HU211906A9 - Inclusion complexes of n-ethoxycarbonyl 1-3-morpholino-sydnonimine or salts formed with cyclodextrin-derivatives, preparation thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

The inclusion complex of 3-morpholino-synthonimine, its salt or tautomeric isomer is rewarded with cyclodextrin or a cyclodextrin derivative.

Description

The present invention relates to inclusion complexes of N-ethoxycarbonyl-3-morpholinosidoniminimine (Molsidomin) or salts thereof with heptakis 2,6-O-dimethyl-4-cyclodextrin (Dimeb), hydroxypropyl-β-cyclodextrin, or β- or γ-cyclodextrin, processes for their preparation and pharmaceutical compositions containing them.

TECHNICAL STATE

Molsidomin is an antianginal and anti-ischemic agent that is widely used for the prevention and treatment of angina pectoris. Its advantage over organic nitrates is that it has a much longer lasting effect and fewer side effects, so it does not lead to habituation, causes less headaches and is less severe. Its anti-arrhythmic, fibrinolysis, platelet aggregation and antihypertensive effects are also outstanding.

Molsidomin is available as tablets containing 2 and 4 mg (conventional) and 8 mg (delayed-release) of the active ingredient, Corvaton (Casella, Riedel), Morial (Takeda). The delayed-release formulation contains the active ingredient in a microencapsulated form in a 1: 4 ratio using special wax, which provides effective plasma concentrations for 12 hours.

Molsidomine is relatively soluble in water (18 mg / ml at 25 ° C) and is stable in water at pH 5-7. Absorption from the gastrointestinal tract does not appear to be the rate-determining step of solubility. It is an oral preparation containing 2 mg of active substance

Effective for 3-5 hours. Maximum blood levels are reached within 1/2 to 1 hour. It is well absorbed throughout the GI tract and is well bioavailable.

The controlled release formulation is the most ideal for the effective use of antianginal compositions for preventive purposes. This provides sustained and controlled drug absorption, consistent and therapeutically effective plasma levels. Side effects can be significantly reduced by eliminating toxic plasma levels that are too high. Particularly preferred is a controlled release transdermal formulation.

The absorption of the drug through the skin depends on the physicochemical properties, lipid solubility and most particularly on the formulation used. Molsidomin alone is slowly and slightly absorbed through the skin, with a relative bioavailability of only 4%, so absorption enhancers are used. Takeda Company No. 127,468. European Patent Specification No. 4,101,121 discloses a percutaneously absorbable formulation of Molsidomin containing a special bi-component absorption enhancer of propylene glycol containing -10% oleic acid.

The mechanism of the exceptionally good 95% bioavailability may be as follows: The oleic acid component changes the permeability of the skin's protective layer (stratum corneum) by dissolving its lipoid components. Through this modified stratum comeum, the Molsidomin is readily absorbed.

Molsidomine and propylene glycol were found to have similar extent and amount of absorption, meaning that only Molsidomine dissolved in propylene glycol is absorbed.

DESCRIPTION OF THE INVENTION

It has been found that the effect of molsidomine or its salts can be retarded by complexation with heptakis-2,6-O-dimethyl-4-cyclodextrin, hydroxypropyl-4-cyclodextrin, or β- or γ-cyclodextrin.

The present invention relates to inclusion complexes of N-ethoxycarbonyl-3-morpholinosidonimine or its salts with heptakis-2,6-O-dimethyl-4-cyclodextrin, hydroxypropyl-4-cyclodextrin, or β or γ-cyclodextrin. The inclusion complexes of the present invention contain from 1 to 40 moles, preferably from 2 to 4 moles, of one of the above cyclodextrin derivatives per mole of N-ethoxycarbonyl-3-morpholinosidnonimine. The inclusion complexes of the present invention may be prepared by reacting the N-ethoxycarbonyl-3-morpholinosidononimine or its salts with the selected cyclodextrin derivative in a solvent medium and, if desired, recovering the complex from the solution by solvent removal. The solvent is water and / or a water-miscible organic solvent, for example C 1 -C 4 alkanols, preferably ethanol. The complexes of the invention can be obtained from the solution by lyophilization and vacuum drying. The complexes of the present invention may also be prepared by treating the components with high energy milling as described and referenced in Hungarian Patent No. T 52,366. The complexes of the present invention are useful in medicine, for example in the form of tablets, dragees, microcapsules, ointments, injections, drops, infusions, preferably once-a-day tablets or microcapsules.

The dosage of the inclusion complexes according to the invention may vary with age, body weight and general condition of the patient, the mode, number of treatments and the like, but is usually in the range of 6-800 mg, preferably 10-400 mg per day. The prolonged action is particularly pronounced for once-a-day tablets, microcapsules or percutaneous ointments particularly suitable. The pharmaceutical compositions of the invention are prepared in a conventional manner. Fillers, diluents, and other excipients used are conventional in pharmaceutical formulations.

The complex interaction in solution is demonstrated by membrane diffusion assay. Visking cellophane membrane (average pore diameter 24 Å) was used. An aqueous solution of Molsidomin 1 and 2 mg / ml was added to the donor cell of the membrane diffusion apparatus and distilled water to the receptor cell. The solution was thermostated at 37 ± 1 ° C and stirred with a magnetic stirrer. At intervals, samples of the receptor solution were taken and the concentration of Molsidomine permeated from the donor cell was determined by UV spectrophotometry. The assay was repeated in the donor cell in the presence of different concentrations of different cyclodextrins.

Table 1 shows the time required for the diffusion of 50% of Molsidomin (T 50%).

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Table 7

Molsidomin diffusion half-life (T 50%) in the presence of cyclodextrins

T 50% (hour) Molsidomin alone 1.0 + PCD 20 mg / ml 1.5 + DIMEB 25 mg / ml 1.3 50 mg / ml 1.8 100 mg / ml 2.4 + ΗΡβΰϋ 50 mg / ml 1.5 100 mg / ml 2.0

The diffusion rate of Molsidomin can be significantly reduced, indicating the interaction between Molsidomin and the cyclodextrins studied.

Only the free (uncomplexed) material can diffuse freely through the membrane used. The concentration of free substance depends on the stability constant of the complex. The lower the stability constant, the higher the concentration of the transdiffused free drug. Otherwise, if the complex is very stable or the concentration of cyclodextrin is sufficiently high (in large excess), the dissociation equilibrium of the complex shifts towards complex formation and diffusion is significantly inhibited. According to the results obtained, in the presence of cyclodextrin according to the invention, the dissolution profile of the molyddomin can be controlled (modified, delayed) through a polymer forming a semipermeable membrane.

The invention is illustrated by the following examples, but the invention is not limited thereto.

EXAMPLES

Example 1

Preparation of Molsidomin-Dimeb Complex by Lyophilization g Dimeb (5 mmol, 2% moisture) was dissolved in 100 mL of distilled water and 0.4 g of Molsidomine was dissolved in the resulting solution. The resulting homogeneous solution is frozen and then freeze-dried to ensure that the solutions are exposed to as little light as possible during the process. It is advisable to wrap the flask in black paper for dissolution. The product obtained is a light, loose powder with an active substance content of 5 ± 0.4% as determined by spectrophotometry, which corresponds to a molar ratio of approximately 1: 3 Molsidomin-Dimeb.

Studies proving the fact of complex formation

Differential Scanning Calorimetry (DSC) curves showed a characteristic difference between the physical mixture and the lyophilized complex with DIMEB. The DSC curves of the physical mixture and the complex have different curves, with the endothermic peak at 140-142 ° C in the physical mixture indicating the melting of Molsidomin. whereas the complex curve exhibits a sharp exothermic peak at this temperature range. The latter can be explained by the chemical decomposition of the complex under the influence of heat.

X-ray diffraction

The X-ray diffraction pattern of the complex indicates the amorphous structure of the complex, although both starting materials are crystalline. Thus, the new type of solid phase structure may be the result of complex formation.

¹³ C-NMR showed that the ethoxycarbonyl group of the Molsidomin molecule is enclosed in the DIMEB cavity. This is evidenced by the chemical shift (Δδ) because the degree of chemical shift refers to the inclusion in the solution. The most significant value is the part of the guest molecule that is enclosed in the cyclodextrin cavity. Δδ = -2.2- +1.3 ppm can be measured on the ethoxycarbonyl portion of the molecule, while practically no chemical shift is detected on the morpholino portion of the foreign molecule.

Example 2

Preparation of Molsidomin-Dimeb complex by spray drying g Dimeb (10 mmol, 2% moisture), and

Molsidomine (1.2 g, 5 mmol) was dissolved in distilled water (180 mL) with sonication. The resulting homogeneous solution was spray-dried with inlet air at 125 ° C and outlet air at 92 ° C. During processing, the solution and container containing the product are protected from light and stirred continuously.

Yield: 10 g.

The product formed is a loose white powder, containing the active ingredient

7.8 ± 0.2% by spectrophotometry, which corresponds to a molar ratio of approximately 1: 2.

Thermalanalytical curves (DSC) of the spray-dried product and Rtg. diffraction powder diagram is the same as that obtained by lyophilization.

Example 3

Preparation of molsidomin-fi-CD complex by kneading

6.6 g of β-CD (5 mmol, 14% moisture) and 0.6 g (2.5 mmol) of molsidomine are homogenized in a mortar, preferably protected from light. 3 ml of 50% ethyl alcohol are added and the thick slurry is stirred for an additional 30 minutes. The resulting hard-to-spread paste-like material is spread on a watch glass and dried in a desiccator in the presence of phosphorus pentoxide to constant weight. The product obtained is pulverized with an active ingredient content of 9 ± 0.5%. spectrophotometrically, which corresponds to a molar ratio of approximately 1: 2.

The DSC curves of the physical mixture and complex of β-cyclodextrins of Molsidomin are significantly different. The 140-142'C endothermic peak disappears completely with the lyophilized and kneaded complex made with PCD. This indicates that the Molsidomin complex is present and that at the temperature range of 130-160 ° C, the endothermic peak characteristic of the melt is not visible even on the curve of the lyophilized complex at a magnification of 50 times. The DSC curves recorded under an argon atmosphere significantly reduce the thermal decomposition of Molsidomin, allowing determination of the amount of free and complexed Molsidomin based on the area of the melting curves.

The melt of pure Molsidomine was ΔΗ = 140 mJ / mg

EN 211 906 A9 enthalpy changes. The total amount of AMolsidomin complexed with the lyophilized complex and less than 10% of the Molsidomin content was adsorbed to the kneading complex.

Example 4

Preparation of Molsidomin HP - $ - CD Complex by Lyophilization g ΗΡ-β-CD (0.01 mol) (DS = 2.7, DS represents the general degree of substitution per molecule of cyclodextrin) is dissolved in 100 ml of distilled water. Molsidomine (0.7 g) is added and the solution is stirred to aid dissolution, protecting the solution from light. The resulting homogeneous solution was dewatered as in the previous examples. The product is a loose white powder with a Molsidomin content of 5 + 0.2% spectrophotometrically, which corresponds to a molar ratio of Molsidomin to HP-P-CD of approximately 1: 3.

Example 5

Preparation of the Molsidomin β-cyclodextrin complex granule by kneading Homogenize g (4.1 mmol) of molsidomine and 11 g of pCD (8.3 mmol, moisture content 14%) in a mortar, add 4 ml of 30% ethyl alcohol, the slurry for 30 minutes. knead. The resulting paste-like material was spread on a watch glass. Dried at 40 ° C for 2 hours. The semi-dry product was then passed through a 1 mm mesh sieve. The resulting granulate was dried at 60 ° C to constant weight and sieved repeatedly through a sieve of the desired particle size.

The drug content, determined by spectrophotometry at 10 ± 0.5%, corresponds to a molar ratio of Molsidomine to CD of approximately 1: 2.

The resulting granules are suitable for the preparation of tablets of suitable powder, low powder fraction, suitable for direct compression or sustained release formulations, direct compression with known matrix-type polymers, or film-coated pellets with the coating as a semipermeable membrane. course. The simplest direct compression tablet is also suitable for the preparation of a controlled release formulation, known in the art as coated with a polymer or polymer blend.

Membrane Permeation Assay The dialysis profile of Molsidomin-β-cyclodextrin granules was investigated in a permeation device as described above. Molsidomine solution (1 mg / ml) and an equivalent amount of complex granules were used for the experiment. The concentrations of Molsidomine measured at different time intervals are as follows:

Table 2 summarizes this

Table 2

Molsidomine concentration in the receptor cell is mg / ml

Time (hours) Molsidomin alone Molsidomin-PCD granule 1 0.20 0.16 2 0.29 0.24 3 0.32 0.27 4 0.34 0.31

100% diffusion corresponds to a concentration of 0.333 mg / ml Molsidomine in the receptor cell

Example 6

Molsidomin tablets containing 2 mg of active ingredient per tablet. Ingredients:

a.) 40 mg of Molsidomin-Dimeb complex containing 5% active ingredient, prepared as described in Example 1.

mg corn starch mg lactose mg magnesium stearate

Total tablet weight: 160 mg.

Example 7

Preparation of an ointment for percutaneous administration in a 2 g gel containing 10 mg of Molsidomin as active ingredient.

Molsidomine-dimeb complex (active ingredient content 5%) is dissolved in 20 ml of distilled water. 50 mg of KLUCEL-HF (hydroxypropyl cellulose) are added under vigorous stirring. A viscous, difficult to mix solution is obtained which is left at room temperature for one day, protected from light. This produces a transparent ointment (gel) containing 2 g of Molsidomine in 2 g.

8.példa

Non-delayed release formulations

the.) Molsidomin P-CD Complex (115% Molsidomin Content) 100 mg 50 150 300 200 250 Na starch glycolate 10 mg 10 15 20 20 20 saccharose 90 mg 125 133 140 13 145 Maize starch 5 mg 5 7 12 10 12 glucose 14 mg 29 20 14 21 23 Silicon dioxide 8 mg 8 12 10 10 11

HU 211 906 A9

Magnesium stearate 3 mg 3 3 4 4 4 Per tablet: Total 230 mg 230 340 500 400 465 b.) Molsidomin P-CD Complex (115% Molsidomin Content) 50 mg 100 150 200 250 300 Silicon dioxide 0.1 mg 0.2 0.3 0.4 0.4 0.5 Ethyl cellulose 20cps L5 mg 3 4 5 5 5 corn starch 45 mg 60 65 70 70 70 Magnesium stearate 1 mg 2 3 4 4 5 polyvidone 4 mg 6 7 8 8 8 talc 3 mg 5 7 8 8 8 milk sugar 125.4 123.8 133.7 104.6 104.6 103.5 Per tablet: Total 230 mg 300 370 400 450 500 c.) Molsidomin p-CD complex (ΟΙ 5% Molsidomin content) 50 mg 100 150 200 250 300 Lactose 25 mg 30 35 35 35 30 polyvidone 10 mg 12 15 15 15 15 Maize starch 37 mg 50 50 50 50 50 talc 10 mg 12 12 15 15 15 Magnesium stearate 3 mg 4 4 4 5 5 saccharose 166 mg 112 114 101 90 85 Per tablet: Total 300 mg 320 380 420 460 500 d.) Molsidomin P-CD Complex (115% Molsidomin Content) 50 mg 100 150 200 250 300 Lacca depurata 8 mg 10 12 14 15 15 saccharose 127 mg 111 103 93 85 80 Maize starch 40 mg 50 50 50 50 50 talc 3 mg 4 5 8 10 10 polyvidone 22 mg 25 30 35 40 45 ! Per tablet: Total 250 mg 300 350 400 450 500 e.) Molsidomin p-CD complex (115% Molsidomin content) 50 mg 100 150 200 250 Manittol 160 mg 129 105.5 102 92 Maize starch 92 mg 80 70 70 60 milk sugar 50 mg 60 70 70 80 hypromellose 4 mg 6 8 10 10 Magnesium stearate 2.5 mg 3 3.5 4 4 Silicon dioxide 1.5 mg 2 3 4 4 Per tablet: Total 360 mg 380 410 460 500 f) Molsidomin P-CD Complex (115% Molsidomin Content) 50 mg 100 150 200 Lactose anhydrous 225 mg 187 186 176 Microcrystalline cellulose 72 mg 90 100 120 Magnesium stearate 3 mg 3 4 4 Per tablet: total 350 mg 380 440 500

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Example 9

Delayed release formulations

the.) Molsidomin p-CD complex (1-15% molsidomin content) 150 mg 200 250 300 350 saccharose 41 mg 55 68 82 95 Maize starch 13 mg 17 22 26 31 polyvidone 6 mg 8 10 12 14 For microencapsulated preparation 210 mg 280 350 420 490

b.) Molsidomin-P-CD Complex (1-15% Molsidomin content) 150 mg 200 250 300 Carboxymethylcellulose (15,000) 115 mg 156 150 130 Lactose H ₂ O 62 mg 60 56 65 Magnesium stearate 3 mg 4 4 5 Per tablet: Total 330 mg 420 460 500

c.) Molsidomin-P-CD Complex (1-15% Molsidomin content) 50 mg 200 250 Kamauba wax 215 mg 220 245 Stearic acid 66 mg 82 100 Magnesium stearate 2 mg 3 3 Per tablet: Total 333 mg 405 500

d.) Molsidomin p-CD complex (1-15% molsidomin content) 150 mg 200 250 PVC 111 mg 120 122 PVA 111 mg 120 122 Magnesium stearate 3 mg 5 6 Per tablet: Total 375 mg 445 500

e.) Molsidomin p-CD complex (1-15% Molsidomin content) 150 mg Ethyl cellulose (300 mPas) 300 mg Ethyl cellulose 30 mPa.s) 48 mg Magnesium stearate 2 mg Per tablet: Total 500 mg

f> Molsidomin-P-CD Complex (1-15% Molsidomin content) 150 mg 200 250 300 350 Calcium diphosphate 39 mg 52 66 78 80 Eudragit (Not 400) 34 mg 45 57 68 70 Magnesium stearate 3 mg 4 5 5 6 talc 4 mg 5 7 9 9 Total for each tablet 230 mg 316 385 460 515

Claims (8)

PATENT CLAIMS CLAIMS 1. An inclusion complex of a 1: 1 to 1:40 molar ratio of N-ethoxycarbonyl-3-morpholinosidnonimine or its salts with a cyclodextrin derivative. 2. N-ethoxycarbonyl-3-morpholinosidnonimine or its salts with heptakis-2,6-O-dimethyl-β-cyclodextrin The inclusion complex of claim 1. The inclusion complex according to claim 1, containing 2-4 moles of heptakis 2,6-O-dimethyl-β-cyclodextrin, based on 1 mole of N-ethoxycarbonyl-3-morpholinosidnimine. The inclusion complex of N-ethoxycarbonyl-3-morpholinosidnonimine or its salts according to claim 1 with hydroxypropyl-β-cyclodextrin. The inclusion complex of N-ethoxycarbonyl-3-morpholinosidnonimine or its salts according to claim 1 with β- or γ-cyclodextrin. 6. A pharmaceutical composition comprising N-ethoxycarbonyl-3-morpholinosidnonimine or salts thereof in a ratio of 1: 1 with heptakis-2,6-O-dimethyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin or β- or γ-cyclodex155. : Contains an effective amount of its 40 molar inclusion complex and conventional pharmaceutical fillers, diluents, and other excipients. The pharmaceutical composition of claim 6 Characterized in that it is formulated as a once-a-day tablet or microcapsule. 8. A method of treating human angina and ischemia, wherein the human treatment is N-ethoxycarbonyl-3-morpholinosidonimine or salts thereof. An effective amount of its inclusion complex with a cyclodextrin derivative according to claim 1.