JP2006104194A - Rebamipide intestinal infusion preparation prepared when needed - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a rebamipide intestinal infusion preparation prepared when needed, required in medical sites and excellent in dispersibility and to provide a method for producing the preparation. <P>SOLUTION: This rebamipide intestinal infusion preparation prepared when needed is intestinally infused in a state dispersed in an aqueous medium when needed and the preparation comprises rebamipide and CMC-Na. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a rebamipide enema formulation prepared at the time of use, a method for producing the formulation, a rebamipide enema formulation in which the formulation is dispersed, and a method for producing these formulations.

  Rebamipide preparation (trade name “Mucosta”, manufactured by Otsuka Pharmaceutical Co., Ltd.) is known as an agent for improving subjective and objective symptoms in diseases such as gastric ulcer, duodenal ulcer and gastritis. It has already been reported that the preparation can be applied to the treatment of ulcerative colitis (see Non-Patent Documents 1-3).

  When rebamipide is applied to the treatment of ulcerative colitis, it is generally administered locally in the lower gastrointestinal tract in the form of a dispersion due to its low solubility in water. In order to increase the retention in the lower digestive tract, it is usually used in the form of an aqueous dispersion (enema preparation) containing carmellose sodium (CMC-Na).

  However, such an enema preparation (rebamipide dispersion) has poor storage stability, and rebamipide particles settle and deposit relatively quickly. The rebamipide particles thus deposited and hardened are not easily redispersed simply by shaking the enema container by hand. Therefore, such a preparation has a drawback that clinical use becomes difficult.

  Moreover, since the said dispersion liquid has the high viscosity based on the mixing | blending of CMC-Na, there exists a disadvantage which cannot perform the filter sterilization currently used widely for the sterilization of a pharmaceutical as a usual simple sterilization method. When sterilization is not performed, it may be possible to add preservatives, preservatives, etc. However, the addition of preservatives, preservatives, etc. itself means the addition of chemical drugs other than active ingredients that are desired to be avoided. Yes. In addition, such preservatives are generally irritating, and when enemas containing these are administered to the lower gastrointestinal tract, the mucous membrane of the patient's administration site is usually damaged, so the patient is particularly irritating. There are drawbacks to feel. Furthermore, for example, benzalkonium chloride, one of the typical preservatives, cannot be used because it reacts with CMC-Na. In addition, organic acid-based preservatives such as sorbic acid lower the pH of the resulting preparation, and this point also has the disadvantage that irritation to patients during enema administration is even more severe. . Preservatives such as parabens have a problem of passing through the preparation container, and their use is not preferred.

  For the reasons described above, rebamipide enema preparations are currently used in medical settings such as hospitals, and each time they are needed, a predetermined amount of rebamipide and CMC-Na are weighed and mixed, and the mixture is pre-sterilized aqueous. It is currently being prepared by dispersing it in a medium.

  However, the operation of preparing an enema preparation by weighing and mixing the components and dispersing them in an aqueous medium in this way is of course very complicated per se, as well as the viscosity of the resulting enema preparation itself. Adjustment and the like require considerable skill, and are not preferable as work in the medical field.

Therefore, in the medical field, development of an enema preparation prepared in advance or a rebamipide enema preparation excellent in dispersibility, which can be easily prepared by a medical person other than an expert at the time of use, is desired.
Kazuya Makiyama: "A trial of enema therapy with Rebamipide for ulcerative colitis" Research project for intractable inflammatory bowel disorder 2001 research report, 2002, pp. 70-71 Takeshi Mori, Mitsuki Miyata, Megumi Komiyama, Masafumi Onishi, Kei Okada (2003), “Stability study of in-hospital preparation rebamipide enema and clinical cases showing efficacy”, Medical Pharmacy [Jpn. J. Pharm. Health Care Sci ., 29/3, 312-317] Miki Miyata, Kunio Kasugai, Shinichi Kagami (2002), "Trial of Rebamipide enema therapy in lower focal ulcerative colitis", "88th Annual Meeting of the Japanese Society of Gastroenterology" S5-10

  In particular, an object of the present invention is to provide an in-use preparation type intestinal preparation capable of preparing a rebamipide enema solution excellent in rebamipide dispersibility and a method for producing the same.

  The present inventors have conducted extensive research to achieve the above object, and as a result, the fact that a solid preparation containing rebamipide and carmellose sodium (CMC-Na), particularly a powder or powder formulation, meets the above object. I found. More specifically, the solid agent has excellent dispersibility, and can be easily prepared by adding it to an aqueous medium at the time of use, so that a “liquid residue” or an agglomerate is not seen, It has been discovered that the resulting dispersion is stable and has moderate viscosity and osmotic pressure as an enema formulation. The present invention has been completed as a result of further research based on this knowledge.

  The present invention provides a rebamipide enema preparation for use according to Item 1-8 and a method for producing the same.

  Item 1. A preparation that can be encapsulated in an aqueous medium at the time of use and administered as a dispersion, and contains rebamipide and carmellose sodium (hereinafter sometimes referred to as “CMC-Na”). A rebamipide enema preparation prepared at the time of use, comprising:

  Item 2. The preparation according to Item 1, wherein CMC-Na is contained in an amount of 100 to 2000 parts by weight per 100 parts by weight of rebamipide.

  Item 3. In the form of powdered powder having an average particle size of 100 to 300 μm, the proportion of particles less than 75 μm is less than 20%, and the proportion of particles of 500 μm or more is 5% or less The formulation described.

  Item 4. The method for producing a preparation according to any one of Items 1-3, wherein rebamipide is prepared in a solid dosage form using CMC-Na as a binder.

  Item 5. Preparation into a solid dosage form is performed by wet kneading a raw material containing rebamipide using CMC-Na as a binder, drying by fluidized bed drying, and sizing A method for producing the described preparation.

  Item 6. The binder is a solution obtained by dissolving CMC-Na in hydrous ethanol having an ethanol concentration of 25 to 75% by weight, wherein CMC-Na is present in the solution at a concentration of 0.1 to 5% by weight. 5. The method according to 5.

  Item 7. A rebamipide enema preparation in the form of a dispersion obtained by dispersing the preparation according to any one of Items 1-3 in an aqueous medium.

  Item 8. A method for producing a rebamipide enema preparation, wherein the preparation according to any one of Items 1-3 is dispersed in an aqueous medium.

  In the present specification, the term “prepared for use” means having a solid agent form different from the practical form during storage, transportation, etc. after production, and is in a practical form immediately before use. It does not mean only those prepared in liquid form. For example, this "prepared for use" is also used when it is prepared in the form of a dispersion intended for its use at a medical site such as a hospital and is put into practical use after being kept in that state for several days to about a month. Shall be included.

  The present invention provides an in-use rebamipide enteral preparation having excellent dispersibility and a method for producing the same. The enema preparation makes use of its excellent dispersibility, disperses very easily and well by being put into an aqueous medium for dispersion such as physiological saline at the time of use, and has an appropriate viscosity and osmotic pressure. The desired rebamipide enema formulation can be prepared. In addition, the preparation does not require any skill. Further, since the enema preparation provided by the present invention itself has a solid dosage form, it has an advantage that it has excellent stability and does not require the use of preservatives, preservatives and the like. Furthermore, since the preparation of the present invention is a solid agent, an operation such as filtration sterilization is unnecessary, and the sterilization operation is simply an aqueous medium for dispersion utilized for preparing the enema preparation of the present invention at the time of use. This sterilization itself has the advantage that it can be carried out very easily. In addition, the preparation of the present invention is advantageous in terms of production cost, transportation cost and the like, and has an advantage of easy production management.

  The preparation of the present invention has excellent water dispersibility based on containing rebamipide and CMC-Na as described above. The fact that the preparation of the present invention has excellent water dispersibility will be described in detail in Examples (test examples) described later.

  As long as the preparation of the present invention has a solid dosage form containing rebamipide and CMC-Na, the production method is not particularly limited, and the raw material mixture containing the above two components is prepared according to various methods known in the pharmaceutical formulation field. It can be manufactured by preparing it into a form.

  As a preferred example of the method for producing the preparation of the present invention, for example, a method in which a raw material containing rebamipide is wet-kneaded using CMC-Na as a binder, dried by a fluidized bed drying method, and then sized. it can. According to this method, a solid agent in the form of powdered powder, in which the proportion of particles less than 75 μm is 20% or less and the proportion of particles of 500 μm or more is 5% or less, can be easily prepared.

  Hereinafter, the production method of the preparation of the present invention will be described in detail by taking this preferable method as a specific example.

Raw Rebamipide Rebamipide used in the preparation of the present invention is a compound known as an active ingredient of the trade name “Mucosta” (manufactured by Otsuka Pharmaceutical Co., Ltd.). The rebamipide can be used in the production of an in-use preparation type enema preparation of the present invention in the form of a generally available bulk powder. Usually, the raw powder has an average particle size of 1.0 μm, a particle size range: 50% D: 0.9 μm and 90% D: 2.9 μm.

  The raw material containing rebamipide used in the method of the present invention can generally contain appropriate amounts of pharmaceutically acceptable carriers (excipients), additives and the like commonly used in the pharmaceutical preparation field together with rebamipide. Typical specific examples of the carrier include lactose, sucrose, D-mannitol, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, sodium silicate and the like. CMC-Na itself may also act as this excipient.

  Various additives well known in this type of formulation field, such as binders, disintegrants, lubricants (anti-aggregation agents), fluidizing agents, pH adjusting agents, isotonic agents, absorption agents. Examples include accelerators.

  Specific examples of the binder include CMC-Na, water, ethanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, sodium carboxyethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, Examples thereof include polyvinyl alcohol, gelatin, dextrin, pullulan and the like.

  Disintegrants include carmellose calcium, low-substituted hydroxypropylcellulose, carmellose, croscarmellose sodium, partially pregelatinized starch, dried starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylene sorbitan oleate), etc. Is mentioned.

  Lubricants (anti-aggregation agents) include talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, hydrous silicon dioxide, synthetic magnesium silicate, particulate silicon oxide, starch, sodium lauryl sulfate, boric acid, oxidation Examples include magnesium, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate and the like. Of these, magnesium stearate is preferred.

  Examples of the fluidizing agent include silicic anhydride (“ADSOLIDA-101” (manufactured by Freund Sangyo Co., Ltd.), “Erogyl” (manufactured by Nippon Aerosil Co., Ltd.)), and the like. The blending ratio of such a fluidizing agent can be selected from the range of about 0.5 to 15 parts by weight, preferably about 1 to 10 parts by weight with respect to 100 parts by weight of rebamipide.

  Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, citric acid, anhydrous citric acid, sodium citrate, sodium citrate dihydrate, anhydrous sodium monohydrogen phosphate, anhydrous sodium dihydrogen phosphate, and the like.

Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like.
Examples of absorption promoters include quaternary ammonium base and sodium lauryl sulfate.

  Furthermore, for example, a coloring agent, a flavoring agent, an antioxidant, an antibacterial agent, an antiseptic, and the like can be blended in the raw material. The amount of these carriers and additives to be added can be appropriately determined according to the type.

CMC-Na
CMC-Na, which is the other essential component used in the preparation of the present invention, is also called carboxymethylcellulose sodium and is a compound conventionally known as laxatives, enemas and the like. In the present invention, as the CMC-Na, those recorded in the Japanese Pharmacopoeia (14th revision) can be used without particular limitation. Among these, it is preferable to use a 2% aqueous solution at 25 ° C. having a viscosity in the range of 100 to 5000 mPa · s, particularly in the range of 300 to 400 mPa · s. Preferable CMC-Na includes “Serogen” (registered trademark) manufactured by Daiichi Kogyo Seiyaku. As the serogen, those of each grade (variety) shown in Table 1 below are known, and any of these can be used in the present invention. Of these, grade F-SC is particularly preferred.

  The compounding amount of CMC-Na in the preparation of the present invention may be slightly different depending on the grade of the CMC-Na, but generally, it is about 50 to 2500 parts by weight, preferably 100 to 100 parts by weight per 100 parts by weight of rebamipide. It can be selected from the range of about 2000 parts by weight, more preferably about 150-1700 parts by weight.

Production method of the preparation of the present invention In wet kneading that can be employed in the method of the present invention, it is preferable to use CMC-Na as a binder. The wet kneading is performed using an appropriate apparatus such as a kneader. That is, using the solution in which CMC-Na is dissolved as a binder, the raw material rebamipide or a raw material mixture containing rebamipide and excipients, additives, and the like is kneaded.

  The solution in which CMC-Na as a binder is dissolved is an aqueous CMC-Na solution or an aqueous alcohol solution of CMC-Na, and an aqueous alcohol solution, particularly an aqueous ethanol solution can be preferably used. The alcohol concentration of the hydrated alcohol used as a solvent for producing such a CMC-Na hydrated alcohol solution is not particularly limited, but generally it is preferably in the range of about 25 to 75%, In particular, about 50% is preferable. Further, the CMC-Na concentration in the CMC-Na solution as the binder is preferably about 0.1 to 5% by weight, particularly around 1% by weight.

  The amount of CMC-Na used as the binder can be selected from the range of 0.5 to 15 parts by weight, preferably 1 to 10 parts by weight, based on 100 parts by weight of rebamipide.

  The wet kneading method used in the present invention is well known as a method for producing granules, powders, etc., particularly in the field of production of pharmaceutical preparations. For example, it is a method in which a drug is finely powdered, an excipient or the like is mixed, an appropriate wetting agent is added to form a soft mass, and then granulated through a coarse sieve. More specifically, first, raw rebamipide and other excipients, additives, and the like are weighed and mixed. Next, the mixture is kneaded using a kneader (for example, NEW SPEED KNEADER NSK-150, manufactured by Gohashi Seisakusho Co., Ltd.) using a solution in which CMC-Na is dissolved as a binding solution. Further, the kneaded product is dried with a fluidized bed dryer (for example, Multiplex Model MP-01, manufactured by POWREC), and the resulting granules are sized. About the lump of the particle size exceeding the predetermined particle size after sizing, this can be further pulverized and prepared to a predetermined particle size. Thus, the preparation of the present invention in the form of powder (powder), fine granules or granules can be obtained.

  The above drying can be carried out by, for example, blow drying or vacuum drying instead of the fluidized bed drying method.

  Moreover, the grinding | pulverization of the said dried material can be performed by various methods. For this operation, for example, a pin mill (sample mill), a speed mill, a new speed mill or the like can be used, and the use of a new speed mill is particularly preferable. In the pulverization, the obtained powder (powdered powder) has an average particle size in the range of about 100 to 300 μm, and in the particle size distribution, the proportion of particles less than 75 μm is 20% or less, and the proportion of particles of 500 μm or more is It is preferable to carry out so that it is 5% or less.

  The preparation of the present invention obtained above can be made into a product without sterilization.

  The preparation of the present invention is not limited to the powder (powder) obtained as described above, and may be in the form of a capsule obtained by filling this into suitable soft and hard capsules.

Rebamipide enema preparation prepared at the time of use in the present invention The solid dosage form that can be taken by the present preparation includes powder (powdered powder) and capsules filled with the capsule. Among these, it is particularly preferable to be in the form of powdered powder having a particle size in the range of about 75 μm to 500 μm. In particular, from the viewpoint of preventing the occurrence of mamako (dama) when dispersed in an aqueous medium, generally, the proportion of particles less than 75 μm is 20% or less, and the proportion of particles of 500 μm or more is 5% or less. preferable.

  As for the solid agent of this invention, the particle | grains which comprise it contain the said rebamipide and CMC-Na in the said particle | grain. Further, when a mixture containing rebamipide and excipients, additives and the like is used as a raw material, the particles contain CMC-Na together with the rebamipide, excipients, additives and the like. The property is generally a white powder and contains about 4 to 6% water.

  The preparation of the present invention in the form of a solid preparation is prepared by adding it to an aqueous medium, for example, an aqueous medium such as purified water, physiological saline, aqueous sodium chloride solution, more preferably, an aqueous sodium chloride solution having a NaCl concentration of about 0.1 to 5% by weight. It has a feature that it can be easily disintegrated and easily prepared in a uniform dispersion state simply by charging. It is preferable that the obtained dispersion is usually prepared within a pH range of 4.8 to 6.8.

  The dispersion thus obtained is useful as an enema solution as an agent for improving subjective and objective symptoms in diseases such as gastric ulcer, duodenal ulcer and gastritis, and a therapeutic agent for ulcerative colitis.

  Hereinafter, examples will be given to describe the present invention in more detail, but the present invention is not limited thereto.

Example 1
The preparation of the present invention comprising the following components was prepared as follows.
Rebamipide 153 mg
Lactose 237 mg
L-HPC 80 mg
CMC-Na 820 mg
CMC-Na 10 mg (as binder)
Stearic acid Mg 5mg
Silica anhydride 5mg
In addition, each component used is as follows.

Rebamipide (Otsuka Pharmaceutical Co., Ltd.)
Lactose (Lactose, Japanese Pharmacopoeia, `` Wyndale lactose 200MESH '' (Lactose company))
L-HPC (low-substituted hydroxypropylcellulose, Japanese Pharmacopoeia, Shin-Etsu Chemical Co., Ltd.)
CMC-Na ("Serogen F-SC", manufactured by Daiichi Kogyo Seiyaku Co., Ltd.)
Purified water (Japanese Pharmacopoeia)
Absolute ethanol (Japanese Pharmacopoeia)
Stearic acid Mg (Japanese Pharmacopoeia, Taihei Chemical Industrial Co., Ltd.)
Silicic anhydride (light anhydrous silicic acid, Japanese pharmacopoeia, “Erogil”, manufactured by Nippon Aerosil Co., Ltd.).

  That is, rebamipide, lactose, L-HPC and CMC-Na were weighed and mixed (the amount to be the final concentration) and mixed (the upper value for CMC-Na). Further, a 1% CMC-Na (F-SC) 50% absolute ethanol solution was prepared as a binder solution (using the lower amount of CMC-Na). The obtained mixture was kneaded using a binder solution using a kneader (New Speed Kneader NSK-150, manufactured by Gohashi Seisakusho). After kneading, it was dried with a fluidized bed dryer (Multiplex Model MP-01, manufactured by POWREC Co., Ltd.). The kneading conditions and drying conditions are as follows.

<Kneading conditions>
・ Kneader: New Speed Kneader NSK-150 used ・ Blade (rpm): 500 → 1500
・ Time (sec): 30 → 30
That is, the blade was moved at 500 rpm for 30 seconds while adding the binder solution to knead the contents, and the blade was further moved at 1500 rpm for 30 seconds to continue the kneading operation.

<Fluidized bed drying conditions>
・ Fluidized bed dryer: Uses Multiplex Model MP-01 ・ Air inlet temperature (℃): 80
・ Air outlet temperature (℃): 45
Inlet air (m ³ / min): 45-50m ³ / hr
-Drying time: about 15 minutes Next, the dried product was sized with a 500 μm sieve, and the sieved product was obtained as granules. Further, the sieved product was pulverized with NEW SPEED MILL Type ND-02 (0.5 mm screen, manufactured by Okada Seiko Co., Ltd.) to obtain a pulverized product. The average particle size of the pulverized product was 100 to 300 μm.

  The average particle size was measured with a robot shifter (RPS-95, manufactured by Seishin Kakuin Co., Ltd.). That is, when each sample is set in the shifter, and the robot shifter is started after setting the sieve to be used, the robot shifter automatically weighs the sieve tare. As the sample is metered in, the sieve moves and the weight of each sieve is measured. Thus, the average particle diameter is automatically calculated and output. According to this method, the particle size distribution can be measured simultaneously.

  Subsequently, the obtained granule and the pulverized product were mixed to prepare a powder.

  To this powder, the predetermined amount of magnesium stearate and anhydrous silicic acid were added and mixed to prepare 1310 mg of enema powder sample having the following particle size and average particle size.

500 (μm) or more 0.5 (%)
500-355 14.5
355-250 22.2
250-150 29.6
150-106 14.4
106-75 9.2
Less than 75 9.6
Average particle size 206μm.

Examples 2-5
In the same manner as in Example 1 or by appropriately changing the kneading conditions and the drying conditions in Example 1, preparations of the present invention comprising the respective components shown in Table 2 below were prepared.

  The upper value of CMC-Na is the amount to be mixed with the powder, and the lower value is the amount to be added to the binder solution.

  Each of the obtained enema powder samples had a particle size of less than 75 μm, which was 20% or less, and a particle size of 500 μm or more was about 5%.

Example 6
A rebamipide enema preparation in the form of a dispersion was prepared by dispersing 1310 mg of the powder sample prepared in Example 1 in 60 mL of purified water.

Test example 1 (water dispersibility test)
Each powder sample prepared in Examples 1 to 5 was subjected to the following tests immediately after preparation and after standing for 1 month at room temperature.

  That is, after putting 30 mL of a 0.73% NaCl aqueous solution into a 50 mL polypropylene conical tube can, 1/2 amount of the powder sample prepared in each Example (for example, 655 mg in the case of the sample of Example 1, in which repamipido 76.5 mg), and the contents were shaken vigorously by shaking the can about 30 times, and the water dispersibility of each sample was evaluated by visually observing the properties (appearance) of the obtained solution. .

  The evaluation was performed in three stages, and those having a good dispersion state were represented by circles, those in which agglomeration was observed were represented by triangles, and those in which agglomerates and “mamako” were observed were represented by x.

  The results obtained are shown in Table 3 below.

As shown in Table 3, it is clear that the rebamipide enema preparation of the present invention has excellent water dispersibility.

Claims (8)

A rebamipide enema preparation at the time of use, which is a preparation that can be dispersed in an aqueous medium at the time of use and can be enema administered in the form of a dispersion, and has a solid dosage form containing rebamipide and carmellose sodium. 2. The preparation according to claim 1, wherein carmellose sodium is contained in an amount of 100 to 2000 parts by weight per 100 parts by weight of rebamipide. The average particle size is in the form of powdered powder having a particle size of 100 to 300 µm, the proportion of particles less than 75 µm is 20% or less, and the proportion of particles of 500 µm or more is 5% or less. Formulation. The method for producing a preparation according to any one of claims 1-3, wherein rebamipide is prepared in a solid dosage form using carmellose sodium as a binder. 5. The solid dosage form is prepared by wet kneading a raw material containing rebamipide using carmellose sodium as a binder, drying by a fluidized bed drying method, and sizing. Preparation method of the preparation. The binding agent is a solution prepared by dissolving carmellose sodium in hydrous ethanol having an ethanol concentration of 25 to 75% by weight, and the carmellose sodium is present in the solution at a concentration of 0.1 to 5% by weight. The method described. A rebamipide enema preparation in the form of a dispersion obtained by dispersing the preparation according to any one of claims 1 to 3 in an aqueous medium. A method for producing a rebamipide enema preparation, comprising dispersing the preparation according to any one of claims 1 to 3 in an aqueous medium.