mg of anhydrous calcium hydrogen phosphate
126.00mg microcrystalline cellulose
105.00mg artificial beef seasoning (PC 0125, Pharma Chemie Inc., Syracuse/USA)
30.00mg Povidone 90 (polyvinylpyrrolidone with K value of 90)
90.00mg copovidone 64 (Kollidon from BASF)VA 64 copolymer of vinylpyrrolidone and vinyl acetate in a ratio of 6: 4)
43.00mg Povidone 25 (polyvinylpyrrolidone with K value of 25)
3.00mg of anhydrous colloidal silica
4.00mg croscarmellose sodium (croscarmellose sodium)
5.00mg magnesium stearate
Comparative example (formulation not according to the invention)
5.00mg Emodepside
50.00mg Praziquantel
30.00mg of anhydrous calcium hydrogen phosphate
63.00mg microcrystalline cellulose
35.00mg artificial beef seasoning
92.00mg hydroxypropyl cellulose M (HPC-M from Nisso, Japan)
1.00mg of anhydrous colloidal silica
3.00mg magnesium stearate
In the USP release test, tablets prepared with the formulation of the comparative example achieved > 80% release of the active ingredient within 12 hours. In the experiment with dogs, incompletely decomposed tablets and tablet residues were found in the feces. When multiple tablets are dosed, there is sticking and caking.
In vitro release
In vitro release of the formulations of the invention was measured in a sink mode using the United States Pharmacopeia (USP) paddle test
FIG. 1 shows the results for a number of Emodepsid/praziquantel tablets:
"Small" represents the tablet of example 1,
"in" represents the tablet of example 2,
"Large" represents a larger tablet containing 30mg of Emodepsid and 150mg of praziquantel per tablet. The tablets have the same percentage composition as those of examples 1 and 2.
Measurement conditions were as follows: 37 ℃ at 75 rpm, pH 3.0 (disodium hydrogen phosphate dihydrate/citric acid monohydrate buffer) in aqueous medium, 0.5% sodium lauryl sulfate. For the mini-and mid-tablets 500ml of release medium were used, for the large tablets 900ml were used.
Figure 1 shows that after 1 to 5 hours, all tablets released more than 90%.
A.Biological examples
I. Pharmacokinetic Studies
The drug to be studied was administered to fasted dogs. At each time point, the plasma level of the one or more active ingredients is determined.
Figure 2 shows the results after administration of the tablet of example 2. It can be seen that there is a significantly delayed decrease in plasma concentrations of both praziquantel and in particular Emodepsid.
Comparison of Analgin tablet formulations with commercially available solutions for intravenous administration
The 6 dogs (weighing 9.9-11.1kg) were divided into two groups of 3 dogs each. A group received intravenous administration of the commercially available injectable preparation MetapyrinAnalgin in form, at a dose of 500 mg/dog. The second group received analgin in the form of the formulation of example 4 administered orally, similarly at a dose of 500 mg/dog. When administered, dogs were fasted.
FIG. 3 shows plasma levels of analgin after administration, showing that the analgin concentration [4-MAA +4-AA ] is a calculated value determined based on the sum of the serum concentrations of the two potent major metabolites 4-MAA and 4-AA, taking into account the molar masses of these two metabolites.
Plasma concentrations following oral administration of one or two analgin tablets
FIG. 4 shows the mean analgin concentration in serum of fasted dogs after oral administration of one or two analgin tablets of example 4 [4-MAA +4-AA ]. It is clear that plasma levels are very relevant to the administered dose.
Claims (14)
1. A solid pharmaceutical formulation with delayed release comprising:
a. at least one pharmaceutically active ingredient, wherein the active ingredient is selected from the group consisting of,
from 15 to 40% by weight of polyvinylpyrrolidone and/or polyvinylpyrrolidone derivatives which are copolymers of vinylpyrrolidone and vinyl acetate in a ratio of 6: 4, the polyvinylpyrrolidone and/or polyvinylpyrrolidone derivatives being a mixture of the following components:
i. short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives having a K value of 17 to 30 and
a longer chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative having a K value of 60 to 120,
c. at least one filler.
2. A solid pharmaceutical formulation according to claim 1 further comprising a disintegrant.
3. A solid pharmaceutical formulation according to claim 2 comprising a disintegrant in an amount of up to 5% (m/m).
4. A solid pharmaceutical formulation according to any of the preceding claims comprising as depsipeptide a compound of general formula (I):
wherein
R1、R3And R5Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can optionally be substituted by one or two benzyloxycarbonyl residues or by one, two, three or four alkyl residues, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl, where halogen, hydroxy, alkyl and alkoxy may be mentioned as substituents,
R2、R4and R6Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkylAlkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl or arylalkyl, where halogen, hydroxy, alkyl, alkoxy may be mentioned as substituents,
or a compound of formula (IIa) PF 1022:
or a compound of formula (IIb):
wherein
Z is N-morpholinyl, amino, mono-or dimethylamino,
or a compound of formula (IIc):
wherein
R1、R2、R3、R4Independently of one another are hydrogen, C1-C10Alkyl or aryl, in particular phenyl, optionally substituted by hydroxy, C1-C10-alkoxy or halogen substitution,
or a compound of the formula (IId)
Wherein
R1a、R2a、R11aAnd R12aIndependently of one another are C1-8Alkyl radical, C1-8-haloalkyl group, C3-6Cycloalkyl, aralkyl, arylThe base group is a group of a compound,
R3a、R5a、R7a、R9aindependently of one another, hydrogen or C, straight-chain or branched1-8-alkyl, which can optionally be substituted by hydroxy, C1-4-alkoxy, carboxyl,Amide group, amide group,Imidazolyl, indolyl, guanidino, -SH or C1-4Alkylthio, which is additionally capable of being substituted by halogen, hydroxy, C1-4Alkyl radical, C1-4-an alkoxy-substituted aryl-or aralkyl group,
R4a、R6a、R8a、R10aindependently of one another, hydrogen, straight chain C1-5Alkyl radical, C2-6-alkenyl, C3-7-cycloalkyl, each of which can be optionally substituted with: hydroxy, C1-4Alkoxy, carboxyl, amido, imidazolyl, indolyl, guanidino, SH or C1-4An alkylthio radical and is optionally substituted by halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy-substituted aryl or aralkyl groups, and optical isomers and racemates thereof.
5. A solid pharmaceutical formulation according to claim 4 wherein the pharmaceutically active ingredient is selected from Emodepsid.
6. A solid pharmaceutical formulation according to claim 5 wherein the pharmaceutically active ingredient is selected from the group consisting of Emodepsid and Praziquantel.
7. The solid pharmaceutical formulation according to any one of claims 1 to 3 wherein the pharmaceutically active ingredient is selected from analgesics.
8. The solid pharmaceutical formulation according to claim 7, wherein the pharmaceutically active ingredient is selected from analgin.
9. A solid pharmaceutical formulation according to any one of claims 1 to 6 wherein the pharmaceutically active ingredient is selected from macrolides.
10. A solid pharmaceutical formulation according to claim 9 wherein the pharmaceutically active ingredient is selected from ivermectin.
11. A solid pharmaceutical formulation according to any one of claims 1 to 3, wherein the pharmaceutically active ingredient is selected from pharmacologically acceptable phosphonic acid derivatives selected from tolodin and butafosinate.
12. A solid pharmaceutical formulation according to claim 11 wherein the pharmaceutically active ingredient is selected from butafosfan.
13. A solid pharmaceutical formulation according to any of claims 4, 5 or 6, characterized in that it releases 80% of the depsipeptide in a leaky tank state at 37 ℃ and 75 rpm in a release medium of disodium hydrogen phosphate dihydrate/citric acid monohydrate buffer at a pH of 3.0 in 1 to 6 hours in a paddle test according to the United states Pharmacopeia with the addition of 0.5% sodium lauryl sulfate.
14. The solid pharmaceutical formulation according to claim 8, characterized in that it releases 80% of analgin in 1 to 6 hours at 37 ℃ and 75 rpm in a leaky tank state in a paddle test according to the United states Pharmacopeia, the release medium used being phosphate buffer, pH 6.8(USP standard release medium).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102008022520A DE102008022520A1 (en) | 2008-05-07 | 2008-05-07 | Solid sustained-release pharmaceutical formulation |
| DE102008022520.7 | 2008-05-07 | ||
| PCT/EP2009/002951 WO2009135593A2 (en) | 2008-05-07 | 2009-04-23 | Solid pharmaceutical formulation with delayed release |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1162936A1 HK1162936A1 (en) | 2012-09-07 |
| HK1162936B true HK1162936B (en) | 2016-05-06 |
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