United States Patent:  6,056,974

Assignee:  Shionogi & Co., Ltd. (Osaka, JP)

Filed:  August 12, 1998

The present invention provides a rapid-release tablet of S1452 at least containing the following components: a. a principal agent comprising (+)-(Z)-calcium 7-[(1R,2S,3S,4S)-3-benzenesulfonaidobicyclo[2.2.1]hept-2-yl]-5-heptenoate dihydrate (S1452), and b. a dispersant in an amount enough to disperse the principal agent after the disintegration of the tablet.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a rapid-release tablet of S1452 (hereinafter referred to as a tablet of the present invention ), which is characterized by at least containing the following components "a" and "b":

a. a principal agent comprising (+)-(Z)-calcium 7-[(1R,2S,3S,4S)-3-benzenesulfonamidobicyclo[2.2.1]hept-2-yl]-5-heptenoate dihydrate (S1452), and

b. a dispersant in an amount enough to disperse the principal agent after the disintegration of the tablet.

The preferred embodiments of a tablet of the present invention are exemplified below.

(1) A tablet of the present invention, wherein the amount of the dispersant is 0.05 to 9 parts by weight to 100 parts by weight of the tablet.

(2) A tablet of the present invention, wherein the amount of the dispersant is 0.1 to 7 parts by weight to 100 parts by weight of the tablet.

(3) A tablet of the present invention, wherein the amount of the dispersant is 0.3 to 5 parts by weight to 100 parts by weight of the tablet.

(4) A tablet of the present invention, wherein the amount of the dispersant is 0.5 to 30 parts by weight to the principal agent.

(5) A tablet of the present invention, wherein the dispersant is silica.

(6) A tablet of the present invention, which comprises as the dispersant 0.3 to 5 parts by weight of silica to 100 parts by weight of the tablet.

(7) A tablet of the present invention, which further comprises a disintegrator.

(8) A tablet of the present invention described in (7), wherein the amount of the integrator is 5 to 30 parts by weight to 100 parts by weight of the tablet.

(9) A tablet of the present invention described in (7), wherein the disintegrator is low-substituted hydroxypropylcellulose.

(10) A tablet of the present invention, which comprises 0.3 to 5 parts by weight of silica and 5 to 30 parts by weight of low-substituted hydroxypropylcellulose to 100 parts by weight of the tablet.

(11) A tablet of the present invention, wherein the dissolving rate of the principal agent is 70% or more at 60 minutes in an acidic solution.

(12) A tablet of the present invention, which further comprises an excipient and/or a binder.

(13) A tablet of the present invention described in (12), which comprises 40 to 90 parts by weight of the excipient and 0.5 to 5 parts by weight of the binder to 100 parts by weight of the tablet.

(14) A tablet of the present invention described in (12), wherein the excipient is lactose, mannitol, and/or starch.

(15) A tablet of the present invention described in (12), wherein the binder is hydroxypropylcellulose.

(16) A tablet of the present invention, wherein the surface is coated with a film base agent containing a polymer soluble in gastoric juice and a plasticizer.

(17) A tablet of the present invention described in (16), wherein the polymer soluble in gastric juice is a cellulose coating agent and the plasticizer is macrogol.

A tablet of the present invention is explained in more detail below.

As to S1452 of the principal agent, the particle size had better be small in the light of solubility, preferably the specific surface area is about 4000 cm² /g or more, more preferably about 7000 to 10000 cm² /g. Though the amount of the principal agent may be appropriately adjusted depending on the kind of diseases, the type of patients to be administered and the like, the range is usually about 1 to 30 parts by weight to 100 parts by weight of the tablet, preferably about 3 to 25 parts by weight. In the case of the concentration of the principal agent being too high, it is susceptible to change on standing and the solubility might be lowered. In the contrary case, the desired pharmacological effect can not be achieved.

The dispersant used in the present invention disperses S1452 of the principal agent after the disintegration in the digestive tract, especially in stomach, thereby enhancing the solubility. In more detail, S1452 is readily dissolved at pH value around neutral, however, the solubility tends to lower under acidic condition, especially at pH 4 or less. The reason is that S1452 dissociates Ca²⁺ in an acidic solution to be an oily free acid (namely, (+)-(Z)-7-[(1R,2S,3S,4S)-3-benzenesulfonamidobicyclo[2.2.1]hept-2-yl]-5-he ptenoic acid), and as a result, the surfaces of the tablet and particles produced by the disintegration are made glutinous and insoluble in water when S1452 is conventionally formulated into tablets. However, through the previous addition of the dispersant together with the principal agent, the agent-containing particles can be prevented from being contacted with each other after the disintegration, thereby the agent can slowly be released into a solution. As a result, the total amount of S1452 dissolved in stomach can be increased, for example, to the level of dissolving rate; about 70 to 95% at 60 minutes.

The dispersant usable in the present invention may be a pharmaceutical additive capable of dispersing the principal agent into a solution after the integration, which includes for example, silica (silicone dioxide), synthetic aluminum silicate, and the like, preferably silica such as Carplex.RTM. (#67, #80, CS-50 etc., Shionogi & Co., Ltd.), aerosil.RTM.. Though the dispersant is to be added enough to disperse the principal agent after the integration, the addition amount is extremely small to the total amount of the tablet, usually about 0.05 to 9 parts by weight, preferably about 0.1 to 7 parts by weight, more preferably about 0.3 to 5 parts by weight to 100 parts by weight of the tablet. In other words, the amount is usually about 0.5 to 30 parts by weight, preferably about 1 to 30 parts by weight to 100 parts by weight of S1452. In the case of the ratio of the dispersant being too low, the solubility of S1452 in gastric juice can not be improved. On the contrary, in the case of the ratio being too high, the contact of each drug particle can be prevented, while the solubility is lowered by the steric hindrance of an excess amount of the disperasnt existing around the surface of the drug, or the other trouble occurs such as powder scattering in the handling, thereby leading to undesirable results.

Preferably, a tablet of the present invention may contain a disintegrator for facilitating the disintegration. As the disintegrator, those well known in the present field may be used, for example, partly pregelatinized starch, sodium carboxymethyl starch, calcium carboxymethylcellulose, low substituted hydroxypropylcellulose (L-HPC), sodium croscarmellose (Ac-Di-Sol, Asahikasei), polyvinylpolypyrrolidone, and the like, preferably L-HPC. The amount of the disintegrator had better be enough to quickly disintegrate the tablet, for example, to complete the disintegration within several ten minutes, preferably several minutes in the first or second fluid regulated in the Japanese Pharmacopoeia, and usually, the amount is about 5 to 30 parts by weight, preferably about 10 to 25 parts by weight to 100 parts by weight of the tablet.

A tablet of the present invention may further contain an optional pharmaceutically acceptable additive such as an excipient, a binder, and a lubricant.

As the excipient, those well known in the technology field may be used, for example, lactose, sucrose, mannitol, corn starch, potato starch, hydroxypropyl starch, and the like, preferably lactose and starch. The amount of the excipient may appropriately be adjusted depending on the amount of the principal agent, the size of the objective tablet, and the like, which is usually about 40 to 90 parts by weight, preferably about 50 to 80 parts by weight to 100 parts by weight of the tablet.

As the binder, those well known in the technology field may be used, for example, methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, polyvinyl alcohol, gelatin, dextrin and the like, preferably hydroxypropylcellulose (L-HPC). The amount of the binder is usually about 0.5 to 5 parts by weight, preferably about 1 to 3 parts by weight to 100 parts by weight of the tablet.

Examples of the lubricant include magnesium stearate, talc, sucrose aliphatic acid ester, and usually the amount is extremely small, for example, about 1 parts by weight to 100 parts by weight of the tablet.

A tablet of the present invention can be prepared with the above materials through steps of mixing, kneading, granulating, drying, adding lubricant, tableting, and the like, each according to the well known methods in this field.

As to the kneading, examples of the equipment include a brabender, a double screw kneader, a high speed mixer, and the like, and preferable is a stirring type such as a double screw kneader capable of relatively slow kneading, because it is desirable to sufficiently knead without causing excessive aggregation of the principal agent in the light of enhancing the solubility.

The tableting may be carried out by using a commercial tablet machine, usually under a pressure of about 0.7 to 1.2 ton.

The surface of a tablet of the present invention obtainable by the above method may be coated with a film base. The coating may be carried out according to the method well known in the field, for example, the coating with a film of about 20 to 30 .mu.m in thickness by a commercial machine. The coating can improve the appearance or the physical and chemical stability of the tablet, or prevent or decrease unpleasant taste of drugs in mouth.

As the film base, suitably used is a polymer soluble in gastoric juice, such as cellulose coating agents, acrylate acid coating agents, polyvinylacetal diethylaminoacetate (AEA, Sankyo), aquacoat (FMC Co.), and the like.

Usually, the cellulose coating agents are relatively easy to coat with and have high water-solubility, which include, for example, hydroxypropylcellulose and hydroxypropylmethylcellulose (HPMC).

The acrylate acid coating agents can readily protect the surface of a tablet and give fine luster thereto, which include, for example, ethyl acrylate/methyl methacrylate copolymer (Eudragit RS, Rohm Co.), ethyl acrylate/butyl methacrylate/dimethylaminoethyl methacrylate copolymer (the same company). Preferable is cellulose coating agents, esp. HPMC which can fairly prevent the solubility of tablets from decreasing due to change on standing even after long period of storage.

The amount of the film base is usually about 1 to 5 parts by weight, preferably about 2 to 4 parts by weight to an naked tablet. In the case of the coating amount being too small, the physical or chemical stability of the obtained tablets might be lowered and unpleasant taste of the principal agent can not be reduced. On the contrary, an excess amount of the coating might bring a bad effect into the disintegration of tablets.

The film base may contain an optional additive such as a plasticizer, a light stabilizer, a lubricant, and the like.

Claim 1 of 11 Claims

1. A rapid-release tablet at least containing the following components:

a. a principal agent comprising (+)-(Z)-calcium 7-[(1R,2S,3S,4S)-3-benzenesulfonaidobicyclo[2.2.1]hept-2-yl]-5-heptenoate dihydrate, and

b. a dispersant in an amount enough to disperse the principal agent after the disintegration of the tablet.

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