INCLUSION COMPLEXES OF N-ETHOXYCARBONYL-3-MORPHOLINO-SYDNONIMINE OR SALTS FORMED WITH CYCLODEXTRIN DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Abstract: The invention relates to inclusion complexes of N-ethoxycarbonyl-3-morpholino-sydnonimine or its salts formed with a cyclodextrin derivative, preparation thereof and pharmaceutical compositions containing the same. The inclusion complex of N-ethoxycarbonyl-3-morpholino-sydnonimine or its salt formed with cyclodextrin derivative is prepared by (a) reacting the N-ethoxycarbonyl-3-morpholino-sydnonimine or its salt and the cyclodextrin derivative in a solvent medium, and if desired recovering the complex from the solution by dehydratation, or (b) high energy milling of the N-ethoxycarbonyl-3-morpholino-sydnonimine or its salt and the cyclodextrin derivative.

Description: Inclusion complexes of N-ethoxycarboπyl-3-π3rpholino-sydπoπimine or salts formed with cyclodextrin derivatives, preparation thereof and pharmaceutical compositions containing the same The invention relates to the inclusion complexes of N-ethoxycar- bonyl-3-morpholino-sydnonimine (Molsidomin) cr its salts formed with heptakis-2,6-0-dimethyl-/3-cyclodextrin (Dimeb), hydroxypropyl-3-cyc¬ lodextrin or with (b - or T-cyclodextrin, to the preparation thereof and to the pharmaceutical compositions containing the same. Molsidomin is an antiangiπic and antiischemic compound which is widespread applied for the prevention and treatment of angina pectoris. Its advantage compared to the organic nitrates is, that its effect is more lasting and it has less side-effects, thus it leads not to habit and it induces rarely and less intensive headache. Its antiarithmic, the fibrinolysis, the blood-platelet aggregation and blood-pressure decreasing effect is distinguished too. The Molsidomin is on the market in the form of tablets containing 2, 4 (traditional) and 8 mg (retard) of the active ingredient, named Corvaton (Casella, Riedel), Morial (Takeda Ltd.). The retard composition is containing the active ingredient in a microencapsulated form applying a special wax in a ratio of 1:4, which is ensuring an effective plasma concentration for 12 hours. The Molsidomin is relatively fairly soluble in water (18 mg/ l at 25 °C), it is stable at a pH value of 5-7 in water. The rate determining step of the resorption from the stomach and of the intes¬ tinal tract is apparently not the solubility. The oral preparation containing 2 mg of the active ingredient is effective for 3-5 hours. The maximal blood-level can be achieved within 1/2-1 hour. It is fairly absorbed along the whole Gi-tract, its bioavailability is satisfactory. Antiaπginal preparations for preventive purposes are formulated must advantageously with controlled release of the active ingredient. It ensures the extended and controlled resorption of the medicament and the long lasting therapeutically effective plasma-level. The side-effects can be decreased significantly by the elimination of the too high toxic plasma-level. The transdermal formulation with a controlled release of the active agent is especially advantageous. The resorption of the active ingredient through the skin depends on their physico-chemical properties and lipoid solubility, and mainly on the formulation applied. Molsidomin itself is resorbεd slowly and in a small extent through the skin, its bioavailability is only 4%, for this reason agents enhancing the resorption are applied. The European Patent Specification No. 127468 of the Takeda Company describes a percutaneous fairly resorbiπg Molsidomin preparation, which contains a special penetration enchancer agent of 2 components - a propyleπεglycol mixture containing 10% of oleic acid. The mechanism of the outstanding bioavailability of 95% may be the following: the oleic acid component modifies the permeability of the skin's protective layer (the stratum corneum) by dissolving the barrier lipoid components of the same. Thus the Molsidomin is fairly resorbed through the modified stratum corneum. It was stated that the resorption of Molsidomin and of propylene- -glycol is of similar extent, and of similar quantity respectively, which means, that only the Molsidomin dissolved in the propylene- -glycol will be resorbed. It was found, that the effect of Molsidomin or its salts can be retarded by complexation with heptakis-2,6-0-dimethyl- -cyclodextrin, hydroxypropyl-/o-cyclodextrin, or with ft) - or ηf- cyclodextrin. The present invention relates to the inclusion complexes of N- -ethoxycarbonyl-3-morpholino-sydπonimine or its salts formed with heptakis-2,6-0-dimethyl-/2?-cyclodextrin, hydroxypropyl- -cyclo¬ dextrin or with fb - or ~- -cyclodextrin. - - - The inclusion complexes according to the invention contain 1-40 moles, advantageously 2-4 moles of the above cyclodextrin deriva- tives related to 1 mole of N-ethoxycarbonyl-3-morpholino-sydπonimin. The inclusion complexes according to the invention can be prepa¬ red in a way, that N-ethoxycarbonyI-3-morpholino-sydnonimin or its salts are reacted in a solvent with the selected cyclodextrin dεri- vative and if desired the complex is recovered from the solution by dehy ratation. As solvent water and/or with water miscible organic solvents, e.g. C, , alcanols, advantageously ethyl alcohol are used. The complexes according to the invention can be recovered from the solution by lyophilizatioπ, by vacuum drying. The complexes according to the invention may be prepared also by high energy milling of the components as described or referred to in Hungarian patent specification T 52366. The complexes of the invention can be used in the therapy, e.g. in the form of tablets, pellets, icrocapsules, ointments, injections, drops,infusions preferably in the form of one a day tablets or micrccapsules. Doses cf the inclusion complexes of this invention may vary with the age, body weight and conditions of the subject, the administration route, the number of administrations or the like , but is in the range cf 6 to 800 mg per day, preferably 10 to A0 ° m S per day. The retard effect prevails particularly in the case of applying the pharmaceutical composition in the form of one-a day tablets, mic¬ rccapsules and ointments exceedingly suitable for percutaneous use, respectively. The pharmaceutical compositions of the invention are prepareα in a customary manner. The adjuvants and carriers are those which are usually used in the field of pharmaceutical preparations. Lo piex interaction in solution can be illustrateo uy wic n.cnιu_.<_u_e permeation test. Visking-type celloρ:__ne membrane (average pore diameter 24 A°) was applied. Aqueous solutions of Molsidomin at a concentration of 1 and 2 mg/ml were put in the donor cell, while distilled water was placed in the receptor compartment of the membrane permeation cell apparatus. The solutions were stirrεd by magnetic stirrers and were kept at 37 + 1 C. At appropriate time intervals samples were pipetted from the receptor solutions and concentration of Molsidomin permeated from the donor cell was measured by UV-spectrophotometry. The test was repeated in the presence of different cyclodextrins at different con¬ centrations in the donor cell compartment. The time required for the diffusion of 50% Molsidomin (T 50%) is listed in Table 1. Table 1. Diffusion half life (T 50 %) of Molsidomin in the presence of cyclodextrins T 50% (hours) Molsidomin alone 1.0 1.5 1.3 1.8 2.4 1.5 2.0 The permeation rate of Molsidomin can be significantly decreased which points to a considerable interaction between Molsidomin and the examined cyclodextrins. Only the free (uncomplexed) drug can permeate freely across the applied membrane. The concentration of the free drug is depending upon the value of the complex stability constant. The smaller the stability constant the greater is the free drug con- concentration available for permeation. On the contrary if the complex is very stable or the cyclodextrin concentration is sufficiently high (is present in hign excess) the complex dissociation equilibrium is shifted towards the complexation, and the diffusion is considerably hindered. The obtained rεsults provide a principlε for controlling (sustaining, modifying) the release profile of Molsidomin across a se ipermεable membrane forming polymεr by means of cyclodextrin complexation according to the invention. The invention is illustrated by the following examples, without restricting the invention to them. E X A M P L E S 1. olsidomin-Di eb complex prepared by lycphilization. 7 g of Dimeb (5 mmolεs, moisturε content 2%) are dissolved in 100 ml of distilled water, thereafter 0,4 g of Molsidomin are dissolved in the solution obtained. The homogenous solution obtained is frozen and subjected to dehydratation by lyophilization, taking carε that in thε coursε cf working processes the solution should be exposed to the slightest possible light effect. It is expedient to wrap up the vessel while dissolving in a black paper. The product obtained is a light, loose powder, its active ingredient content determined spectrcphctcmetrically is 5+_ 0,4%. It corresponds to a molar ratio of about 1:3 Molsidomin-Dimeb. Test proving the fact of complex formation: Differential Scanning Calorimetric (DSC) curves showed characteristic differences between the physical mixture and thε liophylized complex with DIMEB. The DSC curves of the mechanical mixture and of the complex run differently, in case of the mixture a sharp endother ic peak at 140- 142 °C indicated the melting of Molsidomin, while the curve of the complex shows at this temperature range a sharp exothermic peak. This latter can be explained by the heat induced chemical decomposi¬ tion cf thε complex. X-ray diffractometry: X-ray diffraction pattern of the complex revealed an amorphous structure of the complex, though both of the starting species are crystallinε. Therefore a new type solid state structure can be a result of inclusion complex formation. NMR studies proved that the ethoxycarbonyl part of the Molsido¬ min molecule is located insight the cavity of DIMEB. This is illustrated by chemical shifts (Δ σ ), because the degree of chemical shifts indicates the mode cf inclusion in solution. The most pronouncεd values refεr to the part of the guest molecule which is included in the cyclodextrin cavity. o = -2.2 -+ 1.3 ppm can be measured concerning the ethoxycarbonyl part while practically no chemical shifts can be measured on the morpholinc part of the guest molecule. 2. Preparation of the Molsidomin-Dimeb complex by sorav-dryinq. 14 g cf Dimeb (10 mmoles, moisture content 2%) and 1,2 g of Molsidomin (5 mmoles) are dissolved in 180 ml of distilled water by ultrasonication. The obtained homogenous solution is spray- -driεd, temperature of the input air is 125 °C and that of the output air is 92 °C. While processing the solution, and the vessel containing the product, respectively is protected from light and contiπously stirred. Yield 10 g. The product obtained is a loose white powder, their active ingredient content is about 1, 8__ 0,2 % determined by a spectro- photometric method, it corresponds to a molar ratio of about 1:2. The thermoanalytical curves (DSC) of the spray-dried product and the Rtg. diffraction powder diagram of the same are identical with that cf thε complex prepared by lyophilization. 3. Preparation of Molsidomin- β -CD complex by kneading. 6,6 g of -cyclodextriπ (5 mmoles, moisture content 14 %) and 0,6 g (2,5 mmoles) of Molsidomin are homogenized in a friction mortar protected from light if possible. 3 ml of a 50% ethyl alcohol are added and the dense suspension is stirred for further 30 minutes after spreading the product of hard lubricity and paste like consistence on a watch-glaε_, it is dried to constant weight in the presence of phosphorpentoxide in an exsiccator. The product obtained is pulverized, its active iπgre- dient content is 9+_ 0,5% determined by the spectrophotometric - 7 - method, which corresponds to a molar ratio of about 1:2. DSC curves of Molsidomin, its mechanical mixture and its complex with (b -CD are significantly diffεrεnt. Thε εndothεrmic pεak at 5 140-142 °C on thε DSC curve completely disappeared in the case of complεxεs with -CD prεpared by both kneading or liophylization. It indicates that the Molsidomin is complexed, and at 130-160 C tempεrature range not even a 50 fold magnified curve showed 10 eπdothεrmic peak of melting in thε case of complex preparεd by lyophilization. Taking the DSC curve in argon atmosphere the decomposition of Molsidomin is markedly inhibited upon heating, which eπablεs quantitatioπ of frεε and complεxed amount of Molsidomin, based 15 upon the comparation of the melting peak areas. Thε mεlting of purε Molsidomin is rεleatεd to an επthalphy changε of Δ H =140 mJ/mg. Thε εntirε amount of Molsidomin provεd to bε complεxεd in thε case of frεeze dried complex and less than 10% of the Molsidomin 20 content is absorbed in complex prepared by kneading. 4. Preparation of Molsidomin HP-/.3-CD complex by lyophilization. 13 g HP-/3-CD (0,01 mole) (DS = 2,7 DS means the averagε substi¬ tution degrεε per cyclodextrin moleculε) arε dissolvεd in 100 ml 25 of distilled water. 0,7 g of Molsidomin are added and the dissolution is promoted by stirring, the solution is protected from light. The homogenous solution obtained is dehydrated by methods as in former examples. The product is a loose white powder, its Molsidomin content is 5_+ 0,2 % by the spectrophoto- 30 metric method, which corresponds to a molar ratio of about 1:3 Molsidomin : HP- (b -CD. 5. Preparation of Molsidomin- A -CD complex granule by kneading. 1 g (4,1 mmol) of Molsidomin and 11 g of /5-CD (8,3 mmol 35 moisture content 14 %) are mixed in a mortar, 4 ml of 30 ' % ethyl alcohol are added, the dense suspension is kneadεd for 30 minutes. The obtained product of paste likε consistεnce was spread on a tray and driεd at 40 C for two hours. Thεrεaftεr the semidried product was rubbεd through a sieve of pore size 1 mm. The obtained granule was dried at 60 C to constant weight and screεnεd rεpεtεadly through a sieve obtaining grains of thε dεsirεd sizε. Activε ingrεdiεnt content 10+ 0.5 % determined by UV-spectropho- tometry, corresponding approximately to 1:2 molar ratio of Molsidomin,: (b -Cϋ . The obtained granule has appropriate flowing properties with low powder fraction and is applicable to makε a tablet core containing the medicament in the dεsirεd dose by direct compression, or preparing sustained release formulation by direct compression with known matrix forming polymer components, or applying thε fluidization tεchniquε for preparing film coatεd pellets, wherε the coating acts as a semipεrmeable membrane during the dissolution process. The tablet core obtained by the simplest direct compression technology is applicable for prεparing controllεd sustainεd release dosage froms by coating them with polymer or a blεnd of polymεrs known in thε art. Mεmbranε permeation test. Dialysis profile of Molsidomin- -CD granule was examinεd using the same permεation cεll as described above. Molsidomin at a concentration of 1 mg/ml and εquivalεnt amount of complex granule were used in the experiment The measurable Molsidomin concentrations in the receptor cell at different time intervals are listed in Table 2. Table 2 Concentration of Molsidomin in the recεptor cell. Timε (hours) Mols dcmin_alone Molsidomin-j _-CD_granule 9oπceπtratioπ_ rng/rnl2 1 0.20 0.16 2 0.29 0.24 3 0.32 0.27 4 0.3 0_.31 00% diffusion corresponding to 0.33 mg/ml Molsidomin concentrati- on in the receptor cell. p. Molsidomin tablet o_f_ 2_ ___ active inqrεdient content per tablεt. Composition: 40 g of Molsidomin-Dimeb complex with a 5% active iπgrediεnt content, prepared according to example 1. 40 mg of maize starch 78 mg of milk sugar 2 mg of magnesium stearate Total weight of the tablet: 160 mg 7. Preparation of ointment for percutaneous use containing 10 mg of Molsioomin as active agent and 7_ _\ ___ gel Molsidcmin-Dimeb complex (active ingredient content 5%) 2 g are dissolved in 20 ml of distilled water. To the solution 50 mg of KLUCEL-HF (hydroxi-propyl cellulosε) are added while vigorous stirring. A viscous soluticn hardly to stir is obtained which is let to stand for 1 day at room temperaturε, protεctεd from light. Thus a transparent oiπtmεnt is formed, 2 g of which rnrifaliins 10 mg of Molsidomin. 8. Non sustained releasε formulations: b. ) Molsidomin-/?) -CD-complex c) d.) Molsidomin- β-CD-complex (contains 1 to 15% Molsidomin) 50 mg Lacca depurata 8 mg Saccharcsε 127 mg Maize starch 40 mg Talc 3 mg Polyvidonum 22 mg Fδr~δήe " tiblεt7 TUTAL "" 25θ " mg " f . ) Molsidomin- -CD-complex (contains 1 to 15% Molsid Lactose anhydrous Cellulose microcrystalli Magnesium stearate F5r ~ δπε ~ tIbIεtT 9. Sustained release formulation b. ) Molsidomin- (b -CD-complex (contains 1 to 15% Molsidomin) 15000 carboxymethylcellulose Lactose 1 H„0 Magnesium stearate For one tablet: " TOTA = c.) Molsidomin- (b -CD-complex (contains 1 to 15% Molsidomin) Carnauba wax Stεarylic acid Magnεsiu stεarate Fcr ~ δήe~ti5IεtT TOTAL -' d.) Molsidomin- (h -CD-complex (contains 1 to 15% Molsidomin) P.V.C. P.V.A. Magnesium stearate Fδr~δne " tabIetT TOTAL -" e. ) Molsidomin-/i-CD-complεx (contains 1 to 15% Molsidomin) 150 mg Ethylcεllulose 300 mPa.s. 300 mg Ethylcεllulose 30 Pa.s. 48 mg Magnesium stearatε 2 mg Fδr * δni-tibIεtT T5TAL -- ≡ 500 -- mg

Claims: What wε claim is: 1. Inclusion complεx of N-ethoxycarbonyl-3-morpholino-sydnonimiπe or its salt formed with a cyclodextrin derivativε. 2. Inclusion complεx of N-εthoxycarbonyl-3-morpholino-sydnonimiπε or its salt formεd with a heptakis-2,6-0-dimethyl-/ **3 -cyclodεxtriπ. 3. Inclusion complex according to claim 1, containing 1-40 moles, advantageously 2-4 moles of heptakis-2,6-0-dimεthyl-/ϊ> -cyclodεxtrin related to 1 mole of N-ethoxycarboπyl-3-morpholino-sydπonirninε. 4. Inclusion complεx of N-εthoxycarbonyl-3-morpholino-sydnoπimine or its salt formed with hydroxypropyl- -cyclodextrin. 5. Inclusion complex of N-ethoxycarbonyl-3-morpholino-sydπoπimine or its salt formed with (b - or γ-cyclodεxtrin. 6. Procεss fcr thε preparation of the inclusion complex of N-ethoxy- carbonyl-3-morpholino-sydnoπimine or its salt formed with a cyclo¬ dextrin derivative, which comprises a.) reacting thε N-ethoxycarbonyl-3-morpholino-sydnoπimine or its salt and thε cyclodεxtrin derivative in a solvent medium, and if desired recovering the complex from the solution by dehydratation, or b.) high energy milling of the N-ethoxycarbonyl-3-morpholino-sydnon- iminε or its salt and thε cyclodextrin derivative. 7. Process according to claim 6, characterizεd by, that as cyclo- dεxtrin derivative heptakis-2,6-0-dimethyl- f- -cyclodεxtrin, hydroxy¬ propyl- ( -cyclodεxtriπ or /•* - or y-cyclodextrin are used. 8. Process according to claim 6, characterized by, that as solvent water and/or with water miscible organic solvents are used. 9. Process according to claim 8, characterized by, that as with water miscible organic solvents C, -, alcanols, advantageously ethyl alcohol are used. 10. Procεss according to claim 6, charactεrized by, that the complex is recovered from the solution by lyophilization, spray-drying, vacuum drying. 11. Pharmaceutical composition comprising as active ingredient an effective amount of the inclusion complex of N-ethoxycarbonyl-3- -morpholino-sydπoπimine or its salt formed with heptakis-2,6-0-di- εthyl- (b -cyclodεxtriπ or with hydroxypropyl- J-cyclodextrin or (_ - or -y -cyclodextrin and customary pharmaceutical filling, diluting and furthεr auxiliary matεrials. 12. Pharmaceutical composition according to claim 11, charactεrized by, that it is formulated in the form of one-a day tablet or a mic- rocapsule. 13. Procεss for ths prεparation of a pharmaceutical composition characterizεd by, that an effectivε amount of thε inclusion complex of N-ethoxycarbonyl-3-morpholino-sydnσnimine or its salt formed with heptakis-2,6-0-dimεthyl- ft> -cyclodεxtriπ or with hydroxypropyl- - -cyclodextrin or (b - or ~γ -cyclodextrin is admixed with customary pharmaceutical filling, diluting and further auxiliary materials and transformed into a pharmacεutical composition. 14. Pharmaceutical composition comprising as active ingredient an effεctivε amount of N-ethoxycarbonyl-3-morpholino-sydnonimine or its salt and heptakis-2,6-0-dimεthyl- -cyclodεxtrin or hydroxy- propyl- [ -cyclodextrin, or β -, or ~γ- -cyclodextrin and custo¬ mary pharmaceutical filling, diluting and further auxiliary materials. 15. Pharmaceutical composition according to claim 14, characterized by, that it is formulated in the form of one- a day tablet or a mic- rocapsule. 16. Procεss for thε prεparation of a pharmaceutical composition, characterizεd by, that an effective amount of N-ethoxycarbonyl-3- -morpholino-sydnoπiminε or its salt is admixεd with hεptakis-2,6-0- -dimethyl- β> -cyclodextrin, or hydroxypropyl- β -cyclodεxtrin or (b - or y-cyclodεxtrin and with customary pharmaceutical filling, diluting or further auxiliary materials and is transformed into a pharmaceutical composition. 17. Method of treatment of anginic and ischemic diseases in humans which comprises administering to the human an effεctivε amount of an inclusion complεx of N-ethoxycarboπyl-3-morpholino-sydnonimine or its salt formed with a cyclodextrin derivative.

Inventors: GAAL JOZSEF, HERMECZ ISTVAN, HOVARTH AGNES, HOVARTH GABOR, MARMAROSI KATALIN, MUNKACSI IREN, SZEJTLI JOZSEF, VIKMON MARIA, GAAL, JOZSEF, HERMECZ, ISTVAN, HOVARTH, AGNES, Hovarth, Gabor, MARMAROSI, KATALIN, MUNKACSI, IREN, SZEJTLI, JOZSEF, VIKMON, MARIA
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER- ES VEGYESZETI TERMEKEK GYARA RT
Application year: 1991
Main classification: C07D271
IPC codes: A61K31, A61K47, A61P9, C07D271, C07D413, C08B37