RU2456987C1 - Method for producing gelatine capsules of 3,31-diindolylmethane - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a technology of a new dosage form of 3,3¹-diindolylmethane. A method consists in mixing 3,3¹-diindolylmethane and a liquid fatty excipient and adding a wedding agent. In mixing, the prepared mixture is heated to 35-45°C to prepare a solution. Then the prepared solution is cooled to 21-23°C to fill gelatine capsules in the following proportions, g/capsule: 3,3¹-diindolylmethane - 0.01-0.1, the liquid fatty excipient - 0.05-0.1, the wedding agent 0.4-0.45. The prepared drug in the form of soft gelatine capsules containing 3,3¹-diindolylmethane in the form of the solution enables higher bioavailability of the active substance.

EFFECT: prepared drug is non-toxic, safe in prolonged introduction, has no local irritant action, no toxic effect on the immune and reproductive systems.

4 cl, 4 dwg, 7 tbl, 6 ex

Description

The invention relates to the pharmaceutical industry, in particular to a technology for the preparation of a new dosage form of 3.3 ¹ -diindolylmethane, namely, the production of gelatin capsules based on 3.3 ¹ -diindolylmethane.

3,3 ¹ -diindolylmethane (diindolylmethane, DIM) is an oral preparation with a pronounced antitumor effect. It inhibits the expression of oncogenes of VG ⁴ , E ₆ and E ₇ ), thus stopping the carcinogenesis process. Effective in the treatment and prevention of dysplasia and cancer of the cervix, breast tumors, laryngeal papillomatosis.

Diindolylmethane is a crystalline powder from white to white with a creamy tint with a characteristic odor.

It is easily soluble in acetone, 95% little in alcohol, very little soluble in chloroform, practically insoluble in water.

The insolubility of diindolylmethane in water is one of the reasons for the low bioavailability of the drug.

With intravenous administration, the bioavailability of various biologically active substances is maximal, i.e. equal to 100%. With any other route of administration, it never reaches its maximum, since the completeness and rate of absorption depend on many factors of a biological and pharmaceutical nature.

Biological factors include the individual characteristics of the patient's body. Of the pharmaceutical factors, the chemical and physico-chemical properties of the drug substance, the dosage form in which it is prescribed, the nature of the excipients used for the manufacture of the dosage form, the particularities of the production technology of the dosage form, etc. (Lakin K.M., Krylov Yu. F. Biotransformation of medicinal substances, M., 1981).

The drug enters the systemic circulation by releasing it from the dosage form and then absorbing it through biological membranes. The release of a biologically active substance is determined by the rate of disintegration of the dosage form and the time of dissolution of the substance in biological fluids. Evaluation of bioavailability is one of the most important steps in the development and implementation of new dosage forms of biologically active compounds.

The main attention when creating dosage forms of diindolylmethane is focused on creating conditions that increase the bioavailability of the drug.

The bioavailability of diindolylmethane is small, and it is taken into account when choosing a treatment regimen.

Dose (inside) = Avg × (Bioavailability / Interval), where Interval - the interval between drug injections is determined by the amount of active substance contained in the administered drug, which enters the systemic circulation in an unchanged form. Its value is measured by the ratio of the amount of active substance in the blood to the administered dose and is expressed as a percentage.

Various solid dosage forms of diindolylmethane are known (WO 2005107747 A2, 11/17/2005). To increase the solubility and bioavailability of diindolylmethane in this case, cetostearyl alcohol was used, which was heated with diindolylmethane, ceramides or their derivatives were added, cooled and mixed with triglycerides.

But the long-term effect of the triglyceride base had a negative effect on the gastric mucosa.

There is also known a method of obtaining various dosage forms of diindolylmethane using a starch matrix on which it is applied (US 6689387 B1, 02/10/2004). This technique allows you to slightly increase the bioavailability and solubility of the drug, but significantly reduces its stability during storage.

WO 2009032699 A1, March 12, 2009, describes the preparation of various dosage forms of diindolylmethane with increased bioavailability. Diindolylmethane is present in microcrystalline form. However, in this invention, it was not possible to achieve a significant improvement in solubility, because mixtures for filling leforms are dispersed systems of a mainly heterogeneous structure.

A medicament based on 3.3 ¹ -diindolylmethane in the form of a suppository is known (patent RU 2318510 C1, 03/10/2008).

A method of preparing the indicated agent consists in melting the components of the lipophilic base, partly triturated with 3.3 ^1- diindolylmethane to obtain a homogeneous suspension, polyvinylpyrrolidone and an antioxidant are added to the cooled remaining part of the base, the resulting suspension is mixed until homogeneous and the candles are formed by the method pouring into molds of a given size.

As a lipophilic base, it is preferable to use solid confectionery fat, such as type A or B solid fat, but it is possible to introduce additional emulsifiers, phthalic acid esters, alcohol, waxes, paraffin, lanolin, cooking oil, etc.

The disadvantage of this tool is the complexity of the composition, the complexity of the preparation process, low bioavailability (20-30%), as well as the limited use of the drug for the treatment of genital warts and neoplastic diseases of the reproductive organs.

The objective of this group of inventions is to increase the bioavailability of 3,3 ¹ -diindolylmethane, reduce its dose without compromising effectiveness, and also simplify the method of preparation of the drug and the possibility of its use for a wider range of diseases.

The problem is solved due to the fact that a new dosage form of the drug in the form of gelatin capsules based on 3.3 ¹ -diindolylmethane and a method for its preparation have been developed.

The method for producing 3.3 ¹ -diindolylmethane gelatin capsules according to the invention is characterized in that 3.3 ¹ -diindolylmethane is mixed with a liquid fatty filler, a solubilizer is added, the resulting mixture is heated to 35-45 ° C until a solution is obtained, then cool the resulting solution to 21-23 ° C and fill them with gelatin capsules in the following ratio of components, g / capsule:

3,3 ^l- diindolylmethane 0.01-0.1 liquid fatty filler 0.05-0.1 solubilizer 0.4-0.45

It is recommended to use vegetable oil or fish oil as a liquid fat filler.

From vegetable oils, you can use sunflower, corn, olive, soy or castor oil.

It is advisable to use tween-80 as a solubilizer.

Obtained by the described method gelatin capsules containing, g / caps .:

3,3 ^1- diindolylmethane 0.01-0.1 liquid fatty filler 0.05-0.1 solubilizer 0.4-0 45

are an independent object of the invention.

The technical result of the claimed group of inventions is that an experimentally selected ratio of liquid fat filler, solubilizer and heat treatment regimes made it possible to obtain a solution of 3.3 ¹ -diindolylmethane, as a result of which its bioavailability increased by an order of magnitude.

The resulting drug is non-toxic, safe for prolonged (90 days) daily intragastric administration by experimental warm-blooded animals, does not have a local irritant effect, and does not have a toxic effect on the immune and reproductive systems.

The invention is illustrated by the following examples.

Example 1

50 mg of 3.3 ¹ -diindolylmethane is mixed with 100 mg of fish oil, 400 mg of tween-80 are added to the mixture with stirring. The resulting mixture was heated to a temperature of 38 ° C, stirred until a solution was obtained, then cooled to a temperature of 22 ° C and introduced into a soft gelatin capsule.

Thus, a gelatin capsule is obtained containing, g / caps .:

3,3 ^1- diindolylmethane 0.05 fish fat 0.1 twin 80 0.4

Example 2

100 mg of 3.3 ^1- diindolylmethane are mixed with 100 mg of sunflower oil, 450 mg of tween-80 are added with stirring. The resulting mixture was heated to a temperature of 40 ° C, cooled to a temperature of 23 ° C and used to fill soft gelatin capsules.

Get a gelatin capsule containing, g / caps .:

3,3 ^1- diindolylmethane 0.1 sunflower oil 0.1 twin 80 0.45

Example 3

90 mg of 3,3 ¹ -diindolilmetana mixed with 100 mg of olive oil, with stirring, 450 mg of Tween-80. The resulting mixture is heated to a temperature of 42 ° C, the solution is cooled to a temperature of 22 ° C and used to fill soft gelatin capsules.

Get a gelatin capsule containing, g / caps .:

3,3 ^1- diindolylmethane 0.09 olive oil 0.1 twin 80 0.45

Example 4

25 mg of 3,3 ¹ -diindolilmetana mixed with 50 mg of corn oil was added with stirring 400 mg of Tween-80. The resulting mixture is heated to a temperature of 40 ° C, cool the solution to a temperature of 23 ° C and fill them with a soft gelatin capsule. Get a gelatin capsule containing, g / caps .:

3,3 ^1- diindolylmethane 0,025 corn oil 0.05 twin 80 0.4

Example 5

30 mg of 3.3 ^1- diindolylmethane are mixed with 90 mg of soybean oil, 400 mg of tween-80 are added to the mixture with stirring. The resulting mixture was heated to a temperature of 37 ° C, stirred until a solution was obtained, then cooled to a temperature of 21 ° C and introduced into a soft gelatin capsule. Get a gelatin capsule containing, g / caps .:

3,3 ^1- diindolylmethane 0,03 soybean oil 0.09 twin 80 0.4

Example 6

50 mg of 3.3 ¹ -diindolylmethane is mixed with 100 mg of castor oil, 400 mg of tween-80 are added to the mixture with stirring. The resulting mixture was heated to a temperature of 38 ° C, stirred until a solution was obtained, then cooled to a temperature of 22 ° C and introduced into a soft gelatin capsule.

Get a gelatin capsule containing, g / caps .:

3,3 ^1- diindolylmethane 0.05 Castor oil 0.1 twin 80 0.4

A study was made of the comparative pharmacokinetics and bioavailability of the substance 3,3 ¹ -diindolylmethane and gelatine capsules obtained by the claimed method with intragastric administration to rats.

The studied drug:

1. The substance of diindolylmethane.

2. Soft gelatin capsules.

Composition per 1 capsule, g:

3,3 ^1- diindolylmethane 0.1 Oil base 0.1 Twin 80 0.45

The substance is 3,3-diindolylmethane and is a powder that is practically insoluble in water. The drugs have antiandrogenic and antitumor effects. Diindolylmethane binds to androgen receptors, inhibiting the stimulating effect of androgens. As a result of this, regression of prostatic hyperplasia occurs.

Antiandrogenic and vasoprotective actions help to reduce the symptoms of benign prostatic hypertrophy. It is indicated for benign prostatic hyperplasia (adenoma) and uterine myoma.

The studies were performed on 200 rats weighing 0.23 ± 0.02 kg. The animals were kept in standard cages with a 12-hour lighting regime and free access to food and water.

The duration of the quarantine (acclimatization period) of the animals was fourteen (14) days. During quarantine, each animal was examined daily (behavior and general condition).

Samples were administered intragastrically in the morning on an empty stomach. Animals received standard nutrition 2 hours after the start of the experiment. Blood sampling was carried out after decapitation of animals through: 0.25; 0.5; 1.0; 2.0; 4.0; 6.0; 8.0; and 12.0 hours after drug administration.

Blood samples were centrifuged for 15 minutes at 3000 rpm, 1.5-2.0 ml of plasma were taken, frozen and stored at -20 ° C until analysis.

The analysis of the content of diindolylmethane in blood plasma was carried out according to a specially developed quantitative determination technique using high performance liquid chromatography with preliminary extraction from biomaterial (Soloviev V.N., Firsov A.A., Filov V.A. Pharmacokinetics. M .: Medicine, 1980, 423 pp.).

The following reagents and organic solvents were used for chromatographic analysis and drug extraction from the samples taken: acetonitrile, ethyl acetate, dodecyl sulfate, potassium hydrogen phosphate, phosphoric acid, distilled and deionized water.

The samples were centrifuged using an OPN-8 UHL4.2 centrifuge (Russia).

Sample analysis to determine the concentration of diindolylmethane in blood plasma samples was carried out by HPLC on an LC-20 Prominence liquid chromatograph (Beckman, USA) with a Shimadzu SPD M20A UV detector with a diode array.

The chromatographic characteristics of the method for the quantitative determination of diindolylmethane in the blood plasma of experimental animals are presented in table 1.

Table 1 Chromatographic characteristics of the method for the quantitative determination of diindolylmethane in blood plasma Options Designation Value Retention time - 5.07 ± 0.1 Column efficiency (number of theoretical plates) n 15100 Selectivity α 2.4

5 ml of ethyl acetate was added to all blood plasma samples in a volume of 1 ml. the tube was shaken for 2 minutes and then centrifuged for 10 minutes at 4000 rpm. The supernatant was removed, evaporated, 200 μl of acetonitrile was added, and an aliquot was added to the chromatograph.

Similarly, blood plasma samples were analyzed with standard amounts of diindolylmethane introduced.

Quantitative determination of diindolylmethane in blood plasma was carried out by HPLC on an LC-20 Prominence liquid chromatograph (Beckman, USA) with a UV detector with a diode array SPD M20A, Shimazu, wavelength 230 nm.

Column Ascentis, C18, 5 μm (4.6 × 25 mm). Eluent: 70% acetonitrile, 30% aqueous buffer containing 6 mg of dodecyl sulfate, 0.6 mg of potassium hydrogen phosphate per 1 L of H ₂ O, acidified to pH 5 with phosphoric acid.

The elution rate is 1.0 ml / min. Chromatography was performed at room temperature (22-24 ° C). Before chromatography, the mobile phase was degassed and filtered. The volume of sample introduced into the chromatograph was 5 μl. The retention time of diindolylmethane under these conditions is 5.07 minutes.

A linear relationship was established between the concentrations of diindolylmethane and the areas of chromatographic peaks in the range 0.03–2.0 μg / ml. The concentration of the drug substance in the samples was determined by the calibration graph. The minimum sensitivity of the analysis method was 0.03 μg / ml.

The reliability of the results of the quantitative determination of diindolylmethane in blood plasma was evaluated by calculating the metrological characteristics of this technique according to the results of 5 parallel measurements of concentrations in three samples of blood plasma, which are presented in table 2.

table 2 Metrological characteristics of the method for the quantitative determination of diindolylmethane in blood plasma The concentration of the drug, mcg / ml Sample size, n Relative standard deviation,% Relative error,% Introduced Found 0.03 mcg / ml 0.033 5 7.27 8.36 0.30 mcg / ml 0.31 5 0.77 0.89 2.0 mcg / ml 1.96 5 0.12 0.14

As follows from the data of table 2, the indicator characterizing the accuracy of the methodology (relative error of the average value) is 8.36, 0.89, 0.14%. The indicator characterizing the reproducibility of the method — the relative standard deviation — is 7.27, 0.77, 0.12% for the concentration of diindolylmethane 0.03, 0.30, and 2.0 μg / ml plasma, respectively.

The content of the drug in the samples is within the calculated confidence limits, and the methods for the quantitative determination of diindolylmethane in blood plasma are not dependent on systematic errors. The results obtained meet the criteria and standards reflected in the regulatory requirements of the FDA (Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies Conference Report - Pharmaceutical Research, Vol.9, No. 4, 1992).

To describe the pharmacokinetics of the drug in blood plasma, the following indicators were used (in their legend, accepted in the literature (Laboratory control of drug therapy. Analytical procedures (Edited by V.V. Menshikov) Clinical laboratory analytics. M., 1999, v.2 p. 323-346):

β is the constant of decrease on the tail of the distribution (h ^-1 );

T _max - time maximum concentration (h);

C _max - maximum concentration (μg / ml);

AUC ₁₂ is the area under the curve in the range of 0-12 hours (h · μg / ml);

AUC _∞ - total area under the curve (h · μg / ml);

MRT - average retention time (presence) (h);

Cl - total clearance (ml / h / kg);

V _ss is the stationary volume of distribution (ml / kg);

T _1/2 = 0.693 / β - half-life (h);

T _eff = AUC _∞ / C _max - effective duration (h).

Indicators T _max , C _max and β are estimated from the form of the concentration curve. The initial formulas for calculating the remaining indicators are as follows:

where D is the administered dose of the drug.

The calculation of indicators was carried out in a model-independent way using the method of integral moments (Guidelines for conducting qualitative clinical studies of bioequivalence of drugs. Moscow. 2004). The method used does not rely on any assumptions about the internal mechanisms underlying the kinetics of drugs, except for the most general ones, and in this sense is the most stable.

For the calculation, the original program developed at the Institute of Toxicology was used.

The results of measuring the concentration of the substance of diindolylmethane in the blood plasma of rats with intragastric administration are presented in table 3.

Figure 1 shows the averaged dynamics of the concentration of diindolylmethane in the blood plasma of experimental animals with intragastric administration of the substance diindolylmethane, 200.0 mg / kg (in linear coordinates), and in Fig. 2 in logarithmic coordinates.

Table 3. Concentrations of diindolylmethane in the blood plasma of experimental animals (μg / ml) with intragastric administration of the microgenized substance of diindolylmethane, 200.0 mg / kg No. Blood sampling time, hour 0.25 0.5 1,0 2.0 4.0 6.0 8.0 12.0 one 0.05 0.13 0.17 0.12 0.07 0.04 0.03 <0.03 2 0.05 0.12 0.15 0.12 0.06 0.03 0.03 <0.03 3 0.04 0.11 0.16 0.10 0.07 0.04 0.03 <0.03 four 0.03 0.12 0.13 0.11 0.06 0.05 0.04 <0.03 5 0.04 0.13 0.15 0.13 0.06 0.04 0.03 <0.03 6 0.03 0.15 0.14 0.12 0.08 0.03 0.03 <0.03 Arithm. average 0.04 0.13 0.15 0.12 0.07 0.04 0.03 <0.03 Osh. middle 0.00 0.01 0.01 0.00 0.00 0.00 0.00 0.00 Stand. off 0.01 0.01 0.01 0.01 0.01 0.01 0.00 0.0 Coeff. variats. 22.36% 10.79% 9.43% 8.85% 12.25% 19.97% 12.27% Median 0.04 0.13 0.15 0.12 0.07 0.04 0.03 Geom. Wed 0.04 0.13 0.15 0.12 0.07 0.04 0.03

After administration, diindolylmethane began to be detected in the systemic circulation after 15 minutes, the maximum concentration was observed about 1 hour (0.13-0.17 μg / ml). Further, the concentration of diindolylmethane began to gradually decrease and 12 hours after administration, diindolylmethane was determined in the blood in minimal amounts (less than 0.03 μg / ml). The scatter of individual values is moderate: the coefficient of variation of CV was 8-22%.

The results of measuring the concentration of diindolylmethane in the blood plasma of rats with intragastric administration of the capsule - 1 composition are presented in table 4. Figure 3 shows the average dynamics of the concentration of diindolylmethane in the blood plasma of experimental animals with intragastric administration of capsules of 0.10 mg / kg (in linear coordinates), and Fig. 4 - in logarithmic coordinates.

Table 4 The concentration of diindolylmethane in the blood plasma of experimental animals (μg / ml) with intragastric administration of capsules of diindolylmethane No. 1, 0.65 mg / kg No. Blood sampling time, hour 0.25 0.5 1,0 2.0 4.0 6.0 8.0 12.0 one 1.53 1.64 0.16 1.17 0.40 0.30 0.20 0.08 2 1.29 1.50 0.09 0.87 0.47 0.25 0.13 0.16 3 1.31 1.52 0.23 1.05 0.51 0.42 0.24 0.07 four 1.10 1.79 0.16 0.95 0.42 0.26 0.15 0.10 5 1.16 1.59 0.15 0.84 0.47 0.39 0.27 0.13 6 1.14 1.32 0.23 0.99 0.41 0.32 0.16 0.10 Arithm. average 1.26 1.56 0.17 0.98 0.45 0.32 0.19 0.11 Osh. middle 0.06 0.06 0.02 0.05 0.02 0.03 0.02 0.01 Stand. off 0.16 0.16 0.05 0.12 0.04 0.07 0.05 0.03 Coeff. variats. 12.66% 10.05% 31.35% 12.26% 9.67% 21.43% 28.43% 31.79% Median 1.23 1.56 0.16 0.97 0.45 0.31 0.18 0.10 Geom. Wed 1.25 1.55 0.16 0.97 0.44 0.32 0.19 0.10

After administration, diindolylmethane began to be detected in the systemic circulation after 15 minutes, the maximum concentration was observed for about 30 minutes (1.6-1.8 μg / ml), then the concentration decreased by 8-9 times and after 2 hours after administration, a repeated maximum concentration was observed (0.9-1.2 μg / ml).

Further, the concentration of diindolylmethane began to gradually decrease, and 12 hours after administration, diindolylmethane was determined in the blood in minimal amounts (about 0.1 μg / ml). The scatter of individual values is moderate: the coefficient of variation of CV was 6-30%.

Calculation of pharmacokinetic parameters was performed by a model-independent (direct) method based on the method of integral moments. The calculated values of the indicators are shown in tables 5-7.

Table 5 Pharmacokinetics of diindolylmethane in rats with intragastric administration of the substance of diindolylmethane, 200.0 mg / kg No. Indicator T _max C _max AUC ₁₂ AUC ₀₀ MRT Cl V _ss T _1/2 T _eff h mcg / ml mcg · h / ml mcg · h / ml h l / kg / h l / kg h h one 1.00 0.17 0.72 0.75 4.47 252.97 1131.19 2.02 4.43 2 1.00 0.15 0.63 0.65 4.01 344.43 1381.78 2.07 4.30 3 1.00 0.16 0.64 0.67 4.25 260.20 1104.92 2.22 4.18 four 1.00 0.13 0.72 0.75 5.18 312.26 1616.8 2.12 5.80 5 1.00 0.15 0.69 0.71 4.40 311.54 1371.65 1.99 4.76 6 1.00 0.15 0.69 0.72 4.45 276.87 1231.92 2.22 4.82 Arithm. average 1.00 0.15 0.68 0.71 4.46 04/29/04 1306.40 2.11 4.71 Osh. middle 0.00 0.01 0.02 0.02 0.16 14.49 78.15 0.04 0.24 Stand. off 0.00 0.01 0.04 0.04 0.39 35.49 191.44 0.10 0.59 Coeff. variats. 0.00% 8.76% 5.76% 6.25% 8.78% 12.11% 14.65% 4.78% 12.46% Median 1.00 0.15 0.69 0.72 4.43 294.21 1301.78 2.09 4.59 Geom. Wed 1.00 0.15 0.68 0.71 4.45 291.27 1295.11 2.11 4.68

The estimates obtained allow us to draw a number of conclusions about the pharmacokinetics of the substance of diindolylmethane during intragastric administration.

The concentration of diindolylmethane begins to be determined in the systemic circulation after 15 minutes. The maximum concentration C _{max is} reached after 1 hour and is about 0.15 μg / ml (0.15 ± 0.01 μg / ml). A subsequent decrease in concentration is characterized by a half-decrease time T1 / 2 of the order of 2 hours (2.11 ± 0.04 hours). The total average time the drug is present in the body - the MRT indicator is about 4.5 hours (4.46 ± 0.16 hours). The value of the apparent stationary volume of distribution - the indicator V _ss - is about 1300 l / kg.

Table 6 Pharmacokinetics of diindolylmethane in rats with intragastric administration of diindolylmethane capsules No. 1, 0.65 mg / kg No. Indicator T _max C _max 1 C _max 2 AUC ₁₂ AUC ₀₀ MRT Cl V _ss T _1/2 T _eff h mcg / ml mcg / ml mcg · h / ml mcg · h / ml h l / kg / h ml / kg h h one 0.5 2.0 1.64 1.17 4.94 6.04 5.76 15.77 90.88 3.74 5.18 2 0.5 2.0 1.50 0.87 4.40 5.58 6.40 19.93 127.46 4.15 6.41 3 0.5 2.0 1.52 1.05 5.28 6.37 5.86 13.66 80.08 3.87 6.06 four 0.5 2.0 1.79 0.95 4.45 5.39 5.71 21.81 124.56 3.77 5.68 5 0.5 2.0 1.59 0.84 4.98 5.78 5.77 19.23 110.99 3.64 6.88 6 0.5 2.0 1.32 0.99 4.52 5.81 6.43 17.20 110.56 4.19 5.87 Arithm. average 0.5 * 2.0 * 1.56 * 0.98 * 4.76 * 5.83 * 5.99 * 17.93 * 107.42 * 3.89 * 6.01 * Osh. middle 0.00 0.00 0.06 0.05 0.14 0.14 0.14 1.21 7.61 0.09 0.24 Stand. off 0.00 0.00 0.16 0.12 0.35 0.34 0.33 2.97 18.65 0.23 0.59 Coeff. variats. 0.00% 0.00% 10.05% 12.26% 7.46% 5.89% 5.54% 16.57% 17.36% 5.78% 9.77% Median 0.5 2.0 1.56 0.97 4.73 5.80 5.82 18.22 110.77 3.82 5.97 Geom. Wed 0.5 2.0 1.55 0.97 4.75 5.82 5.98 17.72 105.99 3.89 5.99 * - significant differences compared with indicators with the introduction of the substance of diindolylmethane at p <0.05.

The concentration of diindolylmethane begins to be determined in the systemic circulation after 15 minutes. The maximum concentration C _{max is} reached after 0.5 hours of the order of 1.6 μg / ml (1.56 ± 0.06 μg / ml) and 2 hours of the order of 1.0 μg / ml (0.98 ± 0.05 μg / ml). A subsequent decrease in concentration is characterized by a half-decrease time T1 / 2 of the order of 4 hours (3.89 ± 0.09 hours). The total average time the drug is present in the body - the MRT indicator is about 6 hours (5.99 ± 0.14 hours). The value of the apparent stationary volume of distribution - the Vss indicator - is about 108 ml / kg.

The results of a study of the comparative pharmacokinetics and bioavailability of the substance of diindolylmethane with intragastric administration in rats showed (Table 7):

The substance of diindolylmethane.

The concentration of diindolylmethane begins to be determined in the systemic circulation after 15 minutes. The maximum concentration of Cmax is reached after 1 hour and is about 0.15 μg / ml (0.15 ± 0.01 μg / ml). The subsequent decrease in concentration is characterized by a half-time T1 / 2 of the order of 2 hours (2.11 ± 0.04 hours). The total average time the drug is present in the body - the MRT indicator is about 4.5 hours (4.46 ± 0.16 hours). The value of the apparent stationary volume of distribution - the Vss indicator - is about 1300 l / kg.

Soft gelatin capsules.

The concentration of diindolylmethane begins to be determined in the systemic circulation after 15 minutes. The maximum concentration of Cmax is reached after 0.5 hours of the order of 1.6 μg / ml (1.52 ± 0.06 μg / ml) and 2 hours of the order of 1.0 μg / ml (0.98 ± 0.05 μg / ml). A subsequent decrease in concentration is characterized by a half-decrease time T1 / 2 of the order of 4 hours (3.89 ± 0.09 hours). The total average time the drug is present in the body - the MRT indicator is about 6 hours (5.99 ± 0.14 hours). The value of the apparent stationary volume of distribution - the Vss indicator - is about 108 ml / kg.

The results indicate minimal bioavailability with intragastric administration of the substance diindolylmethane, which, apparently, is associated with its practical insolubility in water, as well as inactivation of the active compound with the chemical environment of the gastrointestinal tract. The introduction of the active substance in soft gelatin capsules in the form of a solution in liquid oils of vegetable and animal origin not only protects it from exposure to an acidic gastric environment, but also provides almost 100% bioavailability.

As can be seen from the data presented, the task is solved.

A drug was obtained in the form of soft gelatin capsules containing 3.3 ¹ -diindolylmethane in the form of a solution, which made it possible to increase the bioavailability of the active substance by an order of magnitude and, as a result, reduce its dose. The resulting drug is non-toxic, safe for prolonged administration, does not have a local irritant effect, and does not have a toxic effect on the immune and reproductive systems.

Claims (4)

1. A method of producing gelatin capsules based on 3.3 ¹ -diindolylmethane, characterized in that 3.3 ¹ -diindolylmethane is mixed with a liquid fatty filler, a solubilizer is added, the resulting mixture is heated to 35-45 ° C until a solution is obtained, cooled the resulting solution to a temperature of 21-23 ° C and fill them with gelatin capsules in the following ratio of components, g / capsule:
3,3 ^1- diindolylmethane 0.01-0.1 liquid fatty filler 0.05-0.1 solubilizer 0.4-0.45 2. The method according to claim 1, characterized in that as a liquid fatty filler use vegetable oil or fish oil. 3. The method according to claim 2, characterized in that the vegetable oils use sunflower, corn, olive, soy or castor oil. 4. The method according to claim 1, characterized in that tween-80 is used as a solubilizer.

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