JP2010168371A - Solid pharmaceutical formulation containing ranitidine and method for preparing ranitidine-supporting particle - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid pharmaceutical formulation containing ranitidine that controls discoloration of the ranitidine, and a method for producing a ranitidine-supporting particle to be blended with the formulation. <P>SOLUTION: The solid pharmaceutical formulation containing ranitidine is characterized in that it has acid-controlling power larger than 200 mL which is determined by the acid-controlling power testing method according to the fifteenth Revision of Japanese Pharmacopoeia and that it contains the ranitidine-supporting particle which supports the ranitidine on an inorganic compound containing magnesium and/or calcium having a magnesium and/or calcium content of 20 mass% or higher. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a ranitidine-containing pharmaceutical solid preparation containing ranitidine-carrying particles carrying ranitidine and a method for producing ranitidine-carrying particles.

  Ranitidine is an H2 blocker and is effective in the treatment of gastric / duodenal ulcer, reflux esophagitis, gastritis, upper gastrointestinal bleeding and the like. However, ranitidine or a salt thereof is gradually decomposed by light and temperature, particularly moisture, and thus discolors after long-term storage. Conventionally, ranitidine-containing preparations concealed discoloration by sugar coating or pigment-containing coatings (see Patent Document 1: JP 2001-342185 A, Patent Document 2: JP 2003-128535 A). However, even after coating, moisture and light cannot be completely blocked, so discoloration itself could not be suppressed. Further, there is a problem that the elution rate of the active ingredient is delayed by applying the coating, and it has been difficult to make the coating thickness sufficient for concealment in the fine granules. From the above, a technique for suppressing discoloration of ranitidine overcoming the above has been desired.

JP 2001-342185 A JP 2003-128535 A

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a ranitidine-containing pharmaceutical solid preparation in which discoloration of ranitidine is suppressed, and a method for producing ranitidine-carrying particles to be blended in the preparation.

  As a result of intensive studies to achieve the above-mentioned object, the present inventors suppress the discoloration of ranitidine due to long-term storage by using ranitidine-supported particles in which ranitidine is supported on a specific magnesium and / or calcium-containing inorganic compound. It has been found that this can be done, and the present invention has been made.

Accordingly, the present invention provides the following ranitidine-containing pharmaceutical solid preparation and a method for producing ranitidine-carrying particles.
[1]. The ranitidine support in which ranitidine is supported on an inorganic compound having an antacid power of 200 mL or more and magnesium and / or calcium content of 20% by mass or more required by the fifteenth revised Japanese Pharmacopoeia antacid test method A ranitidine-containing pharmaceutical solid preparation comprising particles.
[2]. The ranitidine-containing solid pharmaceutical preparation according to [1], wherein the inorganic compound is one or more selected from magnesium hydroxide, magnesium oxide, synthetic hydrotalcite, magnesium carbonate, calcium carbonate, and calcium hydroxide.
[3]. The ranitidine-containing pharmaceutical solid preparation according to [1] or [2], wherein the ranitidine-supported particles have a molar ratio of 10 or more, which is represented by magnesium and calcium / ranitidine.
[4]. To an inorganic compound having an antacid power of 200 mL or more and magnesium and / or calcium content of 20% by mass or more determined by the 15th revision Japanese Pharmacopoeia antacid test method, a solution of ranitidine or a salt thereof or A method for producing ranitidine-carrying particles in which ranitidine is carried on the inorganic compound, wherein the dispersion is impregnated and dried.

  According to the present invention, it is possible to provide a ranitidine-containing pharmaceutical solid preparation in which discoloration of ranitidine due to long-term storage is suppressed, and a method for producing ranitidine-carrying particles to be blended in this preparation.

2 is an image showing a dispersion state of ranitidine hydrochloride by near-infrared imaging measurement of Example 1. FIG. 2 is an image showing a dispersion state of carrier particles by near-infrared imaging measurement of Example 1. FIG. 10 is an image showing a dispersion state of ranitidine hydrochloride according to near-infrared imaging measurement of Comparative Example 8. 10 is an image showing a dispersion state of carrier particles by near-infrared imaging measurement of Comparative Example 8.

Hereinafter, the present invention will be described in detail.
The ranitidine-containing pharmaceutical solid preparation of the present invention has an antacid power determined by the Japanese Pharmacopoeia (No. 15) antacid test method of 200 mL or more and a magnesium and / or calcium content of 20% by mass or more. A ranitidine-containing pharmaceutical solid preparation comprising ranitidine-supported particles in which ranitidine is supported in an inorganic compound.

[Ranitidine]
As ranitidine used in the ranitidine-carrying particles of the present invention, ranitidine and pharmaceutically acceptable salts thereof can be used. Specifically, ranitidine hydrochloride is preferable and can be used singly or in appropriate combination of two or more. The content of ranitidine relative to the ranitidine-containing pharmaceutical solid preparation is appropriately selected so as to fall within the range usually used for treatment as ranitidine hydrochloride. For example, the daily dose is appropriately selected to be about 50 to 300 mg, preferably 150 to 300 mg.

[Inorganic compounds]
The inorganic compound containing magnesium and / or calcium used in the ranitidine-carrying particles of the present invention has an antacid power required by the antacid test method of the 15th revised Japanese Pharmacopoeia (hereinafter referred to as No. 15) of 200 mL or more. Preferably, it exceeds 200 mL, and the magnesium and / or calcium content is 20% by mass or more. The antacid power determined by the 15th antacid test method is shown by the consumption (mL) of 0.1 mol / L hydrochloric acid per gram, and in the present invention, 200 mL or more, preferably 260 mL or more, more Preferably it is 290 mL or more. Although an upper limit is not specifically limited, 700 mL or less is preferable, More preferably, it is 600 mL or less. Specific examples include magnesium hydroxide (340 mL), magnesium oxide (480 mL), alumina magnesium hydroxide (300 mL), synthetic hydrotalcite (290 mL), magnesium carbonate (210 mL), calcium carbonate (200 mL), calcium hydroxide. (260 mL). Magnesium and / or calcium content is 20 mass% or more in an inorganic compound, Preferably it is 23 mass% or more, More preferably, it is 24 mass% or more. The upper limit is not particularly limited as long as it is an inorganic compound containing magnesium or calcium. Specifically, magnesium hydroxide (42% by mass), magnesium oxide (60% by mass), magnesium alumina hydroxide (21% by mass), synthetic hydrotalcite (24% by mass), magnesium carbonate (28% by mass), carbonic acid Calcium (40 mass%), calcium hydroxide (54 mass%), etc. are mentioned, It can use individually by 1 type or in combination of 2 or more types. Among these, magnesium hydroxide, magnesium oxide, synthetic hydrotalcite, calcium carbonate, and calcium hydroxide are preferable, and magnesium hydroxide, magnesium oxide, synthetic hydrotalcite, and calcium hydroxide are more preferable. By using an inorganic compound having an antacid power of 200 mL or more and magnesium and / or calcium content of 20% by mass or more determined by the 15th local antacid test, the desired effect of inhibiting discoloration of ranitidine is achieved. Is obtained.

  40-99 mass% is preferable, as for content of the said magnesium and / or calcium containing inorganic compound with respect to a ranitidine containing pharmaceutical solid formulation, 60-96 mass% is more preferable, 60-95 mass% is further more preferable.

  The molar ratio represented by magnesium and / or calcium / ranitidine in the ranitidine-carrying particles is preferably 10 or more from the viewpoint of the discoloration inhibiting effect of ranitidine. In terms of discoloration, which is an effect of the present invention, it is not particularly limited, and is about 9000, although it is determined by the size of the tablet and the pharmaceutical formulation restrictions of the antacid. However, the content can be used up to 5000 mg (daily dose) as the amount used in normal treatment of inorganic compounds.

  In addition to the above, the ranitidine-carrying particles may contain any additive as long as the effects of the present invention are not impaired. For example, excipients such as crystalline cellulose, lactose, starch, maltose, mannitol, xylitol, erythritol, magnesium aluminate metasilicate, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, croscarmellose sodium, Disintegrants such as carmellose, carmellose calcium, carmellose sodium, low-substituted hydroxypropylcellulose, lubricants such as magnesium stearate, hydrogenated castor oil, talc, macrogol, glidants such as light anhydrous silicic acid, etc. In addition, a disintegration aid, a buffering agent, a preservative, a fragrance, a pigment, a corrigent and the like can be used as necessary.

[Ranitidine-supported particles]
The ranitidine-carrying particles of the present invention are those obtained by carrying ranitidine on the inorganic compound containing magnesium and / or calcium. This is because ranitidine or a salt thereof is added to an inorganic compound having an antacid power determined by the antacid test method of the 15th station of 200 mL or more and a magnesium and / or calcium content in the compound of 20% by mass or more. It can be obtained by impregnating the solution or dispersion and drying. Examples of the impregnation method include spraying a solution or dispersion of ranitidine or a salt thereof onto a magnesium and / or calcium-containing inorganic compound and drying, and it may be dried after spraying or dried simultaneously with spraying. Also good. Examples of the solvent used for the solution or dispersion of ranitidine or a salt thereof include water, ethanol, a water-ethanol mixed solution, and the like. Further, in the solution or dispersion of ranitidine or a salt thereof, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin or the like may be blended and granulated. The concentration of ranitidine or a salt thereof in a solution or dispersion of ranitidine or a salt thereof is preferably 10 to 75% by mass, and a binder concentration such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pregelatinized starch or gelatin. Is preferably 1 to 20% by mass. When using the above-mentioned binder, ranitidine or a salt solution or dispersion thereof and a binder solution or dispersion (in this case, the binder concentration is preferably 1 to 20% by mass) are prepared separately. When the solution or dispersion of ranitidine or a salt thereof is sprayed on the inorganic compound and dried as necessary, the effect of suppressing discoloration is further improved by spraying the solution or dispersion of the binder.

  Furthermore, the above-mentioned ranitidine-carrying particles (including granulated products) are mixed with any other additives described above by fluidized bed granulation, stirring granulation, extrusion granulation, rolling granulation, dry granulation or a combination thereof. May be granulated. Drying includes fluidized bed drying, dry oven, freeze drying and the like. Fluidized bed granulation is preferred because it can be performed consistently up to granulation and drying and is efficient. The drying temperature (air supply temperature) time is not particularly limited, and is 40 to 60 ° C. for about 5 to 30 minutes.

The particle size of the inorganic compound serving as the carrier particles is preferably 0.5 to 500 μm, and the particle size of the ranitidine-carrying particles is preferably 0.5 to 850 μm, more preferably 75 to 400 μm. The particle diameter is measured using a laser diffraction scattering method, and the volume-based percentage (%) is converted into an integrated volume-based distribution to determine the median diameter (D ₅₀ ).

  The content of the ranitidine-carrying particles in the ranitidine-containing pharmaceutical solid preparation is appropriately selected in the range of 1 to 100% by mass so that the ranitidine content falls within the above range.

[Ranitidine-containing pharmaceutical solid preparation]
The ranitidine-containing pharmaceutical solid preparation contains the ranitidine-carrying particles and can be obtained by blending these particles, and is suitable as a therapeutic agent for stomach / duodenal ulcer, reflux esophagitis or gastritis. Although the dosage form is not particularly limited, it can be prepared into an oral dosage form such as a tablet, powder, fine granule, granule, capsule, pill, chewable agent, foaming agent, orally disintegrating agent. Among them, it is preferable to prepare a tablet, granule (granule, fine granule, powder) or capsule, and a tablet, granule or fine granule is more preferred. In the case of a tablet, ranitidine-carrying particles can be obtained by granulating and blending with ranitidine-carrying particles as they are or with other tablet components, and compression molding. The compression molding method is not particularly limited as long as it is a conventional method. For example, compression molding with a rotary tableting machine or a single-shot tableting machine can be used. In addition, regarding granule (granule, fine granule, powder), ranitidine-carrying particles can be directly mixed with other components. Alternatively, the ranitidine-carrying particles and some or all of the other components can be granulated using a known granulation method. For granulation, a fluidized bed granulation method, a stirring granulation method, an extrusion granulation method, a rolling granulation method, a dry granulation method, or a combination of these methods can be used. Since the ranitidine-containing pharmaceutical solid preparation of the present invention can suppress discoloration of ranitidine due to long-term storage, it can also have a structure without a sugar coating or a pigment-containing coating. Examples of components blended in the ranitidine-containing pharmaceutical solid formulation other than ranitidine-carrying particles include various active ingredients and additives used in gastrointestinal drugs. As an active ingredient, it is preferable to mix a mucosal repair agent.

  Examples of the mucosal repair agent used in the present invention include, for example, sodium azulene sulfonate, aldioxa, magnesium aluminate metasilicate, glycyrrhizic acid or a salt thereof, licorice or an extract thereof, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium Histidine hydrochloride, methylmethionine sulfonium chloride, red buds, Yoncho cord, sucrose octasulfate aluminum salt (sucralfate), cetraxate hydrochloride, sofalcone, ornoprostil, sulpiride, gefarnate, teprenone, prunotol, aceglutamide aluminum, etc. 1 type can be used individually or in combination of 2 or more types as appropriate. Of these, sucralfate is preferred. Sucralfate can be blended as it is, but granulated particles may be used. The granulation is not particularly limited as long as it is a known granulation method such as fluidized bed granulation, tumbling granulation or kneading granulation, and for example, a slurry obtained by slurrying with a binder such as polyethylene glycol and the like are used. be able to. Examples of such commercially available products include “STOMAXIN: manufactured by Fuji Chemical Industry Co., Ltd.”. The particle size is not particularly limited, but using a sieve having openings of 1000 μm and 850 μm, it is preferable that 1000 μm on is 0% by mass and 850 μm on is 3% by mass or less.

  For ranitidine-containing solid pharmaceutical preparations, other raw materials, for example, excipients such as binders and disintegrants, lubricants, surfactants, fragrances, flavoring agents (sweeteners, acidulants, etc.), coloring, as necessary An appropriate amount of additives such as an agent can be blended singly or in appropriate combination of two or more.

  Examples of the binder include starch, pregelatinized starch, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin and the like. Examples of the disintegrant include carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, and the like. Examples of the excipient include lactose, starch, talc, crystalline cellulose, powdered sugar, mannitol, light anhydrous silicic acid, calcium carbonate, L-cysteine and the like. Examples of the lubricant include magnesium stearate, calcium stearate, polyethylene glycol, talc, stearic acid, and sucrose fatty acid ester.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. Unless otherwise specified, the amounts in the table are pure component amounts.

[Examples 1-15, Comparative Examples 1-7]
Tablets (adult daily dose) having the compositions shown in Tables 1 to 3 were obtained by the following method.
Carrier particles are placed in a fluidized bed granulator MP-01 (manufactured by POWREC), and each carrier particle is sprayed and impregnated with a 50% by mass ranitidine hydrochloride aqueous solution so as to be a predetermined amount, and granulated and dried to be granulated particles. Got. As granulation conditions, air supply temperature: 80 ° C., atomizing air amount: 50.0 L / min. [20 ° C., 1 atm], spray liquid speed: 20 g / min. The drying process was performed until the exhaust air temperature reached 50 ° C. The average particle diameter of the granulated particles was 100 to 300 μm.
Next, the obtained granulated particles and other components excluding magnesium stearate were sufficiently mixed using a Boule container mixer (24 rpm, Kotobuki Kogyo Co., Ltd. Model 20). Magnesium stearate is added to the obtained mixed powder and mixed for 5 minutes using a Boule container mixer (model type 20 manufactured by Kotobuki Kogyo Co., Ltd.), then φ8 mm, two-stage R (R = 9.5 mm, 3. Using a rotary tableting machine (Libra tableting machine: manufactured by Kikusui Seisakusho) equipped with 2 mm) punches and mortars, tableting was performed at a tableting pressure of 1000 kgf to obtain one tablet of 310 mg. In Table 1, “*” indicates that 1180 mg of stomaxin contains 1000 mg of sucralfate, 40 mg of polyethylene glycol 6000, and 140 mg of water, and the composition of stomaxin in Tables 2 and 3 is the same.

  The dispersion state of ranitidine hydrochloride in the tablet obtained in Example 1 was confirmed with a near-infrared imaging apparatus “Synergy (manufactured by Marbern Co., Ltd.)” (FIG. 1). Yellow-red spots with a high concentration indicating the presence of ranitidine are finely and almost uniformly dispersed (note that it appears black on the drawing). In addition, the dispersion state of ranitidine hydrochloride (Fig. 1) and carrier particles (Fig. 2) can be compared, and it can be confirmed that they are supported and impregnated by the overlapping of dark yellow to red spots with high concentrations indicating their respective positions. It was. The color image shown in Fig. 1 and the color image shown in Fig. 2 are submitted as reference photos 1 and 2, respectively.

The obtained tablets were packaged with PTP (polypropylene PTP molded product R-1T-2 manufactured by Kanae Co., Ltd.) and placed in an aluminum gusset. This was stored in a constant temperature layer of 50 ° C. and 75% RH for 2 weeks. The color difference of the tablet after storage was measured with a color difference meter (manufactured by MINOLTA Co., Ltd., spectrocolorimeter CM-2022 type), and discoloration suppression evaluation was performed according to the following evaluation criteria. The results are also shown in the table.
<Evaluation criteria>
Compare the color difference (b *) between the sample stored in the same way as above except that 50 ° C / 75% RH was changed to 5 ° C. Those exceeding 3 or less were evaluated as “◯”, those exceeding 3 or less as “Δ”, and those exceeding 5 as “X”.

[Comparative Example 8]
In Example 1, granulated particles were not produced, and tablets were produced in the same manner as in Example 1 except that ranitidine hydrochloride powder was mixed with synthetic hydrotalcite. The dispersion state of ranitidine hydrochloride in the tablet obtained in Comparative Example 8 was confirmed with a near-infrared imaging device “Synergy (manufactured by Malvern, Inc.)” (FIG. 3). Compared with Example 1 (FIG. 1), the spots of yellow to red having a high density are large and localized, and there is a difference in the degree of dispersion. In addition, the dispersion state of ranitidine hydrochloride (FIG. 3) and carrier particles (FIG. 4) are compared, and the concentration of each presenting position is not supported or impregnated because the dark yellow to red spots do not overlap. It could be confirmed. The color image of FIG. 3 and the color image of FIG. 4 are submitted as reference photographs 3 and 4, respectively. When the discoloration suppression evaluation was performed in the same manner as in Example 1, the result was “x”.

[Examples 16 to 19]
Fine granules (adult daily dose) having the composition shown in Table 4 were obtained by the following method.
Powder A was put into a fluidized bed granulator MP-01 (manufactured by POWREC), and each powder was impregnated with a 30% by mass ranitidine hydrochloride aqueous solution so as to be a predetermined amount, and then hydroxypropylcellulose (HPC- L) The dispersion B prepared so as to have a concentration of 7% by mass was sprayed and granulated. The obtained granulated product was thoroughly mixed with aspartame by hand as necessary to obtain a powder (1). Furthermore, sucralfate and mannitol were placed in a fluidized bed granulator MP-01 (manufactured by Paulek) and granulated by spraying with a 7% by mass hydroxypropylcellulose aqueous solution so as to obtain a predetermined amount to obtain a powder (2). . As granulation conditions of the powders (1) and (2), an air supply temperature: 80 ° C. and an atomized air amount: 50.0 L / min. [20 ° C., 1 atm], spray liquid speed: 20 g / min. The drying process was performed until the exhaust air temperature reached 50 ° C. Powders (1) and (2) were sufficiently mixed using a Boule container mixer (24 rpm, model 20 manufactured by Kotobuki Kogyo Co., Ltd.) to obtain a fine granule.

10 g of the obtained fine granule was placed in an aluminum stick and heat sealed. This was stored in a constant temperature layer of 50 ° C. and 75% RH for 2 weeks. The color difference of the tablet after storage was measured with a color difference meter (manufactured by MINOLTA Co., Ltd., spectrocolorimeter CM-2022 type), and discoloration suppression evaluation was performed according to the following evaluation criteria. The results are also shown in the table.
<Evaluation criteria>
Compare the color difference (b *) between the sample stored in the same way as above except that 50 ° C / 75% RH was changed to 5 ° C. Those exceeding 3 or less were evaluated as “◯”, those exceeding 3 or less as “Δ”, and those exceeding 5 as “X”.

Claims (4)

  The ranitidine support in which ranitidine is supported on an inorganic compound having an antacid power of 200 mL or more and magnesium and / or calcium content of 20% by mass or more required by the fifteenth revised Japanese Pharmacopoeia antacid test method A ranitidine-containing pharmaceutical solid preparation comprising particles.   The ranitidine-containing pharmaceutical solid preparation according to claim 1, wherein the inorganic compound is one or more selected from magnesium hydroxide, magnesium oxide, synthetic hydrotalcite, magnesium carbonate, calcium carbonate and calcium hydroxide.   The ranitidine-containing solid pharmaceutical preparation according to claim 1 or 2, wherein the ranitidine-carrying particles have a molar ratio of 10 or more represented by magnesium and calcium / ranitidine.   To an inorganic compound having an antacid power of 200 mL or more and magnesium and / or calcium content of 20% by mass or more determined by the 15th revision Japanese Pharmacopoeia antacid test method, a solution of ranitidine or a salt thereof or A method for producing ranitidine-carrying particles in which ranitidine is carried on the inorganic compound, wherein the dispersion is impregnated and dried.