SK85291A3 - Inclusion complex of 3-morpholinozydnolimine, its salts or its tautomer, method of its preparation and pharmaceutical agents which containing it - Google Patents

Abstract

Clathrates (I) of 3-morpholino-sydnonimine (II), or its salts or open-ring tautomer (N-nitroso-N-morpholinoamino -acetonitrile), with cyclodextrin derivs. (III) are new. N.B., cpds. (III) include unsubstd. beta- or gamma-cyclodextrins. (II) is an active metabolite of the anti-angina agent molsidomin (N-ethoxycarbonyl-3- morpholino-sydnonimine). (III) are selected from beta- and gamma-cyclodextrin, heptakis-2,6-dimethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and a water-soluble ionic beta-cyclodextrin polymer (CDPSI; see HU191101).

Description

Clad techniques

The invention relates to the inclusion complexes of 3-morpholinosydnonimine (SIN-1) or its salts or its tautomeric chain form with an open chain A (SIN-1A: N-nitroso-N-morpholino-amino-acetonitrile) formed with cyclodextrin derivatives. pharmaceutical compositions containing them as active ingredient. The open ring form ** A has an important task, its formation being dominant for the release of NO / nitrite oxide / radical.

BACKGROUND OF THE INVENTION

Kolsidomin / N-3-ethoxykerbonyl morfolinosydnoni »nin _t SIN10 / entianginálním the well known agents. In therapy, it is widely used to treat or prevent angina in cases of cardiac insufficiency, in a heart attack condition. The therapeutic action of olsidomine can be attributed mainly to its first active metebolite, 3-morpholinosydnonimine, which is mainly due to enzymatic hydrolysis and subsequent action of the decerboxylase enzyme. Therefore, SIN-1 has therapeutic advantages over olsidomine, since its action is faster and many more accurate.

Its disadvantage is moreover that it can be administered by a single form of intravenous injection.

The Sydnonimine derivatives are extremely light sensitive. Hyleys are decomposed by irradiation with artificial or natural light and pc jer. for a short time. Photolysis results in pharmaceutically ineffective but harmful decomposition products such as morphelin, ammonia, ethyl alcohol, carbon dioxide. The heat of some patent publications is the convenience of the sydnonimine derivatives by the addition of various additives. / European Petition No. 2 (.6219 e German Patent No. 3 346638 ·)

Light sensitivities can fairly be prevented in a dry state in the presence of solutions by suitable storage (in a well-sealed dark bottle filled with black epoxy).

It has been reported that sydnonimine derivatives sensitive to extreme values are believed to swell rapidly. The final product of chemical and metebolic decomposition of glandidomine is S1N1C (acid methylenesminomorpholine), which is an ineffective metaboity. The use of S1K1 as a drug has problems in its chemical stability. The substance decomposes rapidly in a neutral aqueous solution, is pH sensitive and is still only in a strong acidic medium / pH 1 to 2. Above pH 2, it decomposes rapidly to the ineffective methebolite SIN 10, resulting in a loss of therapeutic efficacy . Trensformace

SIN 1-SIN 10 is the result of a base to a catalytic hydrolysis decomposition. s ^{If the} rcces''jé'pŕíšn.čz'ávisl^' ria of the pH, '' does not give 'a'dcs'ežérií% degradation 1c / SIN 10/53 sec hodnetč at pH 8, in 15 hours at a pH 6 e at 67 days at pH 4 e at 13 years at pH 1-2. Pharm. Bull. 1979, 1079, 1971./

SIN 1 has also been decomposed in dilute aqueous solution stored under diffusive illumination for as little as 3 days. The decomposition can directly monitor »t by UV spectrum, is ebsorpčního maximum of + 4 SE moves to the procedures of 291-1 nm to 278-1> of & Timcho value of ultraviolet absorption continuous types excit and city, which is in Conformity Parametry with that in the letter Turej _{ζ ί} SSX value of SIN 1 is 291 - 1 nm, coefficient of specific1 · & 4 * absorption A ^v is 520, while for S1M 1C max is 278 - t nm & coefficient of tertiary ebsorption

... ___ *, ¾ 1 ___ <Z, f. rt, ¢ - - i / v v in A - 1 2 c.

i CE ^Ú / <

Silyl administered at a non-linear rate, at a pH of 1 to 2, Slii 1 is likely to be in a strong ionized state favorable for chemical stability, but not conducive to resorption in the stomach and intestinal tract. When proceeding from the stomach in a more basic environment, the above mentioned occurs quickly

to the ineffective S1N 1C metabolite. A low dose of SIN 1 administered is favorable for this trensformation since the hydrolytic decomposition at low concentration (µ / ml order) is more pronounced.

SXN I is commercially available in the form of its hydrochloride salt, for intravenous administration it is in the form of a freeze-dried powder in an ampoule containing 2 tags of active ingredient and 4 mg of sorbitol. Obash ampoules and then dissolve in 1 ml distilled science before use,

It is an object of the invention to provide a novel novel composition which has prevented trensformation

Thus, SIN 1-y SIN 1C in a neutral aqueous solution would remain at its physiological value.

The essence of vynáleau

Accordingly, the present invention is directed to an inclusion complex of 3-cyclinosydnonimine or a salt or tautomeric ester thereof with a cyclodimer derivative. It is known that complexing with cyclodextrin is suitable for stabilizing various agents against the effects of heat, light alkaline or acidic hydrolysis / Szejtli: Cyclodextrin Technolcgy Cyclodextrin Technology - Kluwer, Dordrecht, 1988, p. 211-217].

Cyclodextrins have been found to be effective in stabilizing dilute aqueous solutions obtained from SIN 1 injectable compositions.

The interaction between SIN 1 and cyclodextrins is determined by the following tests;

2e vatŕikovc luminous SIN 1 was prepared, the aqueous Ráztoky koncenti'aci approximate 10 / ug / IAL, and the solution was stirred rozpuetí 20-40 mg of cyclodextrin derivative of cyclodextrin hebo · _IIC cold solution stored? at a room temperature (20-22 ° C) in the diisin light in each time period (daily), the BV spectrum of the solutions is recorded in the interval 20 20 to 2% nm. For comparison, only an aqueous solution of 0.05 N solution is used

hydrochloric acid. The pH of the cyclodextrin solutions is staggered to reveal that the cyclodextrin and its possible derivatives used do not change the significant pH of the science. The pH values of the most recent cyclodextrin solutions used are different from the pH of the distilled water. It has been found that CDPSI, which is ionically soluble (β-cyclodextrin polymer / having a mean molecular weight of 3500, having an A-CD 54 radius of &quot; COO &quot; 4.2 &quot; &lt; / RTI &gt; K. Spectrum shift does not occur after weeks of storage, while an aqueous solution, similar to that stored, is practically transformed to SiN 1C within two to three days.

DIMEB decomposition inhibition (2,6-di-C1-methyl-N-cyclodextrin) is significant in the presence of 20 mg / ml D1MEB exhibits a flux solution shift within 1 nm at six day fading. It has also been found that the stabilizing action of TKili (2,3,6-tri-O-ethyl, N, N-cydipextrin), N-Cp. (). efficiency derived from the UV spectrum is as follows

CDPSI THIMEB *> / 1.CD HP β CD

From the effect on the hydrolytic decomposition of SIN 1 different. cyclodextrin can be attributed to the excellent characteristics of CDPS1

In the early cyclodextrin assays, their derivatives are added in extremely large amounts (10 µg / 1 SXN 1 to about 20 mg, / ml cyclodextrin).

The test series is repeated using CDPSI in multiple and 20-fold excess, corresponding to the mass ratio SIN 1; CDPSI in a complex containing 1 G 7a pOJ / ml of active ingredient. The low therapeutic dose of S1N1 also allows the administration of a complex containing less than 5 ® active ingredient, corresponding to a molar ratio of approximately 1: 2 S1M 1: CDPSI. In the flow field of concen- tration, spectrometric measurement does not give a descriptive image, and therefore the degree of decomposition is determined by thin-film chromatography in the following manner:

10 µl of 6 µl (10 x 10 cm) was poured dropwise from the slides. Mixtures of cycloohexene are used:

Ethyl acetate in 1: 1 ratio. The tube is left unsaturated for 30 minutes. the SIN 1C reference solution is also not applied dropwise. The cap plate is dried with a stream of cold air from the ρϊ-ed light and allowed to receive up to 15 ° C. During this operation, the tube is kept in a dark place. After evaporation of solvent 8, the plate visually evaluates in UV light at 254 nm. SIN 1 has a value of 0.05 R ^ and SIN 1C has an R ^ value. 0.36. In your case, it has been found that in case of CDPSI containing solutions, the intensity of the SIN 1C spot is less than in the case of aqueous solutions.

Since the SIN 1 non-inactive metebolite trensformation is highly pH dependent, measurements are made in phosphate buffer at pH 6φ4; 7.0 e 7.6 in souixiese with ferxnakopoeq. Each pfípedech compared to solutions of the buffer re buffered solutions obaeňující 26 mg / ml CDPSI, .jpŕiôemž always provádčjí UV spectrophotometric Meien the appropriate dilution of the aqueous alcoholic © s tested, the intensity of the SIN 1 decomposition product chromnto- Grafine ¹ in thin layers.

The results of the spectrophotometric measurements are given in Table 1:

Table 1

Change values> max depending on Czech / 1 mg / ml Silicium 1 ♦ mg / ml CDPSI /

A. max

time pH δ • 4 pH 7, 0 pH 7 / Days / buffer ♦ CDI'SI buffer + CDPSI buffer + CO COSI in preparation C 291.5 291, 9 290.6 291.0 291.2 290.9 1 289.6 290.5 280.4 285.5 276.4 278.8 4 284.9 288.5 - - - - 6 279.8 283.9 277.3 278.8 277.6 277.9 hell with maximum UV wavelengths o prihli harvest 13 nm / z 2

nm to 276 nm / means total decomposition of SIN 1 to SIN 1C.

For a pH of 6.4 in the presence of CDPSI after six days, _{Ä is;} 7 nm not unlike the control, where x ·, is. .Ltoreq.2 nm. Reproducibility of UV peaks given

'' · -Ρ Ρ-.ΡΡΙ ΡΡ · • --Λ '^ Γ' · ':'<',:. · ^; ·;

•., - ·; · *> -Ν ^μ conditions is - 0,5 no, so the difference can be considered significant. After one day of monitoring, the difference is still measurable, on the contrary, when evaluating? pH 7.6, stabilizing effect CDPS1 persists more rarely.

For test solutions, the molar ratio of S IN 1: CDPS1 is approximately 1; 2, which is the minimum necessary for solution complexation. A stabilizing effect in a solution with a 1-fold deficiency (10 mg / sEl), corresponding to a 1: 1 molar molar moiety, GDPSI tends to be more rare. SIN 1 spot is intense at values of _Rf, 36 in pH 6.4 buffer E is differs it? after one week of storage, in pH 7 and 7.6 buffer, one day of storage shows a marked difference in stain intensity Sllv 1 at value C, υ4 · SIN 1r is still visible in pli 7 buffer; .

In solution, the dissociation equilibrium of the complex can be shifted by ^: using an excess of cyclodextrin. Using an extremely high excess of CDI / S1 / 1000, the body solution is only spectral

200u times / y cone feeds. 1 nm in distilled water after one week, while the reference solution shows a proxtically complete decomposition.

Quantitative measurement and degradation is performed by HPLC chromatography.

Measurement conditions of IPvC to separate S1N I-SIN 1C

Furnished: Becbmen 114 Ä Solvent Release Module, 165 Feckard Variable Wave Detector 3396 A integrator Lengths, He -ele 11 - column; ultrasound ODS analytical column 4, δ x 15 zluent; 5 / µm C, 05 -4 cc tons of sodium 7 Ov solo ecetonitrií 300 ml t e t r a hy dr c all the time? n 2 e! flow 1, C ml / min pressure 12 Kla measured wavelength .7 K, nm. sample volume 2 V y ^: -l

:. in,·.; speed retention time 1.1 AU 0.5 cm / min S1N _phi t 1: t 2.9 min _E S1N 1CJ 4.2 min

The results;

V R _a cold solution of 0.5 g / ml S1N 1, prepared in fosfátové® hodnotč buffer pH 6.3, before chránčné svčtlem, stored at room temperature · The complex formed with 50 mg / ml / 100 times množetví / CĽPS1 . After storage for 5 weeks, the HFLC chrome ticks are evaluated.

score Active substance content; / mg / ml / S1N 1 SIN 1C Control the * CDPS1 complex 0.016 0.17 0,23 0,16

^x Remark: control measurement values are related to distillation of water / any buffer

DPS1, used in a 100-fold hac-penalty excess (at a molar ratio of approximately 10 µl), prevents significant degradation of SIN 1. The results obtained are in accordance with the thin-layer chromatography assay.

The assay is performed at pH uniformity of phosphate buffer J7 of a choice of similar concentration ratios (0.5 mg / ml SIN 1, 50g / ml CDPSI).

Chromatogram values were obtained after 4 days of scavenging

The active ingredient is circulated / ml SIN 1 S1N 10 Control the CDPS1 complex 0,041 0,230 u, 125 0.064

PH of the residue after storage: control 6.57

CDPSI 6.20

It can be shown that the concentration of CDPS1, even at pH 7, prevents the transition of S1N I to 31N 1C, which is an ineffective metabolite.

The stability of the S1N 1 to be injected in

aqueous solutions

From the lyophilized SIN 1 in washer saipuli pfipreví the aqueous solution at 5 C / ug / ml of PSK was added 20 mg / ml CE.VSI · s <ee _a cold solution stored at room temperature with the wall much občes mncžství SIN 1C decomposition product.

evaluated four days. with chromo-migrants obtained after one, four or more íiodnocení Silos 1C obssh / G / ml time / days / inspection CDPS1 complex default G 1 0.1 1 0, Ei 0.6 4 3.9 G, 94 11 9.6 1.8

SUMMARY OF THE INVENTION Accordingly, the SIN 1 cyclodextrin derivative and method of preparation thereof are stable to aqueous symbiotic at physiological pH values in which the specific SIN 1 C prevents an inactive metabolite from using a cyclodextrin derivative.

It has been surprisingly found that cyclodextrins, especially UDPSI complexed with S1N, also contain! considerable delay of intermediate SIN 1A after preparation of complex · Training process

SIX 1 -> Forces U -> SIN 1C in the key with three cyclodextrins was also tested in a 0.02 L ecotate buffer at a pH value of · 5.5 · The surprise effect of -CC; D is more pronounced, more than 7 more times, SIN was found in the presence of β-CD than in the control sample. (SIT 1A) is determined by chromographic analysis

When investigating the biological action of the present invention, it has been found in vivo that no. until recently SIK 1, pc-gavage oral at 1g / kg did not show efficacy / cardiac-protective efficacy on rats is 11 · · / is essentially a preventive effect of S1N 1 CDPS1 with the percentage of the active substance administered as a percentage

42,2 Ä. ·

The good biological activity of the SIN 1-CDFSI complex in kerdio-protective assays after oral administration can be attributed to &quot; V &quot;.

S1N IA contained in a solid complex. Fbrms A, which is of key importance for biological action, cannot be formed from pH conditions in the stomach environment and can be derived in vitro from the SIN 1 substance by incubation under olefinic pH conditions. The purifying solubilizing CDPSI complex in distilled water may dolomite a considerable amount of S1N IA in aqueous solution.

The S1N 1 - S1N IA transition appears to be promoted by cyclodextrins, while at the same time the highly volatile oxygen-sensitive SIN 1A stabilizes by complexity, resulting in a slower trensformation

SIH IA * SIN 1C

This is due to the slower release of nitric oxide from the complexed SiO2.

In the following table, the content of S 1A 1 of the SIN 1 complex with various cyclodextrins, prepared according to Example 2, measured directly after HKLC Chromatography & Physical Physics of Forces. The same assembly _; is prepared in the same manner by the lactose used for comparative purposes.

Ifebulke / V zore k /

complex

SIN 1 - CDPSI

S1N 1 - β - CD

S IN 1 - D1IÄEB

S1N 1 - n? /..· CD t

SIN I - lectures, erosion pattern

Results and conclusions

Study of relaxing action

S1N U content,% / given in SIN 1C equivalent

1.27 c 0.08

0.06

0.115 S1N-cyclodextrin complexes with normal Sil 1 at a concentration of 1 or 2 µL. All four complexes support a supported contraction of sham depolerized strips with a mexican effect of 43% to 53%. · Strengths 1/1 y / µl / are somewhat more effective with relsxac! 53

The maximum release (relexation) of the SIN 1 complex occurs 23 minutes to 32 minutes after administration, while the T / msx Strength is 18 minutes. This difference is statistically significant. time

. '. ^; ··. ·· '. ? The Si activity, expressed as T / 2, is longer in the case of the cyclodextrin complex (62 minutes to 88 minutes) than in the case of the SIN 1 (47 minutes). This difference is also stetistically significant. SIN 1 -cyclodextrin complexes exhibit a smoother start time and longer duration of action than normal SIN 1 · As the relaxing effect of SIN 1y due to the release of nitric oxide due to the oxidative decomposition process, it is possible that complexe.ee SXN 1 with cyclodextrins slows this the decomposition process, since this is the paler onset of ε prolonged exposure likely to be due to the slowed release of nitric oxide from the SIN-1 e cyclodextrin complex,

In view of the foregoing, the present invention relates to 3-morpholinosydnonimine inclusion camplexes or salts thereof, or a form of open ring teutomeric isomers ^M A formed with cyclodextrin derivatives.

As the cyclodextrin derivative comprises an inclusion complex according to the invention, preferably an ionic, water-soluble cyclodextrin polymer (CDPS1) (molecular weight less than WCCO), heptakis-2,6-diethyl- (β-cyclodextrin) (Dimeb), heptckis-2,3, 6-tri-O-methyl-cyclodextrin (Trimeb) and N-cyclodextrin and γ -'-cy clodextrin.

IN

Hydropropyl-β-cyclodextrin may also be used to prepare the solid inclusion complex.

The inclusion complex of the invention is prepared by resecting 3-morpholinosydnonimine or its salts in a solvent with a derivative, the cyclodextrin or the complex optionally obtained from the solution by dehydration, or the complex is obtained by high energy milling of J-morpholinosydnonimine or its salts and cyclodextrin derivative.

preferably, the complex can be isolated from the solution by lycfilization, spray drying, low-vacuum vacuum firing, and vacuum drying.

SIN 1 dissolves from 1 to 4ϋ mmol of CDPSI or Dimeb in 1 to 500 ml of distilled water, sealing to 1 mmol of the active substance, and dehydrating as described above. Polar ratio CDPSI

’I '/ A p · Λ; · '· - -Λ λ ?.'. '. - - ··· · ·· '. · ''. ». ···· ^; - '· Ρ -11 -

of the polymer is calculated with nephe-CD. Use of a polymer having an approximate range of 50 S & -CD e. with an average molecular weight of 3500 leads to a complex of 1: 1, which corresponds to approximately 8% with a molecular ratio of 2: 1 of 4.5

The interaction of the complex in solution elucidates the membrane permeability test.

Cellophane membranes of the Visking type (mean diameter per 2.4 nm) are used. A 1 mg / ml aqueous solution of SIK 1 is introduced into the donor cell, while distilled water is introduced into the receptor chamber of the permeable membrane device. The solution was stirred with a stirrer and had much mEgnetickým UDI ⁴ Zuji is not 1 at 37 ° C. At appropriate time intervals, receptor solution samples are taken and the concentration of SIN 1 passed from the donor cell is measured by UV spectrometer.

Test ae is repeated in the presence of various cyclodextrins at various concentrations in the donor burner. The time required for the diffusion of 5C.sub.2 ^/ .fwdarw.7 / T in the CDPSI ratio in fusion coricentration is shown in the following table:

Diffusion half-life of SIK 1 in the presence of CDrSI 4 / hour

SXN 1 alone, 9 ♦ CDPS1 25 mg / ml 3.5 mg / ml 5.0 inclusions of the complexes prepared by the process of the invention can be used for the preparation of pharmaceutical compositions, mixed by injection for oral and oral administration.

The dosages of the inclusion complex of the invention may vary according to the age, body weight and condition of the subject to be treated, the route of administration, the number of administrations, or the like, generally from about 6 to about 50 mg. based on body weight, preferably 10 to 20 mg per body weight per day.

Prolonged action is particularly desirable for the administration of the pharmaceutical composition in the form of a single tablet per day, microcapsules and ointments suitable for administration, arsoceutic agents are prepared. in a manner known per se.

'iŕ. f V u

»·>

Auxiliary additives are used which are useful for ferrous metals.

Illustrate the invention! The following non-limiting examples illustrate the invention.

The following examples illustrate the invention

Preparation of the SIN 1 complex

CDPSI by lyophilization

Dissolve 15 g / 6.6 mmol / CDPS1 of polymer in 206 ml of distilled water in a Pek was added to a solution of 1, ug /5.,3 pitches / S1A ^J-1 staff. The materials dissolve almost immediately from obtaining a clear, clear solution which is immediately frozen & dehydrated by lyophilization, taking care to ensure that the fabric is exposed to as little exposure as possible throughout the healing process.

^ ρίί'ϊςίΕό’Έβ'-Ύΐάάύ ^ γΥ ’^ ´ό óό eé róžstéňí ´ perform, wrap with orný pepper. The product obtained is slightly light, it is the free prodrug, the active substance content determined by spectrophotometric method.

sobesa, is 6,5 - o »5 which corresponds to molar drift 1: 1 ·

Tests were carried out to demonstrate that a complex was formed: thermogravimetry (TC), differential, other orbital (c) c / c / thermal evolution analysis (thermel evolution tensile). characterized by differences in SIP and complex. SXN 1-CDPS1 · t ° C is removed at bi water, n decomposition at ° C / start of temperature interval and enelysis by physical discontinuity of the compound of the invention. inorganic substances occur with an explosive force e.

% of the reagent introduced in H 1 similarly

170 to 1 Tightly remove from the system ·

The participation of du / c

23i; The decomposition slowly decreases until the temperature is observed, and a 37% loss of mass is observed. The DSC peak may be used at the temperature of 22 ° C. The DSC peak may be used at 190 ° C. flights 3% ° 1. kd.

or later 2C0 ° C with 19C thermal change enthelpie · .à ·

Cj / C Sj

The thermal curves of the SIN 1-CDPSI physical mixture, prepared immediately prior to mixing, may be attributed to the starting materials.

The curves of the c d nicn complex show a significant difference, with the decomposition peak of S1N 1 missing, meaning that SIN 1 formed an inclusion complex with CDPSI.

Pattern obtained by powder diffraction method according to Bragg. According to X-ray diffraction tests, the structure of SIN 1 - CDPSI is amorphous. The characteristic reflection of the SIN 1 t peak disappears. The amorphous structure of CDPSI is known. Although the crystallization stage of SIN 1 treated similarly but without CDPSI decreases, however, the transition to a total amorphous structure is not possible by so much lyophilization. The two reflective peaks suggesting a non-crystalline form characteristic of free / uncomplexed / SIN 1 are not in the complex diagram.

iŕiKxod c.

Preparation of the SIN 1-CDPSI complex by lyophilization

Dissolve 8¾ 15 g of CDľ-SI polymer (6.6 mmol · /) β-CD content

2GC ml of distilled water. To obtain a solution of X, content. Of a 4.2% by weight solution is dissolved in a 2 ° C vcd solution.

G, 7 g (3.3 mmol) of the SIN 1 of Example 1 in the product obtained is

The GbSuh of the active ingredient corresponds to a molar ratio of 1;

+ "

4,5 - 0,2 C EN

Example 3

Preparation of SIN 1 - CDPSI complex with high, controlled content

The SIN 1 is sublimated for the second weighed water as described in Example 2. The product is dried for three weeks. . ·.

$ 2 “Ta ·

2, when p to constant, a solid product is obtained which is dried to remove complex at about 8 ° C under vacuum after weight. The loss of drying is that the SIN 1A / S1N IC 1 polymer changes from 10 to 17. When storing the dried complexes at room temperature, protected from light for more than three months, the SIN 1A content and the SIN 1A / SIC 1C ratio practically do not change.

In the case of a (non-heat-treated) untreated sample, the addition of SIN 1A also increased from 1.08% to 1.0%. While the SIN 1A / SIN 1C ratio decreases (from 10 to 3).

The preparation of the SIN 1-CDPSI camping complex product with high SIN 1A content and composition control is possible by short-term heat treatment of the lyophilized SIN I-CDFS1 complex.

Example 4

Preparation of SIN 1 Dimeb

Dissolve 14% of Dimeb (10.3 mmol) (moisture content 2%) in 100 ml of distilled water. With stirring, 1.03 µmol / SIN 1 was added to the solution with stirring. The whistled clear solution was treated as described in Example 1 with light protection. the ireduct is a free white powder with an active ingredient concentration of 6.5-0.2% _t molar ratio of about 1; 2 SIN 1; Dimeb.

Example 5

Preparation of percutaneous ointment containing SIN 1 iv mg ε ointment content 1/2 g • 2 SIN 1 - Diaeb, prepared according to Example J, (active ingredient content 6.5 5>) dissolve 151 mg in 20 ml distilled water. To the light-protected solution, 50 mg of hydroxypropylcellulose / KLUCti & Jb-HP is added under vigorous stirring. however, a viscous solution, very difficult to stir, is obtained which is left to stand at room temperature for one day. A translucent gel is formed whose 2 g contain 10 mg of SIN 1.

EXAMPLE 6 Obes containing 2 mg of the active substance S1N1

Prepare your tablets! in a manner known per se using the following components:

mg of Silo · 1 - C.DPS1 complex, active ingredient content 2 * 5 mg corn starch,

128 mg of milk sugar, mg of magnesium stearate, the total weight of the tablet is 250 mg

Industrial usability

3-morpholino-gonosydnonifliin or its salts M or its tautomeric isomer with reduced light sensitivity is suitable for the preparation of fermeaceutic agents.

Claims (13)

An inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with a cyclodextrin derivative; 2. An inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof, formed with an ionic water-soluble cyclodextrin / CDPSI polymer having a molecular weight of less than 10,000. An inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with hydroxypropyl-β-cyclodextrin. An inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with heptakis-2,6-diraethyl-β-cyclodextrin. An inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with heptskis-2,3,6-tri-O-methyl-β-cyclodextrin. 6 ·. Inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with β-cyclodextrin or γ-cyclodextrine. 7. A process for the preparation of an inclusion complex of 3-morpholinosydnonimine or a salt or tautomeric isomer thereof with a cyclodextrin derivative according to items 1 to 6, characterized in that the 3-morpholinosydnonimine or its salt or tautomeric isomer is reacted in aqueous medium with the cyclodextrin derivative. is isolated from the solution by removal of water or 3-morpholinosydnoniraine or its salt or the isutomeric isomer and cyclodextrin derivative are highly energy-milled. 8. The method of claim 7, wherein the cyclodextrin derivative is an ionic, water-soluble polymer having a molecular weight of less than about 10,000, such as hydropropylcyclicextrin, heptakis-2,6.-C'-dimethyl-cyclodextrin. heptakis-2,3,6-tri-methyl-cyclodetrin or β-cyclodextrin. 9. A method according to claims 7 and 8, characterized in that the inclusion complex of 3-morpholinosydnonimine or its salt or the isutomeric isomer formed with the cyclodextrin is isolated by lyophilization, spray drying, vacuum concentration at low temperature and vacuum drying. Pharmaceutical composition, characterized in that it comprises any of the active ingredients 3-morpholincsydnonimine-invasive complex or a salt or tautomeric isomer thereof formed with a cyclodextrin. Pharmaceutically acceptable carriers and adjuvants. 1 1. that is The pharmaceutical preparation is formulated for oral administration. point 10, 10, characterized in that the ionic, in a water-based mass of less than 10 000, which is N-cyclodextrin, hebtakis-6-C-dimethylhept & kis-2,3,6-tri-C'-10-thiyl-β-cyclodextrin, pharmaceutical composition as referred to in point '2. 2. The method according to claim 1, wherein the cyclodextrin derivative comprises a soluble polymer c having a molecular weight of less than 10,000, said hydroxypropyl .beta.-cyclodextrin. γ-cyclodextrin or γ-cyclodextrin. 13. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the inclusion complex of the 3-morpholinosydnonimine or salt or tautomeric isomer of the cyclodextrin derivative is mixed with pharmaceutically acceptable carriers or excipients. 14. A method of treating human and ischemic disease in a human, comprising administering to said human an effective amount of an inclusion complex of 3-morpholinosydnoniiain or a salt or tautomeric isomer thereof with a cyclodextrin derivative.