MX2008000114A - Orally disintegrating powder comprising cilostazol and mannitol. - Google Patents

Abstract

The present invention provides an orally disintegrating powder comprising cilostazol as an active ingredient and mannitol in an amount of 70% by weight or more, which can be taken without water and can be disintegrated in oral cavity. Said powder is suitable for patients to whom cilostazol is applied, especially for aged patients and patients suffering from dysphagia.

Description

ORIGINALLY DISINTEGRABLE DUST THAT COMPRISES CILOSTAZOLE TECHNICAL FIELD The present invention relates to oral powder comprising cilostazol which can disintegrate in the oral cavity.

TECHNICAL BACKGROUND The cilostazol is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) -butoxy] -3,4-dihydrocarbostyril as illustrated in the following formula (1), which exhibits a high inhibitory action for the platelet aggregation as well as an inhibitory action for phosphodiesterase, antitumor activity, hypotensive action, antiphlogistic action, etc. and for this reason it is widely used as an antithrombotic agent, a drug that improves brain circulation, an antiphlogistic, an antitumor drug, an antihypertensive agent, antiasthmatic agent, as well as a phosphodiesterase inhibitor. The cilostazol tablets are called Pletaal 50® tablet and Pletaal 100® tablet (OTSUKA PHARMACEUTICAL CO., LTD.) Has already been on sale (see JP-A-56-49378). In addition, the tablets have been additionally approved as a medicine that has a preventive indication of relapse after treatment of cerebral infarction (except cardiogenic cerebral infarction).

The use status of Pletaal® tablet was investigated (market research between January and June, 2001), and in it the distribution was classified by age grouping showing that patients 65 years or older occupied approximately 74% of the total. According to the distribution classified by age grouping in relation to patients with cerebral infarcts that have been applied recently since 2003, patients aged 65 years or older occupied approximately 83.6% (Table 1). However, it appears as the majority of patients who are administered cilostazol tablets to the elderly.

TABLE 1 The number of patients with cerebral infarction classified by age grouping.

Generally, when a person ages, their eating / swallowing function becomes diminished. Accordingly, it is desired to develop a drug preparation that is easy to be taken by elderly patients to whom the cilostazol tablet is applied. In addition, it is known that there are some patients suffering from dysphagia among patients with cerebral infarcts to whom the cilostazol tablet is applied. When administering a drug to such patients, the drug must be ground and administered via percutaneous endoscopic gastrotomy or tube food in case of severe disorder (eg salivary aspiration, food aspiration). And in case of minor to medium disorder (water aspiration, occasional aspiration), the drug is actually administered orally with some idea, for example, it is given together with jelly, pudding, or cups of rice with milk, etc., or it is administered using the liquid of rice with milk instead of water. It is known that patients suffering from water aspiration or occasional aspiration can swallow saliva although it is difficult for these patients to drink water. In the Silver Science Research that is sponsored by the Japanese Ministry of Health and Welfare since 1988, Sugihara et al. who worked on a section "study to produce a new drug preparation and a new convenient container to administer to the elderly" investigated with a survey what type of drug formulation they expect future people to develop in the future. In the result, it was reported that many patients expected semi-solid formulations such as jelly, yogurt, pudding, etc. In the Investigation, in addition, Sugihara et al. they have been investigating oral dissolution formulations and paste formulations which are possible to be administered orally without water so that elderly patients can be administered a drug in a more secure and infallible way. In their research, they investigated the difficulty in taking a drug preparation or other research article by administering a formulation that is orally dissolved without including a medication to 128 example subjects (average of their ages: 77.4 ± 8.5), and administering a formulation in paste without including a medication to 73 example subjects (average of their ages: 78.4 ± 9.1). In the result, the "easy to take" and "easy to administer" responses were 82.2% and 75.8%, respectively, in the case of the formulation that is dissolved orally; 60.6%, 72.1%, respectively in the case of the paste formulation. In this way, it is concluded that the two drug formulations are easy to be taken for the elderly. Under the situation in which several such formulations are needed, cilostazol has also been studied on the various formulations (see JP-A-2001 -163769), furthermore, it had been desired to develop a drug formulation that is easy to be taken for many patients who are given cilostazol tablets, especially elderly patients and patients suffering from dysphagia to get the medication used properly.

DESCRIPTION OF THE INVENTION Problem to be solved by the invention In compliance with the foregoing indicated needs, the inventors attempted to produce tablets comprising 10% to 30% by weight, ie 50 mg to 100 mg of cilostazol as a single dosage unit and which is a oral disintegration tablet widely used in the art. However, although tablets comprising cilostazol are produced as an oral disintegration formulation, the tablets are difficult to disintegrate due to the insolubility in water of cilostazol, including using sugar or sugar alcohol, which is generally used for the disintegration formulation oral and can promote rapid dissolution. Alternatively, in order to overcome insolubility in water, a solubilizer ratio was increased and a proportion of cilostazol was decreased. However, it became necessary to produce a large tablet because the single dosage unit of cilostazol is high. Accordingly, a tablet having a maximum tablet size that can be prepared in general, such as 12 mm in diameter exhibits a slow disintegration rate, a hard disintegrability in the buccal cavity, a gritty feeling and an ugly feeling in the oral cavity when it is administered In addition, fine-grained powders comprising cilostazol were produced in consideration of the sensation in the oral cavity, however, they could not be taken without water due to a dry or sandy sensation in the oral cavity. Therefore, it had been desired to develop a new formulation of cilostazol that is different from an orally disintegrable tablet and the like and that it is possible to be taken without water, so that it can be easily taken by elderly patients whose swallowing function is inferior or patients suffering from dysphagia as a sequel to cerebral infarction.

Means to solve the problem The present inventors have extensively studied a variety of formulations of cilostazol preparations to achieve the above object, and have found that a powder formulation thereof where formulated in mannitol could be an orally disintegrable formulation. In the intrabuccal disintegration of the powder, the excipients are disintegrated in the oral cavity and then the cilostazol powder is again in a dispersed state. The dimension of the cilostazol particles is approximately 20 μm, and the particle is adapted to the oral cavity and is easy to swallow. In addition, other sugars or sugar alcohols with the exception of mannitol are not convenient because they are too sweet or of high wetting, the present inventors have studied extensively and have found that a powder comprising cilostazol which further comprises 70% in weight or more of mannitol has a speed of rapid total disintegration and a totally pleasant sensation in the oral cavity. The present invention has been completed based on these results. As far as the present inventors know, there is so far no pharmaceutical powder designed to achieve disintegration in the oral cavity and that can be taken without water. Even when such dust exists, it is thought to be inferior. An object of the present invention is to provide an orally disintegrable powder comprising cilostazol which can disintegrate in the oral cavity and can be taken without water by many patients to whom cilostazol is applied, especially elderly patients and patients suffering from dysphagia The present invention provides an orally disintegrable powder comprising cilostazol as an active ingredient further comprising mannitol, preferably 70% by weight or more mannitol, which can be disintegrated in the oral cavity and can be taken without water. In addition, the present invention provides the above-described orally disintegrable powder comprising cilostazol wherein an amount of cilostazol is from 10 wt% to 30 wt%. In addition, the present invention provides the above-described orally disintegrable powder comprising cilostazol wherein a single dosage unit of cilostazol is 50 mg to 100 mg.

The preferable mannitol is D-mannitol. The sensation of the powder in the oral cavity is especially preferable when using D-mannitol derived from corn starch, ie D-mannitol whose starting material is corn starch. In addition, an orally disintegrable powder comprising cilostazol wherein the average particle size of mannitol indicated above is from 20 micrometers to 80 micrometers is convenient. One embodiment of the present invention includes the orally disintegrable powder indicated above comprising cilostazol which further comprises 5% by weight or less of the microcrystalline cellulose. The powder indicated above may optionally comprise an ingredient (s) for a pharmaceutical preparation which can generally be formulated in a pharmaceutical preparation, and examples of the ingredient include excipients, binders, lubricants, disintegrating agents, colorants, flavors, sweeteners, lubricants, stabilizers, etc. One embodiment of the present invention includes the orally disintegrable powder indicated above which comprises cilostazol which is used to prevent relapse of cerebral infarction. The cilostazol can be prepared according to the method described, for example, in JP-A-56-49378. Mannitol used in the present may include, but is not limited to, D-mannitol: PEARLITOL 50C® (manufactured by ROQUETTE); D-mannitol: Mannit Kyowa® (manufactured by KYOWA HAKKO KOGYO Co., Ltd.); etc. The microcrystalline cellulose used herein may include, but is not limited to, Ceolus PH301 (manufactured by AsahiKASEl), etc. The term "orally disintegrable powder" used herein means a powder wherein the excipients disintegrate in the oral cavity and then the cilostazol powder becomes in a dispersed state, which is adapted to the oral cavity and is easy to be swallowed Effect of the invention According to the modalities indicated above, the present invention provides a new formulation of cilostazol that can disintegrate in the oral cavity and can be taken without water by many patients to whom cilostazol is applied, especially the elderly patients and patients they suffer from dysphagia. In the orally disintegrable powder comprising cilostazol of the present invention, preferably 70% by weight or more of D-mannitol is formulated, and it is desirable that the particle size of D-mannitol be from 20 microns to 80 microns. Furthermore, the sensation of the powder in the oral cavity is especially preferable when D-mannitol comes from a starting material such as corn starch and the formulated amount of microcrystalline cellulose is 5% by weight or less.

Hereinafter, the orally disintegrable powder of the present invention will be explained by illustrating Examples, and the experimental results of the sensation in the oral cavity will also be explained using the above powder in comparison with the sensation of an orally disintegrable tablet and conventional powder correspondent.

EXAMPLE 1 About 795 g of D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE) and 200 g of cilostazol powder were loaded in a vertical granulator (VG-10, produced by Powrex corp.) And then mixed. To them were added 125 g of 4% by weight of hydroxypropylcellulose (HPCL, manufactured by NIPPON SODA CO., LTD.) And the mixture was granulated. The produced granules were dried at 70 ° C in a tray-type dryer and then sieved by means of a 500 micrometer aperture filter to give a powder containing 20% by weight of cilostazol.

EXAMPLE 2 In a similar manner as that described in Example 1, using 770 g of D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE), 25 g of microcrystalline cellulose (Ceolus PH301, manufactured by AsahiKASEl) and 200 g of cilostazol powder, A powder containing 20 wt% of cilostazol was prepared.

EXAMPLE 3 About 766 g of D-mannitol (PEARLITOL 50C, manufactured by ROQUETTE), 25 g of microcrystalline cellulose (Ceolus PH301, manufactured by AsahiKASEl) and 200 g of cilostazol powder were loaded in a vertical granulator (VG-10, produced by Powrex corp.) and then mixed. To them were added 125 g of 4% by weight of hydroxypropylcellulose (HPC-L, manufactured NIPON SODA CO., LTD.) And the granules of the mixture were dried at 70 ° C in a tray type dryer and then sieved through of the 500 micrometer filter. To them was added 5 g of light anhydrous silicic acid (ADSOLIDER 101, manufactured by Freund Industrial Co., Ltd.) when a lubricant was added, and the mixture was stirred to give a powder containing 20 wt.% Of cilostazol .

REFERENCE EXAMPLE 1 About 192 g of erythritol (manufactured by Nikken Chemicals Co., Ltd.) and 100 g of corn starch (Nisshoku corn starch, manufactured by NIHON SHOKUHIN KAKO CO. LTD.), 8 g of hydroxypropyl cellulose (HPC-L, manufactured by NIPPON SODA CO., LTD.) and 100 g of cilostazol powder were loaded in a Multiplex fluidized bed granulator / dryer apparatus (MP-01, produced by Powrex corp.). The mixture was granulated during the spraying of purified water as a binder and the resulting granules were dried directly to give granule A. For 400 g of granule A, 40 g of PVP-XL (manufactured by ISP) as a disintegrating agent and g of magnesium stearate as lubricant were added to granule A. And the mixture was compressed by means of a continuous tablet forming machine 812HUK (manufactured by Kikusui Seisakusho Ltd.) to give tablets containing 100 mg of cilostazol (weighing 442 mg per tablet and with 12 mm diameter) REFERENCE EXAMPLE 2 Some 94 g of corn starch (Nisshoku corn starch, manufactured by NIHON SHOKUHIN KAKO CO. LTD.), 6 g of hydroxypropyl cellulose (HPC-L, manufactured by NIPPON SODA CO., LTD.) And 100 g of powder cilostazol were loaded in a granulation / drying apparatus Multiplex fluid bed (MP-01, produced by Powrex corp.). The mixture was granulated during the spraying of purified water as binder and the resulting granules were dried directly to give granule B. By granule B, 0.5% by weight of magnesium stearate was added as a lubricant to granule B. And the mixture was compressed by medium of a continuous tablet forming machine 812HUK (manufactured by Kikusui Seisakusho Ltd.) to give tablets containing 100 mg of cilostazol (weighing 201 mg per tablet and with 9 mm in diameter).

REFERENCE EXAMPLE 3 560 g of lactose (manufactured by HMS), 300 g of corn starch (Nisshoku corn starch, manufactured by NIHON SHOKUHIN KAKO CO. LTD.) And 100 g of cilostazol powder were loaded in a granulation / drying apparatus of Multiplex fluid bed (MP-01, produced by Powrex corp.). The mixture was granulated during the spraying of 3% by weight of hydroxypropylcellulose (HPC-L, manufactured by NIPPON SODA CO., LTD.) As a binder (the sprayed amount of hydroxypropylcellulose as a solid was 30 g). The resulting granules were dried directly to give the granule C. The granule C was sifted by means of a 500 μm filter that opened and to it was added 10 g of light anhydrous silicic acid (Aerosil, Nippon Aerosil) and was mixed to give a powder containing 10% by weight of cyclatazol.

Experiment 1 Each of the preparations of Examples 1 to 3 and Reference Examples 1 to 3 wherein each includes 100 mg of cliclostazol was introduced into the mouth of a subject and then disintegrated with its tongue. And the disintegration time obtained from each trial was compared with the other. In the case of the powders of Examples 1 to 3 and Reference Examples 1 to 3, the disintegration time was defined as the time taken until the subject had an adequate sensation, and the comparison was made with all the previous ones.

TABLE 2 As illustrated in Table 2, with respect to the powders of Examples 1 to 3, each time taken until the subject begins to feel satisfied was brief, and each sensation in the oral cavity was good. On the other hand, with respect to the tablets of Reference Examples 1 and 2 and the powder of Example 3, each disintegration time was prolonged, and each sensation of disagreement in the oral cavity continued even after the disintegration.

Experiment 2 Each 500 mg of the powders of Examples 1 and 2 or 1,000 mg of the powder of Reference Example 3 was placed in the subject's mouth and then disintegrated on his tongue. And the sensation in the oral cavity obtained from each trial was compared with the other. The evaluation of the sensation in the oral cavity was made with 10 subjects as an indicator and was based on a sandy sensation in the oral cavity or a taste of it during the disintegration of the same. The sensation in the oral cavity was evaluated in three levels, meaning "Good" means that a sensation in the oral cavity was good, "No tan mai" means that the sensation in the oral cavity is not bad, and "Bad" means that the sensation in the oral cavity is bad. The results are illustrated in Table 3.

TABLE 3 As illustrated in Table 3 above, the powders of Examples 1 and 2 were compliant and the sensation in the oral cavity was good. On the other hand, with respect to the powder of Reference Example 3, the subjects They feel gritty in their oral cavity and the sensation in the oral cavity was bad. In such a way that it was thought that the dust is difficult to swallow.

INDUSTRIAL APPLICABILITY As mentioned above, the cilostazol powders of the present invention have orally disintegrating properties that have never been known in a powder formulation, and can be taken without water and be disintegrated in the oral cavity, which is convenient for many patients to whom cilostazol is applicable to patients, especially of advanced age and patients suffering from dysphagia and, the present powder can be widely used in the pharmaceutical field.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - An orally disintegrable powder comprising cilostazol as an active ingredient and mannitol.

2. The powder according to claim 1 further characterized in that an amount of the mannitol is 70% by weight or more.

3. The powder according to claim 1 or 2 further characterized in that an amount of cilostazol is 10% by weight to 30% by weight.

4. The powder according to any of claims 1 to 3, further characterized in that a single unit of cilostazol dosage is 50 mg to 100 mg.

5. The powder according to any of the claims 1 to 4, further characterized in that mannitol is D-mannitol.

6. The powder according to any of claims 1 to 5 further characterized in that mannitol is derived from corn starch. The powder according to any of claims 1 to 6, further characterized in that the mannitol has an average particle size of 20 micrometers to 80 micrometers. The powder according to any of claims 1 to 7, further characterized in that it additionally comprises 5% by weight 0 less microcrystalline cellulose. 9. The powder according to any of the claims 1 to 8, further characterized because it is used to prevent relapse of cerebral infarction.