JP2011153119A - Tablet containing vancomycin or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet containing vancomycin or a pharmacologically acceptable salt thereof as an active ingredient. <P>SOLUTION: The tablet is prepared using (1) spray-granulated vancomycin or a pharmacologically acceptable salt thereof, (2) silicic acid or a salt thereof, (3) a disintegrator and (4) a lubricant. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a tablet containing vancomycin or a salt thereof (hereinafter also referred to as “vancomycins”). More specifically, the present invention relates to a tablet (vancomycin preparation having a tablet form) containing vancomycins having hardness required for practical use and excellent disintegration and dissolution properties.

  The only oral vancomycin formulation currently approved in Japan is powder. Since this powder is a preparation in a vial, it is orally administered after being dissolved in water for injection. At this time, vancomycin hydrochloride, which is an active ingredient, has a problem that it is difficult to take because it has strong pessimism, and this also causes a decrease in compliance. In order to alleviate puffing, a method of adding a flavoring agent such as simple syrup and orally administering it is also recommended, but since it is too strong, it cannot be said that it is a very effective method.

  In addition, since conventional vancomycin preparation (powder) is divided and administered in water after injection with water for injection, contamination may occur, and the formulation form of powder in a vial is vancomycin for injection. Since it is similar to the hydrochloride formulation, there is a new danger that both may be mistaken.

  Therefore, while maintaining almost the same dissolution properties as conventional powder vancomycin preparations, it is easy to take by alleviating or eliminating itchiness, and has a form without risk due to the complexity of dispensing. Development is required.

“Glycopeptide antibiotic preparations” prescription drug vancomycin hydrochloride 0.5 g (Shionogi Pharmaceutical Co., Ltd.) Internet <URL: http: // www. shionogi. co. jp / med / kihon / img / pdf / VCMP. pdf>

  In view of such circumstances, the present invention provides a vancomycin preparation in a tablet form that is easy to take without complicated complications from the viewpoint of improving patient compliance and risk management without significantly impairing the dissolution property of a conventional vancomycin preparation in powder form. The purpose is to provide. Specifically, we offer vancomycin formulations in tablet form that have the required hardness for practical use, but have excellent disintegration and dissolution properties and can exhibit the same or almost the same biological effects as conventional powder formulations. The purpose is to do.

  The inventors of the present invention have been diligently researched to solve the above problems. As a result, vancomycin used as an active ingredient is spray granulated, that is, vancomycin obtained by spray drying an aqueous solution in which vancomycin is dissolved. In addition to excipients, in addition to excipients, it is used in combination with silicic acid or its salts and a disintegrant, so that it has the hardness required for practical use without tableting trouble. In addition, it was found that a tablet excellent in disintegration and dissolution can be prepared. Furthermore, tablets having such characteristics cannot be prepared by (i) direct tableting method or wet granulation method, but can be prepared by using the spray granulated vancomycin, and (ii) It was confirmed that it could not be prepared by removing silicic acid or a salt thereof or removing a disintegrant from the inside, but could be prepared by combining both silicic acid or a salt thereof and a disintegrant.

  The present invention has been completed based on such knowledge, and includes the following embodiments.

(I) Vancomycin preparation having tablet form (I-1) Tablet containing the following components (1) to (5):
(1) spray-granulated vancomycin or a pharmaceutically acceptable salt thereof,
(2) silicic acid or a salt thereof,
(3) a disintegrant, and (4) a lubricant.

(I-2) The tablet according to (I-1), further containing an excipient.
(I-3) The tablet according to (I-1) or (I-2), which has a hardness of 3 kgf or more and has a disintegration time of 80 seconds or less based on the disintegration test method stipulated in the 15th revision of the Japanese Pharmacopoeia.
(I-4) Silicic acid or a salt thereof is light anhydrous silicic acid, hydrous silicon dioxide, hydrous amorphous silicon oxide, synthetic aluminum silicate, calcium silicate, magnesium silicate, hydrous magnesium silicate, magnesium aluminum silicate, And the tablet according to any one of (I-1) to (I-3), which is at least one selected from the group consisting of magnesium aluminate metasilicate.

  (I-5) The disintegrant is at least one selected from the group consisting of cellulose, cellulose derivatives, crospovidone, carboxymethyl starch, hydroxypropyl starch, and salts thereof (I-1) to The tablet according to any one of (I-4).

  (I-6) The cellulose derivative is methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropylmethylcellulose (hypromellose), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose (carmellose, (Including croscarmellose) and a sodium salt or calcium salt thereof, crystalline cellulose, crystalline cellulose carmellose, and crystalline cellulose carmellose sodium, at least one selected from (I-5) Pills.

(I-7) The tablet according to any one of (I-2) to (I-6), wherein the excipient is at least one selected from the group consisting of a water-soluble sugar and a sugar alcohol .
(I-8) The water-soluble sugar is at least one selected from the group consisting of glucose, sucrose, fructose, sucrose, lactose, anhydrous lactose, reduced maltose starch syrup, and trehalose, and the water-soluble sugar alcohol is mannitol. The tablet according to (I-7), which is at least one selected from the group consisting of erythritol, erythritol, sorbitol, xylitol, and maltitol.
(I-9) Any one of (I-1) to (I-8), wherein the proportion of vancomycin or a pharmaceutically acceptable salt thereof contained in 100% by mass of the tablet is 10 to 80% by mass in total Tablets described in 1.

(I-10) The tablet according to any one of (I-1) to (I-9), wherein the proportion of silicic acid or a salt thereof contained in 100% by mass of the tablet is 1 to 50% by mass in total.
(I-11) The tablet according to any one of (I-1) to (I-10), wherein the proportion of the disintegrant contained in 100% by mass of the tablet is 1 to 20% by mass.
(I-12) The tablet according to any one of (I-2) to (I-11), wherein the proportion of the excipient contained in 100% by mass of the tablet is 1 to 53% by mass.

(II) Production method of vancomycin preparation (tablet) (II-1) (a) Spray granulation of vancomycin or a pharmaceutically acceptable salt thereof,
(B) a step of sizing the spray granule obtained above,
(C) A step of blending and mixing silicic acid or a salt thereof and a disintegrant into the granulated product obtained above, and (d) blending a lubricant with the above mixture and compression-molding it into a tablet shape ( Tableting),
A method for producing a tablet according to any one of (I-1) to (I-10).

(II-2) The step (c) is a step of blending and mixing silicic acid or a salt thereof, a disintegrant and an excipient into the sized product obtained in the step (b). -1) The manufacturing method described.
(II-3) The step (d) is a step of tableting the mixture containing the lubricant at a tableting pressure of 0.3 to 3 ton / cm ² (II-1) or (II-2) The production method described in 1.

(III) Method for improving disintegration characteristics of vancomycin preparation (III-1) A method for improving disintegration characteristics of a tablet containing vancomycin or a pharmaceutically acceptable salt thereof as an active ingredient, comprising vancomycin or a pharmacological agent thereof In addition to an acceptable salt spray granulate and a lubricant, silicic acid or a salt thereof and a disintegrant are incorporated.

(III-2) The method according to (III-1), wherein a tablet is prepared by tableting at a tableting pressure of 0.3 to 3 ton / cm ² .
(III-3) The method according to (III-1) or (III-2), wherein the disintegration time is 80 seconds or less based on the disintegration test method defined in the 15th revision of the Japanese Pharmacopoeia.

  According to the present invention, vancomycin or a salt thereof is excellent in disintegration and dissolution properties while having a tablet hardness that is practically required so that it is not damaged even during removal from a PTP package and in the process of carrying and distribution. It can be provided as a tablet. In particular, according to the present invention, an antibiotic preparation containing vancomycin or a salt thereof as an active ingredient can be provided as a tablet that can be expected to improve compliance by improving the feeling of administration and handling.

The 125 mg tablet (n = 12) and the standard preparation (n = 12) of the present invention were subjected to “(1) dissolution test solution (pH 1.2, temperature 37) using the paddle method according to the dissolution test method prescribed in the Japanese Pharmacopoeia. (± 0.5 ° C.), paddle rotation speed: 50 rotations / minute ”shows the results of the dissolution test. A result is shown as an average value of 12 samples (hereinafter the same in FIGS. 2 to 10). The 125 mg tablet of the present invention (n = 12) and the standard preparation (n = 12) were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 4.0, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 50 rotations / minute” is shown. The 125 mg tablet of the present invention (n = 12) and the standard preparation (n = 12) were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 50 rotations / minute” is shown. The 125 mg tablet of the present invention (n = 12) and the standard preparation (n = 12) were prepared using the paddle method in the same manner as described above, “(2) Dissolution test solution (water, temperature 37 ± 0.5 ° C.), paddle rotation The result of having carried out the dissolution test under the condition “number: 50 rpm” is shown. The 125 mg tablet of the present invention (n = 12) and the standard preparation (n = 12) were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 100 rotations / minute” is shown. The 250 mg tablet (n = 12) and the standard preparation (n = 12) of the present invention were subjected to “(1) dissolution test solution (pH 1.2, temperature 37) using the paddle method according to the dissolution test method prescribed in the Japanese Pharmacopoeia. (± 0.5 ° C.), paddle rotation speed: 50 rotations / minute ”shows the results of the dissolution test. A result is shown as an average value of 12 samples (hereinafter the same in FIGS. 2 to 10). The 250 mg tablet (n = 12) and the standard preparation (n = 12) of the present invention were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 4.0, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 50 rotations / minute” is shown. The 250 mg tablet (n = 12) and the standard preparation (n = 12) of the present invention were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 50 rotations / minute” is shown. The 250 mg tablet of the present invention (n = 12) and the standard preparation (n = 12) were prepared using the paddle method in the same manner as described above, “(2) Dissolution test solution (water, temperature 37 ± 0.5 ° C.), paddle rotation The result of having carried out the dissolution test under the condition “number: 50 rpm” is shown. The 250 mg tablet (n = 12) and the standard preparation (n = 12) of the present invention were prepared using the paddle method in the same manner as described above using “(2) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), The result of having carried out the dissolution test under the condition of “paddle rotation speed: 100 rotations / minute” is shown.

(I) Vancomycin preparation (tablet) and production thereof The tablet of the present invention is a tablet containing vancomycin or a pharmaceutically acceptable salt thereof (collectively referred to as “vancomycins”) as an active ingredient, It is characterized by containing vancomycin in the form of a spray granulated product and containing silicic acid or a salt thereof and a disintegrating agent in addition to a lubricant as other additive components.

(1) Vancomycin or a salt thereof Vancomycin is a glycopeptide antibiotic having an action of binding to e-bacterial cell wall synthase D-alanyl-D-alanine to inhibit cell wall synthase and thereby preventing bacterial growth. It is. Most gram-positive bacteria have bactericidal action, and have bacteriostatic action against enterococci. Moreover, since it is hardly absorbed even if it is taken, it is effective for bacteriostasis and sterilization in the digestive tract such as the intestine, and is used for treatment of infectious enteritis and sterilization in the digestive tract at the time of bone marrow transplantation. The pharmaceutically acceptable salts of vancomycin include alkali metals (eg, sodium, potassium, etc.) and alkaline earth metals (eg, magnesium, calcium, etc.) as the metal capable of forming a salt. Examples of acids that can be formed include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid) and organic acids (eg, acetic acid, fumaric acid, etc.). An aqueous inorganic acid salt of vancomycin such as vancomycin hydrochloride or vancomycin sulfate is preferable, and vancomycin hydrochloride is more preferable.

  Vancomycin hydrochloride can be produced, for example, by the method described in US Pat. No. 30,670,995. Commercially available pharmaceutical grade drug substances can also be used.

  The spray granulated product of vancomycins can be prepared by dissolving vancomycins in water and drying and granulating it with a spray dryer or the like. Here, the water is not particularly limited as long as it can be used for the preparation of pharmaceuticals. For example, distilled water, sterilized water, ion exchange water, water for injection and purified water can be used.

  The spray dryer is not particularly limited as long as it can dry-granulate (spray granulate) vancomycin from an aqueous solution (vancomycin-containing aqueous solution) in which vancomycin is dissolved. Can be preferably used. The fluidized granulation spray dryer is equipped with a fluidized bed granulator equipped with a stirring mechanism at the bottom of the spray dryer drying chamber, and a fluidized bed drying / cooling device is joined for finish drying and cooling of the product. In this apparatus, a granulated product can be obtained directly from a liquid raw material (an aqueous solution containing vancomycins in the present invention).

  Although it does not restrict | limit as a density | concentration of vancomycins containing aqueous solution with which it uses here for spray * dry granulation, Usually, 1-60 mass%, Preferably it is 10-40 mass%, More preferably, it is 13-50 mass%.

  The granulated product thus obtained is then preferably subjected to a crushing / sizing process or a sizing process to adjust the particle size distribution. Such a crushing / sizing process or a sizing process is an important process for ensuring the uniformity of tablet functions (disintegration and dissolution, and biological functions based on them). The crushing / sizing step is a step of crushing the granulated product obtained in the granulation step and adjusting the particle size, and the granulating step is a step of adjusting the particle size of the granulated product obtained in the granulation step. is there. Both are common in that they pass through a screen of a desired size and collect a granulated product having a desired particle size. The apparatus to be used may be an apparatus having a treatment for finally passing a screen of a desired size, and is not particularly limited. For example, a power mill, a speed mill, a comb mill, a sieve sieve, a nebulizer (milling) Type granulator), Xebu (crushing granulator with classification function), Fitz mill (crushing granulator), Malmerizer (spherical granulator) and the like.

  Thus, the granulated product of vancomycin used in the present invention is preferably adjusted so that the average particle size is about 50 to 400 μm. The average particle size is preferably about 70 to 340 μm, more preferably about 77 to 310 μm. The average particle size can be measured by using a laser diffraction / scattering particle size distribution measuring apparatus.

  In the present invention, the granulated product (spray granulated product) of vancomycins consists essentially of vancomycins. However, as long as the effects of the present invention are not impaired, other components can be blended up to 50 mass% per 100 mass% of the spray granulated product. Examples of such components include silicic acid or silicate.

  The proportion of the granulated product (spray granulated product) of vancomycin thus prepared in 100% by mass of the final tablet is usually 10 to 80% by mass, preferably 20 to 70% by mass, more preferably 30 to 30%. 60% by mass.

(2) Silicic acid or a salt thereof The silicic acid or silicate used in combination with the granulated product of vancomycin is not particularly limited as long as it is a silicic acid or silicate that can be used as a raw material for pharmaceuticals. Specifically, light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide, hydrous amorphous silicon oxide, synthetic aluminum silicate, calcium silicate, magnesium silicate, talc (hydrous magnesium silicate), magnesium aluminum silicate And magnesium metasilicate aluminate. Preferred are light anhydrous silicic acid, calcium silicate, hydrous silicon dioxide, and magnesium aluminate metasilicate. These silicic acids or silicates may be used alone or in combination of two or more.

  These silicic acids or silicates are all characterized by being porous. The term “porous” means that the solid has a large number of small voids inside or on the surface. Here, the void means a pore-like one that usually leads to the outside, but also includes a bubble-like void (that is, a void that does not lead to the outside) (“Porosity” in “Chemical Dictionary”). Column, Kyoritsu Publishing, issued on December 1, 1975). The porosity can be evaluated using, for example, a pigment test method defined in JIS K5101. Although it does not restrict | limit, The silicic acid or silicate whose oil absorption measured using such a method is 0.4 ml / g or more is used suitably.

  The form of silicic acid or silicate used is powdery or granular. Although not limited, in order to ensure the uniformity of the final tablet, it is preferable to use powdered or granular silicic acid or a salt thereof having an average particle size of about 1 to 300 μm, preferably about 1 to 200 μm. . The average particle size can be measured by using a laser diffraction / scattering particle size distribution measuring apparatus (hereinafter the same).

  The ratio of the silicic acid or the silicate to be blended with the vancomycin spray granule is usually 1 to 50% by mass as the content (total amount) in 100% by mass of the final tablet. Preferably it is 1-40 mass%, More preferably, it is 4-30 mass%. Moreover, as a ratio of silicic acid or a silicate with respect to 100 mass parts of vancomycins contained in the tablet, the total amount is 2-110 mass parts, preferably 2-90 mass parts, more preferably 9-70 mass parts. Can be mentioned.

(3) Disintegrants As disintegrants, disintegrants commonly used in the field of solid preparations can be widely used. Preferred examples include cellulose, cellulose derivatives, crospovidone, hydroxypropyl starch, carboxymethyl starch, and salts thereof. Here, the salt includes alkali metal salts such as sodium and potassium, and alkali metal earth salts such as magnesium and calcium.

  Cellulose derivatives or salts thereof include methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose (including carmellose and croscarmellose) and Mention may be made of the sodium or calcium salts thereof, crystalline cellulose, crystalline cellulose carmellose and crystalline cellulose carmellose sodium. Preferred are low-substituted hydroxypropyl cellulose, carboxymethyl cellulose (including carmellose and croscarmellose) or a sodium salt or calcium salt thereof, and crystalline cellulose.

  These disintegrants can be used alone or in combination of two or more.

  Here, crospovidone is a cross-linked homopolymer of 1-ethenylpyrrolidin-2-one and is a component widely used as a pharmaceutical additive (such as a disintegrant). Also in the present invention, crospovidone defined by pharmaceutical additive standards can be widely used. Such crospovidone can be obtained commercially, such as Kollidon CL (manufactured by BASF), polyplastidone XL, polyplastidone XL-10, and polyplastidone INF-10 (manufactured by ISP). Can be mentioned.

  Examples of the low-substituted hydroxypropylcellulose include a low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content (hereinafter sometimes abbreviated as HPC group content) in hydroxypropylcellulose of about 7 to 13% by weight. Can do. Among these, low substituted hydroxypropylcellulose having an HPC group content of about 7 to 9.9% by weight is preferable from the viewpoint of improving disintegration. These low-substituted hydroxypropyl celluloses can be obtained commercially, for example, from Shin-Etsu Chemical Co., Ltd., LH-11, LH-21, B1 and LH-31 (HPC group content: 10 12.9%), and LH-22 and LH-32 (and above, HPC group content: 7.0-9.9%).

  Carmellose is a polyvalent carboxymethyl ether of cellulose, also called carboxymethyl cellulose, CMC, or fibrin glycolic acid, and is a component that is widely used as a pharmaceutical additive (such as a disintegrant). Also in the present invention, carmellose defined by the Japanese Pharmacopoeia can be widely used. Both carmellose and its calcium salt are commercially available. For example, NS-300 (Gotoku Pharmaceutical Co., Ltd.) is used as carmellose, and E. C. And G-505 (Gotoku Pharmaceutical Co., Ltd.).

  Moreover, croscarmellose is a crosslinked polyvalent carboxymethyl ether of cellulose and is also referred to as an internally crosslinked carboxymethyl cellulose. As a sodium salt of croscarmellose, croscarmellose sodium defined by the Japanese Pharmacopoeia can be widely used in the present invention. Such croscarmellose sodium can be obtained commercially, for example, Akjisol (Dainippon Sumitomo Pharma Co., Ltd.).

  The disintegrant used is in the form of powder or granules. Although not limited, in order to ensure the uniformity of the final tablet, it is preferable to use a powdery or granular disintegrant having an average particle diameter of about 1 to 300 μm, preferably about 1 to 200 μm.

  The ratio of the disintegrant to be blended with the vancomycin spray granulated product can usually include 1 to 20% by mass as the content (total amount) in 100% by mass of the final tablet. Preferably it is 1-15 mass%, More preferably, it is 5-10 mass%. Moreover, as a ratio of the disintegrant with respect to 100 mass parts of vancomycins (spray granulated product) contained in the tablet, the total amount is 2-45 mass parts, preferably 2-30 mass parts, more preferably 10-20 masses. Part.

(4) As a lubricant or a lubricant, conventionally used pharmaceutical additives for improving the fluidity of powder and facilitating compression formation in tablet production can be used. Examples of such lubricants include stearic acid, magnesium stearate, talc, hydrogenated vegetable oil, sucrose fatty acid ester, polyethylene glycol, and sodium stearyl fumarate. Preferred are magnesium stearate and sodium stearyl fumarate.

  As a ratio of 100% by mass of such a lubricant, usually 0.1 to 5% by mass can be mentioned. Preferably it is 0.1-3 mass%, More preferably, it is 0.1-2 mass%. Moreover, as a ratio of the excipient | filler with respect to 100 mass parts of vancomycins (spray granulation product) contained in the tablet, 0.2-11 mass parts, Preferably 0.2-7 mass parts, More preferably, it is 0. 2 to 4.5 parts by mass can be mentioned.

(5) Other components Unless the effect of the present invention is impaired, the tablet of the present invention is an additive other than the above-mentioned pharmaceutical additives, and an additive generally used for tablet production is blended. You can also. Examples of such additives include excipients (bulking agents), flavoring agents (including sweeteners), acidulants, fragrances, coloring agents, and solubilizing agents.

  Here, as the excipient, an excipient conventionally used in the field of solid preparation can be widely used. Although not limited, it is preferably a water-soluble sugar or sugar alcohol. Examples of water-soluble sugars include glucose, sucrose, fructose, sucrose, lactose, anhydrous lactose, reduced maltose starch syrup, and trehalose. Water-soluble sugar alcohols include mannitol (D-mannitol), erythritol, sorbitol (D- Sorbitol), xylitol, maltitol and the like. A sugar alcohol such as mannitol is preferred. These excipients may be used alone or in combination of two or more.

  The excipient used is in the form of powder or granules. Although not limited, in order to ensure the uniformity of the final tablet, it is preferable to use a powdery or granular excipient having an average particle size of about 1 to 300 μm, preferably about 1 to 200 μm.

  The ratio of the excipient | filler mix | blended with the spray granulated material of vancomycin can mention 1-53 mass% normally as content (total amount) in 100 mass% of final tablets. Preferably it is 5-53 mass%, More preferably, it is 10-46 mass%. Moreover, as a ratio of the excipient | filler with respect to 100 mass parts of vancomycins (spray granulation product) contained in a tablet, 2-118 mass parts in total amount, Preferably it is 11-118 mass parts, More preferably, it is 22-103. Part by mass can be mentioned.

  Here, as a flavoring agent (including a sweetener), sugar, starch sugar, lactose, honey, sugar alcohol, a high-intensity sweetener, and the like can be used. Examples of the sugar include sucrose, coupling sugar, fructooligosaccharide, and palatinose; examples of the starch sugar include glucose, maltose, powdered rice cake, starch syrup, and isomerized sugar (fructose); examples of the lactose include lactose and isomerized lactose. (Lactulose), reduced lactose (lactitol), etc .; Examples of sugar alcohols include sorbitol, erythritol, mannitol, reduced maltose starch syrup (maltitol), reduced starch saccharified product, xylitol, reduced palatinose, etc. Examples of the high-intensity sweetener include saccharin sodium, aspartame, sucralose, stevia, glycyrrhizin tripotassium, licorice, and acesulfame.

  Examples of acidulants include citric acid, tartaric acid, and malic acid; examples of flavors include menthol, peppermint oil, lemon oil, orange oil, and grapefruit oil; examples of colorants include edible yellow No. 5, edible red No. 2, and edible An edible pigment such as Blue No. 2, an edible lake pigment, or iron oxide such as Bengala can be used.

  The tablet of the present invention can be produced by mixing the above-described various components using a conventional method in the field of pharmaceutical preparation and forming into a tablet form. Specifically, the above-mentioned various components [(2) and (3), and further (5) as necessary, particularly shaped, are added to the spray granulated vancomycin first granulated and sized by the above-mentioned method. Agent] is mixed and mixed.

  Here, the mixing can be performed using a machine such as a V-type mixer (manufactured by Tokuju Kogakusho Co., Ltd.), a twin blade type mixer, a stirring mixer (manufactured by Dalton Co., Ltd.), or the like.

Next, the lubricant described in the above (4) is blended in the mixture obtained by the mixing step, mixed, compressed and molded into a tablet form. The compression molding uses a tableting machine usually used in the art such as a hydraulic hand press machine, a single tablet machine, or a rotary tableting machine, and is usually 0.3 to ³ ton / cm ² , preferably 0.3. It is performed by tableting at a pressure of ˜2 ton / cm ² .

  If the tablet of this invention is a tablet form, the specific shape will not be ask | required in particular, For example, a disk shape, an ellipse disk shape, a polygonal plate shape, a spherical shape, a football shape, a caplet shape, a donut shape etc. are mentioned. Can do. A disk shape is preferred. The size is not limited as long as it contains 100 to 1000 mg, preferably 100 to 750 mg, more preferably 100 to 400 mg of vancomycin which is an active ingredient per tablet. As an example of the size, a major axis 12.7 mm: a minor axis 5.8 mm: a thickness 4 to 6 mm, preferably a thickness 4.5 to 5.5 mm, more preferably 4.7 to 5.3 mm can be exemplified. .

  Moreover, it is preferable that the tablet of this invention is equipped with the hardness which is not damaged, for example by taking out from a PTP package, and carrying. Such hardness can include 3 kgf or more. From the balance between breakage resistance and disintegration in the body after administration, the tablet hardness is preferably 3 to 20 kgf, more preferably 5 to 15 kgf. The tablet hardness is measured after the tablet to be measured is compressed and stored under conditions of room temperature and a relative humidity of 60% or less, and the tablet breaking strength measuring instrument (for example, TH-203MP, manufactured by Toyama Sangyo Co., Ltd.) within 8 hours. ) To measure the intensity in the diameter direction.

  The tablet of the present invention thus prepared has the hardness required for practical use as described above, and is characterized by excellent disintegration in the body (intestine) after oral administration, and thus excellent dissolution. And

  Such disintegration can be judged based on the disintegration test method stipulated in the 15th revision of the Japanese Pharmacopoeia, and when measured without using an auxiliary plate using water (temperature 37 ± 2 ° C.) as a test solution Furthermore, it is preferable that the time required for the collapse is usually within 90 seconds. More preferably, it is within 80 seconds, More preferably, it is within 75 seconds.

  The dissolution behavior can also be judged based on the disintegration test method defined in the Japanese Pharmacopoeia 15th revision. Preferably, in the dissolution test method stipulated by the Japanese Pharmacopoeia, the dissolution rate of vancomycins 30 minutes after the start of the test is 80% or more, more preferably 90% or more, and further the dissolution of vancomycins 5 minutes after the start of the test. The rate is preferably 80% or more.

  Since the tablet of the present invention contains vancomycins having antibacterial activity against Gram-positive bacteria as an active ingredient, infectious enteritis (applicable bacterial species: methicillin resistant to vancomycin is applied based on its efficacy and effects. Staphylococcus aureus (MRSA), Clostridium difficile, indications: infectious enteritis (including pseudomembranous colitis)), used as a drug (antibiotic) for gastrointestinal sterilization during bone marrow transplantation.

  The dose of the tablet of the present invention varies depending on the disease to be treated and the degree of symptoms of the patient. For example, in the case of infectious enteritis (including pseudomembranous colitis), usually vancomycin per administration for an adult 0.125 to 0.5 g (titer) is orally administered at a rate of 4 times a day. In addition, for sterilization of the gastrointestinal tract at the time of bone marrow transplantation, usually 0.5 g (titer) of the amount of vancomycin per adult dose is used in combination with a non-absorbable antibacterial or antifungal agent. Orally administered at a rate of 4-6 times a day.

(II) Method for improving disintegration characteristics of tablets containing vancomycins as an active ingredient, and the present invention provides a method for improving disintegration characteristics for tablets containing vancomycin or a salt thereof (vancomycins) as an active ingredient. . In the production of tablets, a spray granulated and sized product (spray granulated product) is used as a form of vancomycin as an active ingredient, and at least silicic acid or a salt thereof, a disintegrant, and a lubricant are used. It can be carried out by blending and preparing a preparation.

  Vancomycins, silicic acid or salts thereof, disintegrants and lubricants and their proportions, other optional ingredients and their proportions, and vancomycin spray granules and final tablets The manufacturing method is as described in (I).

  According to the method of the present invention, that is, the tablet of the vancomycin spray granulated product is mixed with silicic acid or a salt thereof and a disintegrant to produce a tablet, the vancomycin is used as an active ingredient. The disintegrating property of the tablet to be improved can be improved. Specifically, it requires disintegration when measured without using an auxiliary plate using water (temperature 37 ± 2 ° C.) as a test solution based on the disintegration test method stipulated in the 15th revision of the Japanese Pharmacopoeia. Time can be reduced within 90 seconds. More preferably, it is within 80 seconds, More preferably, it is within 75 seconds.

  In addition, according to the method of the present invention, not only the disintegration characteristics of the final tablet are improved, but also granulated products (spray granulated products) that have been spray granulated and sized in advance as vancomycins in the production process are used. Compared with dry blending of ingredients and wet granulation method, tablets can be produced without tableting trouble, and the hardness required for practical use of the produced tablets (specifically, tablet hardness is preferably 3 to 20 kgf, more preferably 5 to 15 kgf), it can be provided with breakage resistance such that it is not easily damaged by removal from the PTP package or carrying.

  Hereinafter, the contents of the present invention will be specifically described using the following experimental examples. However, the present invention is not limited to these experimental examples. In the following experimental examples, “%” means “mass%” and “part” means “part by mass” unless otherwise specified.

Experimental example 1
(1) Preparation of test sample (see FIG. 1)
According to the prescription described in Table 1, 280 mg of 1 tablet, 12.7 mm of major axis, 5.8 mm of minor axis, and 5.2 mm thickness (test samples 1 to 5) were prepared.

Specifically, first, 1200.0 g (titer) of vancomycin hydrochloride was dissolved in 3.6 L of purified water, and this was dissolved in an intake air temperature of 85 using a fluidized bed granulator (FLO-5M: manufactured by Freund Sangyo Co., Ltd.). The mixture was granulated at 0 ° C. and dried until the exhaust temperature reached 50 ° C. to obtain a spray granulated product (step a). Next, the obtained granulated product was crushed and sized with a 20-mesh screen using a sizing machine (P104S: manufactured by Dalton Co., Ltd.) (step b). In 600 g of the obtained sized product, D mannitol, calcium silicate, and various disintegrants (crospopidone, primogell, croscarmellose Na) as excipients are listed in Table 1 in 280 mg of the final tablet. Were mixed using a twin blade type mixer (TBM-6: manufactured by Tokuju Seisakusho Co., Ltd.) (step c). Lubricant (magnesium stearate) is added to and mixed with the prepared granules, and then compressed and compressed with a rotary tableting machine (VIRG 0512SS2AZ, Kikusui Seisakusho) at a pressure of 0.5 to ¹ ton / cm ^2. By molding, 280 mg tablets containing 125 mg vancomycin hydrochloride as an active ingredient per tablet were obtained.

(2) Evaluation of test sample About each tablet (test sample 1-5) prepared by (1), tablet hardness and disintegration time were measured according to the following test method.

(2-1) Hardness test The hardness in the minor axis direction of each tablet was measured using a tablet breaking strength meter (TH1203MP, manufactured by Toyama Sangyo Co., Ltd.). The test was performed within 8 hours after the tablet to be measured was compressed and stored under conditions of room temperature and a relative humidity of 60% or less. Moreover, the test was done 5 times and the average value was calculated | required.

(2-2) Disintegration time Each tablet is tested based on the “disintegration test method” (test solution: water, no auxiliary plate) prescribed in the 15th revision of the Japanese Pharmacopoeia until the tablets disintegrate and disperse. Time was measured. In addition, when the residue of the sample was not recognized in the glass tube, or even if it was recognized, it was a spongy substance, or when the soft substance or the muddy substance became slight, the disintegration and dispersion were finished. The test was performed 5 times, and the average value was obtained.

  The results are also shown in Table 1. Table 1 shows the content (mg) of each component per tablet (280 mg).

  As can be seen from these results, when focusing on the two components of the porous material (silicate) and the disintegrant, the disintegration of the porous material alone (test sample 1) and the disintegrant alone (test sample 2) is 5 Even when two types of disintegrants are used in combination (test samples 4 and 5), the disintegration time is reduced, but disintegration still takes 3 minutes or more. On the other hand, it was confirmed that the disintegration time can be shortened within 1 minute with little influence on the tablet hardness by using a porous material and a disintegrant in combination (test sample 3: Example 1).

  As can be seen from these results, in tablets containing vancomycin or a salt thereof as an active ingredient, a combination of a porous substance (silicate) and a disintegrant is used to reduce the disintegration time without impairing tablet hardness (3 kgf or more). The tablet can be shortened (within 60 seconds) and excellent in hardness and disintegration.

Experimental example 2
(1) Preparation of test sample According to the formulation described in Table 2 in the same manner as described in Experimental Example 1 (1), 125 mg (44.6 mass) of vancomycin hydrochloride as an active ingredient per tablet (280 mg) %), About 127 mg (45.4 mass%) of D-mannitol as an excipient, 12.5 mg (4.5 mass%) of a porous substance (silicate), 14 mg (5 mass%) of various disintegrants, Tablets (test samples 6 to 9: Examples 2 to 5) having a major axis of 12.7 mm, a minor axis of 5.8 mm, and a thickness of 5.2 mm containing 1.4 mg (0.5% by mass) of the preparation were prepared.

(2) Evaluation of test sample About each tablet (test sample 6-9: Examples 2-5) prepared by (1), tablet hardness and disintegration time were measured according to the test method described in Experimental example 1 (2). .

  The results are also shown in Table 2. In Table 2, as in Table 1, the content (mg) of each component per tablet is described.

  As can be seen from this result, even if the type of disintegrant is changed, there is no significant change in tablet hardness and disintegration time. In tablets containing vancomycin salt as an active ingredient, a porous substance (silicate) and disintegrant are added. When used in combination, it was found that the disintegration time can be shortened (within 71 seconds) without impairing the tablet hardness (3 kgf or more), and a tablet excellent in hardness and disintegration can be prepared.

Experimental example 3
(1) Preparation of test sample In accordance with the formulation described in Table 3 in the same manner as described in Experimental Example 1 (1), 125 mg (44.6 mass) of vancomycin hydrochloride as an active ingredient per tablet (280 mg) %), About 77.1 to 133.3 mg (27.5 to 47.6% by mass) of D-mannitol as an excipient, 6.3 to 62.5 mg of porous material (silicic acid or silicate) (2 25 to 22.3 mass%), disintegrating agent (crospopidone) 14 mg (5 mass%), lubricant 1.4 mg (0.5 mass%), major axis 12.7 mm, minor axis 5.8 mm, Tablets having a thickness of 5.2 mm (test samples 10 to 14: Examples 6 to 10) were prepared.

(2) Evaluation of test sample About each tablet (test sample 10-14: Examples 6-10) prepared by (1), tablet hardness and disintegration time were measured according to the test method described in Experimental example 1 (2). .

  The results are also shown in Table 3. Table 3 shows the content (mg) of each component per tablet as in Table 1.

  As can be seen from this result, even if the disintegrant is constant and the type (silicic acid and silicate) and amount of the porous material are changed, there is no significant fluctuation in tablet hardness, and as the amount of porous material increases A tendency to shorten the decay time was observed. In addition, not only calcium silicate as a porous material but also light anhydrous silicic acid has been observed to have the same effect. It is considered to be a porous material such as acid or silicate.

  For tablets containing vancomycin salt as an active ingredient, use a combination of a porous substance (silicate or silicic acid) and a disintegrant to shorten the disintegration time without impairing tablet hardness (3 kgf or more). (Within 73 seconds), it was found that tablets with excellent hardness and disintegration can be prepared.

Experimental Example 4 Dissolution Test A dissolution test method according to the 15th revision of the Japanese Pharmacopoeia for tablets containing 125 mg and 250 mg of vancomycin hydrochloride, each of which has the composition described in Table 4 and was produced in the same manner as described in Experimental Example 1. The dissolution test was conducted based on the above.

<Test method>
The 125 mg and 250 mg tablets were each subjected to a dissolution test under the following five conditions using the paddle method.
(1) Dissolution test solution (pH 1.2, temperature 37 ± 0.5 ° C.), paddle rotation speed: 50 rotations / minute (2) Dissolution test solution (pH 4.0, temperature 37 ± 0.5 ° C.), paddle rotation Number: 50 revolutions / minute (3) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), Paddle rotation number: 50 revolutions / minute (4) Dissolution test solution (water, temperature 37 ± 0.5 ° C.) ), Paddle rotation speed: 50 rotations / minute (5) Dissolution test solution (pH 6.8, temperature 37 ± 0.5 ° C.), paddle rotation speed: 100 rotations / minute.

  The amount of vancomycin eluted was measured over time, and the ratio (dissolution rate%) in the total amount of tablets was calculated. The amount of vancomycin eluted was determined by measuring the absorbance at 280 nm of the elution test solution by an ultraviolet-visible absorbance measurement method. As a control test, a dissolution test was similarly performed using 0.5 mg (standard preparation) of vancomycin hydrochloride (manufactured by Eli Lilly Japan).

<Test results>
The results of dissolution tests performed on the 125 mg tablet (n = 12) and the standard preparation (n = 12) under the conditions (1) to (5) are shown in FIGS. 1 to 5, and the 250 mg tablet (n = 12) and The results of dissolution tests performed on the standard preparation (n = 12) under the conditions (1) to (5) are shown in FIGS. In addition, a result is shown as an average value of the dissolution rate of 12 tablets.

  As a result, the tablets of the present invention prepared by combining a spray granulated vancomycin with a silicic acid or a silicate and a disintegrant had a dissolution rate of almost 125 mg and 250 mg tablets 5 minutes after the start of the test. It was 85% or more and showed almost the same dissolution behavior as that of the standard preparation as a powder. From this, it was found that the preparation of the present invention is excellent not only in hardness and disintegration as shown in Experimental Examples 1 to 3, but also in dissolution.

Claims (6)

(1) spray-granulated vancomycin or a pharmaceutically acceptable salt thereof,
(2) silicic acid or a salt thereof,
(3) A tablet containing a disintegrant and (4) a lubricant. The tablet according to claim 1, having a hardness of 3 kgf or more and having a disintegration time of 80 seconds or less based on the disintegration test method stipulated in the 15th revision of the Japanese Pharmacopoeia. Silicic acid or its salt is light anhydrous silicic acid, heavy anhydrous silicic acid, hydrous silicon dioxide, hydrous amorphous silicon oxide, synthetic aluminum silicate, calcium silicate, magnesium silicate, hydrous magnesium silicate, magnesium aluminum silicate And the tablet according to claim 1 or 2, which is at least one selected from the group consisting of magnesium aluminate metasilicate. The disintegrant is at least one selected from the group consisting of cellulose, cellulose derivatives, crospovidone, hydroxypropyl starch, carboxymethyl starch, and salts thereof, according to any one of claims 1 to 3. tablet. (A) spray granulating vancomycin or a pharmaceutically acceptable salt thereof,
(B) a step of sizing the spray granule obtained above,
(C) a step of blending and mixing silicic acid or a salt thereof, and a disintegrant into the granulated product obtained above, and (d) a step of blending a lubricant with the mixture and tableting.
The method for producing a tablet according to claim 1, comprising: The production method according to claim 5, wherein the step (d) is a step of tableting the mixture containing the lubricant at a tableting pressure of 0.3 to 3 ton / cm ² .

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