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Back to the List of the Granted Patents                                      Click here to download KE000181 PDF(11) Patent Number: KE 181
 (45) Date of grant: 06/07/2004
 
(12) PATENT
(51) Int.Cl.7: A 6IK 47/40
(21)Application Number: 2003/000221
(22) Filling Date: 31/01/2001
(30) Priority data: P20000765A 10/11/200 HR
(87) PCT details: WO 02/38186   16/05/2002
(73) Owner: PLIVIA, Farmceutska Industrija, Dionicko Drustvo Utica grade Vukovara 49, H-10000 Zagred., Croatia
 
(72) Inventor:
DUMIC, MILJENKO; FILIC, Darko; KLEPIC, Bozena; DANILOVSKI, Aleksander and TUDJA, Marijan
(74) Agent/address for correspondence: Waruinge & Wauruinge Advocate P.O. Box 72384-00200. Nairobi
 
(54) Title: COMPOSITIONS OF N-(1VIETHYLETHYLAIVIINOCARBONYL)-4-(3-METHYLPHENYLAMINO)-3- PYRIDVLSULFONAMIDE AND CYCLIC OLIGOSACCHARIDES



(57) Abstract:
The invention relates to compositions of N-(1-methylethylaminocarbonyI)-4-(3methylphenylamino)-3-pyridyisulfonamide and cyclic oligosaccharides with increased release, to methods for their preparation, to pharmaceutical thorns containing them as well as to their use.
 
COMPOSITIONS OF N-(NETNYLETNYLAMINOCARBONYI) -4 -(3 -METHYLPRENYLAMINO) -3 - PYRIDYLSOLFONAMIDE AND CYCLIC OLIGOSACCHARIDES
The present invention relates to compositions of N-(1-methylethylaminocarbony1)-4- (3-methylphenylamino)-3-pyridylsulfonamide (further in the text referred to by its generic name "torasemide") and cyclic oligosaccharides with increased release, to methods for their preparation, to pharmaceutical forms containing them as well as to their use.

Torasemide is a new potent diuretic in the class of the so-called "loop diuretics", which is described in the Example 71 of BE patent 25 15 025. Structurally, it entirely differs from diuretics of the same class such as furosemide, bumetanide and azoseraide. In addition to diuretic properties it also possesses antihypertensive properties.
As a diuretic of Henle's loop it is interesting as an agent for preventing heart damages or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Batter's syndrome, tumours, glaucoma, decrease of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
 
It is well known that torasemide can exist in four crystal modifications: polymorph 1 (Acta Ctyst B34 (1978) 1304-1310], polymorph II (Acta Cryst 1134, (1978) 2659-26621, polymorph III (PCT/WO 00/20395) and polymorph V (HR Patent Application No, P 20000328A), and in one amorphous modification (HR Patent Application No. P 20000162A)
Modifications of torasemide (polymorphs I-V) are very hydrophobic and practically insoluble in water. Very poor water-solubility and wettability of torasemide represents a problem in the preparation of pharmaceutical preparations with good dissolution and uniform bioavailability.
The problem of increasing the dissolution rate of active substances that are poorly soluble in water covers many areas ranging from phytopharmaceuticals to pesticides and, in general, all those areas where bioactive substances are used.
The dissolution rate is determined by physical-chemical characteristics of the active substance and particularly by its solubility in water. Thus, the dissolution rate of an active substance is the limiting factor in the absorption process and in the therapeutic activity of the substance. Additionally, disintegration products of the active substance formed in pharmaceutical preparations may also cause different side effects. Therefore an increased solubility and stability achieved .by the preparation of a suitable formulation results in an increased efficiency of the active substance. In pharmaceutical industry, the increase of the dissolution rate and of the stability of poorly soluble active substances has been solved by various methods e.g. by roicronization, by preparing amorphs, clatbrates, by chemical modifications, by pH adjustment and very often by preparing solid compositions of the active substance and physiologically suitable additives making possible the desired physical-chemical transformation of the active substance i.e. improving the dissolution rate and the wettability of the active substance. M physiologically suitable additives there are usually used e.g. polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropyl- cellulose and, with increasing frequency, cyclodextrins, commercially available cyclic oligosaccharides consisting of 6, 7 and 8 linked glucopyranose units (α-, β- and γ- cyclodextrins and their derivatives).
Solid compositions active substance/physiologically suitable additive can be prepared by blending, milling, precipitation, evaporation, lyophilization, spray-drying and melting.
Properties of cyclodextrins are well known and have been described in detail in reviews in periodicals [Szejtli J., Cyclodextrin Technology (1988) Kluwer Academic Publishers, Dordrecht; Szejtli J., Cyclodextrins in drug formulations: Part I, Pharm. Techn. Int. 3 (1991) 15-22; Szejtli J., Cyclodextrins in drug formulations: Part II, Pharm. Techn Int. 3 (3) (1991) 16-24; T Loftson, Pharmaceutical Application of (3-Cyclodextrin, Pharm. Techn.Eur.11 (1999) 20; W. Saenger, Cyclodextrin Inclusion Compounds in Research and Industry, Angaw. Chest Int. Ed Engl. 19 (1980) 344]
Cyclodextrins are characterized by the shape of their molecule in the form of a cylinder. Inside the cylinder there is an intramolecular cavity which is hydrophobic, whereas the outer side is hydrophilic. The hydrophobic character of the intramolecular cavity enables other molecules or parts of molecules known as "guest" molecules to penetrate into the host molecule thereby forming inclusion complexes.
Au inclusion complex can be stabilized by numerous forces including also Van der Wallis' attracting forces and hydrogen bonds. Inclusion complexing of the corresponding "guest" molecule with cyclodextrins may result in numerous physical-chemical changes in the properties of the "guest" molecule. The melting point is changed, the ER spectrum and X-ray powder pattern of the complex are relatively different from those of the pure "guest" molecule or of a simple (not complexed) mixture of the "host" molecule and the "guest" molecule. By means of cyclodextrin inclusion complex, water-insoluble "guest" molecules become more soluble. In many cases chemically unstable compounds are stabilized by inclusion complexing. The said changes in physical-chemical properties of the "guest" molecule resulting from inclusion comptexing with cyclodextains represent a proof that the cyclodextrin inclusion complex represents a unique form of the solid state of a "guest" molecule.

Though by the preparation of the solid compositions active substance/physiologically suitable additive an increased dissolution rate has been noticed in a large number of poorly soluble pharmaceutically active substances, this cannot be accepted as a rule. Namely, for each active substance and physiologically suitable additive it has to be established which preparation method, physiologically suitable additive and molar ratio active substance/physiologically suitable additive, solvent, time, temperature of the preparation etc. will give a solid composition making possible the desired dissolution rate of the active substance.
Solid compositions of cyclodextrin with various pharmaceutically interesting active substances have been known from patents as well as from the literature and just a few examples are cited here.
Thus, M. I. La Rotunda et al. compared solid compositions of the non-steroid anti-inflammatory drug nimesulide and 11-cyclodextrin (molar ratio 1:1) prepared by physical blending, evaporation, lyophiliration, spray-drying and kneading and reported that the dissolution rate depends on physical-chemical properties of each solid composition. In comparison to nimesulide alone, the dissolution of nimesulide from solid compositions was significantly accelerated and the solid compositions obtained by lyophilization and spray-drying showed to be the forms with the fastest dissolution of nimesulide [S.T.P. Pharma Sri. 10 (2000) 157].
 
P. R. Vavia et al. also compared solid compositions of nimesulide with ft-cycIodextrin and HP [3-cyclodextrin in a molar ratio 1:1 (physical mixtures and lyophilizates). As stated by the authors, in contrast to physical mixtures, the inclusion complexes prepared by lyophilimtion increased the dissolution of nimesulide, and particularly by the inclusion complex nimesulide/1-1P-P-cyclodextrin a significantly higher dissolution was achieved [Drug Develop. Ind Pharm. 25 (1999) 543].
J. R. Mayano et al. prepared, by physical mixing spray-drying and kneading, solid compositions of the drug oxazepam with P-cyclodextrin in molar ratios 1:1 and 1:2, and all solid compositions accelerated the dissolution of oxazepam in comparison to oxazepam alone. In the case of physical mixtures, both molar ratios of oxazepam to 13- cyclodexirin showed an equal influence on the dissolution of oxazepam whereas the solid compositions prepared by kneading and spray-drying with the molar ratio 1:2 considerably accelerated the dissolution of oxazepam in comparison to those with the molar ratio 1:1 [Int. J. Pharm. 114 (1995) 95].
Further, M. Guyot et al. prepared physical mixtures and inclusion complexes of the drug norfloxacin with P-cyclodextrin and HP-f3-cyclodextrin in molar ratios 1:1 and 1:2. Physical mixtures as well as inclusion complexes significantly increased the dissolution in comparison to norfloxacin alone. No influence of molar ratios on dissolution was noticed [Int. J. Pharm. 123 (1995) 53]
Besides, M. Pedersen et al. stated that physical mixtures of the antimicotic miconazole and 3-cyclodextrin with the molar ratio 1:2 show a faster dissolution in comparison to the inclusion complex with P-cyclodextrin [Drug. Develop. Ind. Pharm. 25 (1999) 1241]
 
In US patent 5,849,329 the authors protected a process for preparing pharmaceutical compositions with controlled dissolution, prepared by grinding or dry-mixing active substances also with, inter alia, a-, y- and ITP-13-cyclodextrins and their derivatives. As active substances there were cited nallazone, terfenadine, carbamazepine, glicazide, glibenclamide, bifonazole as well as nifedipine, diazepam and ketoprofen.
In US patent 5,449,521 the authors protected pharmaceutical compositions containing griseofulvin, pirmdcam, diacerein, diltiazem, megesirol acetate, nifedipine, nicergoline, ketoprofen, naproxen, diclofenac, ibuprofen, lorazepam, oxazepam as an active substance and, inter alict, cross-linked polymeric cyclodextrin. The cited pharmaceutical compositions were prepared by grinding the active substance and a suitable additive in mills saturated with the vapours of a solvent or of a mixture of solvents.
Besides, in US patent 5,010,064 the authors protected an inclusion complex of dipyrimidole and β-cyclodextrin (molar ratio from 1:1 to 1:12), whereas in US patent 5,019,563 a complex of ibuprofen sodium salt and B-cyclodextrin (molar ratio 1:0, 2 to 1:0.75) was protected.
Further, in US patent 5,674,854 the authors described and protected the preparation and an inclusion complex of pharmaceutically suitable salts of diclofenac and β- cydodextrin (molar ratio 1:1) and in US patent 5,744,165 the authors protected inclusion complexes of alkali metal salts and earth alkali metal salts of nimesulide with α-, β- and γ-cycloclextrins and derivatives thereof.
In the patent publication WO 93/00097 the authors claimed stable pharmaceutical preparations containing torasemide or its salts and additives such as hydroxy-propylcellulose, polyvinylpyrrolidone,' sodium-croscarmellose, cros-povidone,




 
 
 
 
 
 
Example 1
The modification I of torasemide according to PCT/WO 00/20395 (0.50 g) and an equimolar amount of P-cyclodextrin were homogenized in a mixer for 24 hours.
Differential scanning calorimetry (DSC) curve represented in Fig. 3 comprises exothermic peaks of the modification I of torasemide and 0-cyclodexirin. The DSC analysis was performed on the apparatus Perkin-Elmer; model DSC7 at a heating rate of 25°C/min.
The IR spectrum represented in Fig. 7 comprises characteristic peaks of the modification I of torasemide and I3-cyclodexlrin. The IR spectrum was recorded on the IR spectrophotometer Nicolet; model Magna 760 in the range from 4000 to 600 cm-1

The representative X-ray powder pattern is represented in Fig, 11 and was recorded on the diffractometer PHILIPS, model PW 3710 in the range 2θ = 5-40° using CuKα rays = 1.541 A. The recording step was 0.029° and the recording time was is per step.

Example 2
 
The differential scanning calorimetry (DSC) curve represented in Fig. 4 does not comprise strong peaks characteristic of the modification I of torasemide and of β- cyclodextin.
The ER spectrum represented in Fig. 8 strongly differs from the IR Spectrum of the modification I of torasemide and from the IR spectrum of 13-cyclodextrin represented in Figs. 5 and 6.

The X-ray powder pattern represented in Fig. 12 strongly differs from the X-ray powder pattern of the modification 1 of torasemide and the X-ray powder pattern of is cyclodextrin represented in Figs. 10 and 11.
Example 4
β-Cyclodextrin (0.28 g) was dissolved in 50 ml of demineralised water, the solution was heated to 80°C under vigorous stirring, it was stirred for 60 minutes and then an equimolar amount of the modification I of torasemide prepared according to PCT/WO 00/20395 was added over 90 minutes. Subsequently, the hot solution was filtered, cooled to room temperature, whereupon water was removed by lyophilization.
The IR spectrum of the thus obtained sample was identical to the IR spectrum of the sample prepared according to the Example 3 of the present invention.
 
 

6. Physical mixtures according to claim 1, characterized in that torasemide and cyclodexirins or cyclodextrin derivatives are in a molar ratio from 1:0.1 to 1:5.
7. A method for the preparation of physical mixtures according to claim 1, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are homogenized.
8. A method for the preparation of physical mixtures according to claim 7, characterized in that the said homogenization is carried out in a mortar or in mixers.
9. A method for the preparation of physical mixtures according to claim 7, characterized in that the said mixing is carried out at temperatures from 10°C to 100°C.
10. A method for the preparation of physical mixtures according to claim 7, characterized in that the said mixing is carried out from 0.1 hour to 24 hours.
11. Physical mixtures according to claim 1, characterized in that they are used as a diuretic' and as an agent for preventing heart. damages or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension; nephroedema, pulmonary edema, primary and secondary aldosteronism, Batter's syndrome, tumours, glaucoma, decrease of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by hymn, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
 
2-hydroxyethy113-cyclodextrin, 2-hydroxyethyll-cyclodextrin, 2,6-dimethyl-f3¬cyclodextrin and (2-carboxymetboxy)-propyl-f3-cyclodextrin.
18. Inclusion complexes according to claim 14, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are in a molar ratio from 1:0.1 to 1:5.
19. A method for the preparation of inclusion complexes according to claim 14, characterized in that torasemide and cyclodextrins or cyclodextrin derivatives are reacted in water with or without an aqueous solution of a base.
20. A method for the preparation of inclusion complexes according to claim 19, characterized in that as the aqueous solution of a base an aqueous ammonia solution is used.
21. A method for the preparation of inclusion complexes according to claim 19, characterized in that it is carried out at temperatures from 10°C to 100°C.
22. A method for the preparation of inclusion complexes according to claim 19, characterized in that it is carried out for from 0.1 hours to 7 days.
23. A method for the preparation of inclusion complexes according to claim 19, characterized in that after formation of the said inclusion complex, the water and the base are removed by drying.
24. A method for the preparation of inclusion complexes according to claim 23, characterized in that the said drying is carried out by lyophilization, spray-drying, vacuum evaporation or vacuum drying.
 
25. Inclusion complexes according to claim 14, characterized in that they are used as a diuretic and as an agent for preventing heart damages or heart tissue damages caused by metabolic or ionic abnormalities associated with ischemia, in the treatment of thrombosis, angina pectoris, asthma, hypertension, nephroedema, pulmonary edema, primary and secondary aldosteronism, Batter's syndrome, tumours, glaucoma, decrease of intraocular pressure, acute or chronic bronchitis, in the treatment of cerebral edema caused by trauma, ischemia, concussion of the brain, metastases or epileptic attacks and in the treatment of nasal infections caused by allergens.
26. A pharmaceutical form, characterized in that it comprises inclusion complexes according to claim 14 as the active ingredient in combination with one or more pharnweutically acceptable additives such as sugar, starch, starch derivatives, cellulose, cellulose derivatives, mould release agents and antiadhesive agents and optionally agents for flowability regulation.
27. A pharmaceutical form according to claim 26, characterized in that it is a tablet, a capsule, an injection or a spray.

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