JP2015096483A - Tablet with easy swallowing and dividing property - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a tablet containing levofloxacin of a high content which is not difficult to swallow actually, and also does not give an impression of difficulty of swallowing from the appearance.SOLUTION: The invention provides an elliptical tablet containing 500 mg of levofloxacin, and having a mass of 570-700 mg. The major axis/minor axis ratio is in a range of 2.00-2.50, the major axis is 14-18 mm, the hardness of the tablet is 30-300 N. The tablet has a cleavage line for division, and the area of the fracture surface of the tablet when it is divided by the cleavage line is 15-33 mm. The tablet is obtained by preparing granules containing levofloxacin, adding a lubricant to the granules and tableting, and applying film coating to the obtained uncoated tablet.

Description

  The present invention relates to a high content tablet of levofloxacin which is excellent in dosing and splitting properties.

  Levofloxacin is a quinolone synthetic antibacterial agent with excellent antibacterial activity and high safety. Levofloxacin is evaluated to be resistant to resistant bacteria, but the expression of resistant bacteria is still confirmed and increased (Non-patent Document 1).

  In Japan, levofloxacin has been applied to orally administer various infectious diseases since the launch in Japan: 100 mg once or twice a day or 200 mg once a day three times a day. It was. In recent years, the quinolone synthetic antibacterial drug has changed the way of thinking about the dosage and administration of quinolone from the viewpoint of obtaining an excellent therapeutic effect and at the same time suppressing the development of resistant bacteria. Dose is being recommended. For levofloxacin, except for Japan, the daily dosage of 500 mg or 750 mg was orally administered, but the dosage and dosage were reviewed in Japan, and after clinical trials, levofloxacin 500 mg Was approved for oral dosage once daily. Currently, two types of tablets, 500 mg tablets and 250 mg tablets, have been manufactured and sold since July 2009 as tablets containing a high content of levofloxacin (Non-patent Documents 1 and 2).

Cravit (registered trademark) 250 mg, Crabit (registered trademark) 500 mg, Crabit (registered trademark) fine granules 10%, interview form, March 2012 revised edition (8th edition) [I. Items related to the overview (Interview Forms 1 and 2); II. Items related to names (same, page 3); IV. Items related to pharmaceutical preparations (pages 8-11)] Cravit (registered trademark) tablets 250mg, Crabit (registered trademark) tablets 500mg, Crabit (registered trademark) fine granules 10%, package insert, revised November 2011 (7th edition)

  Tablets containing a high content of levofloxacin, especially 500 mg tablets, contain a large amount of the active ingredient, and the size of the tablets inevitably increases. Problems such as difficulty in taking large pills are likely to occur, and particularly elderly people are said to have a lower frequency of swallowing ability and more difficult to take than non-elderly people. In addition, even though it is not so difficult to swallow in practice, compliance due to the patient's abandonment of taking a dose due to the impression difficulty received from the appearance of the tablet, that is, the apparent difficulty of taking it, is psychologically strong. There is a concern that there will be a decrease in the number of patients, or that doctors will hesitate to prescribe, especially prescriptions for the elderly.

  Therefore, it is an object of the present invention to provide a tablet containing a high content of levofloxacin, which is not difficult to take when actually taken and does not give an impression that it is difficult to take from the appearance.

  In addition, because the dosage of levofloxacin is adjusted, even large tablets can be easily divided into tablets, and on the other hand, tablets with sufficient hardness not to cause cracks or chipping during production or transportation It is also an object of the present invention to provide

  The present inventors have improved the difficulty in taking conventional tablets containing 500 mg of levofloxacin, which has been manufactured and sold since July 2009, and do not give the impression that it is difficult to take from the appearance. Research was conducted with the aim of providing More specifically, the overall shape of the tablet is changed to achieve easy dosing, and it has good splitting properties. At the same time, tablet damage such as cracking and chipping occurs during manufacturing and transportation. In the present specification, a tablet containing 500 mg of levofloxacin may be abbreviated as “500 mg tablet”.

  In order to alleviate the difficulty of taking both the actual dose and the impression from the appearance, it is important to focus on the elliptical shape of the conventional 500mg tablet and reduce the area (projected area) of this elliptical surface. It is thought that it is effective in mitigating Increasing the tablet thickness is inevitable when the area of the elliptical shape is reduced, but according to the study by the present inventors, the projected area of the elliptical shape is reduced even when the tablet thickness is increased. In the 500mg tablet, difficulty of taking is reduced.

  On the other hand, tablets that cause cracking and chipping during production and transportation cause a decrease in productivity, and shape stability as products to be distributed to the market is impaired. . For example, the 500mg tablet released in July 2009 has little damage to the tablet such as cracks and chipping. Further, in this conventional tablet, a dividing line is provided on one side of the tablet surface so that it can be divided by hand, but it is possible to easily divide the tablet along the dividing line by applying light force by hand, At that time, the tablet does not collapse, and the tablet does not break at any place other than the secant line. Against this background, even with newly provided tablets with increased tablet thickness, it is possible to use a tablet with the same hardness as that of conventional tablets or by providing a dividing line with the same shape as conventional tablets. It seemed to be able to provide tablets that could be easily divided.

  However, it was found as a new problem that 500 mg tablets with increased tablet thickness are extremely difficult to perform manual division. This problem has been recognized for the first time by the present inventors. In order to solve this new problem, the present inventors have intensively studied the ease of dividing a tablet whose tablet thickness has increased, for example, the shape and depth of the secant provided on the tablet, but can be easily divided. However, the general rules for providing large tablets that do not crack or chip are not clear. As a result of further research, the inventors made, for example, the dividing line strength when dividing the tablet along the dividing line with a dividing line, and the fracture area for the specific range, etc. It has been found that the use of this means is extremely effective in the ease of division and suppression of tablet breakage. By appropriately adopting these means, it has become possible to provide a 500 mg tablet that is easy to take, does not easily crack or chip, and has excellent splitting properties. The present invention has been completed based on these findings.

That is, the present invention relates to each of the following.
[1] An easily splittable tablet containing 500 mg of levofloxacin, having a mass of 570 mg to 700 mg, a projected area on a plan view of 90 to 125 mm ² and a hardness of 30 to 300 N;
[2] The tablet according to [1], which has an elliptical shape;
[3] The tablet according to any one of [1] or [2], which is a tablet having a secant;
[4] The tablet according to any one of [1] to [3], wherein the major axis / minor axis ratio of the tablet is in the range of 2.00 to 2.50 and the major axis is 14 to 18 mm;
[5] The tablet according to any one of [1] to [3], wherein the major axis / minor axis ratio of the tablet is in the range of 2.00 to 2.20, and the major axis is 14 to 18 mm;
[6] The tablet according to [4] or [5], wherein the major axis is in the range of 15.0 to 18.0 mm;

[7] The tablet according to any one of [1] to [6], wherein the tablet has a fracture surface area of 15 to 33 mm ² when divided by a secant line;
[8] The tablet according to any one of [1] to [6], wherein the tablet has a fractured surface area of 20 to 33 mm ² when divided by a secant line;
[9] The tablet according to any one of [1] to [8], wherein the secant strength is 46 N or less;
[10] The tablet according to any one of [1] to [8], wherein the secant strength is 42 N or less;
[11] The tablet according to any one of [1] to [8], wherein the secant strength is in the range of 20 to 46N;
[12] The tablet according to any one of [1] to [8], wherein the secant strength is in the range of 20 to 42N;
[13] The tablet according to any one of [1] to [12], wherein the tablet has a hardness of 50 to 280 N;
[14] The tablet according to any one of [1] to [12], wherein the tablet has a hardness of 70 to 250 N;

[15] An elliptical tablet containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, the major axis / minor axis ratio is in the range of 2.00 to 2.50, the major axis is 14 to 18 mm, and the tablet hardness is A tablet having a dividing line for splitting and having a dividing line strength of 46 N or less;
[16] An elliptical tablet containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, the major axis / minor axis ratio is in the range of 2.00 to 2.20, the major axis is 14 to 18 mm, and the tablet hardness is A tablet having a dividing line for splitting and having a dividing line strength in the range of 20-42N;
[17] 500 mg of levofloxacin, 8.5-45.5 mg of crystalline cellulose, 38-49 mg of carmellose, 17-20 mg of hydroxypropylcellulose, and 24-27 mg of sodium stearyl fumarate, any one of [1] to [16] A tablet according to claim 1;
[18] The tablet according to any one of [1] to [16], containing 500 mg of levofloxacin, 45.5 mg of crystalline cellulose, 49 mg of carmellose, 20 mg of hydroxypropylcellulose, and 27 mg of sodium stearyl fumarate;
[19] Any of [1] to [18] obtained by preparing granules containing levofloxacin, adding a lubricant to the granules and compressing the tablets, and subjecting the resulting uncoated tablets to film coating The tablets described;
Etc.

  The levofloxacin 500 mg tablet of the present invention is visually smaller than the conventional tablet despite being a high-dose large tablet, so that the visual anxiety that it is difficult for patients to take It is characteristic that it is actually easy to swallow. In addition, as a means for facilitating the division, for example, by providing a dividing line, and further, for example, by setting the dividing line strength to a specific range, it is the same as a conventional tablet even though the tablet thickness is increased. Can be achieved. Therefore, the tablet of the present invention provided as a tablet that can be easily divided by appropriately adopting these means can be easily divided by hand, and other than tablet disintegration or secant There is also a feature that problems such as cracking and chipping do not occur. Further, since it has a sufficient tablet hardness, it does not cause tablet breakage problems such as cracks and chipping during storage and distribution.

The measuring method of secant strength using an autograph is shown. The relationship between secant strength and the splitting property of the sensory test is shown. The relationship between a fracture area and secant strength is shown.

The present invention is described in detail below.
The present invention relates to a tablet containing a high content of levofloxacin hydrate, but in particular to a tablet containing 500 mg of levofloxacin. Levofloxacin has the chemical name (3S) -9-fluoro-3-methyl-10- (4-methylpiperazin-1-yl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3 -de] [1,4] benzoxazine carboxylic acid. In this specification, the term “levofloxacin” means a free compound that is not a hydrate and does not contain any adduct other than water, and is defined as an INN (International Nonproprietary Name). The same definition is used. Although levofloxacin exists as a hydrate under normal conditions, levofloxacin hydrate and other solvates may be referred to generically, and may be referred to as “levofloxacin” as a generic name for compounds. .

  The main drug contained in the levofloxacin-containing tablets currently produced and sold is levofloxacin hydrate, which is a half hydrate of the above compound. The tablet of the present invention preferably contains 512.5 mg of levofloxacin hydrate, that is, levofloxacin hemihydrate as the main drug. The levofloxacin contained in the tablet of the present invention is preferably in a crystalline form, but amorphous levofloxacin or levofloxacin which is a mixture of amorphous and crystals may be used. Preferably, levofloxacin hemihydrate crystals can be used. 512.5 mg of this 1/2 hydrate corresponds to 500 mg of levofloxacin in terms of anhydride. The content of the levofloxacin may be increased or decreased within the allowable range when the tablet is actually manufactured. Therefore, all levofloxacin 500 mg tablets in such an allowable range are subject to the present invention. It is. In Japan, levofloxacin was approved in Japan for the first time as a 100mg tablet was approved, and in the present specification, "high content" means that the amount is higher than 100mg per tablet. .

  Tablets containing levofloxacin 500 mg (hereinafter referred to as “conventional product”) sold since July 2009 have an elliptical shape as the projected shape of the plan view, as is clear from the description in the package insert and interview form. It has a major axis of 18.2 mm, a minor axis of 8.2 mm, and a tablet thickness of about 5.0 mm. Levofloxacin 500 mg tablets are often provided to doctors and patients in a state where the shape of the ellipsoid can be seen and stored in a so-called PTP for each tablet. Therefore, the doctor or patient first makes an impression about the size of the tablet according to the size of the area of the ellipsoid visible from the PTP. In order to relieve the impression received from the “size of the ellipsoid”, it is effective to reduce the size of the ellipsoid that is first seen. For example, since the major axis of the conventional product is 18.2 mm, when the elliptical shape is the same as that of the conventional product, the value of the major axis is smaller than the conventional product, for example, in the range of 14 mm to 18.0 mm. The impression that it is a tablet can be given. As for the minor axis, for example, the major axis / minor axis ratio may be in the range of 2.00 to 2.50, more preferably in the range of 2.00 to 2.20.

  Reducing the area of the ellipsoid will affect the lock thickness. The reduction in the area of the ellipsoid increases the tablet thickness unless the tablet component composition is changed. The tablet thickness is the height of the tablet in the side view of the tablet. In order to give an impression that the tablet is small, it is possible to reduce the area of the ellipsoid by increasing the tablet thickness. However, there is a concern that tablets with extremely thick tablets will deteriorate the actual dose and that the apparent dose will also deteriorate because the tablets are nearly spherical. Therefore, it is necessary to set an appropriate value as the tablet thickness.

  From such a point of view, when adopting an elliptical shape as the tablet shape, as a tablet in which the major axis and minor axis and the tablet thickness are appropriately balanced, for example, the major axis is 16.2 mm and the major axis / minor axis ratio is 2.05. A degree tablet can be selected. If it is a tablet of this shape and size, it will give the impression that it is a miniaturized tablet, and the actual ingestion can be improved. As the shape of the tablet of the present invention, the projected shape of the plan view is preferably an elliptical shape, and the major axis value is preferably in the range of 14 mm to 18.0 mm, more preferably in the range of 15.0 mm to 18.0 mm. More preferably, it is in the range of 15.2 mm to 17.2 mm (16.2 mm ± 1 mm), and the major axis / minor axis ratio is in the range of 2.00 to 2.10, preferably about 2.05. Hereinafter, specific tablets having this shape and size (hereinafter sometimes referred to as “tablets of the present invention”) will be described in more detail. The shape and size of the tablets of the present invention are described above. It is not limited to things. Incidentally, among the tablets of the present invention, a placebo tablet was prepared for two types of tablets and a conventional product having a major axis of 16.2 mm and a major axis / minor axis ratio of 2.05, and sensory evaluation of ingestion in several subjects As a result, it was revealed that the tablet of the present invention is superior in dosage, and it was confirmed that excellent dosage can be achieved with this shape and size.

For the elliptical tablet of the present invention having a major axis of 16.2 mm and a major axis / minor axis ratio of 2.05, the projected area of the projected shape of the plan view of the ellipse was about 11.2 mm ² . Therefore, the tablet of the present invention may have a projected area in the range of 90 to 125 mm ² , more preferably in the range of 100 to 116 mm ² , and a tablet having a projected area in these ranges. If there is, it is possible to provide good dosage. Note that the calculation of the projected area can be obtained by employing the method described later. This “projection shape of plan view” is a shape that can be grasped when observed from the upper surface (or the lower surface) so that the elliptical shape of the tablet can be confirmed. It is the direction that can observe only at the same time. For example, three types of tablets are listed in Table 2, and among these, the shapes described at the left end and the center are shown. Of the tablet shapes in the table, the shape shown at the right end is the shape when the tablet is observed from the side so that only the long diameter and the tablet thickness can be grasped. "Thickness" is the thickness of the tablet, and is often described with the value of the thickest part of the tablet, that is, the maximum value.

  In the present specification, the term “elliptical shape” means that the projected shape of the plan view of the tablet is an elliptical shape, but this elliptical term naturally includes an ellipse based on a geometric definition. In addition to the shape of a conventional product and a shape called an ellipse in this field, for example, a shape obtained by changing four corners of a rectangle into an arc, and the like are also included. Therefore, the term oval must be interpreted in the broadest sense, including a wider range of shapes than the geometric definition, and should not be interpreted in any way restrictive.

  Moreover, the shape which can be employ | adopted for the levofloxacin 500 mg containing tablet of this invention is not limited to the above ellipse shape, There will be no restriction | limiting in particular if it is a shape which is not circular. For example, a rhombus can be adopted. Needless to say, the term rhombus includes a shape whose corner is changed to an arc due to a manufacturing problem. Such a shape to which changes obvious to those skilled in the art are added is also included in the tablet shape of the present invention.

  Furthermore, regarding the circular tablet, the shape of the tablet called a circle as a whole is a shape that can be recognized as a thin cylindrical shape or a disk shape, It is expressed as a rectangle (quadrangle), and usually refers to a circular projection surface from the upper surface. Further, even though it is cylindrical, it may be chamfered from the viewpoint of manufacturing. In the present specification, the “non-circular shape” means not having a circular shape as described above.

  Among the tablets of the present invention, in the case of an elliptical tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05, for example, the formulations shown in Table 1 can be adopted, and the following formulation 1 is particularly preferred. Although it is preferable, it is not limited to this prescription, and it goes without saying that those skilled in the art can make appropriate changes and modifications to the components and blending amounts. For example, each component can be appropriately increased or decreased within the range of the amounts shown in Formula 1 and Formula 2, and each component can be increased appropriately within a range not exceeding 700 mg in total.

  The production of the tablet employing the above formulation is not particularly limited. For example, first, levofloxacin-containing granules are granulated, and a lubricant is added to the granules to obtain tablets to obtain plain tablets. It can carry out by the process of applying a film coating to the uncoated tablet.

  That is, an excipient such as crystalline cellulose and a disintegrant such as carmellose are added to the drug substance levofloxacin hydrate and mixed. This mixture is granulated, for example using a fluidized bed granulator / dryer, with the binder added. Examples of the binder include hydroxypropyl cellulose, which can be sprayed as an aqueous solution and granulated. After granulation, it can be dried, and the resulting dried product can be granulated to produce granules.

  Next, a lubricant, such as sodium stearyl fumarate, is added and mixed using, for example, a V-type mixer to prepare tablet granules. Thereafter, tableting is performed. For example, the tablet granule can be tableted by a rotary tableting machine to produce a tablet. Furthermore, the obtained tablet can be film-coated to obtain a levofloxacin 500 mg tablet as a film-coated tablet.

  In addition to the above-described methods, other methods usually performed in this field can be adopted for the above-described granule production process, tableting process, and film coating process. For example, stirring granulation and dry granulation can be employed in the granule production process.

  Moreover, about each component to add, it can select and mix | blend from what is normally used in this field | area. Examples of excipients include lactose hydrate, mannitol, corn starch and the like in addition to crystalline cellulose. Examples of the disintegrant include crospovidone, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, and the like, in addition to carmellose. Examples of the binder include hypromellose, polyvinyl alcohol, polyvinyl pyrrolidone and the like in addition to hydroxypropylcellulose. Examples of the lubricant include magnesium stearate and calcium stearate in addition to sodium stearyl fumarate. As the coating agent, hypromellose, titanium oxide, talc, macrogol, polyvinyl alcohol and the like may be used in combination. Furthermore, yellow iron sesquioxide and iron sesquioxide can also be added as a colorant during coating.

  Thus, the levofloxacin 500 mg-containing tablet of the present invention can be obtained, and the mass of the tablet of the present invention may be 570 mg to 700 mg, more preferably 600 mg to 700 mg. As a preferable formulation included in this weight range, the above Formula 1 and Formula 2 can be mentioned.

  Further, the tablet of the present invention thus obtained, for example, an elliptical tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05, has the composition of Formula 1 or Formula 2 of Table 1. A tablet obtained by tableting / coating the granules preferably has sufficient hardness. The hardness of the tablet may be, for example, 30N or more, preferably 50N or more, more preferably in the range of 30 to 300N, still more preferably in the range of 50 to 280N, and even more preferably in the range of 70 to 250N. It is a range.

  The tablets of the present invention are preferably provided as easily splittable tablets. As used herein, “dividing” means preparing a plurality of, preferably two, partial tablets by dividing one tablet under stress. Further, in the present specification, "easible to divide" or a synonym thereof can be divided only by a human hand (finger) without using a tablet dividing device or device when dividing the tablet, It means that it can be divided without applying a particularly large stress. As a means for that, for example, a secant can be provided in the tablet of the present invention. Although the dividing line is not essential in the tablet of the present invention, it is generally preferable to provide a dividing line.

  The “secant” is provided on the surface of the tablet, preferably on one side of the elliptical surface or back surface, or on both sides of the front surface and back surface as necessary to facilitate the division of the tablet. Is a dent extending straight. As the cross-sectional shape of the depression, a triangle is generally adopted, but other shapes such as a square, a rectangle, or a semicircle may be used. In addition, the cross-sectional shape of a hollow is a shape observed as a hollow in the part which should be divided | segmented in the cross section cut | disconnected along the major axis of a tablet, A triangle can mention wedge shape, V shape, etc. as a synonym. The cross-sectional shape may be constant or may be appropriately changed depending on the surface shape of the tablet, but is not particularly limited.

The conventional product has a straight line with a triangular section as shown in Table 2 below (excerpt from the interview form) so that it can be divided into two parts. Can be easily divided along this secant line. In addition, the projection area of the projection shape of the elliptical plan view is about 128.8mm ² ; the secant shape is a triangle, the angle is 90 °, and the depth of the secant is about 0.42mm (Type E secant in Table 3) 1).

  However, in the case of preparing an elliptical tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05 according to the above-mentioned prescription 1, the same scored tablet as the conventional product (examples in the examples of the present specification) In the case of preparing a tablet indicated as 9 for comparison, which may hereinafter be referred to as the tablet of “Example 9”), there are cases where the splitting performance is not sufficient. In other words, in the sensory evaluation regarding the splitting performance of the tablets prepared in this way, most of the evaluations have an evaluation score of “Does not break even if force is applied” or “Cannot be split unless force is applied”. It was found that it was not suitable as a product (Table 10). The conventional product has a "shallow and narrow secant" on one side, that is, the secant shown as type 1 in Table 2 is applied only on one side (Table 3). The shape of this secant is directly adopted for the tablet of the present invention. That is not preferable.

  Of the tablets of the present invention, an elliptical tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05 and having the composition of Formula 1 or Formula 2 is provided on at least one side or both sides of the tablet. Tablets with the secant shown in the above were prepared and their splitting performance was examined.

  The result is an elliptical tablet with a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05. In the case of a tablet of the composition of prescription 1, both sides are the same in the case of type 2 and type 3 secant. Or a tablet given in combination with each other, or in the case of 4. type secant, only on one side, or 4. if it is a secant tablet given in combination with type 2, 2. or 3. It turned out to be a tablet with excellent splitting properties. In the case of an oval tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05, and a tablet having the composition of Formula 2, even a tablet with only a 1. type dividing line on one side has improved splitting performance. It was also found to be excellent.

  The splitting performance shown above is based on the results of human sensory tests. That is, it is the result of evaluating the ease of cracking and the difficulty of cracking by actually dividing a tablet with various secant lines by a human hand. Set a score of 6 levels for this evaluation [5: Divide without much effort; 4: Divide with slight effort; 3: Divide with little effort; 2: With effort Splitting is possible: 1: Cannot be split without significant effort; 0: Does not break even with effort.] Based on this score, splitting characteristics were evaluated.

  Paying attention to the situation of the dividing performance of each tablet, measure the size of the input required for dividing at the secant part, and the relationship between the type of the dividing line and the input strength required for the tablet with the scored line. investigated. An autograph (manufactured by SHIMADZU), which is a test force measuring device, was used as an input device in order to measure the input intensity necessary for dividing at the secant part (hereinafter referred to as “secant intensity”). During the measurement, two foundations are placed facing each other at a certain distance to reproduce the situation when the human splits. The distance between the two bases is set so that the end surface of the long diameter of the tablet is placed at 1 mm or 1.5 mm from the end of the base. In this method, a tablet is placed so as to straddle the two bases installed in this way, and a load is applied with an autograph scissors to measure the input strength at the time of fracture. By this method, it is possible to measure the strength based on the dividing line applied to the surface on the opposite side to the surface in contact with the tablet and the dividing line on the side not in contact with the tablet when there are a plurality of dividing lines. The unit of the intensity value when measured by the test force measuring device is Newton (N).

  From the secant strength data thus obtained, the secant strength of the tablet of Example 9, ie, the tablet with insufficient splitting performance, was 54.2N. On the other hand, in each tablet of the present invention having excellent splitting performance, the secant strength showed a value of 30.9N to 44.0N. That is, it is determined that a tablet having a dividing line with excellent dividing characteristics may be any tablet whose strength at the dividing line is about 46 N or less. Furthermore, the more preferable secant strength should just be 42N or less.

  When the secant strength is within the above range, if the hardness of the tablet itself is low, the strength of the whole tablet is lowered, so that the splitting performance may be improved. However, tablets with low hardness may easily cause tablet breakage such as cracking or chipping during production or transportation, thereby reducing the production efficiency and reducing the stability of the product shape. Therefore, the tablet of the present invention needs to have sufficient hardness. Usually, it is considered that such a problem hardly occurs if the hardness of the tablet is 30 N or more, and more preferably 50 N or more. The tablet hardness can be generally measured using a tablet hardness meter, but the hardness of the tablet of the present invention may be 30N or more, preferably 50N or more, more preferably in the range of 30 to 300N. More preferably, it is in the range of 50 to 280N. Within this range, it is more preferably 70 to 250N.

From the above viewpoint, the secant strength in the tablet of the present invention should be set together with the tablet hardness, but when selecting the above range as the tablet hardness, the secant strength may be 20 N or more, and the preferred range is 20 to 46N, more preferably in the range of 20-42N.
Examples of combinations of secant strength and tablet hardness include the following combinations:
The secant strength is 20N or more, and the tablet hardness is 30N or more,
Preferably, the secant strength is 20N or more, and the tablet hardness is in the range of 30 to 300N,
Furthermore, the secant strength is 20N or more, and the tablet hardness is in the range of 50 to 280N,
And when the secant strength is 20N or more and the tablet hardness is in the range of 70 to 250N;
More preferably, the secant strength is in the range of 20 to 46N, and the tablet hardness is in the range of 30 to 300N,
Furthermore, the secant strength is in the range of 20 to 46N, and the tablet hardness is in the range of 50 to 280N,
Further, when the secant strength is in the range of 20 to 46 N and the tablet hardness is in the range of 70 to 250 N; and particularly preferably, the secant strength is in the range of 20 to 42 N and the tablet hardness is in the range of 30 to 300 N. Yes,
Furthermore, the secant strength is in the range of 20-42N, and the tablet hardness is in the range of 50-280N,
Furthermore, the case where the secant strength is in the range of 20 to 42 N and the tablet hardness is in the range of 70 to 250 N can be exemplified, but it is not limited thereto.

In addition, it is considered that the secant strength of the tablet is important in terms of the area of the fractured surface when divided along the secant (hereinafter referred to as “breaking area”). This fractured surface is a part where two divided pieces are joined, and when this area is a specific value, excellent dividing performance can be obtained. The fracture area of the tablet of the present invention that gives good splitting performance is, for example, 15 to 33 mm ² , more preferably the area of the fracture surface is 20 to 33 mm ² . In the tablet of Example 9 in which the division performance is poor, the area of the fracture surface is 35.40 mm ² . The area of the fracture surface can be calculated by taking a fracture surface drawn by CAD based on the measured dimensions of each part of the divided tablet into a computer with a microscope and measuring the area.

On the other hand, in the case of a tablet without a score line, that is, an elliptical tablet with a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05, and a non-secant tablet in the case of a tablet of the composition of Formula 1, the central point of the major axis The area of the cross section in the minor axis direction was about 36.7 mm ² . Therefore, the fracture area relative to the cross-sectional area of the scored tablet corresponded to about 55% to 89%. That is, the fracture area of the scored tablet may be in the range of 50 to 90% of the cross-sectional area of the same-shaped scored tablet. If this is shown by the reduction rate of the cross-sectional area, it is in the range of 10 to 50%.

  Since a good correlation is observed when the score between the secant strength and the score in the sensory test, and the correlation between the fracture area and the secant strength is obtained, in order to provide the tablet of the present invention having excellent splitting characteristics, What is necessary is just to set the fracture | rupture area of the tablet at the time of dividing | segmenting into said range. Therefore, there is no need to consider any particular restrictions on the cross-sectional shape and length of the dividing line applied to obtain a fracture area in this range, or the dividing line shape, such as which side of the tablet the dividing line is applied to. That is, the degree of freedom of design regarding the dividing line is high, and various dividing lines can be employed.

For example, the secant shown in Table 3, but the secant design is based on the American Pharmacists Association classification method (TABLETING SPECIFICATION MANUAL, 2006, 7th edition, p.69; published by American Pharmasis Association) Employs a design classified as E or D. Table 3 shows that the angle of the secant line is set to 90 ° at which the planes constituting the secant line intersect, and the depth shown in the figure is adopted from the end face of the tablet. In addition, from the point of tablet splitting performance, it has been found that if the angle of the secant is in the range of 30 ° to 120 °, a tablet with excellent splitting performance can be obtained, but preferably 30 to 90 °. Range. Moreover, the depth of the dividing line should just be the range of 0.4 mm to 2 mm. Preferably, it may be in the range of 0.7 mm to 1.5 mm.
The specific shape of these secant lines, i.e., design, angle, and depth, will affect tablet splitting performance, but it will also be necessary to consider factors other than splitting performance such as tablet manufacturing factors. .

In the case of an elliptical tablet having the composition of Formula 1 in Table 1 of the present invention, the major axis is about 16.2 mm, the minor axis is about 7.9 mm, and the tablet thickness is about 5.6 mm. It is preferably applied to both sides and the fracture area is about 24 mm ² . An example of such a tablet is shown in Table 4 below. In this tablet, the projected area of the ellipsoidal plan view is about 111.2 mm ² ; the secant shape is a triangle, the angle is 90 ° (right isosceles triangle), the depth of the secant is about 1.2 mm on both sides Has been granted. Furthermore, the tablet hardness is 225 N, the secant strength is 40.7 N, and the breaking area is about 23.97 mm ² .

  The various dimensions mentioned in this specification, particularly the dimensions related to the size of the tablet, are defined by the tool used for tableting, and the error of the dimension generated in the manufactured tablet is generally However, an error of about 0.1 to 0.2 mm, preferably 0.1 mm or less, more preferably 0.05 mm or less is allowed.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[Evaluation of sensory properties for taking 500mg tablets]
(1) Preparation of 500 mg placebo tablets:
With regard to levofloxacin 500mg tablet, the conventional product shape (major axis: 18.2mm, by the same formulation and manufacturing method) except that lactose hydrate (512.5mg) is blended instead of levofloxacin hydrate (512.5mg) which is the active ingredient Two types of placebo tablets that have a preferred shape (long diameter: 16.2 mm, short diameter: 7.9 mm, lock thickness: about 5.6 mm) among the tablets of the present invention (short diameter: 8.2 mm, tablet thickness: about 5.0 mm) Was prepared.

(2) Have 6 subjects, 4 males and 2 females, take the above two types of placebo tablets, and determine which of the following scores applies to each tablet. investigated. The numbers in parentheses shown for each are evaluation points.

Evaluation criteria:
We were able to take without problem [3]
It was difficult to take a little, but was able to take [2]
It was quite difficult to take, but was able to take [1]
I could not take [0]

As a result, in placebo tablets in the form of this tablet,
Can take without problems: 3 people
Slightly difficult to take but could take: 2 people
It was quite difficult to take, but I was able to take it.

On the other hand, in the placebo tablet of the conventional product shape,
Can take without problems: 1 person
Slightly difficult to take but able to take: 4 people
It was quite difficult to take, but I was able to take it.

In other words, the number of evaluators who rated “It was difficult to take a little but was able to take” was the same as the number of five. On the other hand, the number of evaluators who said that they were able to take it without any problems, which was the highest level of evaluation, was 1 for the conventional placebo tablet, but increased significantly to 3 for the placebo tablet in the form of this tablet. did. Furthermore, the number of evaluators who said that “it was difficult to take a little but was able to take” was 4 in the case of the placebo tablet in the conventional product form, but decreased to 2 in the placebo tablet in the form of this tablet. The rating of “difficult” has decreased.
From the above results, it was shown that the tablet of the present invention has a good dosage.
The average evaluation score was “2.0” for the conventional product shape and “2.4” for the tablet shape of the present invention, which was a higher evaluation value.

[Examples 1 to 7]
Based on the formulations of Examples 1 to 7 shown in Table 5, tablets containing 500 mg of levofloxacin having the secant shown in Table 6 were prepared. That is, levofloxacin hydrate (Daiichi Sankyo Propharma Co., Ltd.), crystalline cellulose (Theolas PH-101, Asahi Kasei Chemicals), carmellose (NS-300, Nichirin Chemical Industries) was fluidized bed granulator (FLO) -120, Freund Sangyo), and granulated by spraying an aqueous solution of 6% hydroxypropylcellulose (Nippon Soda) separately prepared. After granulation, the product was sufficiently dried, and the resulting dried product was sized with a sanitary lead dresser (Asano Iron Works) to produce granules. To this granule, sodium stearyl fumarate (Nissei Chemical Industry) was added and mixed with a V-type mixer (V-600) to prepare granules for tablets. Thereafter, the granules for tableting were tableted with a rotary tableting machine using a punch having a score line shown in Table 6 to produce tablets. The obtained tablets were film-coated with a dispersion of OPADRY 01F43013 (Nihon Colorcon) using a high coater mini (Freund Sangyo) to prepare tablets of Examples 1-7. The tablet of Example 7 has the same shape as the conventional tablet shown in Table 2.

[Example 8]
According to the formulation of Example 8 in Table 5, tableting was performed with a scissors having a secant shown in Table 6 in the same manner as in Examples 1 to 7 to produce tablets. The obtained tablets were film-coated with a dispersion of OPADRY 01F430001 (Nihon Colorcon) using Hicoater Mini (Freund Sangyo) to prepare the tablets of Example 8.

[Example 9]
Based on the formulation of Example 9 in Table 5, tableting was performed with a punch shown in Table 6 in the same manner as in Examples 1 to 7 to produce tablets. The obtained tablets were film-coated with a dispersion of OPADRY 01F43013 (Nihon Colorcon) using Hicoater Mini (Freund Sangyo) to prepare the tablets of Example 9.

  Table 6 shows the secant shape used for the study. Each of the scissors with the secant shown in this table was produced (Ichibashi Seiki Co., Ltd.), and tablets with different fracture areas were produced by variously combining the upper and lower punches.

[Measurement Example 1] Measurement of fracture area The produced tablet is divided along the score line, and the area of the obtained cross section is defined as the fracture area. Based on the measured dimensions of each part of the divided tablets, a fracture surface was drawn by CAD, and the fractured surface was taken into a computer with a microscope and area measurement was performed to calculate the fracture area. Table 7 shows the measurement results of the break area when dividing each of the tablets having the combination of the secant shapes shown in Table 6 at the secant part, and Table 8 shows the results of Example 9.

[Measurement Example 2] Resolution (human sensory test)
The splitting property was evaluated by selecting the ease of splitting based on the criteria (score) shown below when the subject placed the thumb on the opposite side of the dividing line and pushed the dividing line apart. When there were secant lines on both sides of the tablet, both sides were examined and the splitting ability due to the difference in secant line shape was evaluated. In addition, only one side was evaluated when the same dividing line was contained in both surfaces. There are a total of 10 subjects: 5 men (Subjects No. A to E) and 5 women (Subjects No. F to J).

Evaluation criteria
5: Can be divided without much effort
4: Can be divided with a little effort
3: Divided with some effort
2: Divided with effort
1: Cannot be divided without considerable effort
0: Does not break even when force is applied

  The results of resolution determined in the sensory test are shown in Table 9 for Examples 1 to 7 and in Table 10 for Example 9.

[Measurement Example 3] secant strength using autograph As shown in Fig. 1, using autograph (SHIMADZU), load is applied at a compression speed of 10 mm / min, and the maximum load when the tablet is broken is the secant strength. (Average value of 3 tablets). The distance from the tablet edge to the base edge was 1 mm for Examples 1-6, 8 and 9, and 1.5 mm for Example 7. (This distance is determined by the stability of the tablet at the time of measurement, and the tablet is stable. The shortest distance that can be fixed to is adopted.) Moreover, when the dividing line shape was different between the front and back of the tablet, the evaluation target dividing line surface was arranged below, and the measurement was performed on both sides. The results are shown in Table 11.

[Measurement Example 4] Tablet hardness Tablet hardness was measured with a tablet hardness meter (ERWEKA TBH20) (average value of 3 tablets). The measurement was performed such that a compressive force was applied in the major axis (major axis) direction of the tablet. The results for the tablets of Examples 1-8 of the present invention are shown in Table 11. The results for Example 9 are shown in Table 12. The hardness of the preparation of the present invention was 206 to 235N, and it was confirmed that all tablets had a hardness that caused no problem in distribution.

[Relationship between secant strength and sensory test resolution]
The relationship between the secant strength of the tablets of Examples 1 to 7 and Example 9 and the resolvability of the sensory test is shown in FIG. A good correlation was observed between them, and it was revealed that the tablet was separable if the secant strength was 46 N or less.

[Break area and secant strength]
Next, the secant strength was plotted against the fracture area, and the results are shown in FIG. When the fracture area was 33 mm ² or less, the secant strength was below 46 N, indicating that the splitting property was good.

[Ratio of break area of tablet with scored line to tablet without score line]
The tablet of Examples 1 to 8 having no secant, that is, an oval tablet having a major axis of 16.2 mm and a major axis / minor axis ratio of about 2.05, and a tablet having the composition of Formula 1 In the case of tablets, the area of the cross section in the minor axis direction at the center point of the major axis was calculated by a computer and found to be about 36.73 mm ² . Based on this, the ratio of the break area of the scored tablet to the cross-sectional area of the scored tablet for the break areas of the tablets of Examples 1 to 8 is shown in Table 13.

  Although the tablet of the present invention is a large tablet with a high content, it is visually reduced in size as compared with the conventional tablet, and does not give a visual anxiety that it is difficult for patients to take, Since it is actually easy to swallow, patient compliance can be improved. In addition, since the tablet can be easily divided, the dosage can be easily adjusted. On the other hand, the tablet has sufficient hardness so that it does not crack or chip during production or transportation. It has been avoided.

Claims (3)

An elliptical tablet containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, the major axis / minor axis ratio is in the range of 2.00 to 2.50, the major axis is 14 to 18 mm, and the tablet hardness is 30 to 300 N A tablet having a dividing line for dividing and having a tablet fracture surface area of 15 to 33 mm ² when divided by the dividing line. An elliptical tablet containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, the major axis / minor axis ratio is in the range of 2.00 to 2.20, the major axis is 14 to 18 mm, and the tablet hardness is 50 to 280 N A tablet having a dividing line for dividing and having a tablet fracture surface area of 20 to 33 mm ² when divided by the dividing line. The tablet according to claim 1 or 2, which is obtained by preparing granules containing levofloxacin, adding a lubricant to the granules and compressing the tablets, and subjecting the resulting uncoated tablets to film coating.

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