Oral preparations with favorable disintegration characteristics
View Patent ↗The present invention provides oral preparations with good disintegration containing a slightly water-soluble active ingredient, which comprise a mixture of a solid formed product (e.g. a granule) and a second disintegrant wherein said solid formed product comprises a slightly water-soluble active ingredient, a first disintegrant and a water-soluble excipient which is formed by using a water-soluble polymer binder; or comprises a solid formed product prepared from a slightly water-soluble active ingredient, a disintegrant and a sugar alcohol by using a water-soluble polymer binder. When orally administered, these oral preparations exhibit excellent dissolution characteristics of the active ingredient in the digestive tract, and further, these preparations can show equivalent dissolution profile even at different amounts of the active ingredient, and thus enable the selection of the most suitable medicament for each patient, which makes these preparations highly useful in the clinical field.
1. A rapidly disintegrating oral preparation comprising:
i) granules, said granules comprising:
a water-soluble excipient selected from either one or both of lactose and mannitol;
a first disintegrant selected from one or more of corn starch, microcrystalline cellulose, low substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium and crosspovidone;
a water-soluble polymer binder selected from one or more of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and partially saponified polyvinyl alcohol; and
an active ingredient that is N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylenebutyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride; and
ii) a second disintegrant selected from one or more of lactose, anhydrous dibasic calcium phosphate, dibasic calcium phosphate, microcrystalline cellulose, low substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl starch sodium, and crosspovidone;
wherein said granules are mixed in said second disintegrant, and
wherein said active ingredient is contained in an amount of 5 to 40 mg, and
wherein said water-soluble excipient is contained an amount of 200 to 2000% by weight of the active ingredient, and
wherein said first disintegrant is contained in an amount of 5 to 300% by weight to the weight of the active ingredient, and
wherein said water-soluble polymer binder is contained in an amount of about 1 to 5% by weight to the total weight of said preparation, and
wherein said second disintegrant is contained in amount of 20 to 1200% by weight to the weight of the granule.
2. The rapidly disintegrating oral preparation of claim 1 , in which the water-soluble excipient is lactose.
3. The rapidly disintegrating oral preparation of claim 1 , in which the water-soluble excipient is mannitol.
4. The rapidly disintegrating oral preparation of claim 3 , in which the dissolution rate of the N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylenebutyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in diluted McIlvaine buffer (pH: 4.0) is at least 85% within 15 minutes.
5. The rapidly disintegrating oral preparation of claim 2 , in which the dissolution rate of the N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-(2R,3R)-2,3-tetramethylenebutyl]-(1′R,2′S,3′R,4′S)-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in diluted McIlvaine buffer (pH: 4.0) is at least 80% within 15 minutes.
6. The rapidly disintegrating oral preparation of claim 3 , in which the mannitol is contained in an amount of 250 to 1200% by weight based on the weight of the active ingredient.
7. The rapidly disintegrating oral preparation of claim 1 , in which the first disintegrant is contained in an amount of 30 to 150% by weight based on the weight of the active ingredient.
8. The rapidly disintegrating oral preparation of claim 1 , that dissolves rapidly in a solution of pH from 3 to 5.
9. The rapidly disintegrating oral preparation of claim 1 , in which said granule is prepared by fluidized bed granulation.
10. The rapidly disintegrating oral preparation of claim 1 , wherein said granule has a layered structure comprising an internal layer of said first disintegrant and a water-soluble excipient, upon which is set a layer comprising said active ingredient.
11. The rapidly disintegrating oral preparation of claim 1 , wherein the dissolution percentage of said oral preparation is at least 59% after 5 minutes and at least 92% after 45 minutes.