Title:  Granular preparation and producing process thereof

United States Patent:  6,217,910

Assignee:  Daiichi Pharmaceutical Co., Ltd. (Tokyo, JP)

Filed:  April 28, 1998

PCT NO:  PCT/JP96/02028

102(e) Date:  April 28, 1998

PCT PUB. Date:  February 6, 1997

Foreign Application Priority Data:  Jul 21, 1995[JP] (7-206726)

A granular preparation comprising particles prepared by melt granulation of a powdered low-melting oily substance and a powdered medicine, the particles being coated with a finely powdered hydrophobic and oil-absorbing high polymeric compound (if desired, together with a finely powdered diluent) by melt coating, and a producing process thereof. The preparation does not cake even under heat and humid conditions and is effective for masking bitterness of a medicine.

DISCLOSURE OF INVENTION

The invention relates to a granular preparation comprising particles prepared by melt granulation of a powdered low-melting oily substance and a powdered medicine, the particles being coated with a finely powdered hydrophobic and oil-absorbing polymeric compound (if desired, together with a finely powdered diluent) by melt coating, and a producing process thereof.

The low-melting oily substance which can be used in the invention is not particularly limited as long as it is an oily substance having a melting point of 30 to 100^oC., preferably 50 to 80^oC. Examples of suitable low-melting oily substances include esters, such as glycerol monostearate, acetylated glycerol monostearate, sorbitan monostearate, hexadecyl palmitate, and octadecyl stearate; waxes, such as carnauba wax and bees wax; hydrocarbons, such as paraffin and microcrystalline wax; and fats and oils, such as hydrogenated oil, Japan wax, and cacao butter; with glycerol monostearate being preferred.

The low-melting oily substance having a particle size of 100 to 850 .mu.m is usually used for preference, but a preferred particle size varies depending on the dosage form. For example, particles of 360 to 850 .mu.m, preferably 350 to 700 .mu.m, in a particle size are used for the preparation of granules; and particles of 100 to 250 .mu.m, preferably 110 to 200 .mu.m, in a particle size are used for the preparation of fine granules.

The terminology "particle size" as used herein except for Reference Examples and Examples is intended to mean an average particle size.

The low-melting oily substance is usually used in an amount of 0.01 to 0.5 part by weight, preferably 0.05 to 0.3 part by weight, per part by weight of the finally obtained granular preparation.

While the medicine for use in the present invention is not particularly limited, those having bitterness, such as Nefilacetam, Levofloxacin, Ecabapide, etc., are preferred to the object and effect of the present invention.

The medicine is used in a powdered form having a particle size of not greater than 50 .mu.m, preferably several to 10 .mu.m. The medicine is usually used in an amount of 0.01 to 0.5 part by weight per part by weight of the finally obtained granular preparation. When the medicine and the low-melting oily substance are granulated by a method of melt granulation, powdered diluents such as corn starch, lactose, and talc may be used in combination, if desired. In general, diluents having a particle size of not greater than 50 .mu.m are used in an amount of about 0.02 to 0.3 part by weight per part by weight of the finally obtained granular preparation.

The terminology "melt granulation" as used herein is intended to mean a method in which mononyclear particles are prepared by adhering uniformly the powdered medicine (and the diluent if used) to the oily substance as a core with using the resulting stickness from heat melting of the oily substance in a fluidized bed system (see Ryushi Sekkei to Seizai Gijutsu, pp. 130-132, Yakugyo Jihosha (Oct. 30, 1994)). More specifically, melt granulation is carried out by mixing a finely powdered low-melting oily substance, a powdered medicine, and, if desired, a powdered diluent, agitating the mixed powder to make a fluidized powder bed while heating to a temperature at or above the melting point of the low-melting oily substance, followed by cooling to uniformly adhere the medicine and the diluent around the low-melting oily substance as a core, and cooling below the melting point to obtain mononuclear particles.

The heating temperature for melt granulation is usually about 5 to 45^oC. higher than the melting point of the low-melting oily substance. The granulation time, though varying depending on the raw materials used and the scale of production, is usually 10 to 30 minutes in a production scale of about 1 to 10 kg.

The resulting particles are then coated with a coating agent comprising a finely powdered hydrophobic and oil-absorbing polymeric compound and, if desired, fine powder of a diluent such as talc, by melt coating to obtain the granular preparation of the invention.

The term "hydrophobic" as used for the polymeric compound is intended to mean "being compatible with oil more than with water". Substances with such properties are almost insoluble in water but are easily soluble in oil or nonpolar solvents. The term "oil-absorbing" as used here means properties of absorbing oil selectively and swelling with oil.

Cellulose derivatives, such as ethyl cellulose, are included in the hydrophobic and oil-absorbing polymeric compounds. Those having a particle size of not greater than 10 .mu.m are usually used. The hydrophobic and oil-absorbing polymeric compound is used in an amount of about 0.0001 to 0.5 part by weight, preferably 0.001 to 0.1 part by weight, per part by weight of the resulting granular preparation.

The diluent which may be used in melt coating usually has a particle size of not greater than 50 .mu.m and is used in an adequate amount, usually about 0.1 to 0.5 part by weight per part by weight of the resulting granular preparation.

The terminology "melt coating" as used in the invention means a technique comprising mixing the particles prepared by melt granulation with a finely powdered coating agent and heating the mixed powder in a fluidized bed system at or above the melting point of the low-melting oily substance, thereby to make the low-melting oily substance melt and bleed on the surface of the particles and to adhere the coating agent around the particles with using the stickiness of the molten oily substance (see Ryushi Sekkei to Seizai Gijutsu, pp. 132-134, Yakugyo Jihosha (Oct. 30, 1994)).

Melt coating in the invention can be carried out by mixing the particles prepared by melt granulation as described above with a finely powdered hydrophobic and oil-absorbing polymeric compound and, if desired, a finely powdered diluent, heating the mixed powder at or above the melting point of the low-melting oily substance while fluidizing, tumbling or agitating thereby to adhere the polymeric compound around the particles to form a coating layer comprising the low-melting oily substance, the polymeric compound and, if used, the diluent.

Sufficient effects of melt coating can be expected by using the heating conditions and the granulation time similar to those employed in the melt granulation.

Cooling after melt coating gives a granular preparation as an objective product.

The powdered materials used in the invention, i.e., the powdered low-melting oily substance, the powdered medicine, the powdered diluent, and the powdered polymeric compound, are prepared by grinding the raw material by means of a generally employed pulverizer, such as a ball mill or a jet mill, and sieving the powder to obtain particles of desired size, if necessary.

The particle size of the prepared granular preparation can be made more uniform by passing through a sieve of desired mesh.

Mixing of the resulting granular preparation with an appropriate glidant and/or a coating agent can provide a granular preparation having a greater effect on preventing of caking. Usable glidants include talc, silicic acid anhydride, magnesium aluminometasilicate, a mixture thereof and the like. Usable coating agents include, titanium oxide, magnesium oxide, a mixture thereof and the like. The glidant and/or coating agent are usually used in an amount of 1 to 5% by weight based on the total weight of thus prepared granular preparation. The particle size of the glidant agent or the coating agent is in accordance with the standard of commercially available glidant agents or coating agent, and such size is usually in the rage of 0.001 to 75 .mu.m in the form of a particle size.

Claim 1 of 14 Claims

What is claimed is:

1. A granular preparation comprising core granular particles prepared by melt granulation of a powdered low-melting oily substance and a powdered medicine, and melt coating the core granular particles with a finely powdered hydrophobic and oil-absorbing polymeric compound.

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