# US 9,750,727 B2 · Tuberculosis drug based on 4-thioureido-iminomethylpyridinium perchlorate: method of preparation and treatment

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- Number: US 9,750,727 B2
- Document ID: US9750727B2
- Status: Granted
- Kind: B2
- Application number: 13/657,168
- Filed: 2012-10-22
- Published: 2013-02-28
- Granted: 2017-09-05
- Earliest claimed: 2010-04-20
- Assignees: Joint Stock Company “Pharmasyntez”
- Applicants: Joint Stock Company “Pharmasyntez”
- Inventors: Aleksander Sergeevich Gushchin; Tatiana Ivanovna Vinogradova; Petr Kazimirovich Yablonskiy; Gennady Andreevich Batyunin; Natalya Vyacheslavovna Zabolotnyh; Svetlana Nikolaevna Vasilieva; Alexey Vladimirovich Maligin
- Web page: https://patentgrep.com/patent/US9750727B2

## CPC

- A61K 31/4425: Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/02: Suppositories; Bougies; Bases therefor; {Ovules}(apparatus for making A61J3/08; devices for introducing into the body A61M31/00)
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2846: {Poly(meth)acrylates}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 31/133: having hydroxy groups, e.g. sphingosine
- A61K 31/395: having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/7036: having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/06: for tuberculosis
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 6)

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.

### Claim 8 (depends on 1)

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.

### Claim 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.

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 9)

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

### Claim 12 (depends on 9)

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

### Claim 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.

### Claim 14 (depends on 13)

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.

### Claim 15 (depends on 1)

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.