Tuberculosis drug based on 4-thioureido-iminomethylpyridinium perchlorate: method of preparation and treatment

Abstract

This invention relates to the field of chemical-pharmaceutical industry, specifically a new tuberculosis treatment that contains, as an active ingredient, 4-thioureido-iminomethylpyridinium perchlorate at a therapeutically effective and safe level and pharmaceutically acceptable excipients. In addition, this treatment relates to a method of the preparation of the new drug, providing a high yield of the new treatment. The new treatment has a higher tuberculostatic activity (200 times as high) and lower toxicity (2.4 times as low), as compared to a prototype drug, and is stable during long-term storage. This medicament may be used for treating and preventing all forms of pulmonary and extrapulmonary TB by using the new treatment in combination with other TB drugs.

Claims

1. A composition, comprising: a therapeutically effective and safe amount of an active ingredient, wherein the active ingredient is 4-thioureido-iminomethylpyridinium perchlorate or a combination of 4-thioureido-iminomethylpyridinium perchlorate and other anti-tubercular drugs; wherein 4-thioureido-iminomethylpyridinium perchlorate is in an amount of 8.0% to 90.0% w/w; a combination of pharmaceutically acceptable excipients, wherein the combination of pharmaceutically acceptable excipients are: colloidal silicon dioxide in an amount of 0.56% to 5.1% w/w; crosspovidone in an amount of 1.94% to 17.9% w/w; magnesium stearate in an amount of 0.28% to 2.59% w/w; povidone in an amount of 0.56% to 5.1% w/w; microcrystalline cellulose in an amount of 6.66% to 61.3% w/w; wherein the amounts are percent by weight of the pharmaceutical composition.

2. The composition of claim 1, wherein 4-thioureido-iminomethylpyridinium perchlorate is between 10 mg and 1000 mg.

3. The composition of claim 1, wherein the povidone is in an amount of 0.9% to 5.1% w/w of the composition; the microcrystalline cellulose is in an amount of 6.66% to 18.0% w/w of the composition; and the colloidal silicon dioxide is in an amount of 0.56% to 3.6% w/w of the composition.

4. The composition of claim 1, further comprising: a coating comprising copolymers of methacrylic acid and ethyl acrylate, triethyl citrate, macragol, talc, and ferric oxide dye, wherein the methacrylic acid and ethyl acrylate copolymer is in an amount of 3.0% to 4.0% w/w of the composition; triethyl acetate is in an amount of 0.8% to 1.8% w/w of the composition; macragol is in an amount of 0.2% to 0.4% w/w of the composition; talc is in an amount of 0.9% to 1.3% w/w of the composition; and ferric oxide dye is in an amount of 0.2% and 0.3% w/w of the composition.

5. The composition of claim 1, further comprising: at least one additional tuberculosis agent in an amount of not more than 90% w/w of the composition.

6. The composition of claim 5, wherein the additional tuberculosis agents are selected from the group consisting of isoniazid, pyrazinamid, rifampicin, rifabutin, amikacin, ethambutol, and fluoroquinolone antibiotic.

7. The composition of claim 6, wherein the 4-thioureido-iminomethylpyridinium perchlorate is between 10 mg and 1000 mg; and the isoniazid is at between 10 mg and 500 mg, the rifampicin is at between 10 mg and 667 mg, the rifabutin is at between 8.5 mg and 284 mg, the amikacin is at between 20 mg and 667 mg, the ethambutol is at between 20 mg and 667 mg, or the ofloxacin is at between 20 mg and 667 mg.

8. The composition of claim 1, wherein the composition is in a form selected from the group consisting of film-coated tablets, combined tablets, capsules, granules, suppositories, and suspensions.

9. A method of treating and preventing pulmonary and extrapulmonary tuberculosis, the method comprising the step of: administering a composition in a therapeutically effective amount to a patient in need thereof, wherein the composition comprises: a therapeutically safe and effective amount of 4-thioureido-iminomethylpyridinium perchlorate or a combination of 4-thioureido-iminomethylpyridinium perchlorate and other anti-tubercular drugs; wherein 4-thioureido-iminomethylpyridinium perchlorate is in an amount of 8.0% to 90.0% w/w; and a combination of pharmaceutically acceptable excipients; colloidal silicon dioxide in an amount of 0.56% to 5.1% w/w; crosspovidone in an amount of 1.94% to 17.9% w/w; magnesium stearate in an amount of 0.28% to 2.59% w/w; povidone in an amount of 0.56% to 5.1% w/w; microcrystalline cellulose in an amount of 6.66% to 61.3% w/w; wherein the amounts are percent by weight of the pharmaceutical composition.

10. The method of claim 9, wherein the composition is administered by oral or parenteral route.

11. The method of claim 9, wherein 4-thioureido-iminomethylpyridinium perchlorate is administered at between 10 mg/kg and 30 mg/kg.

12. The method of claim 9, wherein the 4-thioureido-iminomethylpyridinium perchlorate is administered in a single daily dose of 20 mg/kg.

13. The method of 9, further comprising administering at least one additional tuberculosis agent, wherein the at least one additional tuberculosis agent is selected from the group consisting of isoniazid, pyrazinamid, rifampicin, rifabutin, amycacin, ethambutol, and fluoroquinolone antibiotic.

14. The method of claim 13, wherein the isoniazid is administered at between 10 mg/kg and 15 mg/kg, the rifampicin is administered at between 10 mg/kg and 20 mg/kg, the rifabutin is administered at 8.5 mg/kg, the amikacin is administered at 20 mg/kg, the ethambutol is administered at 20 mg/kg, or the ofloxacin is administered at 20 mg/kg.

15. The composition of claim 1, further comprising: a coating covering the 4-thioureido-iminomethylpyridinium perchlorate and the combination of pharmaceutically acceptable excipients, wherein the coating comprises: hypromellose E5 in an amount of 0.12% w/w of the composition; hypromellose E15 in an amount of 2.07% w/w of the composition; yellow ferric oxide in an amount of 0.14% w/w of the composition; macrogol 6000 in an amount of 0.43% w/w of the composition; talc in an amount of 0.35% w/w of the composition; propylene glycol in an amount of 0.17% w/w of the composition; and titanium dioxide in an amount of 0.17% w/w of the composition.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) For a fuller understanding of the invention, reference should be made to the following detailed description, taken in connection with the accompanying drawings, in which:

(2) FIG. 1 is a table showing the effect of the new treatment on therapeutic effectiveness of TB drugs when used in combination (42 days of treatment).

(3) FIG. 2 is a table showing the effect of the new treatment on therapeutic effectiveness of TB drugs when used in combination (42 days of treatment).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(4) The following examples serve to illustrate (without limiting the scope of claims) the most preferable variants of the embodiment of the invention and prove the possibility to prepare the new treatment.

(5) As used herein, a therapeutically effective amount refers to that amount of the compound of the invention or other active ingredient sufficient to provide a therapeutic benefit in the treatment or management of tuberculosis or to delay or minimize symptoms associated with tuberculosis.

(6) As used herein, a therapeutically safe amount refers to that amount of the compound of the invention or other active ingredient sufficient to induce a positive benefit while concurrently avoiding serious side effects, in particular avoiding unacceptable drug related adverse events, as determined within the scope of sound judgment of a skilled artisan.

(7) A prophylactically effective amount refers to that amount of compound of the invention sufficient to result in the prevention, recurrence, or spread of disease. The prophylactically effective amount may refer to the amount sufficient to prevent initial disease, recurrence or spread of the disease or the occurrence of the disease in a patient, including, but not limited, to patients particularly susceptible to the disease, or occurrence of disease in another patient, i.e. spread of disease.

Example 1

(8) The formulation is in tablet dosage form and has the following composition (expressed as percent by weight of the tablet core).

(9) Composition Per Tablet:

(10) TABLE-US-00008 % (mg)* Core composition: 4-thioureido- 8.0 (23.2) 50.0 (145.0) 68.97 (200.0) 90 (261.0) iminomethylpyridinium perchlorate Colloidal silicon dioxide 5.1 (14.9) 2.78 (8.05) 1.72 (5.0) 0.56 (1.61) Crosspovidone 17.9 (51.8) 9.72 (28.19) 6.03 (17.50) 1.94 (5.64) Magnesium stearate 2.59 (7.5) 1.39 (4.03) 0.86 (2.50) 0.28 (0.81) Povidone 5.1 (14.9) 2.78 (8.05) 1.72 (5.0) 0.56 (1.61) Microcrystalline cellulose 61.3 (177.7) 33.34 (96.68) 20.69 (60.0) 6.66 (19.3) Tablet core weight (mg): 290.0 .sup. 290.0 .sup. 290.0 .sup. 290.0 .sup. Coating composition: Hypromellose E 5 0.12 (0.35) 0.12 (0.35) 0.12 (0.35) 0.12 (0.35) Hypromellose E 15 2.07 (6.0) 2.07 (6.0) 2.07 (6.0) 2.07 (6.0) Yellow ferric oxide 0.14 (0.40) 0.14 (0.40) 0.14 (0.40) 0.14 (0.40) Macrogol 6000 0.43 (1.25) 0.43 (1.25) 0.43 (1.25) 0.43 (1.25) Talc 0.35 (1.0) 0.43 (1.25) 0.43 (1.25) 0.43 (1.25) Propylene glycol 0.17 (0.50) 0.17 (0.50) 0.17 (0.50) 0.17 (0.50) Titanium dioxide 0.17 (0.50) 0.17 (0.50) 0.17 (0.50) 0.17 (0.50) Coated tablet weight (mg) 300.0 .sup. 300.0 .sup. 300.0 .sup. 300.0 .sup. *expressed as percent by weight of the tablet core
Modified Release Tablets 100, 200, 400, 800, and 1000 mg
Composition Per Tablet, mg:

(11) TABLE-US-00009 4-thioureido- 100.0 200.0 400.0 800.0 1000.0 iminomethylpyridinium perchlorate Colloidal silicon dioxide 1.5 3.0 6.0 12.0 15.0 Calcium hydrophosphate 12.5 25.0 50.0 100.0 125.0 Povidone 2.5 5.0 10.0 20.0 25.0 Magnesium stearate 1.5 3.0 6.0 12.0 15.0 Ammonium methacrylate 12.5 25.0 50.0 100.0 125.0 copolymers Talc 1.5 3.0 6.0 12.0 15.0 Microcrystalline 17.5 35.0 70.0 140.0 175.0 cellulose Ethylcellulose 0.5 1.0 2.0 4.0 5.0 Tablet weight (mg) 150.0 300.0 600.0 1200.0 1500.0
Enteric Coated Tablets 200, 400, 500, 600, and 800 mg
Composition Per Tablet, mg:

(12) TABLE-US-00010 Core composition: 4-thioureido- 200.0 400.0 500.0 600.0 800.0 iminomethylpyridinium perchlorate Colloidal silicon dioxide 5.0 10.0 12.5 15.0 20.0 Crosspovidone 17.50 35.0 43.75 52.5 70.0 Magnesium stearate 2.50 5.0 6.25 7.5 10.0 Povidone 5.0 10.0 12.5 15.0 20.0 Microcrystalline 60.0 120.0 150.0 180.0 240.0 cellulose Tablet core weight 5% 290.0 580.0 725.0 870.0 1160.0 Coating composition: Methacrylic acid-ethyl 16 32 40 48 64 acrylate copolymers Yellow ferric oxide 2 4 5 6 8 Macrogol 0.75 1.5 1.875 2.25 3 Talc 7 14 17.5 21 28 Triethyl acetate 4.25 8.5 10.625 12.75 17 Enteric coated tablet 320.0 640.0 800.0 960.0 1280.0 weight (mg):

Example 2

(13) The formulation is in solid dosage form: coated granules. The coating is applied to provide stability of composition during storage and enhance the appearance and organoleptic properties.

(14) Coated Granule Dosage Form

(15) Composition Per 100 g:

(16) TABLE-US-00011 Core composition: 4-thioureido- 5 50 70 80 90 iminomethylpyridinium perchlorate Sucrose 50.4 25.2 14 8.4 2.8 Colloidal silicon dioxide 3.6 1.8 1 0.6 0.2 Povidone 14.4 7.2 4 2.4 0.8 Microcrystalline 18 9 5 3 1 cellulose Ethylcellulose 3.6 1.8 1 0.6 0.2 Granule core weight: 95 95 95 95 95 Coating composition: Methacrylic acid 3.0 3.0 3.0 3.0 3.0 copolymers Macrogol 0.2 0.2 0.2 0.2 0.2 Yellow ferric oxide 0.2 0.2 0.2 0.2 0.2 Talc 0.85 0.85 0.85 0.85 0.85 Triethyl acetate 0.75 0.75 0.75 0.75 0.75 Coated granule weight 100 100 100 100 100 (mg):

(17) The coating composition (expressed as percent by weight of the granule core) may be as follows:

(18) Methacrylic acid and ethyl acrylate copolymers: 3.0-4.0

(19) Triethyl acetate: 0.8-1.2

(20) Macragol: 0.2-0.4

(21) Talc: 0.9-1.3

(22) Ferric oxide dye: 0.2-0.3.

Example 3

(23) Pills 100, 200, 300, and 400 mg

(24) Composition Per Pill:

(25) TABLE-US-00012 4-thioureido- 100.0 200.0 300.0 400.0 iminomethylpyridinium perchlorate Colloidal silicon dioxide 2.5 5.0 10.0 10.0 Sucrose 21.0 42.0 63.0 84.0 Magnesium stearate 1.2 2.4 3.6 4.8 Povidone 6.0 12.0 18.0 24.0 Microcrystalline 22.0 44.0 66.0 88.0 cellulose Macrogol 1.3 2.6 3.9 5.2 Yellow ferric oxide 1.0 2.0 3.0 4.0 Talc 3.5 7.0 10.5 14 Titanium dioxide 1.5 3.0 4.5 6.0 Coated pill weight 160.0 320.0 480.0 640.0 (mg):

Example 4

(26) Capsules 50, 100, 200, 300, and 400 mg

(27) Composition Per Capsule:

(28) TABLE-US-00013 Unit, Ingredient name mg 4-thioureido- mg 50.0 100.0 200.0 300.0 400.0 iminomethylpyridinium perchlorate Potato or corn starch mg 4.0 8.0 16.0 24.0 32.0 Colloidal silicon mg 0.5 1.0 2.0 3.0 4.0 dioxide Crosspovidone mg 2.0 4.0 8.0 12.0 16.0 Magnesium or calcium mg 0.5 1.0 2.0 3.0 4.0 stearate Microcrystalline mg 3.0 6.0 12.0 18.0 24.0 cellulose Capsule content weight: mg 60.0 120.0 240.0 360.0 480.0 Gelatin capsule pcs. 1 1 1 1 1

(29) TABLE-US-00014 Unit, Ingredient name mg % (mg) 4-thioureido- mg 75 (180.0) 83.33 91.7 (220.0) iminomethylpyridinium (200.0) perchlorate Potato or corn starch mg 13.3 (24.0) 8.0 (16.0) 3.6 (8.0) Colloidal silicon mg 1.7 (3.0) 1.0 (2.0) 0.45 (1.0) dioxide Crosspovidone mg 6.7 (12.0) 4.0 (8.0) 1.82 (4.0) Magnesium or calcium mg 1.7 (3.0) 1.0 (2.0) 0.45 (1.0) stearate Microcrystalline mg 10.0 (18.0) 6.0 (12.0) 2.73 (6.0) cellulose Capsule content weight: mg 240.0 240.0 240.0 Gelatin capsule pcs. 1 1 1

Example 5

(30) Suspension Dosage Form

(31) 4-thioureido-iminomethylpyridinium perchlorate powder for oral suspension (100 ml vials) 200 mg/5 ml, 300 mg/5 ml, 400 mg/5 ml

(32) Composition Per 100 ml:

(33) TABLE-US-00015 Unit, 200 mg/ 300 mg/ 400 mg/ Ingredient name mg 5 ml 5 ml 5 ml 4-thioureido- mg 4,000.0 6,000.0 8,000.0 iminomethylpyridinium perchlorate Colloidal silicon dioxide mg 40.0 60.0 80.0 -cyclodextrin mg 400.0 600.0 800.0 Citric acid mg 200.0 300.0 400.0 Povidone mg 1,400.0 2,100.0 2,800.0 Sucrose (or sorbitol) mg 3,950.0 5,925.0 7,900.0 Vanilla, apple, or banana mg 10.0 15.0 20.0 flavor Weight of powder for mg 10,000.0 15,000.0 20,000.0 3% suspension: 3% 3%

(34) TABLE-US-00016 Unit, Ingredient name mg % (mg) 4-thioureido- mg 36 40.0 44 iminomethyl- (3600.0) (4000.0) (4400.0) pyridinium perchlorate Colloidal silicon mg 1.19 1.0 0.82 dioxide (43.0) (40.0) (36.0) -cyclodextrin mg 11.94 10.0 8.18 (430.0) (400.0) (360.0) Citric acid mg 5.83 5.0 4.09 (210.0) (200.0) (180.0) Povidone mg 41.39 35.0 28.64 (1490.0) (1400.0) (1260.0) Sucrose (or sorbitol) mg 116.94 98.8 80.91 (4210.0) (3950.0) (3560.0) Vanilla, apple, or mg 0.31 0.25 0.2 banana flavor (11.0) (10.0) (9.0) Weight of powder for mg 10,000.0 10,000.0 10,000.0 suspension For suspension: Purified water mg 90,000.0 90,000.0 90,000.0 Suspension weight: mg 100,000.0 100,000.0 100,000.0

(35) All components and ratios of components are determined experimentally and are optimal, which makes it possible to prepare a TB treatment meeting the requirements of the state pharmaceutical authorities.

Example 6

(36) Rectal Suppositories 50, 100, 200, and 300 mg

(37) TABLE-US-00017 Unit, Ingredient name mg 4-thioureido- mg 50.0 100.0 200.0 300.0 iminomethylpyridinium (46.0-54.0) (95.0-105.0) (190.0-210.0) (285.0-315.0) perchlorate -cyclodextrin mg 40.0 80.0 160.0 240.0 Glycerol mg 10.0 20.0 40.0 60.0 Macragol mg 100.0 200.0 400.0 600.0 Witepsol mg 400.0 800.0 1,600.0 2,400.0 suppository basis Suppository mg 600.0 1,200.0 2,400.0 3,600.0 weight (570.0-630.0) (1,140.0-1,260.0) (2,280.0-2,520.0) (3,420.0-3,780.0)

Example 7

(38) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 44.5% w/w

(39) Sieved powders of 4-thioureido-iminomethylpyridinium perchlorate at the level of 70.0 g, microcrystalline cellulose 5.0 g, colloidal silicon dioxide 1.0 g, and ethylcellulose of 1.0 g are put into a mixer and mixed for 5-10 min at the rate of 25 rpm. To the resulting mixture is added an aqueous solution of povidone and sucrose, which consists of 4.0 g of povidone, 14.0 g of sucrose, and 28 ml of water; the wet mass is passed through a granulator; the wet granules are rolled to make them of desired size and dried at 40-45 C. until the residual moisture content in granules is 1.5-4.5%. The resulting granule cores are passed through 1.0-3.0 mm sieves. The granule cores of 1.0-3.0 mm in diameter are film-coated with suspension prepared on the basis of methacrylic acid copolymers.

(40) A total of 0.85 g of talc and 0.2 g of ferric oxide dye are mixed with 0.2 g of macrogol and 5 ml of water to obtain a cream-like consistency and then are mixed with 3.0 g of copolymer of methacrylic acid dispersed in 15 ml of water. The granule cores, when heated up to 45-50 C., are film-coated, with constant mixing and simultaneous drying with hot air to obtain 100.0 g of granules with uniform coating. The granules obtained meet the requirements of the state pharmaceutical authorities.

Example 8

(41) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 11.0% w/w

(42) Target additives are the same as in Example 6, although amounts of components are different.

(43) Sieved powders of 4-thioureido-iminomethylpyridinium perchlorate of 90.0 g, microcrystalline cellulose of 1.0 g, colloidal silicon dioxide of 0.2 g, and ethylcellulose of 0.2 g are put into a mixer and mixed for 5-10 min at the rate of 25 rpm. To the resulting mixture is added an aqueous solution of povidone and sucrose, which consists of 0.8 g of povidone, 2.8 g of sucrose, and 6 ml of water; the wet mass is passed through a granulator; the wet granules are rolled to make them of desired size and dried at 40-45 C. until the residual moisture content in granules is 1.5-4.5%. The resulting granule cores are passed through 1.0-3.0 mm sieves. The granule cores of 1.0-3.0 mm in diameter are film coated with suspension prepared on the basis of methacrylic acid copolymers.

(44) A total of 0.85 g of talc and 0.2 g of ferric oxide dye are mixed with 0.2 g of macrogol and 5 ml of water to obtain a cream-like consistency and then are mixed with 3.0 g of copolymer of methacrylic acid dispersed in 15 ml of water. When the granule cores are heated up to 45-50 C., film coating is performed, with constant mixing and simultaneous drying with hot air to obtain 100.0 g of granules with uniform coating. The granules obtained are of yellow or red colour, are round or irregular in shape, and meet the requirements of the state pharmaceutical authorities.

Example 9

(45) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 100% w/w

(46) Target additives are the same as in Example 6, although amounts of components are different. Sieved powders of 4-thioureido-iminomethylpyridinium perchlorate of 50.0 g, microcrystalline cellulose of 9.0 g, colloidal silicon dioxide of 1.8 g, and ethylcellulose of 1.8 g are put into a mixer and mixed for 5-10 min at the rate of 25 rpm. To the resulting mixture is added an aqueous solution of povidone and sucrose, which consists of 7.2 g of povidone, 25.2 g of sucrose, and 50 ml of water; the wet mass is passed through a granulator; the wet granules are rolled to make them of desired size and dried at 40-45 C. until the residual moisture content in granules is 1.5-4.5%. The resulting granule cores are passed through 1.0-3.0 mm sieves. The granule cores of 1.0-3.0 mm in diameter are film coated with suspension prepared on the basis of methacrylic acid copolymers. A total of 0.85 g of talc and 0.2 g of ferric oxide dye are mixed with 0.2 g of macrogol and 5 ml of water to obtain a cream-like consistency and then are mixed with 3.0 g of copolymer of methacrylic acid dispersed in 15 ml of water.

(47) When the granule cores are heated up to 45-50 C., film coating is performed, with constant mixing and simultaneous drying with hot air to obtain 100.0 g of granules with uniform coating. The granules obtained meet the requirements of the state pharmaceutical authorities.

Example 10

(48) Powders of 4-thioureido-iminomethylpyridinium perchlorate, colloidal silicon dioxide, crosspovidone, magnesium stearate, povidone, microcrystalline cellulose, hypromellose, talc, macrogol, propylene glycol, titanium dioxide, and yellow ferric oxide, all taken in required amounts as in Example 1, are independently sifted through sieves.

(49) To prepare a humectant, estimated amounts of purified cold water and povidone are introduced into a reactor and mixed for 30 min at 60 C. until a clear, homogenous solution of light-yellow colour is obtained. Estimated amounts of 4-thioureido-iminomethylpyridinium perchlorate and microcrystalline cellulose are put into a mixer and mixed for 15 min, and then a humectant is added and mixed for at least 15 min until a uniform homogenous mass is obtained. The mass is subjected to wet granulation in a fluidized bed. Wet granulated material is dried for 20 min at 0.2 mPa and 552 C. until the residual moisture content is 1.0-2.0. The dried granulated material is subjected to dusting and dry granulation and is poured into the vibrosieve hopper; then the dried granulated material and dusting powder (aerosil, crosspovidone, and magnesium stearate) are put into the mixer, avoiding dust generation; the semi-product is mixed for 15 min to obtain mass for tabletting. The resulting mass is compressed in the tablet press.

(50) Tablet cores are film coated with aqueous suspension containing hypromellose mixture, yellow ferric oxide, macrogol, talc, propylene glycol, and titanium dioxide to obtain the new treatment as in claim 1.

Example 11

(51) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 20.0% w/w

(52) Sieved powders of 4-thioureido-iminomethylpyridinium perchlorate of 200.0 g, dry potato starch of 16.0 g, microcrystalline cellulose of 12.0 g, crosspovidone of 8.0 g, colloidal silicon dioxide of 2.0 g, and magnesium stearate of 2.0 g are put into a mixer and mixed for 5-10 min at the rate of 50 rpm until a uniform distribution of the active ingredient is obtained. The moisture content in the mixture is 1-3%. The resulting mass is put into automatic capsule filling machines and filled into capsules. Loose dust adhered to the capsules is removed, and the capsules are packed either in plastic bottles or in blister packs. The yield is 1,000 capsules of the new treatment with a total weight of 240.0 g or 0.24 g10%, each capsule contains 0.20 g10% of active ingredient. The capsules obtained meet all requirements for pharmaceutical products.

Example 12

(53) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 33.3% w/w

(54) Target additives are in the same amount as in Example 1, but corn starch is taken instead of potato starch and 4-thioureido-iminomethylpyridinium perchlorate is taken in amount of 180 g. The yield is 1,000 capsules of the new treatment with a total weight of 240.0 g or 0.24 g10%, each capsule contains 0.20 g10% of active ingredient. The capsules obtained meet all requirements for pharmaceutical products.

Example 13

(55) Target Additives: 4-Thioureido-Iminomethylpyridinium Perchlorate 9.1% w/w

(56) Target additives are in the same amount as in Example 1, but calcium stearate is taken instead of magnesium stearate and 4-thioureido-iminomethylpyridinium perchlorate is taken in amount of 220 g.

(57) The yield is 1,000 capsules of the new treatment with a total weight of 240.0 g or 0.24 g10%, each capsule contains 0.20 g10% of active ingredient. The capsules obtained meet all requirements for pharmaceutical products.

Example 14

(58) Manufacture of suppositories involves a molding process. Amounts of ingredients are calculated to have a yield of 100 suppositories. A total of 5.0 g of 4-thioureido-iminomethylpyridinium perchlorate, 4.0 g of 3-cyclodextrin, and 1.0 g of glycerol are put into a miller and are ground for 30 min. The resulting suspension is mixed in a reactor with 15.0 g of suppository base and macrogol heated up to 45 C. The resulting concentrate is cooled and then is ground for 3 h in a three-roller ointment grinder to obtain a required dispersion of the new treatment. The finished concentrate is mixed with 35.0 g of suppository base and macrogol at 48 C. until a uniform mass is obtained. The resulting mixture is poured into molds and packed. The yield is 100 suppositories meeting the following requirements: mean mass and uniformity of mass: 0.60 g5%; melting temperature: not higher than 37 C.; amount of 4-thioureido-iminomethylpyridinium perchlorate per suppository: 0.05 (0.046-0.054).

Example 15

(59) Sieved powders of 4-thioureido-iminomethylpyridinium perchlorate of 4.0 g, -cyclodextrin of 0.40 g, and povidone of 1.40 g are put into a ball mill and are ground for 3 h. To the resulting complex, sieved powders of sucrose of 3.95 g, citric acid of 0.20 g, and vanilla flavour of 0.01 g are added and ground for 1 h. The ground powder is put into a mixer and is mixed with 0.04 g of colloidal silicon dioxide for 5-10 min at the rate of 50 rpm until a uniform mixture is obtained. The resulting mixture is automatically filled into vials, 10.0 g per each vial. Vials are hermetically sealed with caps and are packed into a box, with a 5 ml spoon. The obtained suspension meets the following requirements: variation of the vial content: 9.7 g to 10.3 g; water content in powder: not more than 2%; pH: 5-8; sedimentation stability of suspension: not less than 24 h.

(60) For oral administration, dissolve the powder with 90 ml of water to the mark and use 5 ml spoon. Each 100 ml of suspension contains 20 doses, each containing 200 mg of active ingredient 4-thioureido-iminomethylpyridinium perchlorate.

Example 16

(61) Combined Preparation in the Form of Capsules 100 mg+100 Mg, 150 mg+200 mg (Rifampicin+Perchlozone)

(62) Composition Per Capsule:

(63) TABLE-US-00018 Unit, Ingredient name mg 4-thioureido-iminomethylpyridinium mg 100.0 200.0 perchlorate Rifampicin mg 100.0 150.0 Potato or corn starch mg 38.0 76.0 Colloidal silicon dioxide mg 1.0 2.0 Crosspovidone mg 4.0 8.0 Magnesium or calcium stearate mg 1.0 2.0 Microcrystalline cellulose mg 6.0 12.0 Capsule weight: mg 250.0 450.0 Gelatin capsule pcs 1 1