HU201782B - Process for producing cyclodextrine-polymere iodine inclusion complex of controlled iodine release and powder containing them as active component - Google Patents

Abstract

The invention relates to cyclodextrin polymer/iodine inclusion compounds with controlled release of iodine.

Description

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of a controlled release cyclodextrin-polymer-iodine inclusion complex and a dry-stable, disinfectant wound dressing powder containing such an active ingredient, the release of which is controlled by the quality and proportion of the additive (s) used. The antiseptic effect of iodine was already known in ancient times, and it has not been excluded from the medical toolbox to this day. Its complexes with soluble polymers (such as polyvinylpyrrolidone) are also used in ointments for the treatment of burns, and as a general disinfectant in lotions. It also complexes with insoluble, particulate polymers that can be used as swab powder to heal wounds.

The carboxymethylated cross-linked dextran gel, marketed in several countries under the trade name Iodosorb (or Cadexomer lod), contains 1% iodine and an equivalent alkali metal iodide [Ergebnisse dér Angiologie, Ed. Schattauer Verlag Stuttgart, New York, 1983.]. Japanese researchers absorb iodoform into zeolite and use the product to treat wounds [Nippon Halogen Kagaku KK., Nippon Mining Co. Ltd., Jpn. Kokai JP 60.01108]. By our own process according to the present invention, we have prepared a carpet powder composition which, as a filler, diluent, carrier, alpha, beta-cyclodextrin or their polymers, as well as perfumes, colorants and the like. it contains biologically active organic substances (eg lidocaine, salicylic acid, vitamin A, chamomile oil, etc.) in the form of a cyclodextrin inclusion complex. (Hungarian Patent Number 196306)

Iodine inclusion complexes of various cyclodextrins are known. Among these, the α-cyclodextrin-iodine complex is particularly stable, the β-cyclodextrin-iodine complex is less stable and the inclusion complex with γ-cyclodextrin is even less stable (Diard JP, Saint-Aman E., Serve D .: J. Electroanal. Chem. Interfacial Electrochem. 189/1985/113). Due to its microbicidal action, the β-cyclodextrin-iodine complex has been used in many applications, e.g. for the preparation of a microbicidal deodorant aerosol (Japanese Patent Application No. 77 / 15,809) or for the preparation of a mouth disinfectant (Japanese Patent Application No. 58 / 152,808).

The water-insoluble but swellable cyclodextrin polymers bind iodine with high affinity (British Patent No. 1,091,637). However, it is not known how to control the release of cyclodextrin-polymer-iodine complexes, nor are the cyclodextrin complexes of interhalogen ions (UBr ^- , I2Cl ^- ).

It is an object of the present invention to provide a dressing powder which has a disinfectant effect and the degree and time distribution of the disinfectant effect can be varied and controlled.

Surprisingly, it has been found that for this purpose, talcum powder, which contains iodine as the disinfectant, has a matrix structure of a talc powder as a cyclodextrin polymer (hereinafter CDP) and iodine forms an inclusion complex with CDP. When the inclusion complex comes into contact with water or an aqueous solution (such as a wetting wound) it releases iodine.

It has further been found that if iodine and / or bromide solutions are added to the iodine solution, the release of the iodine is affected. Thus, in addition to molecular I2, the iodine solution may contain I3 ”UBr ^- and small amounts of Γ and Br ^- anions as well as alkali metal cations. As this solution comes into contact with a CDP, the components form an inclusion complex with cyclodextrin.

The inclusion constant complex formation constants of the I2,13 ^- , P and Br ^- substrates in aqueous solutions of various CD species (alpha, beta, and gammaCD) have been measured by several methods. For example, potentiometric measurement using a rotating platinum electrode and a caliper electrode. (Diard, JP et al., J. Elektromol. Chem. 1985, 1-8 and Gelb. I. et al., J. Phys. Chem. 87/1983 / 3349-3354).

However, no data were found in the literature on the stability of the UBr ^- mixed halide ion CD complex. The reason for this is that it is difficult to measure it using previously available methods. First, the spectroscopy can not be applied for this purpose, as a result of CDs virtually no change in the LBR ^- spectrum, on the other hand neither potentiometry, whereas the sensitivity of the ezüstjodid / Pt electrode is reduced significantly higher concentration of Br "ion present.

It is known in the literature that the order of stability, regardless of CD type, is:

K13- K12> Kf K _Br

However, irrespective of the substrate variety, alpha-CD complexes are more stable than beta-CDs and gamma-CDs form the least stable complexes. (Szejtli, J.: Cyclodextrins and their Inclusion Complexes, Akadémiai Kiadó, Budapest, 1982.)

CDs also retain their inclusion complexing ability in the form of their polymer derivatives. The inclusion complexes of CD polymers generally have greater stability than the base CD. The reason for this is that the rings are fixed in space in the polymer so that no so-called "ring" can be formed. channel complexes, the most typical example of which is the iodine complex (Noltenmeyer, M., Saenger, W .: J.A.C.S., 102/1980/2710). In the case of larger guest molecules with multiple binding sites, the cooperativity of the linked CD rings may also occur when two or more rings are involved in the complex formation (Harada et al., Macromolecules, 2, 1976/705709).

However, due to crosslinking in polymers, highly substituted rings are often difficult to access for the foreign molecules, and spherical inhibitions are favored. Which of the listed effects will occur is not predictable and can only be determined experimentally.

The order of stability of CD complexes is not always the same as that of CDP complexes. It is possible (eg amphotericin) that a foreign molecule does not form a β-CD

-2EN 201782 Β complex only with γ-CD, but δ-CDP still binds strongly and releases slowly.

Examination of the stability relationships of CD complexes and CDP complexes in our case showed that, as a result of the above-mentioned effects, β-CD binds 13 ^- ion more strongly than in its native form, but also in the form of a polymer derivative. the I ₂ molecule.

Experiments were performed to determine the effect of halide ions on the iodine release of the complexes.

For comparison, Iodosorb, a marketed cross-linked linear dextran gel matrix containing equivalent amounts of iodine and alkaline iodide (Γ / Ι ₂ = 15), was tested.

1.0). The alkali-iodide additive, while inhibiting to some extent iodine sublimation, does not substantially affect the release rate. The dissolution studies performed show that 80% of the iodine in the powdered powder is dissolved in 1 minute and 90% of the iodine in 5 minutes. In the wash-off experiment, the number of fractions is only 2, in the first fraction about 76% of the iodine comes down, in the second the remaining 24%, after which the sample becomes completely colorless.

However, in our studies of CDP-iodine complexes, it has surprisingly been found that the rate of iodine release of CDP-iodine inclusion complexes is significantly influenced by halide ions, thus their addition can be controlled by the presence of,, and the Br- and its presence enhances the release of iodine.

The former can be explained by the fact that CDs form a more stable complex with the 13 - ion than with the I ₂ molecule. There is no data available on the stability of AI ₂ Br '-CD inclusion complexes, but it is believed that its formation constant is lower than that of the I ₂ complex and therefore is more readily released from the polymer. Thus, only the ion-ion produces an excessively long-lasting effect, and only the Br '-ion achieves an excessively rapid release. In the case of a formulation containing two types of ions, the two effects are combined: first, a high concentration of the active ingredient is dissolved, followed by a slow, time-consuming dissolution.

AI3 ^- and / or I2Br ^_, and Γ and / or Br ^- I2 solution containing 45 iono- MOT CDP reacts with molecules of the individual components mainly include a multi CDgyűrűk, those forming the inclusion complex, but to a lesser extent the possibility of physical adsorption, not be excluded. Another advantage of the presence of halide ions is that it improves the storage stability of the formulation. The only I ₂ -containing sebhintőporból a portion of the iodine sublimes thereby agent content reduced slightly during storage. In the presence of Γ 55 and / or Br ions, sublimation was not observed if the ratio of halide ions was greater than Γ / Ι ₂ = 0.1 and BR ′ / I ₂ = 0.5, respectively.

The fact that such a small excess of halide is already sufficient to prevent sublimation is a new discovery. The sublimation-reducing effect is partly driven by I3-- and I _2, Br ₂ I-ions in the molecule of larger size, partly attributable to the strength of the inclusion complex formation. Washout experiments were performed here and found that even after 400-500 ml (16-20 fractions) flowed through, CDP-based iodine talc powder did not decolorize.

Storage stability studies were performed to compare the known Iodosorb with the CDP-iodine complex of the present invention. At 40 'Con, 75% relative humidity, samples were stored for 6 days, and after looking at% change in I ₂ content during storage, we found that about 80% of the total iodosorb content was (7 pl) the total iodine content of CDP-iodine produced as a powder is reduced to 98%. Even taking into account the order of magnitude difference between Γ / Ι ₂ ratios, the greater stability of the CDP complexes and the better control ability of the halide additives used can be considered proven. Thus, the process of the present invention is based on the recognition that the stability of inclusion complexes of interhalogen complexes with cyclodextrin is different from that of the iodine complex. So far, only 13 "complexes have been studied, but no literature has been found on the interaction of the I ₂ Br" complex with cyclodextrin.

In our experience, the stability order of inclusion complexes with cyclodextrin is as follows:

I3> I2 I ₂ Br 'I ₂ C1

This is used to control the iodine release of wound powder. The addition of Γ resulted in a lower dissolution rate due to the high stability of the resulting l3 ^- -CD complexes, while the addition of Br ^- increased the dissolution rate due to the lower stability of the resulting I ₂ Br ^_ -CD complexes.

According to our measurements Cl ^- ions can enhance jódkioldódását, but these samples have Cl- / ₂ = I 2 ratio of the iodine is sublimated, and therefore the process of the invention is not used as the ion Cl ^_ jódfelszabadulás accelerating.

The present invention therefore relates to a process for the preparation of a controlled iodine release cyclodextrin polymer orthodox complex by adding iodine solution and a solution of an alkali iodide and / or an alkali bromide in a quantity of 0.1 to 5 millimole equivalent / g of cyclodextrin polymer, wherein the molar ratio of alkaline odide to alkali bromide and / or alkali bromide to iodine (0.1 to 2.5) is 1, then the resulting complex is isolated and dried.

Accordingly, the invention is carried out by that I3 ^- and / or sucked up further I2Br ^_ I2 aqueous solution containing Γ and / or Br ions CDP-on, which forms the matrix of talcum powder. This gives a controlled release disinfectant wound powder containing iodine. In a most preferred embodiment of the process of the invention, the iodine solution containing the additives is added dropwise to the CDP with agitation and shaking, until the CDP particles are uniformly brown in color. It is then filtered, if desired, and then dried.

The CDP used in our process can be prepared from any of the CD types (alpha, beta, or gammaCD), or derivatives thereof,

-3EN 201782 Β preferably from a carboxyl or acetyl derivative. The most preferred form of CDP is a bead polymer or a block polymer. (Their preparation is described in Hungarian Patent No. 177,419.)

The swelling capacity of the polymers in water may vary from 2 to 5 ml / g, preferably from 4 to 6 ml / g.

An aqueous or water miscible organic solvent is used to dissolve the iodine, as it is desirable that the organic solvent solution contains at least 5% water. The most suitable solvents are dissolved in an aqueous solution of aliphatic alcohols having from 1 to 4 carbon atoms, preferably methanol, ethanol, 1-propanol, 2-propanol.

The additive to the iodine solution is suitably an aqueous solution of alkali iodide and / or alkaline bromide, preferably potassium iodide, sodium iodide and / or potassium bromide, sodium bromide. The amount of alkali iodide and / or alkaline bromide added to CDP and iodine is 0.1-0.8): 1. The formation of the CD-I inclusion complex is carried out at 5 to 70 ° C, preferably at room temperature (20 to 22 ° C).

The process of the present invention can be carried out in two ways:

a) combining the aqueous alcoholic iodine solution and the aqueous alkaline iodide and / or alkaline bromide solution and adding to the CDP,

b) co-preparing an aqueous and / or alcoholic solution of iodine and alkaline iodide and / or alkali bromide and adding it to CDP.

The product obtained has an iodine content of 2-40% based on CDP, including a molar ratio of iodine to iodide and bromide of 1: 0.2-2.3. The wound powder produced by the process of the present invention is useful for treating both positive wounds and chronic ulcers (ulcus cruris postthrombicum, ulcus trophicum, etc.) and epithelial deficiencies (traumatic and burn injuries) in acne. When applied to the wound surface, it works by sorbing the inflammatory secretion, including the pathological metabolic product of the inflamed area, as well as the bacteria themselves. The products of wound degradation, as well as bacteria and their toxins, are trapped in the space between the polymeric particles, thus providing a highly effective fluid, mucus removal process. As a result, the surface of the wound 45 is continuously cleaned and, on the other hand, the blood supply needed to supply the tissues is improved and thus the tissue that develops faster. Collagen formation and fibroblast activity is increased due to improved microcirculation and local ecological changes. Pure corpus luteum starts to exfoliate under much more favorable conditions and becomes visible with a reduction in ulcer size. The swellable polymer swells the iodine, which has a bactericidal action, to minimize the risk of over-contamination. CD cavities vacated by iodine release may form inclusion complexes with prostaglandins, peptides, etc. in the wound secretion.

A further advantageous feature of wound-powder is the well-known fact that microbes do not develop resistance to this halogen material, as opposed to a large number of antibiotics. Considering that the average topical treatment cycle is two weeks and the affected areas have poorer blood supply than intact areas, the iodine in the wound powder and the iodide and / or bromide ions used as an additive do not cause any skin lesions (haloderma), or internal organ damage (eg kidney) such as iodine and iodides, bromides for several months and can be caused by prolonged oral intake for years (Dermatology, Moschella-Pilsbury-Hurley, Vol. 1, Saunders, Philadelphia-London-Toronto, 1975).

The present invention is illustrated by the following non-limiting examples.

Example 1

To 3.5 ml of 0.74 N ethyl alcohol iodine solution is added 1.5 ml

the water,

(b) 2N potassium iodide solution,

c) 2 N potassium bromide solution.

0.8-0.8 ml of the mixture was added dropwise to 2-2 g of a beta-CD bead polymer (CD content: 53%, moisture content: 9.8%, particle size: 0.10-0.15 mm, with stirring). gel volume in water is 5.2 ml / g). Stirring is continued until a uniform color product is obtained (a and b in brown, c in orange) and air-dried in a thin layer. The product characteristics are summarized in Table I:

Measurement methods:

Table I

Iodine content dissolved iodine (%) washed iodine szubli- (Meq / g) After 1 minute After 5 minutes fractions maximum number of place value (fraction (mg / number) / 25 ml) mation

the) 0.19 46.5 55.4 10 1-2 2 b) 0.43 (0.1912 + 0.24 Γ) 8.1 14.6 12 6 1.7 c) 0.19 73.0 73.0 8 1-2 3.5 -

meq = millimole equivalent meq / g = millimole equivalent iodine / g CDP

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In determining the iodine content (I2 and Γ together), the iodide ions and elemental iodine in the polymer are oxidized to IO3 with vinegar Bn solution. The IO3 ion forms a complex with less stability than the Γ ion with CD, e.g. for K1- / K103 ^- alpha-CD 5 20.6; for beta-CD 2.9 (Gelb et al., J. Phys. Chem. 87/1983 / 3349-3354). Excess Br2 is reduced with formic acid and the solution is filtered. The IC3 content of the filtrate was adjusted to 12 by adding KI and titrated with Na2S2O3. The presence of Br ^- 10 does not interfere with the measurement.

To determine the content of the products, excess ascorbic acid is reduced in h and the remaining ascorbic acid is back-titrated with 12 volumes. 15

When measuring dissolution, 0.15 g of the iodine-containing preparation is sprayed into 100 ml of 0.1% NaCl solution and its 12 content is continuously measured on an AgI / Pt electrode system]. Up to 0.01 molar concentrations, neither mér nor Br will interfere with the measurement. 20

After washing the iodine, 0.5 g of the iodine-containing preparation was placed in a column (d = 1.2 cm) and distilled water was passed through it. Fractions of 25 ml were collected and titrated 12 with Na2S2O3.

A simple method for detecting sublimation: the yellow coloration of the polyethylene cap on sample bottles indicates iodine sublimation.

Example 2

Dissolve 0.08 g (0.48 mmol) of potassium iodide and 0.2 g (1.68 mmol) of potassium iodide in 1 mL of water. Add to that

a) 7 ml of 0.68 N methanolic solution I2 (4.76 mmol) and 0.5 ml of this mixture are added dropwise to 2 g of bead polymer (properties of bead polymer see example 1),

b) 5.8 ml of a 0.83 N solution of I2 in ethanol (4.81 mmol) and 0.45 ml of this is added dropwise to 2 g of the bead polymer,

c) 5.4 ml of a 0.9 n solution of n-propanol I2 (4.86 mmol), of which 0.4 ml is added dropwise to 2 g of the lump polymer,

d) 8.5 ml of a solution of 0.57 n in i-propanol I2 (4.85 mmol) and 0.6 ml of this is added dropwise to 2 g of a gel polymer.

The characteristics of the samples mixed at room temperature and then dried are shown in Table II. is summarized in Table.

II. spreadsheet

l2-round. (Meq / g) Γ-round. dissolved iodine (%) sublimation lperc after After 5 minutes a) 0.12 0.03 38.1 46.6 - b) 0.13 0.05 45.8 61.0 - c) 0.12 0.06 44.8 44.8 - d) 0.12 0.03 26.9 35.6 (+)

meq = millimole equivalent

Example 3

The procedure of Example 2 / b is followed except that

(a) Alpha-CD bead polymer (particle size 0.05-0.15 mm, gel bed volume 5.9 ml / g, CD content 48%),

b) A gamma-CD bead polymer (particle size 0.03-0.20 mm, gel bed volume 6.3 ml / g, CD content 52%).

The characteristics of the products obtained are given in Annex III. Table.

III. spreadsheet

12 holds. (Meq / g) Γ-round. dissolved iodine (%) 1 minute 5 minutes after sublimation a) 0.13 0.04 3.3 6.1 - b) 0.13 0.03 27.6 50.3 -

Example 4 One ml of 0.035 N aqueous iodine solution (0.7 meq) containing 1.05 mmol of potassium iodide was poured onto 2 g of CD-polymer (see Table IV for the properties of the various CD polymers). . Shake for half an hour and filter. The 12 content of the filtrate was measured with 0.01 N Na ₂ S ₂ O ₃ . The wet wet precipitate was dried at 70 ° C under vacuum. The properties of the products are given in Annex IV. are summarized in Table. No sublimation was observed in either. In comparison, a linear dextran bead polymer (Sephadex G-25) was also tested.

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10

ARC. spreadsheet

CDP Properties Product

the crosslinking agent or substituent used gélágy- volume (Ml / g) CD- content (%) particle size (Mm) l2-round. Γ-round. (Meq / g) Discharge (%) lperc after After 5 minutes the) epichlorohydrin + ethylene glycol diepoxypropyl ether 5.0 57.0 0.13 to 0.20 0.28 0.17 4.2 12.5 b) epichlorohydrin + ethylene glycol 5.8 53.0 0.08 to 0.32 0.27 0.20 2.0 7.7 c) epichlorohydrin 3.1 51.1 0.05-0.10 0.27 0.19 5.5 10.5 d) butylene glycol diepoxypropyl ether (pearl polymer) 3.7 51.5 0.08 to 0.20 0.25 0.16 9.1 17.5 e) butylene glycol diepoxypropyl ether (block polymer) 13.5 55.0 0.10 to 0.25 0.24 0.16 1.0 1.7 f) carboxymethylated bead polymer COOH / CD = 0.2 4.0 47.8 0.08 to 0.20 0.27 0.16 5.7 14.6 g) acetylated bead polymer Ac / CD = 1.1 10.7 44.8 0.08-0.13 0.30 0.31 9.0 14.4 h) Sephadex G-25 5.0 - from 0.08 to 0.15 0,005 0,020 90 100

In the table, Ac / Cd - represents the number of acetyl groups per CD unit.

In the table, COOH / CD - represents the number of carboxyl groups per CD unit

Example 5

Dissolve 0.380 g iodine (2.99 meq) and 0.500 g potassium iodide (3.01 meq) in 5 ml

a) 30 vol%

b) In 50% (v / v) ethanol-water mixture, 2 - 2 ml of this are added dropwise to 5-5 g of the vial polymer described in Example 1.

The product is air dried.

The characteristics of the products obtained are shown in Table V.

Table V.

l2-round. (Meq / g) Tart-Tart. dissolved iodine (%) 1 minute 5 minutes after sublimation a) 0.20 0.22 4.5 11.1 4.7 11.2 b) 0.20 0.25 -

Example 6 60

0.1 N aqueous iodine solution containing 0.15 moles of sodium iodide per liter

a) 10 ml

b) 20 ml was poured onto 1 g of CD bead polymer (CD content 50.9%, gel bed volume 4.8 in water 65 ml / g, moisture content 1.3%, particle size 0.10-4), 30 mm) .

water bath

a) at 40 'C,

b) Hold at 70 ° C for 30 minutes, then filter and wash the samples with 10 mL of water.

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11 12 It is then dried in vacuo The characteristics of the products obtained are given in Annex VI. table table a) at 40 ° C effective ingredients. (b) at 70 ° C to constant weight.

VI. spreadsheet

The filtrate l2-round. (MEq) Washers hold l2. (MEq) The product Discharge (%) Szubli- mation l2-round. (Meq / g) Γ-round. (Meq / g) After 1 minute After 5 minutes a) 0.015 0,015 0.73 0.36 6.5 14.1 - b) 0.27 0.057 1.02 0.41 5.4 12.3 -

Example 7

Dissolve 0.100 g (0.39 mmol) of iodine in 2.5 ml of ethanol and 0.015 g (0.09 mmol) of potassium iodide and 0.100 g (0.83 mmol) of potassium bromide in 2.5 ml of water. The two solutions were combined and added dropwise with stirring to 20 g of the bead polymer described in Example 1. The product has a Ia content of 0.029 meq / g, a Γ content of 0.014 meq / g, and after 1 minute, 36% of iodine is dissolved, and after 5 minutes, 43%.

Example 8

Rocking powder composition I.

g CDP-iodine complex (prepared according to any one of 1-7)

49.5 gCDP

A mixture of aerosil (0.5 g) was prepared.

Example 9

Rocking powder composition II.

Prepare a mixture (g) of CDP-iodine complex g of CDP-g (powdered).

Example 10

Rocking powder composition III.

A mixture of g of CDP-iodine complex is prepared.

Claims (6)

PATENT CLAIMS CLAIMS 1. A process for preparing a controlled iodine release cyclodextrin polymer-iodine inclusion complex comprising adding to the cyclodextrin polymer an iodine solution and an alkali iodide and / or alkali bromide solution in an amount of 0.1 to 5 millimole equivalents / g of cyclodextrin polymer. wherein the molar ratio of alkali iodide and / or alkali bromide to iodine (0.1-2.5): 1, then 20 complexes were isolated and dried. Process according to Claim 1, characterized in that the iodine solution is an iodine solution in an aqueous solution of a C1-C4 aliphatic alcohol, preferably methanol, ethanol, 1-propanol, 2-propanol. 25 3. Process according to any one of claims 1 to 3, characterized in that the alkali iodide and / or alkali bromide solution is water-dissolved alkali iodide and / or alkali bromide, preferably potassium iodide, sodium iodide and / or potassium bromide, sodium 30 bromide. 4. Process according to any one of claims 1 to 3, characterized in that the aqueous alcoholic iodine solution is combined with the aqueous solution of alkaline iodide and / or bromide, and the resulting solution is added to the cyclodextrin po aqueous and / or alcoholic solutions are prepared together and added to the cyclodextrin polymer. 5. The process according to any one of claims 1 to 3, characterized in that the reaction of the cyclodextrin polymer and the iodine solution is carried out at a temperature of 5 to 70 ° C, preferably at room temperature (20 to 22 ° C). 6. Procedure for Controlled Iodine Release, Dry Stable, Disinfectant, Contains Iodine 45 pumice powder compositions, wherein the cyclodextrin-polymer-yeast-inclusion complex prepared according to claim 1 is in an amount of 0.1 to 99.9% by weight with conventionally used fillers, diluents and other excipients. We present it in the form of 50 powders.