Oral formulation comprising biguanide and an organic acid

Details Oral formulation comprising biguanide and an organic acid Oral formulation comprising biguanide and an organic acid

2000-10-27

2003-02-11

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S440000, C424S441000, C424S464000, C424S439000, C514S784000, C514S866000, C514S974000

Reexamination Certificate

active

06517870

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an oral fomulation comprising a biguanide and an organic acid.
BACKGROUND OF THE INVENTION
Biguanides such as metformin have unpleasant tastes such as bitterness and saltiness. The dosages of metformin are about 250 mg per dose in Japan and about 850 mg per dose in United States of America. In spite of such big dosages, only tablets are on sale at present.
There are several known methods for masking bitterness of bitter drugs, for instance, for solid formulations, sugar coated tablets, film coated tablets, capsules and the like are useful. Powders, fine granules and granules are formulated with sweetening agents or flavors; microcapsules, non-enteric coated formulation, spray-dried formulation with low melting point wax, formulation with lecithin (JP 62-265234-A) and the like may also be used. For solutions, there are formulations with water-insoluble high molecular weight compound such as ethylcellulose and hydroxypropylmethylcellulose phthalate (JP 52-41214-A); formulations with acidic phospholipids or lyso-phospholipids (JP 7-67552-A); and formulations with a large amount of citric acid (JP 4-58452-B).
DISCLOSURE OF THE INVENTION
The inventors of the present invention have intensively carried out research, and found that an oral formulation comprising a biguanide and an organic acid has less unpleasant tastes such as bitterness and saltiness. Thus, the present invention has been accomplished.
The present inventions includes:
[1] An oral formulation comprising a biguanide and an organic acid.
[2] An oral formulation comprising a biguanide, an organic acid and a sweetening agent.
[3] An oral formulation according to [1] or [2] wherein the biguanide is metformin or a pharmaceutical salt thereof.
[4] An oral formulation according to any one of [1] to [3] wherein the organic acid is malic acid, citric acid, tartaric acid or mixture thereof.
[5] An oral formulation according to any one of [1] to [4] wherein the sweetening agent is aspartame™, saccharine, saccharine sodium, stevioside or mixture thereof.
[6] An oral formulation according to any one of [1] to [5] wherein the ratio (w/w) of the biguanide to the organic acid is 1:0.1 to 1:50.
[7] An oral formulation according to any one of [2] to [6] wherein the ratio (w/w) of the biguanide to the sweetening agent is 1:0.001 to 1:10
[8] An oral formulation according to any one of [1] to [7] wherein the formulation is solution, jelly, gum drops, dry syrup, powders, fine granules or granules.
[9] An oral formulation according to any one of [1] to [8] wherein the pH of the solution is 3.5 to 6 in case that the formulation is solution, and the pH of the solution which is formed by dissolving or dispersing the formulation to 10 times more (w/w) volume of water, is 3.5 to 6 in case that the formulation is not solution.
DETAILED DESCRIPTION OF THE INVENTION
“Biguanide” includes compounds having a biguanide structure such as metformin, buformin, phenformin and pharmaceutically acceptable salts thereof.
“Organic acid” includes malic acid, citric acid, tartaric acid, ascorbic acid, succinic acid, fumaric acid, maleic acid, gluconic acid, glucuronic acid and mixtures thereof. Preferable organic acids are organic acids having 2 or 3 carboxyl groups such as malic acid, citric acid and tartaric acid, more preferably malic acid. The ratio (w/w) of the biguanide to the organic acid is, for example, 1:0.01 to 1:50, preferably 1:0.02 to 1:10, more preferably 1:0.05 to 1:1. In the case of malic acid, the preferable ratio (w/w) of the biguanide to malic acid is 1:0.05 to 1:0.5.
“Sweetening agent” includes aspartame™, saccharin, saccharin sodium, stevioside, thaumatin, erythritol, sorbitol, xylitol, glycerin and mixtures thereof. Preferable sweetening agents are aspartame™, saccharin, saccharin sodium and stevioside. The ratio (w/w) of the biguanide to the sweetening agent is, for example, 1:0.001 to 1:10, preferably 1:0.02 to 1:1.
When the formulation is a solution, preferably the pH of the solution is 3.5 to 6, more preferably 4 to 6, to decrease the unpleasant tastes and to keep the biguanide stable. If the formulation is not a solution, the preferable pH of the solution or dispersion which is formed by dispersing the formulation in water (1 part of the formulation to 10 parts of water, by weight), is 3.5 to 6, more preferably 4 to 6; This is in order to decrease the unpleasant tastes and to keep the biguanide stable.
“Oral formulation” includes solution, jelly, gum drops, dry syrup, powders, fine granules and granules. Preferably the formulation is not in the form of tablets.
The formulation of the present invention may include at pharmaceutically acceptable non-toxic and inactive additives. Additives include excipients such as corn starch, potato starch, white sugar, mannitol, xylitol, sorbitol, talc, kaolin, calcium monohydrogen phosphate, calcium sulfate, calcium carbonate, crystalline cellulose; lubricants such as magnesium stearate and potassium stearate; disintegrators such as carboxymethylcellulose calcium and low substituted hydroxymethylcellulose; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinypyrrolidone, gelatin, methylcellulose, Arabia gum and polyvinylalcohol; coloring agents; correctives; adsorbents; preservatives; stabilizers; moistening agents; de-charging agents; pH adjusters; and the like.
The formulation may include flavors such as lemon, orange, grapefruit, pine, banana, chocolate and yogurt to decrease the unpleasant tastes more.
The formulation of the present invention can be prepared by well known methods. In the case of solid formulations, the formulation can be prepared, for example, by extruding granulation methods, crushing granulation methods, dry granulation methods, fluidized bed granulation methods, tumbling granulation methods, high shear mixing granulation methods, wet compression methods, direct compression methods and the like.
The formulation of the present invention will contain the conventional amounts of active ingredient (biguanide) and will be used in conventional manner to administer doses in accordance with normal practice by routes and according to dosage regimes which are familiar to pharmacologists and medical practitioners.


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