JP6073543B2 - Method for producing loratadine-containing orally disintegrating tablet - Google Patents

Description

  The present invention relates to a method for producing an orally disintegrating tablet containing loratadine useful as a therapeutic agent for allergic diseases such as allergic rhinitis and urticaria.

  Orally disintegrating tablets can be taken without water and are easy to drink for elderly people, children, patients with difficulty swallowing, etc., and their significance is due to the arrival of an aging society and improved patient compliance. It has come to be regarded as important.

  Conventionally, as a loratadine-containing orally disintegrating tablet, a so-called Zydis technique obtained by suspending a drug in an aqueous solution of a carrier substance such as gelatin, filling a container such as a tray and then freeze-drying (Patent Document) 1) is commercially available. However, in order to apply this Zaydis technology commercially, special manufacturing equipment is required, and the manufacturing process is complicated and expensive. In addition, Zydis type orally disintegrating tablets are extremely excellent in solubility in the oral cavity, but since tablets are very soft and easy to absorb moisture, a completely moisture-proof and sturdy packaging form is essential. Not only is it impossible to apply it to an automatic packaging machine, but it tends to be broken or chipped when taking out tablets from a container. Therefore, development of a loratadine-containing orally disintegrating tablet that can be produced by ordinary production equipment and can be easily handled in the medical field is demanded.

  As a loratadine-containing orally disintegrating tablet that can be produced by a general tablet production facility and production method, for example, the oral cavity obtained by mixing granulated mannitol, crystalline cellulose, crospovidone, and the like with loratadine powder and tableting Disintegrating tablets (see Patent Document 2), colloidal silicon dioxide and the like mixed with loratadine powder, granulated, further mixed with mannitol and the like, and then orally disintegrating tablets obtained by tableting (see Patent Document 3), Oral disintegrating tablets obtained by mixing loratadine powder with mannitol, sorbitol, and calcium silicate to form a composite material, and further mixing starch, croscarmellose sodium, calcium silicate, etc. (Patent Document) 4) has been proposed. However, all of these loratadine-containing orally disintegrating tablets have a drawback that the dissolution property (that is, drug release property) of loratadine is insufficient.

Japanese Examined Patent Publication No. 62-50445 JP 2009-114113 A Special table 2009-521523 Special table 2009-532343 gazette

  The object of the present invention is obtained by a production method capable of obtaining a loratadine-containing orally disintegrating tablet excellent in both orally disintegrating property and drug releasing property without using a special production facility, and the production method. Another object is to provide an orally disintegrating tablet containing loratadine.

  As a result of intensive studies to achieve the above object, the present inventor conducted loratadine in a solution state or a suspension state to produce a loratadine-containing orally disintegrating tablet, and performed a two-step granulation process. When the ratio of the granulated product at the stage is 50% by weight or less of the tablet weight, it has been found that the release property of loratadine from the tablet is improved and the oral disintegration property of the obtained tablet is also excellent. It was. As a result of further studies based on this knowledge, the present inventor has completed the present invention.

  This invention provides the manufacturing method of the loratadine containing orally disintegrating tablet shown below, and the loratadine containing orally disintegrating tablet obtained by this manufacturing method.

  1. A method for producing a loratadine-containing orally disintegrating tablet, wherein loratadine is used in a solution state or a suspension state, a two-step granulation step is performed, and a ratio of the first-step granulated product is determined as a tablet weight. The manufacturing method of the loratadine containing orally disintegrating tablet characterized by being 50 weight% or less of this.

  2. Item 2. The method for producing a loratadine-containing orally disintegrating tablet according to Item 1, wherein the first-stage granulation is performed by fluidized bed granulation.

  3. Item 3. The method for producing a loratadine-containing orally disintegrating tablet according to Item 1 or 2, wherein the second-stage granulation is performed by fluidized bed granulation.

  4). Item 4. The method for producing an orally disintegrating tablet containing loratadine according to any one of Items 1 to 3, wherein the granulation in the third stage is further performed by fluidized bed granulation after the granulation in the second stage.

  5. Item 5. The method for producing a loratadine-containing orally disintegrating tablet according to any one of Items 1 to 4, wherein the ratio of the first-stage granulated product is 30 to 45% by weight of the tablet weight.

  6). The loratadine containing orally disintegrating tablet obtained by the manufacturing method in any one of said items 1-5.

  According to the method for producing a loratadine-containing orally disintegrating tablet of the present invention, the following remarkable effects can be obtained.

  (1) In the production method of the present invention, at the time of producing a loratadine-containing orally disintegrating tablet using a pharmaceutical raw material containing loratadine, excipients and the like, loratadine is used in a solution state or a suspended state, and at least 2 By performing the step granulation step and setting the ratio of the first step granulated product to 50% by weight or less of the tablet weight, the release of loratadine from the orally disintegrating tablet is remarkably improved.

  (2) In addition, the obtained loratadine-containing orally disintegrating tablet usually has an oral disintegration time of about 30 seconds or less and is excellent in oral disintegration. Moreover, it has a tablet hardness applicable to an automatic packaging machine while having excellent oral disintegration properties.

  (3) Therefore, according to the production method of the present invention, a loratadine-containing orally disintegrating tablet excellent in both orally disintegrating property and drug releasing property can be obtained without using special production equipment.

Method for producing loratadine-containing orally disintegrating tablet The method for producing the loratadine-containing orally disintegrating tablet of the present invention comprises using loratadine in a solution state or in a suspended state, performing a two-step granulation step, and the first step. The ratio of the granulated product is 50% by weight or less of the tablet weight.

  In the method for producing a loratadine-containing orally disintegrating tablet of the present invention, it usually contains loratadine and an additive that is an excipient, a binder and a disintegrant, and if necessary, a lubricant, a corrigent and the like. A loratadine-containing orally disintegrating tablet is prepared by performing a tableting step after performing a first granulation step and a second granulation step using a pharmaceutical raw material containing other additives. Here, the addition timing of excipients other than loratadine, binders, disintegrants, and other additives used as necessary is not particularly limited, and can be added in any step. Any additive may be added multiple times in one step or multiple steps.

Loratadine loratadine is a medicinal component of the orally disintegrating tablet of the present invention, and its chemical name is ethyl 4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohepta [1,2-b] pyridine. -11-ylidene) -1-piperidinecarboxylate. Loratadine has a persistent selective H ₁ receptor antagonistic action and is useful as a therapeutic agent for allergic diseases.

Additives In the process for producing the loratadine-containing orally disintegrating tablet of the present invention, various pharmacologically acceptable additives usually used in the pharmaceutical field, such as excipients and binders, as pharmaceutical raw materials other than loratadine. Additives such as disintegrants, lubricants, and flavoring agents can be used in appropriate combinations.

  Examples of the excipient include dextrin, sucrose, fructose, lactose, corn starch, starch, sodium carboxymethyl starch, partially pregelatinized starch, hydroxypropyl starch, mannitol, erythritol, sorbitol, xylitol, trehalose, maltitol, lactitol, Low substituted hydroxypropyl cellulose, crystalline cellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, light anhydrous silicic acid, magnesium oxide, magnesium carbonate, calcium carbonate, calcium citrate, synthetic aluminum silicate, etc. . These excipients can be used alone or in combination of two or more.

  Examples of the disintegrant include carmellose calcium, carmellose sodium, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, and various starches. These disintegrants can be used alone or in combination of two or more.

  Examples of the binder include saccharides such as sucrose, gelatin, gum arabic powder, methyl cellulose, ethyl cellulose, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose (carmellose), crystalline cellulose / sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol , Macrogol, pullulan, dextrin, tragacanth, sodium alginate, xanthan gum, partially pregelatinized starch, agar and the like. These binders can be used alone or in combination of two or more.

  The ratio of these additives can be selected from the range of about 100 to 12000 parts by weight with respect to 100 parts by weight of loratadine, and is usually about 300 to 10000 parts by weight, preferably about 500 to 8000 parts by weight.

  In the present invention, in addition to the excipient, the disintegrant, and the binder, other additives used as necessary include, for example, a lubricant, a corrigent, a fluidizing agent, an antistatic agent, a colorant, and a fragrance. , Surfactants, wetting agents, fillers, extenders, adsorbents, preservatives (for example, preservatives), buffers and the like.

  Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, light anhydrous silicic acid, sodium stearyl fumarate, talc, sodium lauryl sulfate, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol And so on. Examples of the corrigent include citric acid, anhydrous citric acid, sodium citrate, tartaric acid, malic acid, glycine, alanine, sucrose, lactose, mannitol, xylitol, saccharin, sodium saccharin, aspartame, stevioside and the like. Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, magnesium metasilicate aluminate, and talc. . Examples of the antistatic agent include light anhydrous silicic acid. Examples of the colorant include tar dye, iron oxide, caramel, bengara, titanium oxide, and natural dye. Examples of the fragrances include strawberry flavor, lemon flavor, lemon lime flavor, orange flavor, l-menthol and peppermint oil.

  These other additives can be used alone or in combination of two or more. These other additives are not particularly limited in content in the final formulation.

First granulation step In the method for producing a loratadine-containing orally disintegrating tablet of the present invention, first, as the first granulation step, loratadine and at least one additive such as a binder, an excipient, and a disintegrant are added. Granulate. Here, it is essential to use loratadine in a solution state or a suspension state. Loratadine may be in a solution state, a suspension state, or a partial solution state and a remaining suspension state (in a suspended state in appearance). When loratadine is used in a solid state such as a powder, drug releasability is greatly reduced. Usually, loratadine is preferably used as an ethanol solution or ethanol suspension. The amount of ethanol used may be determined as appropriate as long as loratadine is in a solution state or a suspension state. In addition, it is preferable to use the binder in a solution state such as an aqueous solution because this tends to improve the drug release property.

  The first granulation step can be performed by fluidized bed granulation, stirring granulation or the like, but it is particularly preferable to perform granulation by fluidized bed granulation. In the first granulation step, for example, using a fluidized bed granulator, a mixed liquid of an ethanol solution of loratadine and an aqueous solution containing a part of the binder and additives is sprayed on a powdery excipient or the like. However, it is preferable to mix and granulate. What is necessary is just to determine suitably the temperature conditions, spray speed, etc. of fluid bed granulation. As the fluidized bed granulator, commercially available products such as “MP-1” (manufactured by POWREC) and “FLO-5” (manufactured by Freund) can be used.

  The granulated product obtained in the first granulation step is preferably sized using a sizing machine after drying. There are no particular restrictions on the apparatus used for sizing, but for example, “Power Mill” (produced by Fuji Paudal Co., Ltd.), “Komil” (produced by Powrec), “Roll Granulator” (Nippon Granulator Co., Ltd.) )) And the like. Moreover, you may size-size using a sieve etc.

Second granulation step Next, in the second granulation step, the granulated product obtained in the first granulation step is combined with at least one additive such as an excipient, a binder, a disintegrant, and a corrigent. Then granulate further. Moreover, it is necessary to adjust the usage-amount of the granulated material of a 1st granulation process so that it may become about 50 weight% or more of the tablet weight finally obtained. If the granulated product in the first granulation step exceeds 50% by weight of the tablet weight, it is not preferable because the release of loratadine from the tablet decreases. The amount of the granulated product used in the first granulation step is preferably adjusted to be about 30 to 45% by weight of the tablet weight.

  The second granulation step can be performed by fluidized bed granulation, stirring granulation, or the like. In particular, it is preferable to perform granulation by fluidized bed granulation from the viewpoint of improving production efficiency. In the second granulation step, for example, using a fluidized bed granulator, a mixed solution of a binder and an aqueous solution containing a part of the additive is used as a granulated product and an excipient in the first granulation step. It is preferable to mix and granulate while spraying the powder mixture with the additive. The temperature conditions of the fluidized bed granulation, the spray speed, etc., and the fluidized bed granulator can be appropriately determined as in the case of the first granulating step.

  The granulated product obtained in the second granulation step is preferably sized using a granulator after drying. The apparatus used for sizing may be the same as in the first granulation step, or may be sized by a sieve.

  In the production method of the loratadine orally disintegrating tablet of the present invention, it is essential to perform the two-stage granulation process of the first granulation process and the second granulation process, and the loratadine from the tablet can be obtained only by one-stage granulation. There is almost no improvement in release.

In the method for producing the loratadine orally disintegrating tablet of the present invention such as the third granulation step, in addition to the two-step granulation step of the first granulation step and the second granulation step, the third step is further performed as necessary. You may perform the above granulation process. The third granulation step and the subsequent granulation step can be performed by fluidized bed granulation, stirring granulation, etc., usually using additives, as in the second granulation step. Granulation is preferably performed by layer granulation from the viewpoint of improving production efficiency.

Tableting Step Next, the granulated product obtained by at least two granulation steps is usually mixed with at least one additive such as a lubricant and a disintegrant, and then tableted by a conventional method. . The tableting machine is not particularly limited as long as it can be used for the production of pharmaceuticals. For example, a rotary tableting machine or a single-shot tableting machine is used.

  When the thus obtained loratadine-containing orally disintegrating tablet of the present invention is used, a therapeutically effective amount for allergic diseases such as allergic rhinitis and urticaria may be administered to humans. The dose may vary depending on the patient's age, body weight, symptoms, sex, etc., but is usually divided into one or several times per day, and converted to loratadine, for example, about 5 to 20 mg without water, It can be administered orally with saliva alone. In this case, the loratadine orally disintegrating tablet of the present invention has good orally disintegrating properties, usually within about 30 seconds, and withstands extrusion from PTP packaging while having excellent orally disintegrating properties. Has hardness.

  The loratadine orally disintegrating tablet of the present invention may be usually packaged in PTP or bottle (eg, plastic bottle, glass bottle, aluminum can). Moreover, those packaged tablets may be further subjected to secondary packaging such as pillow packaging. A deodorant, a desiccant, an oxygen scavenger and the like may be enclosed during packaging.

  EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.

In each example and comparative example, the dissolution rate was determined by the following dissolution test.
Dissolution test Fifteenth revision Japanese Pharmacopoeia dissolution test was conducted in accordance with Method 2 (Paddle Method), and dissolution rate (%) after 15 minutes and 30 minutes was measured using HPLC method. .
Sample volume: 1 tablet.
Test solution: McIlvaine buffer (37 ° C, pH 4.0) 900 mL
Paddle rotation speed: 50rpm
The test was performed 3 times and the average value was shown.

Example 1
540 g of an aqueous solution of D-mannitol (9.0 g) and hydroxypropylcellulose (12.6 g) was added to 1080 g of an ethanol solution of loratadine (90.0 g) and mixed. A part of the obtained mixture (1440 g) was sprayed onto a mixture of D-mannitol (323.2 g) and low-substituted hydroxypropylcellulose (57.6 g) to perform fluidized bed granulation ( Fluidized bed granulator: model “MP-01” manufactured by Paulec. The obtained granulated powder was sized using a No. 22 sieve to obtain sized powder A.

  A mixture of sized powder A (168.0 g), D-mannitol (186.1 g), low-substituted hydroxypropyl cellulose (30.2 g) and aspartame (8.4 g) was added to hydroxypropyl cellulose (1.3 g) and Fluidized bed granulation was performed by spraying 140 g of an aqueous solution of citric acid hydrate (0.8 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized using a No. 22 sieve to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Example 2
To 720 g of an ethanol solution of loratadine (60.0 g), 360 g of an aqueous solution of D-mannitol (6.0 g) and hydroxypropyl cellulose (8.4 g) was added and mixed. The obtained mixed liquid (1080 g) was sprayed onto a mixture of D-mannitol (348.0 g) and low-substituted hydroxypropylcellulose (57.6 g) to perform fluidized bed granulation (fluidized bed granulation). (Apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain sized powder B.

  To a mixture of sized powder B (160.0 g), D-mannitol (177.2 g), low-substituted hydroxypropylcellulose (28.8 g) and aspartame (8.0 g), hydroxypropylcellulose (1.4 g) and Fluidized bed granulation was performed by spraying 100 g of an aqueous solution of citric acid hydrate (0.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (11.4 g), light anhydrous silicic acid (3.8 g) and sodium stearyl fumarate (7.6 g) were added to and mixed with a portion (358.1 g) of the obtained sized powder, and loratadine was mixed. A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 200 mg per tablet.

Example 3
To a mixture of sized powder B (160.0 g), D-mannitol (237.8 g), low-substituted hydroxypropyl cellulose (38.4 g) and aspartame (9.6 g), hydroxypropyl cellulose (4.8 g) and Fluidized bed granulation was performed by spraying 100 g of an aqueous solution of citric acid hydrate (0.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets having a loratadine content of 10 mg and a tablet weight of 240 mg per tablet.

Example 4
To 1020 g of an ethanol solution of loratadine (85.0 g), 510 g of an aqueous solution of D-mannitol (17.0 g) and hydroxypropylcellulose (23.8 g) was added and mixed. Fluidized-bed granulation was performed by spraying 1530 g of the obtained mixed liquid onto a mixture of D-mannitol (323.0 g) and low-substituted hydroxypropylcellulose (61.2 g) (fluidized-bed granulator: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder C.

  A portion (140 g) of an aqueous solution of hydroxypropylcellulose (4.4 g) and citric acid hydrate (2.9 g) was adjusted to a sized powder C (168.0 g), D-mannitol (186.1 g), low substitution The mixture was sprayed onto a mixture of hydroxypropylcellulose (30.2 g) and aspartame (8.4 g) to perform fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Example 5
540 g of an aqueous solution of D-mannitol (27.0 g) and hydroxypropylcellulose (37.8 g) was added to 1080 g of an ethanol solution of loratadine (90.0 g) and mixed. Fluidized bed granulation was performed by spraying 1620 g of the obtained mixed liquid onto a mixture of D-mannitol (320.4 g) and low-substituted hydroxypropylcellulose (64.8 g) (fluidized bed granulating apparatus: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder D.

  A portion (140 g) of an aqueous solution of hydroxypropylcellulose (4.4 g) and citric acid hydrate (2.9 g) was mixed with sized powder D (168.0 g), D-mannitol (186.1 g), low Fluidized bed granulation was carried out by spraying onto a mixture of substituted hydroxypropylcellulose (30.2 g) and aspartame (8.4 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Example 6
To 720 g of an ethanol solution of loratadine (60.0 g), 360 g of an aqueous solution of D-mannitol (3.0 g) and hydroxypropyl cellulose (4.2 g) was added and mixed. By spraying 1080 g of the obtained mixed liquid onto a mixture of D-mannitol (355.2 g) and low-substituted hydroxypropylcellulose (57.6 g), fluidized bed granulation was performed (fluidized bed granulating apparatus: (Pauleck, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder E.

  A part (100 g) of an aqueous solution of hydroxypropylcellulose (6.8 g) and citric acid hydrate (1.2 g) (100 g) was mixed with sized powder E (160.0 g), D-mannitol (239.2 g), low Fluidized bed granulation was carried out by spraying a mixture of substituted hydroxypropylcellulose (38.4 g) and aspartame (9.6 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets having a loratadine content of 10 mg and a tablet weight of 240 mg per tablet.

Example 7
To 9920 g of an ethanol solution of loratadine (660.0 g), 3960 g of an aqueous solution of D-mannitol (66.0 g) and hydroxypropylcellulose (33.0 g) was added and mixed. By spraying a part (10800 g) of the resulting mixed solution 11880 g onto a mixture of D-mannitol (2478.0 g) and low-substituted hydroxypropylcellulose (432.0 g), fluidized bed granulation was performed ( Fluidized bed granulator: model “FLO-5” manufactured by Freund Corporation. Part of the resulting granulated powder was sized to obtain sized powder F.

  A portion (1250 g) of an aqueous solution of hydroxypropylcellulose (39.0 g) and citric acid hydrate (9.0 g) was mixed with sized powder F (1500.0 g), D-mannitol (2240.0 g), low Fluidized bed granulation was performed by spraying onto a mixture of hydroxypropylcellulose (360.0 g) and aspartame (90.0 g) (fluidized bed granulating apparatus: model “FLO-5” manufactured by Freund Corporation). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (121.5 g), light anhydrous silicic acid (40.5 g) and sodium stearyl fumarate (81.0 g) were added to and mixed with a part (3807.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a rotary tableting machine (trade name “VIRGO-512”, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet with a loratadine content of 10 mg and a tablet weight of 180 mg per tablet. It was.

Example 8
480 g of an aqueous solution of D-mannitol (8.0 g) was added to 960 g of an ethanol solution of loratadine (80.0 g) and mixed. By spraying 1440 g of the resulting mixture to a mixture of D-mannitol (323.2 g), low substituted hydroxypropylcellulose (57.6 g) and hydroxypropylcellulose (11.2 g), fluid bed granulation (Fluidized bed granulator: manufactured by Paulek, model “MP-01”). Part of the resulting granulated powder was sized to obtain sized powder G.

  Part (150 g) of 500 g of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) was sized powder G (180.0 g), D-mannitol (199.4 g), low substitution The mixture was sprayed onto a mixture of hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) to perform fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Comparative Example 1
To 504 g of an ethanol solution of loratadine (42.0 g), 252 g of an aqueous solution of D-mannitol (4.2 g), hydroxypropylcellulose (5.9 g) and citric acid hydrate (1.3 g) was added and mixed. By spraying a portion (630 g) of the resulting mixture onto a mixture of D-mannitol (375.6 g), low substituted hydroxypropylcellulose (63.0 g) and aspartame (10.5 g), a fluidized bed. Granulation was performed (fluidized bed granulator: manufactured by Paulek, model “MP-01”). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Comparative Example 2
To a mixture of sized powder B (240.0 g), D-mannitol (146.4 g), low-substituted hydroxypropyl cellulose (25.2 g) and aspartame (9.0 g), hydroxypropyl cellulose (1.5 g) and Fluidized bed granulation was performed by spraying 150 g of an aqueous solution of citric acid hydrate (0.9 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.8 g), light anhydrous silicic acid (0.6 g) and sodium stearyl fumarate (1.2 g) were added to and mixed with a part (56.4 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

Comparative Example 3
196.0 g of an aqueous solution of hydroxypropylcellulose (9.8 g) and D-mannitol (7.0 g) was added to loratadine (70.0 g), D-mannitol (282.8 g) and low-substituted hydroxypropylcellulose (50.4 g). ) Was sprayed onto the mixture to obtain fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the obtained granulated powder was sized to obtain sized powder H.

  Part (150 g) of 500 g of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) was mixed with sized powder H (180.0 g), D-mannitol (199.4 g), low Fluidized bed granulation was performed by spraying onto a mixture of substituted hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder is tableted using a rotary tableting machine (trade name “VIRGO-512”, manufactured by Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a loratadine content of 10 mg and a tablet weight of 150 mg per tablet. It was.

Comparative Example 4
140.0 g of an aqueous solution of D-mannitol (7.0 g) was added to loratadine (70.0 g), D-mannitol (282.8 g), low-substituted hydroxypropylcellulose (50.4 g) and hydroxypropylcellulose (9.8 g). ) Was sprayed onto the mixture to obtain fluidized bed granulation (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC, Inc.). Part of the resulting granulated powder was sized to obtain sized powder I.

  A portion (150 g) of an aqueous solution of hydroxypropylcellulose (4.5 g) and citric acid hydrate (3.0 g) (150 g) was mixed with sized powder I (180.0 g), D-mannitol (199.4 g), low Fluidized bed granulation was performed by spraying onto a mixture of substituted hydroxypropylcellulose (32.4 g) and aspartame (9.0 g) (fluidized bed granulating apparatus: model “MP-01” manufactured by POWREC). Part of the obtained granulated powder was sized to obtain a sized powder. Crospovidone (1.5 g), light anhydrous silicic acid (0.5 g) and sodium stearyl fumarate (1.0 g) were added to and mixed with a part (47.0 g) of the obtained sized powder, and loratadine A mixed powder was obtained. This loratadine-containing mixed powder was tableted using a single tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 150 mg per tablet.

  Tables 1 and 2 show the addition state of loratadine and a binder (hydroxypropylcellulose) in the first granulation step (referred to as “granulation step 1” in the table) in each Example and Comparative Example, the first granulation step Weight per tablet (mg) (A), tablet weight (mg) (A) and ratio of these weights [(A) / (I ]], Granulation method, number of granulations, and dissolution rate.

  As is clear from Tables 1 and 2, the tablets of each Example were the tablets of Comparative Example 1 (number of granulation times 1) and Comparative Example 2 [(A) / (I) exceeds 0.5]. In comparison, the dissolution of loratadine is excellent. That is, loratadine and a binder (hydroxypropylcellulose) are each used as a solution, a two-step granulation process is performed, and a loratadine is used in a tablet in which the first-stage granulation process is 50% by weight or less of the tablet weight. Was significantly improved.

  In addition, when both loratadine and a binder (hydroxypropylcellulose) were added in a powder state (Comparative Example 4), the dissolution rate did not satisfy 85% of the lower limit substantially acceptable in 30 minutes, and the binder ( Even when only hydroxypropylcellulose) was added in the solution state (Comparative Example 3), the increase in elution rate was only about 90% in 30 minutes, which was insufficient. On the other hand, the dissolution properties of Examples 1 to 7 in which both loratadine and a binder (hydroxypropylcellulose) were added in a solution state were very rapid. The dissolution rate for 15 minutes was 92.5% or more, and the dissolution rate for 30 minutes. Was a very high value of 97.6% or more. Further, when loratadine was added in a solution state and a binder (hydroxypropylcellulose) was added in a powder state (Example 8), the elution rate was slightly low at 90.7% in 15 minutes, but 96 in 30 minutes. 0.7%, indicating a practically sufficient elution rate.

Example 9
To 6000 g of ethanol solution of loratadine (500.0 g), 3000 g of an aqueous solution of D-mannitol (50.0 g) and hydroxypropyl cellulose (35.0 g) was added and mixed. By spraying 9000 g of the resulting solution onto a mixture of D-mannitol (2935 g) and low-substituted hydroxypropylcellulose (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by Freund Corporation, model: “FLO” −5 ”). The obtained granulated powder was sized to obtain sized powder J.

  By spraying 1440 g of an aqueous solution of hydroxypropylcellulose (6.0 g) and D-mannitol (144.0 g) onto the sized powder J (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by POWREC, Model: “MP-01”), then D-mannitol (138.4 g), low-substituted hydroxy in a fluidized bed granulator (fluidized bed granulator: manufactured by Paulek, model: “MP-01”) After mixing with propylcellulose (33.0 g) and aspartame (9.5 g), 125 g of an aqueous solution of hydroxypropylcellulose (2.5 g) and citric acid hydrate (0.5 g) was sprayed to produce fluidized bed granulation ( Fluidized bed granulator: manufactured by POWREC Co., Ltd., model: “MP-01”), a granulated powder was obtained. After sizing part of the obtained granulated powder, crospovidone (11.4 g), light anhydrous silicic acid (3.8 g), stearic acid is added to a part (357.1 g) of the obtained sized powder. Magnesium (0.1 g) and sodium stearyl fumarate (7.6 g) were added and mixed to obtain a loratadine-containing mixed powder. This loratadine-containing mixed powder was tableted using a tableting machine (Kikusui Seisakusho) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 190 mg per tablet.

Example 10
To 300 g of an ethanol suspension of loratadine (60.0 g), 600 g of an aqueous solution of D-mannitol (6.0 g) and hydroxypropylcellulose (4.2 g) was added and mixed. By spraying 900 g of the obtained solution onto a mixture of D-mannitol (352.5 g) and low-substituted hydroxypropylcellulose (57.6 g), fluidized bed granulation (fluidized bed granulating apparatus: manufactured by POWREC, model: "MP-01"). The obtained granulated powder was sized to obtain sized powder K.

  By spraying 1440 g of an aqueous solution of hydroxypropylcellulose (6.0 g) and D-mannitol (144.0 g) onto the sized powder K (480.0 g), fluidized bed granulation (fluidized bed granulator: manufactured by POWREC, Model: “MP-01”), then D-mannitol (138.4 g), low-substituted hydroxy in a fluidized bed granulator (fluidized bed granulator: manufactured by Paulek, model: “MP-01”) After mixing with propylcellulose (33.0 g) and aspartame (9.5 g), 125 g of an aqueous solution of hydroxypropylcellulose (2.5 g) and citric acid hydrate (0.5 g) was sprayed to produce fluidized bed granulation ( Fluidized bed granulator: manufactured by POWREC Co., Ltd., model: “MP-01”), a granulated powder was obtained. After sizing part of the obtained granulated powder, crospovidone (11.4 g), light anhydrous silicic acid (3.8 g), stearic acid is added to a part (357.1 g) of the obtained sized powder. Magnesium (0.1 g) and sodium stearyl fumarate (7.6 g) were added and mixed to obtain a loratadine-containing mixed powder. This loratadine-containing mixed powder was tableted using a tableting machine (Kikusui Seisakusho) to obtain tablets with a loratadine content of 10 mg and a tablet weight of 190 mg per tablet.

  In Table 3, the addition state of loratadine and a binder (hydroxypropylcellulose) in the first granulation step (referred to as “granulation step 1” in the table) in Examples 9 and 10, the granulation product in the first granulation step ( Weight per tablet (mg) (A) in the table (mg) (A), tablet weight (mg) (A) and ratio of these weights [(A) / (I)] The grain method, the number of granulations, and the dissolution rate were shown.

  As is apparent from Table 3, the dissolution when loratadine is added in a suspended state is very rapid, similar to the case where loratadine is added in a solution state, and the dissolution rate for 15 minutes is as high as 96.7%. Value.

The loratadine orally disintegrating tablet obtained by the production method of the present invention is excellent in both orally disintegrating property and drug releasing property, and is useful as a therapeutic agent for allergic diseases, and the present invention is effective in the pharmaceutical industry. Used.

Claims (4)

A method for producing a loratadine-containing orally disintegrating tablet comprising:
Granulating the first stage using loratadine in solution or suspension,
The granulated product obtained by the first stage granulation was further granulated in the second stage together with at least one additive, and obtained by the first stage granulation. A method for producing a loratadine-containing orally disintegrating tablet, wherein the ratio of the granulated product is 30 to 45% by weight of the tablet weight.   The manufacturing method of the loratadine containing orally disintegrating tablet of Claim 1 which performs granulation of the 1st step by fluidized bed granulation.   The method for producing an orally disintegrating tablet containing loratadine according to claim 1 or 2, wherein the granulation in the second stage is performed by fluidized bed granulation. The method for producing a loratadine-containing orally disintegrating tablet according to any one of claims 1 to 3, wherein the granulation in the third stage is further performed by fluidized bed granulation after the granulation in the second stage.