Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-04-26
2004-02-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S468000, C424S469000, C424S470000, C424S474000, C424S482000, C424S501000, C424S499000
Reexamination Certificate
active
06692768
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a preparation method of drug-containing spherical fine particles that are useful in the production of easily-swallowed, controlled-release preparations.
BACKGROUND ART
Research has been conducted on various types of controlled-release preparations in order to reduce the number of medication times and alleviate adverse side-effects in the case of oral administration of a medication to a patient, and such preparations are widely used clinically as well.
However, since controlled-release preparations of the prior art are used primarily in the form of tablets, granules, capsules and so forth, they have problems in terms of being accompanied by difficulties in swallowing the medication for infants, elderly persons, seriously ill patients and so forth having decreased swallowing abilities. Thus, there is a need for more improved, easily-swallowed, controlled-release preparations.
In order to solve the above problems, orally rapid-disintegrating tablets and suspensions, etc. that contain controlled-release fine particles have been proposed. However, it is preferable that the particle size of these preparations be 200 &mgr;m or less to avoid an unpleasant sensation in the oral cavity when taken (see International Journal of Pharmaceutics 109, 271-281 (1994)), or it is necessary to improve the content of pharmaceutical in controlled-release fine particles in order to reduce the amount taken.
Consequently, when producing an easily-swallowed, controlled-release preparation, a method is required for efficiently producing particles having a high pharmaceutical content at the core of the particles, small particle size, narrow particle size distribution width, high sphericity and a smooth surface that is easily coated.
As an example of a granulation technology of the prior art, although a method for producing coating cores for fine granules by granulation is described in Japanese Unexamined Patent Publication No. 6-56700, the content of pharmaceutical in the coating cores is 5% or less, and the mean particle size is 270&mgr; or more.
In addition, Japanese Unexamined Patent Publication No. 5-229961 describes in Example 2 that particles produced by centrifugal fluidizing granulation after adding water to lactose and cellulose crystals are spherical, and that 80% of the particles have a particle size within the range of 150-250 &mgr;m. However, this relates to a method for producing particles used as an excipient that does not contain a pharmaceutical.
In general, the efficient production of particles of 200 &mgr;m or less by agitating granulation has been considered to be difficult (see 7th Eudragit Seminar, 1997, pp. 39-54).
DISCLOSURE OF THE INVENTION
The present invention provides a method for efficiently producing particles having a high drug content, small particle size, high sphericity, smooth surface and an easily coated form required for the production of easily-swallowed, controlled-release preparations.
As a result of conducting various studies, the inventors of the present invention discovered that drug-containing spherical fine particles for easily-swallowed, controlled-release preparations can be efficiently produced by a simple means comprising adding a binder solution to a mixture containing a drug powder and an excipient powder having the property of retaining solvent, followed by high-speed mixing granulation, thereby leading to completion of the present invention.
Namely, the present invention relates to a preparation method of drug-containing spherical fine particles having a mean particle size of 200 &mgr;m or less comprising: adding a binder solution to a mixture containing an excipient powder having the property of retaining a solvent and said drug powder, and granulating by high-speed mixing.
To begin with, the following provides an explanation of the materials used in the method of the present invention.
[1] The excipient used in the method of the present invention having the property of retaining solvent (to be abbreviated as the solvent-retaining excipient) is an excipient that has the property of non-bonding absorption of solvent and can be formed into fine particles. This excipient is suitably selected according to the type of drug, solvent and so forth. The excipient is preferably that in which the solvent retention rate is 2-50% of its dry weight, and particularly preferably 5-30%.
Furthermore, the solvent retention rate here refers to the proportion of the maximum amount of solvent retained internally by the excipient at room temperature and under normal pressure to the weight of the excipient in the form of having retained solvent (including the solvent weight), expressed as a percentage. This can be calculated by measuring the weight during maximum retention of solvent in the excipient and the weight when the solvent has been completely removed.
A water-retentive excipient is preferably used as the solvent-retaining excipient, specific examples of which include celluloses such as microcrystalline cellulose, methyl cellulose, sodium carmelose, calcium carmelose and low-substituted hydroxypropyl cellulose, and starches such as wheat starch, rice starch, corn starch, potato starch, hydroxypropyl starch, sodium carboxymethyl starch, &agr;-cyclodextrin and &bgr;-cyclodextrin. The most preferable examples of solvent-retaining excipients are microcrystalline cellulose and corn starch.
The solvent-retaining excipient is used in the form of a powder, has a mean length of the long axis of 40 &mgr;m or less, and preferably 1-30 &mgr;m, and that smaller than the mean length of the long axis of the drug particles mentioned below is preferable.
Although the amount of solvent-retaining excipient used varies according to the solubility of the drug in the solvent, the type of solvent, amount of solvent and so forth, it is normally 3-50 wt % of the drug, and preferably 5-30 wt % of the drug.
[2] The drug used in the method of the present invention dissolves in the solvent and can be formed into fine particles. A drug having solubility in the solvent at 25° C. of 1 g in 1 liter of solvent, and preferably 10 g or more in 1 liter of solvent, is used.
Specific examples of drugs are listed below.
(1) Antipyretics, analgesics and antiphlogistics such as indometacin, aspirin, diclofenac sodium, ketoprofen, ibuprofen, mefenamic acid, azulene, phenacetin, isopropyl antipyrine, acetaminophen, benzadac, phenylbutazone, flufenamic acid, sodium salicylate, salicylamide, sazapyrine and etodolac; (2) steroid antiinflammatory drugs such as dexamethasone, hydrocortizone, prednisolone and triamcinolone; (3) antiulcer drugs such as ecabet sodium, enprostil, sulpiride, cetraxate hydrochloride, gefarnate, irsogladine maleate, cimetidine, ranitidine hydrochloride, famotidine, nizatidine and roxatidine acetate hydrochloride; (4) coronary vasodilators such as nifedipine, isosorbide dinitrate, diltiazem hydrochloride, trapidil, dipyridamole, dilazep hydrochloride, verapamil, nicardipine hydrochloride and verapalimil hydrochloride;
(5) peripheral vasodilators such as ifenprodil tartrate, cinepacide maleate, ciclandelate, cynnaridine and pentoxyphylin; (6) antibiotics such as ampicillin, amoxicillin, cefalexin, erythromycin ethyl succinate, vacampicillin hydrochloride, minocycline hydrochloride, chloramphenicol, tetracycline, erythromycin, ceftazidime, cefuroxime sodium, aspoxicillin and lichipenam acoxyl hydrate; (7) synthetic antimicrobials such as nalidixic acid, piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride and sulfamethoxazole-trimethoprim; (8) antiviral agents such as aciclovir and ganciclovir; (9) anticonvulsants such as propantheline bromide, atropine sulfate, oxitropium bromide, timepidium bromide, scopolamine butylbromide, trospium chloride, butropium bromide, N-methylscopolamine methylsulfate and methyloctatropine bromide;
(10) antitussives such as tipepidine hibenzate, methylephedrine hydrochloride, codeine phosphate, tranilast, dextromethorphan hydrobromi
Ikegami Kengo
Ishibashi Takashi
Mizobe Masakazu
Nagao Keigo
Yoshino Hiroyuki
Bennett Rachel M.
Tanabe Seiyaku Co. Ltd.
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