JP6160813B2 - High content levofloxacin tablets - Google Patents

Description

  The present invention relates to a miniaturized levofloxacin tablet containing a high content of levofloxacin, an antibacterial drug, and having improved dosing properties.

  Levofloxacin is a new quinolone antibacterial agent that is widely used for various infections including respiratory infections and has been highly evaluated for its effects. However, with the promotion of the use of antibacterial drugs, the emergence of resistant bacteria has become a problem. As the development of new antibacterial agents is not easy, it is a challenge for the future of infectious disease treatment to appropriately use useful antibacterial agents and suppress the emergence of resistant bacteria.

  From this point of view, a high-dose formulation (preparation containing 250 mg and 500 mg as levofloxacin anhydride) was developed for levofloxacin for the purpose of suppressing the appearance of resistant bacteria based on the PK / PD theory. However, it is suggested that the enlargement of the tablet accompanying the increase in the dosage may impair the ease of swallowing of the patient to be treated and reduce the compliance. Decreasing medication compliance leads to reduced therapeutic effects and increased risk of resistant bacteria in antibacterial drugs. Therefore, improving the dosage by reducing the size of tablets is effective from the perspectives of treating infectious diseases and suppressing the appearance of resistant bacteria. It becomes a means.

  On the other hand, reducing the size of the tablet means reducing the amount of additives. In particular, in order to develop a tablet with a high content while reducing the size, the amount and type of additives that are important for molding the tablet are limited, so that the occurrence of tableting troubles during compression molding occurs, and the resulting tablet Problems such as degradation of the formulation function such as disintegration and dissolution properties of the product are likely to occur, making formulation difficult.

  The levofloxacin tablets that have been developed so far include tablets with a levofloxacin hydrate content of 60.4% by weight (Patent Document 1) and tablets with 78.4% by weight (Patent Document 2). , 3) are known. However, in Patent Document 1, in levofloxacin tablets containing pharmaceutical additives such as levofloxacin, a disintegrant, a binder and an excipient, a practical tablet hardness can be obtained simply by adjusting the amount of disintegrant and binder used. In addition, it is described that the drug release property cannot be obtained. Further, in Patent Documents 2 and 3, a tablet containing 512.5 mg of levofloxacin hydrate (500 mg as levofloxacin anhydride) corresponding to the maximum therapeutic dose using the formulation technique of 78.4% by weight corresponding to the highest content When the product is manufactured, its weight is as large as 654 mg, and it is desired to reduce the size of the tablet in order to improve the dosage.

JP2009-35505A JP2007-254461 JP 2008-150364 A

  An object of the present invention is to provide a novel miniaturized levofloxacin tablet containing a high content of levofloxacin for the purpose of improving the dosage of a high dose levofloxacin tablet.

  As a result of intensive studies to solve the above problems, the present inventor has completed a miniaturized levofloxacin tablet in which levofloxacin hydrate has a high content of 85% by weight or more based on the weight of the uncoated tablet. Furthermore, it has been found that this miniaturized levofloxacin tablet can improve the compression moldability even with a small amount of additive and can be made into a high-content formulation by using hydroxypropylmethylcellulose or methylcellulose as a binder. . And it discovered that the said formulation is a tablet excellent in practicality without the problem of tableting at the time of compression molding, and without the problem of the disintegration fall of the obtained tablet.

That is, the present invention
(1) A levofloxacin-containing tablet having a levofloxacin hydrate content of 85% by weight or more with respect to the uncoated tablet weight,
(2) The tablet according to (1) above, which contains hydroxypropylmethylcellulose or methylcellulose as a binder,
(3) The tablet of the above (2) containing less than 8% by weight of hydroxypropyl methylcellulose or methylcellulose based on the weight of the uncoated tablet,
(4) The tablet of any one of the above (1) to (3), wherein the content of levofloxacin hydrate relative to the weight of the uncoated tablet is 85 to 95% by weight,
(5) The tablet according to (4) above containing 2 to 6% by weight of hydroxypropyl methylcellulose or methylcellulose based on the weight of the uncoated tablet,
(6) The tablet according to (2) above, wherein the uncoated tablet is composed of 85% by weight or more of levofloxacin hydrate, hydroxypropylmethylcellulose or methylcellulose as a binder, a disintegrant and a lubricant, based on the uncoated tablet weight,
(7) The tablet according to (6), wherein the uncoated tablet further contains a fluidizing agent,
(8) The tablet according to any one of (1) to (7) above, which is produced by a fluidized bed granulation method.

  According to the present invention, it has become possible to provide a solid preparation with improved dosing for patients requiring treatment by downsizing levofloxacin tablets that require a high dose to suppress the emergence of resistant bacteria .

  The levofloxacin hydrate contained in the tablet of the present invention is preferably in the form of 1/2 hydrate.

  In order to reduce the size of the tablet, the content of levofloxacin with respect to the uncoated tablet weight is preferably 85% by weight or more, more preferably 85 to 95% by weight, and particularly preferably 85 to 90% by weight.

  Hydroxypropyl methylcellulose used as a binder in the present invention is a mixed ether of cellulose methyl and hydroxypropyl. Four grades 1828, 2208, 2906 and 2910 are known depending on the type of substitution. Especially, when manufacturing the tablet in this embodiment, the grade of 2208 or 2910 is more preferable.

  In order to reduce the size of the tablet, the content of hydroxypropylmethylcellulose with respect to the weight of the uncoated tablet is preferably less than 8% by weight, more preferably 2 to 8% by weight, and particularly preferably 2 to 6% by weight. preferable.

  The methyl cellulose used as a binder in the present invention is a methyl ether of cellulose. Especially, when manufacturing the tablet in this embodiment, the grade whose display viscosity is less than 600 mPa * s is more preferable.

  In order to reduce the size of the tablet, the content of methylcellulose relative to the weight of the uncoated tablet is preferably less than 8% by weight, more preferably 2 to 8% by weight, and particularly preferably 2 to 6% by weight.

In producing the tablet of the present invention, in addition to the binder, optionally an excipient, a disintegrant, a lubricant, a pH adjuster, a surfactant, a stabilizer, a sour agent, a fragrance, a fluidizing agent, etc. Can be used. However, it is preferable not to use or to use a small amount of optional additives in order to reduce the size of the tablet.
In the tablet of the present invention, levofloxacin hydrate, uncoated tablet consisting only of hydroxypropylmethylcellulose or methylcellulose as a binder, a disintegrant and a lubricant is preferable, and further an uncoated tablet containing a fluidizing agent, that is, levofloxacin hydrated The uncoated tablet which consists only of a product, the hydroxypropyl methylcellulose or methylcellulose as a binder, a disintegrating agent, a lubricant, and a fluidizing agent is more preferable.

  As used herein, “excipients” include lactose, sucrose, fructose, powdered reduced maltose starch syrup, glucose, trehalose, D-mannitol, xylitol, erythritol, D-sorbitol, xylitol, maltose, crystalline cellulose, dextrin, corn starch Potato starch, wheat starch, hydroxypropyl starch, pregelatinized starch, partially pregelatinized starch, calcium hydrogen phosphate, calcium dihydrogen phosphate, precipitated calcium carbonate, light anhydrous silicic acid, etc., especially lactose, corn starch, Mannitol or crystalline cellulose is preferred.

  In the present specification, examples of the “disintegrant” include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, partially pregelatinized starch, sodium starch glycolate, and the like. Hydroxypropyl cellulose and carmellose are preferable, and carmellose is particularly preferable. In order to reduce the size of the tablet, the content of the disintegrant relative to the weight of the uncoated tablet is preferably less than 8% by weight, more preferably 2 to 8% by weight, and particularly preferably 2 to 6% by weight. .

  In this specification, examples of the “lubricant” include stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated oil, sodium stearyl fumarate, sucrose fatty acid ester, and the like, and magnesium stearate or sodium stearyl fumarate is used. Particularly preferred is sodium stearyl fumarate. In order to reduce the size of the tablet, the content of the lubricant with respect to the weight of the uncoated tablet is preferably less than 6% by weight, more preferably 0.5 to 6% by weight, and 0.5 to 4% by weight. It is particularly preferred.

  Examples of the “pH adjusting agent” in the present specification include hydrochloric acid, citric acid, sodium citrate, acetic acid, tartaric acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, lactic acid and the like.

  Examples of the “surfactant” in the present specification include sodium lauryl sulfate, polyoxyethylene, polyoxypropylene, polysorbates and the like.

  Examples of the “stabilizer” in the present specification include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins.

  Examples of the “acidulant” in the present specification include citric acid, tartaric acid, malic acid, ascorbic acid and the like.

  Examples of “fragrance” in the present specification include menthol, mint oil, orange oil, lemon oil and the like.

  Examples of the “fluidizing agent” in the present specification include light anhydrous silicic acid and hydrous silicon dioxide, and light anhydrous silicic acid is particularly preferable. In order to reduce the size of the tablet, the content of the fluidizing agent relative to the weight of the uncoated tablet is preferably less than 4% by weight, more preferably 0.5 to 4% by weight, and 0.5 to 2% by weight. It is particularly preferred.

  Two or more of the above-mentioned additives may be mixed and used in an arbitrary ratio.

  When manufacturing the tablet in this embodiment, it is preferable to manufacture by a wet method. The wet method means a method including a drying step in the manufacturing process. As an example, it is a method of granulating using an appropriate solvent while mixing an active ingredient and an additive, drying the granulated product, and compression-molding to produce a tablet. If necessary, an additive can be further added to the obtained granulated product.

  When manufacturing the tablet in this embodiment, it is particularly preferable to manufacture by a fluidized bed granulation method. The fluidized bed granulation method includes all of the conventional techniques, but for example, “a method of granulating by forming a fluidized layer of a raw material powder by an air stream and spraying a binder solution while drying, Granulated by repeated spraying of solution and drying with hot air ”(Pharmacology (5th revised edition), Nanedo Co., Ltd., issued April 25, 1997).

In producing the tablet in the present embodiment, it is preferable to use hydroxypropyl methylcellulose or methylcellulose as a solution.
Examples of the solvent that can be used when preparing the solution include water, methanol, ethanol, 2-propanol, and the like, preferably water or ethanol, and more preferably a water / ethanol mixed solvent.

  The concentration of hydroxypropyl methylcellulose or methylcellulose in preparing the solution can be arbitrarily set, but is preferably 1 to 15 w / w%, more preferably 3 to 10 w / w%.

  The tablet in this embodiment may be a film-coated tablet with an appropriate coating agent. Examples of suitable coating agents include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, macrogol, titanium oxide, talc, carnauba wax and the like. The coating agent can also be colored by adding edible lake pigments such as edible yellow No. 5, edible red No. 2 and edible blue No. 2, ferric oxide, yellow ferric oxide.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, this invention is not limited by a following example.

435.6 g of levofloxacin hemihydrate and 27.2 g of carmellose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and hydroxypropyl methylcellulose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd., substitution degree type 2910). ) 17.2 g was dissolved in a mixed solvent of water / ethanol to make a solution of 343.4 g and granulated. The obtained granulated product was dried and sieved with a JIS 18 mesh sieve.
The obtained sized product was mixed with 5.3 g of magnesium stearate and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 571 mg tablets per tablet.

435.6 g of levofloxacin hemihydrate and 24.7 g of carmellose were introduced into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and hydroxypropylmethylcellulose (TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd., substitution degree type 2910). ) 19.4 g was dissolved in a water / ethanol mixed solvent to make 387.6 g, and granulated by spraying. The obtained granulated material was dried and sized with a sizing machine (Paulec: QC-197S).
4.8 g of magnesium stearate was mixed with the obtained sized product and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 570 mg tablets per tablet.

435.6 g of levofloxacin hemihydrate and 24.7 g of carmellose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and hydroxypropyl methylcellulose (SB-4, manufactured by Shin-Etsu Chemical Co., substitution degree type 2208). ) 19.4 g was dissolved in a water / ethanol mixed solvent to make 387.6 g, and granulated by spraying. The obtained granulated product was dried and sieved with a JIS 18 mesh sieve.
4.8 g of magnesium stearate was mixed with the obtained sized product and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 570 mg tablets per tablet.

435.6 g of levofloxacin hemihydrate and 24.9 g of carmellose are charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 19.4 g of methylcellulose (METOLOSE SM-4, manufactured by Shin-Etsu Chemical) is added to water. A solution made up to 387.6 g by dissolving in a mixed solvent of / ethanol was sprayed and granulated. The obtained granulated product was dried and sieved with a JIS 18 mesh sieve.
The obtained granulated product was mixed with 3.7 g of magnesium stearate and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 569 mg tablets per tablet.

5264.6 g of levofloxacin hemihydrate was put into a fluidized bed granulator (Freund Sangyo: FLO-5M type), and 238 g of hydroxypropyl methylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd., substitution degree type 2910) was added to water. A solution made up to 4760 g by dissolving in a mixed solvent of / ethanol was sprayed and granulated. The obtained granulated product was dried, 60 g of light anhydrous silicic acid was added, and the particle size was adjusted with a particle sizer (product of Paulek: QC-197S). The obtained sized product was mixed with 289.4 g of carmellose (NS-300) and 188 g of sodium stearyl fumarate, and compression-molded using a rotary tableting machine (manufactured by Hata Plant, HT-AP18 type). 295 mg tablets were obtained per tablet. Using 86 g of hydroxypropylmethylcellulose, 64 g of macrogol 6000, 20 g of titanium oxide, 19 g of talc, 1.4 g of yellow iron sesquioxide and 0.06 g of carnauba wax, the film coating was coated by a conventional method, and levofloxacin 1 / tablet Film-coated tablets having a dihydrate content of 256.2 mg and a tablet weight of 304 mg were obtained.

  5264.6 g of levofloxacin hemihydrate was put into a fluidized bed granulator (Freund Sangyo: FLO-5M type), and 238 g of hydroxypropyl methylcellulose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd., substitution degree type 2910) was added to water. A solution made up to 4760 g by dissolving in a mixed solvent of / ethanol was sprayed and granulated. The obtained granulated product was dried, 60 g of light anhydrous silicic acid was added, and the particle size was adjusted with a particle sizer (product of Paulek: QC-197S). The obtained sized product was mixed with 289.4 g of carmellose (NS-300) and 188 g of sodium stearyl fumarate, and compression-molded using a rotary tableting machine (manufactured by Hata Plant, HT-AP18 type). 590 mg tablets were obtained per tablet. 69 g of hydroxypropylmethylcellulose, 50 g of Macrogol 6000, 16 g of titanium oxide, 15 g of talc, 0.175 g of iron sesquioxide, 0.35 g of yellow iron sesquioxide and 0.06 g of carnauba wax, Film-coated tablets with a levofloxacin hemihydrate content of 512.5 mg and a tablet weight of 605 mg per tablet were obtained.

（比較例１）

(Comparative Example 1)

435.6 g of levofloxacin hemihydrate and 24.7 g of carmellose were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 19.4 g of polyvinylpyrrolidone (Prasdon K-29 / 32, manufactured by ISP). Was dissolved in water to make 387.6 g and granulated. The obtained granulated material was dried and sized with a sizing machine (Paulec: QC-197S).
4.8 g of magnesium stearate was mixed with the obtained sized product and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 570 mg tablets per tablet.

（比較例２）

(Comparative Example 2)

435.6 g of levofloxacin hemihydrate and 24.7 g of carmellose were put into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 19.4 g of hydroxypropyl cellulose (HPC-SSL, manufactured by Nippon Soda) was added. A solution obtained by dissolving in absolute ethanol to 387.6 g was sprayed and granulated. The obtained granulated material was dried and sized with a sizing machine (Paulec: QC-197S).
4.8 g of magnesium stearate was mixed with the obtained sized product and compression-molded using a rotary tableting machine (manufactured by Hata Seiko Co., Ltd .: HT-EX18 type) to obtain 570 mg tablets per tablet.

[Test example]
<Tablet obstruction, tablet hardness, disintegration time>
The tablets obtained in Examples and Comparative Examples were measured for tableting failure, tablet hardness, and disintegration time.
The hardness test was performed using a load cell type tablet hardness tester. The disintegration test was conducted according to the disintegration test method described in the 16th revision Japanese Pharmacopoeia using water as a test solution.
The test results are shown below.

-No tableting failure + Sticking occurred ++ Unable to tablet due to severe sticking

In the comparative example, the occurrence of tableting trouble was remarkable, but the tableting trouble did not occur in the preparation according to the present invention. Furthermore, the hardness of the tablet, the disintegration property in water, and the dissolution property were the same as those of the commercial product.
<Miniaturization of tablets>
A commercially available film-coated tablet containing 500 mg of levofloxacin in terms of anhydride has a major axis of 18.2 mm × minor axis of 8.2 mm, whereas the film-coated tablet of Example 6 of the present invention has a major axis of 15.5 mm × short The diameter is 6.8 mm. Moreover, in patent document 2, 3, when the weight of the uncoated tablet containing 500 mg of levofloxacin converted to an anhydride is 654 mg, the weight of the uncoated tablets of Examples 1 to 4 and Example 6 of the present invention is 569 to 590 mg. From these facts, the film-coated tablet and the plain tablet of the present invention have an effect of downsizing as compared with conventionally known tablets.

  According to the present invention, it is possible to obtain a miniaturized levofloxacin tablet with a high content that has never been obtained. This preparation is a tablet excellent in practicality, free from tableting problems during compression molding, and free from problems such as reduced disintegration of the obtained tablet.

Claims (7)

A levofloxacin-containing tablet having a levofloxacin hydrate content of 85% by weight or more based on the weight of an uncoated tablet, comprising hydroxypropylmethylcellulose or methylcellulose as a binder . Tablet of claim 1, wherein the uncoated tablet weight relative contains less than 8 wt% hydroxypropyl methylcellulose or methylcellulose. The tablet according to claim 1 or 2 , wherein the content of levofloxacin hydrate with respect to the weight of the uncoated tablet is 85 to 95% by weight. The tablet according to claim 3 , containing 2 to 6% by weight of hydroxypropyl methylcellulose or methylcellulose based on the weight of the uncoated tablet. Plain tablet is levofloxacin hydrate least 85% by weight relative to uncoated tablet weight, hydroxypropyl methylcellulose or methylcellulose as a binding agent, composed only of disintegrants and lubricants, tablet of claim 1, wherein. The tablet according to claim 1 , wherein the uncoated tablet is composed of 85% by weight or more of levofloxacin hydrate, hydroxypropyl methylcellulose or methylcellulose as a binder, a disintegrant, a lubricant, and a fluidizing agent . It manufactures by the fluidized-bed granulation method, The manufacturing method of the tablet of any one of Claims 1-6 characterized by the above-mentioned.