ORAL ANTIMICROBIAL PHARMACEUTICAL COMPOSITIONS

Abstract

The present invention relates to oral pharmaceutical compositions with controlled and/or programmed release containing at least one active ingredient having antimicrobial and/or anti-infectious activity for the treatment of infections of the large intestine, in particular the colon.

Claims

1. A method of treating an infection of the large intestine in a patient, comprising administering to said patient a pharmaceutical composition comprising: (1) a tablet core comprising a homogenous structure comprising: (a) a therapeutically effective amount of rifamycin SV; (b) at least one hydrophilic substance; (c) at least one lipophilic substance; and (d) optionally at least one amphiphilic substance; and (2) a coating on said tablet core, said coating comprising a gastro-resistant substance.

2. The method of claim 1, wherein said at least one hydrophilic substance is from at least one of carboxyvinyl polymers, carboxyvinyl copolymers, hydroxyalkyl celluloses, alkyl celluloses, carboxyalkyl celluloses, polysaccharides, pectins, hyaluronic acid, glucuronic acid and glucosamines.

3. The method of claim 2, wherein said at least one hydrophilic substance is chosen from at least one of carboxyvinyl polymers and carboxyvinyl copolymers.

4. The method of claim 1, wherein said at least one lipophilic substance has a melting point less than about 90° C.

5. The method of claim 4, wherein said at least one lipophilic substance is selected from stearic acid, beeswax, carnuba wax, palmitic acid, and palmitostearate.

6. The method of claim 1, wherein said at least one amphiphilic substance is selected from the group consisting of lecithin, polyoxyethylenated sorbitan monooleate, sodium lauryl sulfate, sodium dioctyl sulphosuccinate, and ethylene and/or propylene block copolymers.

7. The method of claim 1, wherein said coating on said tablet core is selected from acrylic and methacrylic acid esters and/or cellulose phthalate.

8. The method of claim 1, wherein: (a) said at least one hydrophilic substance is selected from at least one of carboxyvinyl polymers, carboxyvinyl copolymers, hydroxyalkyl celluloses, alkyl celluloses, carboxyalkyl celluloses, polysaccharides, pectins, hyaluronic acid, glucuronic acid and glucosamines; and (b) said at least one lipophilic substance has melting point less than about 90° C.

9. The method of claim 8, wherein said at least one amphiphilic substance is lecithin.

10. The method of claim 1, wherein said rifamycin SV is in the form of a sodium salt.

11. The method of claim 1, wherein said pharmaceutical composition comprises from about 10% to about 90% by weight of said rifamycin SV.

12. The method of claim 1, wherein said pharmaceutical composition comprises from about 20% to about 60% by weight of said rifamycin SV.

13. The method of claim 1, wherein said pharmaceutical composition comprises from about 1% to about 3.4% by weight of said at least one lipophilic substance.

14. The method of claim 1, wherein said pharmaceutical composition comprises from about 8.4% to about 23% by weight of said at least one hydrophilic substance.

15. The method of claim 1, wherein said pharmaceutical composition comprises: (a) from about 10% to about 90% by weight of said rifamycin SV; (b) from about 1% to about 3.4% by weight of said at least one lipophilic substance; and (c) from about 8.4% to about 23% by weight of said at least one hydrophilic substance.

16. The method of claim 1, wherein said pharmaceutical composition is resistant to dissolution for 2 hours in an environment at pH 1.

17. The method of claim 1, wherein said pharmaceutical composition is resistant to dissolution for 1 hour in an environment at pH 6.4.

18. The method of claim 1, wherein said infection of the large intestine in said patient is infectious colitis, bacillary dysentery, pseudomembranous colitis, diarrhea, or diverticulitis.

19. The method of claim 18, wherein said infection of the large intestine in said patient is diarrhea.

20. The method of claim 19, wherein said infection of the large intestine in said patient is traveler's diarrhea.

Description

EXAMPLE 1

[0038] 200 g of rifamycin SV are mixed with 5 g of stearic acid, 7 g of carnauba wax, 8 g of sodium dioctyl sulphosuccinate, 100 g of lactose and 10 g of sodium edetate and granulated with a solution containing 25 g of low-viscosity polyvinylpyrrolidone in 0.2 litre of purified water. When the granulate has been dried, it is mixed with 100 g of sodium carboxymethylcellulose, 25 g of silica, 5 g of glycerol palmitostearate and 10 mg of talcum before being subjected to compression to the unit weight of 495 mg/tablet. The cores so obtained are then film-coated with a hydroalcoholic dispersion of acrylic and methacrylic acid esters, titanium dioxide, talcum and triethyl citrate, which confers on the product resistance to disintegration in a strongly acidic environment, simulating the environment of the stomach and the small intestine. The dissolution of the tablets is practically zero in pH conditions of less than 7 and is progressive in an enteric buffer at pH 7.2 with the following percentage quotas: [0039] less than 20% after 1 hour's residence, [0040] less than 50% after 3 hours' residence, [0041] more than 70% after 8 hours' residence.

EXAMPLE 2

[0042] 500 g of rifamycin SV are mixed with 10 g of stearic acid, 10 g of beeswax, 10 g of sodium lauryl sulphate, 200 g of mannitol and 10 g of sodium edetate and granulated with a solution containing 50 g of hydroxypropylcellulose in 0.5 litre of water. When the granulate has been dried, it is mixed with 150 g of sodium hydroxypropylmethylcellulose, 25 g of silica, 5 g of glycerol palmitostearate and 10 mg of talcum before being subjected to compression to the unit weight of 490 mg/tablet. The cores so obtained are then film-coated with an aqueous dispersion of acrylic and methacrylic acid esters, iron oxide, talcum and triethyl citrate, with confers on the product resistance to disintegration in an acidic environment, simulating the environment of the stomach and the small intestine. The dissolution of the tablets is practically zero in pH conditions of less than 7 and is progressive in an enteric buffer at pH 7.2 with the following percentage quotas: [0043] less than 30% after 1 hour's residence, [0044] less than 60% after 3 hours' residence, [0045] more than 80% after 8 hours' residence.

EXAMPLE 3

[0046] 2.5 kg of metronidazole are mixed with 70 g of stearic acid, 70 g of beeswax, 400 g of saccharose, 140 g of hydroxypropylmethylcellulose and 20 g of polysorbate and wet-granulated by the addition of purified water to a suitable consistency. The granulate is then dried and standardized in terms of dimensions before the addition of a further 200 g of hydroxymethylpropylcellulose, 600 g of microcrystalline cellulose, 30 g of glycerol palmitostearate and 70 g of silicon dioxide. After mixing, the powder is sent for compression to the unit weight of 450 mg/tablet.

[0047] The cores so obtained are then subjected to film-coating with a hydroalcoholic dispersion of acrylic and methacrylic acid esters, iron oxide, talcum and triethyl citrate, which confers on the product resistance to disintegration in an acidic environment. The dissolution of the tablets is practically zero in pH conditions of less than 7 and is progressive in an enteric buffer at pH 7.2 with the following percentage quotas: [0048] less than 25% within the first hour of residence, [0049] more than 25% and less than 70% within the third hour of residence, [0050] more than 80% after 8 hours' residence.

EXAMPLE 4

[0051] 500 g of metronidazole are mixed with the components of the lipophilic/amphiphilic matrix, 5 g of stearic acid and 5 g of soya lecithin, some of the hydrophilic polymer, 100 g of hydroxypropylcellulose, and diluents, 150 g of mannitol.

[0052] The mixture is then made into a paste with a solution of low-viscosity hydroxypropylcellulose in purified water until a consistent granulate is obtained. After drying, the granulate obtained is mixed with a further 100 g of hydroxypropylcellulose, to which are added flow agents and lubricants, 5 g of silica, 5 g of talcum and 5 g of magnesium stearate, then compressed to a final weight of 925 mg/tablet. The tablets are finally coated with an alcohol-based suspension of acrylic and methacrylic copolymers capable of imparting to the tablets efficacious gastroresistance.

[0053] The rate of dissolution of those tablets is progressive and controlled, with approximately 20% of the active ingredient being released after the first hour of residence in enteric juice at pH 7.2, 50% after 2 hours and more than 80% after 4 hours, these figures being understood as quotas that are clearly subsequent to 2 hours' exposure at pH 1 and 1 hour's exposure at pH 6.4, reflecting the environment of the stomach and of the small intestine, respectively.