TW201402155A - Tablet having ingestion easiness and dividability - Google Patents

Abstract

A tablet which is easy to ingest, contains 500 mg of levofloxacin, has a mass of 570 to 700 mg, a projected area of 90 to 125 mm2 on a plan view and a hardness of 30 to 300 N, and can be divided easily.

Description

Lozenges with easy to take and split

The present invention relates to a high-content ingot of levofloxacin which is excellent in take-up and segmentation.

Levofloxacin is a synthetic quinolone synthetic antibacterial with excellent antibacterial activity and high safety. In addition, it was confirmed that levofloxacin was difficult to produce resistant bacteria, but even this was confirmed to increase the number of resistant bacteria (Non-Patent Document 1).

By oral administration of various infections of levofloxacin, in Japan, once 100 mg, once or twice, or once, 200 mg, once a day, 3 times, oral administration The dosage is applicable since its listing. In recent years, the use of quinolone-based synthetic antibacterial agents to obtain excellent therapeutic effects and at the same time inhibit the occurrence of resistant bacteria, and the change in the usage and dosage of quinolones has gradually recommended the use of high doses once a day. Dosage. Levofloxacin is administered in an amount of 500 mg or 750 mg per day in addition to Japan. The dosage and dosage are administered orally once, but in Japan, the usage and dosage are corrected. After clinical trial, it is approved once a day. With 500 mg of levofloxacin (Levofloxacin) usage and dosage. Now, as a lozenge containing a high content of levofloxacin, two kinds of tablets of 500 mg ingot or 250 mg ingot have been manufactured and sold since July 2009 (Non-Patent Documents 1 and 2).

Prior technical literature Non-patent literature

Non-patent document 1: CRAVIT (registered trademark) ingot 250mg, CRAVIT (registered trademark) ingot 500mg, CRAVIT (registered trademark) fine grain 10%, Interviewform, March 2012 revised edition (8th edition) [I. Summary related items (Interviewform, pages 1, 2); II. Name related items (ibid., p. 3); IV. Formulation related items (ibid., pp. 8-11)

Non-Patent Document 2: CRAVIT (registered trademark) ingot 250mg, CRAVIT (registered trademark) ingot 500mg, CRAVIT (registered trademark) fine grain 10%, attachment, revised in November 2011 (7th edition)

The high content of levofloxacin contains an ingot, and in particular, the blending amount of the main drug of 500 mg ingot is large, and the tablet is inevitably enlarged. Large-sized tablets are prone to problems such as difficulty in taking them, and in particular, the ability of the elderly to swallow is lowered, and the frequency of taking them is more difficult than that of non-aged people. In addition, even if it is not difficult to swallow, it is considered to be accepted by the appearance of the tablet. Difficulties in taking, that is, the difficulty of taking the appearance is psychologically strong, because the patient abandons taking it and the medical treatment is reduced or the doctor prescribes, especially for the prescription of the elderly, which is detrimental to the effective treatment of the infection. The situation.

Therefore, it is a subject of the present invention to provide a tablet containing a high content of levofloxacin, which is not difficult to take when it is actually taken, and which is not given an impression of difficulty in taking it.

In addition, in order to adjust the administration amount of levofloxacin, it is possible to provide a tablet having a sufficient hardness even if it is a large tablet, and can be easily divided into tablets, and on the other hand, without cracking or defect during production or handling. The agent is also a subject of the present invention.

The present inventors have made it difficult to take a tablet which contains a high content of 500 mg of levofloxacin, which has been manufactured and sold in July 2009, and which is not difficult to take. research. More specifically, it is an object to provide a lozenge which is easy to take into the shape of the tablet and which is easy to take, and which has good splitability and which can suppress the occurrence of cracks or defects during production or transportation. For review (hereinafter, the tablet containing 500 mg of levofloxacin in the present specification is sometimes referred to as "500 mg ingot").

In order to alleviate the difficulty of taking any of the actual taking and appearance impressions, focusing on the oval shape of the traditional 500mg ingot, it is considered to reduce this ellipse The area of the circular shaped surface (projected area) effectively alleviates the difficulty of taking. When the area of the ellipse is reduced, although the thickness of the ingot is inevitably increased, according to the study by the inventors of the present invention, even if the thickness of the ingot is increased, the 500 mg ingot having a reduced projected area of the ellipse is eased. Sex.

On the other hand, since the tablet which causes cracks or defects during production or transportation causes a decrease in productivity, the shape stability of the product which is distributed on the market is impaired, so a certain hardness or more is required as a tablet. For example, in the case of the 500 mg ingot sold in July 2009, the tablet or the like has less damage to the tablet. In addition, although the conventional tablet is designed with a dividing line on one surface of the surface of the tablet, it can be divided by hand, and the tablet can be easily divided along the dividing line by gently applying a force by hand, and there is no The tablet disintegrates or the tablet breaks outside the dividing line. From this background, it is considered that even if a new tablet having an increased ingot thickness is provided, it is possible to provide the hand with ease by making the same degree of tablet hardness as a conventional tablet or by designing a dividing line having the same shape as a conventional tablet. Separated lozenges.

However, it has been found that the new problem is that it is obviously difficult to divide the 500 mg ingot having an increased thickness of the ingot by hand. This problem is a problem that was originally recognized by the inventors. The inventors of the present invention have made an effort to review the ease of division of the tablet having an increased thickness of the ingot for solving the novel problem, for example, the shape or depth of the dividing line provided on the tablet, but to provide easy segmentation and non-occurrence The general rule for large lozenges that are broken or defective is not clear. As a result of further research by the present inventors, for example, by dividing a line, the dividing line intensity when the tablet is divided along the dividing line is within a specific range, and thus the breaking area is A means such as a specific range has been found to be extremely effective for facilitating the division and inhibiting the breakage of the tablet. By appropriately adopting such means, it is possible to provide a 500 mg ingot which is easy to take, is less prone to cracking or chipping, and is also excellent in segmentation. The present invention is based on such findings.

That is, the present invention relates to the following.

[1] Containing 500mg of levofloxacin, the mass is 570mg~700mg, the projected area on the plan is 90~125mm ² , and the tablet with easy hardness of 30~300N; [2] oval [1] The lozenge according to any one of [1] or [2], wherein the long diameter/short diameter ratio of the tablet is between 2.00 and 2.50. The long-diameter/short-diameter ratio of the [5] lozenge is in the range of 2.00 to 2.20, and the long diameter is 14~. a lozenge according to any one of [1] to [3]; [6] a long-diameter lozenge of [4] or [5] in the range of 15.0 to 18.0 mm; [7] The lozenge according to any one of [1] to [6], wherein the fracture surface area of the tablet is 15 to 33 mm ² ; [8] the fracture surface area of the tablet when divided by the dividing line is 20 to 33 mm ² of [1] to [6] of any one of claims lozenges; [9] parting line strength of 46N or less [1] to [8] according to any one of the lozenge; [10] dividing line intensity The lozenge according to any one of [1] to [8], wherein the separation line strength is in the range of 20 to 46 N, and the lozenge according to any one of [1] to [8]. [12] The strength of the dividing line is in the range of 20 to 42 N in the range of [1] to [8]; [13] the hardness of the tablet is 50 to 280 N [1] to [12] The tablet according to any one of [1] to [12]; [15] containing 500 mg of levofloxacin having a mass of 570 mg; ~700mg elliptical tablet, the long diameter / short diameter ratio is in the range of 2.00~2.50, the long diameter is 14~18mm, the hardness of the tablet is 30~300N, with the dividing line for segmentation, and the dividing line strength is 46N The following lozenges; [16] are lozenges containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg. The long diameter/short diameter ratio is in the range of 2.00 to 2.20, and the long diameter is 14 to 18 mm. The hardness is 50~280N, which has a dividing line for division, and the dividing line strength is in the range of 20~42N; [17] contains 500mg of levofloxacin, 8.5~45.5mg of crystalline cellulose, 38 ~49mg of carboxymethylcellulose (carmellose), 17~20mg of hydroxypropylcellulose and 24~27mg of sodium stearyl fumarate [1] to [16] a recorded ingot [18] containing 500 mg of levofloxacin, 45.5 mg of crystalline cellulose, 49 mg of carboxymethylcellulose (carmellose), 20 mg of hydroxypropylcellulose, and 27 mg of sodium succinate stearate The tablet according to any one of [1] to [16]; [19] preparing particles containing levofloxacin, adding a slip agent to the particles, performing ingot casting, and applying a film coating to the obtained ingot. The lozenge described in any one of [1] to [18];

The levofloxacin 500 mg ingot of the present invention is a large-sized lozenge of a high dosage, but because it is visually miniaturized as compared with a conventional lozenge, it is not visually disturbing to the patient, and actually Easy to swallow. Further, as means for facilitating the division, for example, by providing the dividing line and further, for example, by setting the dividing line intensity to a specific range, even if the ingot thickness is increased, the same dividing performance as that of the conventional tablet can be achieved. Therefore, the tablet of the present invention which is provided as an easily detachable tablet by appropriately adopting such means can easily divide the tablet by hand, and for the tablet division, there is also a so-called tablet disintegration or division. Characteristics of problems such as ruptures or defects outside the line. Further, since the tablet hardness is sufficient, the problem of breakage of the tablet such as cracking or chipping does not occur during storage or distribution.

[Fig. 1] shows the dividing line strength using an intensity tester (autograph) Method of measurement.

Fig. 2 shows the relationship between the strength of the dicing line and the severability of the functional test.

[Fig. 3] shows the relationship between the fracture area and the division line strength.

The best form for implementing the invention

The present invention will be described in detail below.

The present invention relates to lozenges containing high levels of levofloxacin hydrate, especially for lozenges containing 500 mg of levofloxacin. The chemical name of levofloxacin is: (3S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H -pyrido[1,2,3-de][1,4]-benzoxazinecarboxylic acid ((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 the present specification, the term "Levofloxacin" means a compound which is a non-hydrate and further contains no free form of an adduct other than water, and is used as an INN (International Nonproprietary Name). The stipulated person has the same definition. In addition, Levofloxacin is a hydrate in the normal state, but Levofloxacin hydrate or other solvate is sometimes referred to as a general name of the compound "Levofloxacin".

Levofloxacin, now sold, is sold The main drug contained in the ingot is levofloxacin hydrate, 1/2 hydrate of the above compound. The tablet of the present invention is preferably a levofloxacin hydrate containing 512.5 mg of a main drug, that is, a 1/2 hydrate of levofloxacin. The levofloxacin contained in the tablet of the present invention is preferably in a crystalline form, but an amorphous levofloxacin or a mixture of amorphous and crystalline levofloxacin may also be used. It is preferred to use a crystal of 1/2 hydrate of levofloxacin. 512.5 mg of this 1/2 hydrate is equivalent to 500 mg of levofloxacin in terms of anhydrate. Further, this content is naturally increased or decreased within the allowable range when the tablet is actually produced. Therefore, all of the levofloxacin 500 mg ingots in such a permissible range are all levofloxacin ingots to be used in the present invention. In addition, Levofloxacin (Levofloxacin) was first approved and manufactured in Japan, and the "high content" in this specification means a blending amount higher than 100 mg per one spindle.

A lozenge containing 500 mg of levofloxacin (hereinafter referred to as "traditional product") sold in July 2009 is shown in the attachment or Interviewform, and has a plan view projection shape having an elliptical shape with a long diameter of 18.2. Mm, the short diameter is 8.2 mm, and the ingot thickness is about 5.0 mm. Levofloxacin 500 mg ingots are often supplied to a physician or patient in a direction in which the shape of the elliptical surface is visible, that is, a state in which one tablet is contained in PTP (medicinal aluminum foil). Therefore, the physician or patient First, based on the size of the elliptical surface seen by PTP, an impression of the size of the tablet is formed. In order to alleviate the impression received from the "size of the ellipse", it is applicable to reduce the size of the first seen ellipse. For example, since the long diameter of the conventional product is 18.2 mm, when it is the same elliptical shape as the conventional one, as the value of the long diameter, for example, in the range of 14 mm to 18.0 mm, a small ingot can be given as compared with the conventional product. Impression of the agent. Regarding the short diameter, for example, the long diameter/short diameter ratio may be limited to the range of 2.00 to 2.50, and the range of 2.00 to 2.20 is particularly preferable.

Decreasing the area of the elliptical surface will affect the thickness of the ingot. The reduction in the area of the elliptical surface will increase the thickness of the ingot as long as the composition of the tablet is not changed. The so-called ingot thickness is the height of the tablet in the side view of the tablet. In order to give the tablet a small impression, the thickness of the ingot can be increased to reduce the area of the elliptical surface. However, the tablet having an extremely thick ingot has a practical deterioration in the ingestibility, and the tablet is nearly spherical, and the appearance is deteriorated. Therefore, setting an appropriate value as the ingot thickness is necessary.

In this regard, when an elliptical shape as a tablet shape is used, for example, a tablet having a long diameter of 16.2 mm and a long diameter/short diameter ratio of about 2.05 can be selected as an appropriate balance between the long diameter and the short diameter and the thickness of the ingot. Lozenges. If the tablet is of a shape and size, the impression of the miniaturized tablet is given, and the actual take-up property can be improved. The shape of the tablet of the present invention is preferably an elliptical shape in a plan view, and the long diameter 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, and further preferably 15.2 mm. The range of 17.2mm (16.2mm±1mm) is better, and the long diameter/short diameter ratio is in the range of 2.00 to 2.10 to 2.05. Degree is appropriate. Hereinafter, a specific tablet having such a shape and size (hereinafter sometimes referred to as "the tablet of the present invention") will be more specifically described, but the shape and size of the tablet of the present invention are not limited to the above specific ones. Further, regarding the lozenge of the present invention, a lozenge having a long diameter of 16.2 mm and a long diameter/short diameter ratio of 2.05 and a conventional product are prepared, and a comforting ingot is prepared, and the functional evaluation is performed for the employability of the digital tester. As a result, it was revealed that the tablet of the present invention has good applicability, and it has been confirmed that excellent applicability can be achieved by the shape and size.

For the elliptical tablet of the present invention having a long diameter of 16.2 mm and a long diameter/minor diameter of 2.05, the projected area of the elliptical plan view has a projected area of about 111.2 mm ² . Therefore, as the tablet of the present invention, the projected area of the projected shape may be in the range of 90 to 125 mm ² , preferably in the range of 100 to 116 mm ² , and if it is a tablet having a projected area of the above range, Good to take. Further, the calculation of the aforementioned projected area can be obtained by a method described later. This "projection shape of the plan view" is a shape that can be grasped when viewed from above (or below), and the elliptical shape of the tablet can be confirmed. The "from the top" can only observe the direction of the long diameter and the short diameter at the same time. For example, Table 2 describes three types of tablets, and the shapes shown in the left end and the center are shown. The shape described in the right end of the tablet shape in the same table is the shape when the tablet is viewed from the side, and the long diameter and the thickness of the ingot can be grasped. The distance between the upper and lower sides is the thickness of the tablet of the "ingot thickness", which is mostly based on the ingot. The value of the thickest part of the agent, that is, the maximum value.

The term "oval" in this specification means that the projected shape of the plan of the tablet is elliptical, and the term of the ellipse of course includes an ellipse based on geometric definition, except for the shape of a conventional product or the ellipse in this field. shape In addition to the shape, for example, the shape obtained by changing the four corners of the rectangle into a circular arc is included. Therefore, the term "ellipse", which encompasses a wider range of geometric shapes, must be interpreted in the broadest sense, even in any sense.

Further, the shape in which the levofloxacin 500 mg of the levofloxacin of the present invention can be used is not limited to the above-described elliptical shape, and is not particularly limited as long as it is not a circular shape. For example, a diamond shape can also be used. In addition, in terms of manufacturing, etc., the term of the diamond shape also includes the shape in which the angle is changed to an arc. Additional shapes known to those skilled in the relevant art are also included in the shape of the tablet of the present invention.

Further, when it is said that the circular lozenge is referred to as a circular lozenge shape as a whole, it can be recognized as a cylindrical or disc-shaped shape having a small thickness, and if viewed in a three-sided projection view, It is expressed as a circle or a rectangle (a square shape), and generally means that the projection surface from the top is a circle. In addition, even if it is called a cylindrical shape, it has a shape of a chamfer from the viewpoint of manufacture. The term "non-circular shape" as used in the present specification means a shape that does not have a circular shape as described above.

In the tablet of the present invention, an elliptical tablet having a long diameter of 16.2 mm and a long diameter/short diameter ratio of about 2.05, for example, a formulation shown in Table 1 can be used, and the following formulation 1 is particularly preferable, but is not limited thereto. Formulation, with regard to the ingredients or blending amount, of course, the relevant industry can make appropriate changes or modifications. For example, each component may be appropriately increased or decreased in the range of the amounts shown in Formulation 1 and Formulation 2, and further, each component may be appropriately added in a range not exceeding 700 mg in total.

The tablet preparation using the above-mentioned formulation is not particularly limited. For example, it is possible to carry out granulating levofloxacin-containing granules, adding a slip agent to perform ingoting on the granules, and obtaining a bismuth ingot, and applying a film coating step to the bismuth ingot. .

That is, the levofloxacin hydrate of the original drug is mixed with an excipient such as crystalline cellulose followed by a disintegrating agent such as carboxymethylcellulose. This mixture is granulated by, for example, using a fluidized bed granulation dryer and adding a binder. As such a binder, for example, hydroxypropylcellulose can be mentioned, and this can be granulated by spraying as an aqueous solution. After granulation, it is dried, and the obtained dried product is granulated to produce granules.

Next, a slip agent such as sodium fumarate stearate is added, for example, mixed using a V-type mixer to prepare pellets for ingots. Thereafter, tableting is carried out, for example, by using a rotary tableting machine, and ingots are used to form ingots, and a tablet can be produced. Further, the obtained tablet was coated to obtain a levofloxacin 500 mg ingot as a film-coated ingot.

Regarding the above steps of the particle production step, the tableting step, and the film coating step, other methods generally carried out in the field may be employed in addition to the foregoing methods. For example, in the production step of the granules, stirring granulation or dry granulation may also be employed.

Further, the ingredients to be added may be blended from the usual user selection in the field. Examples of the excipient include, in addition to crystalline cellulose, lactose hydrate, mannitol, corn starch, and the like. Further, examples of the disintegrating agent include carboxymethylcellulose (Carmellose), croscarmellose (Crospovidone), croscarmellose sodium, carboxymethylcellulose calcium, and carboxymethyl group. Sodium starch, low-substituted hydroxypropyl cellulose, and the like. Examples of the binder include hydroxypropylcellulose, and also, methyl hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and the like. Examples of the slip agent include sodium stearate stearate, magnesium stearate, and calcium stearate. As the coating agent, methyl hydroxypropyl cellulose (Hypromellose), titanium oxide, talc, polyethylene glycol (Macrogol), polyvinyl alcohol or the like may be used in combination. Further, yellow ferric oxide or ferric oxide may be added as a coloring agent for coating.

In this way, the lovofloxacin 500 mg containing ingot of the present invention can be obtained, but the lozenge mass of the present invention may be 570 mg to 700 mg, preferably in the range of 600 mg to 700 mg. As a suitable formulation included in this weight range, Formulation 1 and Formulation 2 mentioned above can be mentioned.

In addition, the tablet of the present invention which can be obtained in this manner, for example, an oval tablet having a long diameter of 16.2 mm and a long diameter/short diameter of about 2.05, will have Table 1 The granules of the composition of Formula 1 or Formula 2 are preferably tableted or coated to have a sufficient hardness. The hardness of the tablet may be, for example, 30 N or more, preferably 50 N or more, more preferably 30 to 300 N, still more preferably 50 to 280 N, and still more preferably 70 to 250 N.

The tablet of the present invention is preferably provided as a tablet which can be easily divided. The term "dividing" as used in the present specification means that a plurality of tablets are divided by applying stress to prepare a plurality of tablets, and two partial tablets are preferably used. In addition, in the present specification, "can be easily divided" or a synonym thereof means a divided tablet, and a device or device for dividing without using a tablet can be divided only by a human hand (finger), even if a particularly large stress is not applied. segmentation. As a means for this, for example, a dividing line can be provided in the tablet of the present invention. The dividing line in the tablet of the present invention is not essential, but it is generally preferable to provide a dividing line.

The "dividing line" is a line that is easy to divide the tablet, and if necessary, on the surface of the tablet, on one side of the elliptical surface or the back side, or on both sides of the front and back sides, generally the deepest part is linear. Extending the recess. The cross-sectional shape of the recess is generally a triangle, but may be other square, rectangular or semi-circular shapes. Further, the cross-sectional shape of the recess is a cross section cut along the long diameter of the tablet, and is a shape observed as a recess of the separable portion. The synonym of the triangle is a wedge shape, a V shape, or the like. The cross-sectional shape is not limited to the case where the surface shape of the tablet is constant or may be appropriately changed.

The traditional line can be divided into two, as shown in the following Table 2 (from the summary of Interviewform), which is provided with a straight line and a triangular shape with a cross-sectional shape. By applying the stress to both ends of the tablet, This dividing line makes it easy to divide the tablet. The projected area of the projection shape of the other elliptical plan is about 128.8 mm ² ; the divided shape is a triangle, the angle is 90°, and the depth of the dividing line is about 0.42 mm (the shape of the E-shaped dividing line of Table 3). .

However, according to the above formula 1, when an elliptical tablet having a long diameter of 16.2 mm and a long diameter/minor diameter ratio of about 2.05 is prepared, a tablet having the same split line shape as the conventional one is prepared (in the embodiment of the present specification, When the tablet for comparison shown in Example 9 is sometimes referred to as "tablet of "Example 9"), the division performance may be insufficient. That is, regarding the functional evaluation of the segmentation performance of the tablet prepared by such operation, almost all of the evaluations are in accordance with the score of "that is, the force cannot be divided" or "must be very hard to be divided", and it is judged that it is not suitable as a product (Table 10). The traditional line is applied with a "shallow and narrow dividing line" on one side, that is, the dividing line indicated by Type 1. in Table 2 is applied to only one side (Table 3), and it is not suitable to directly use this dividing line. A lozenge shaped in the present invention.

In the tablet of the present invention, the long diameter is 16.2 mm, and the long diameter/short diameter ratio is about An oval lozenge of 2.05, for a tablet having the composition of Formula 1 or Formula 2, at least one side of the tablet, or a tablet of the dividing line indicated in Table 3 on both sides, and the splitting property is reviewed.

The result is an elliptical tablet having a long diameter of 16.2 mm and a long diameter/short diameter ratio of about 2.05. When the tablet consisting of the formula 1 is a type 2 and a type of dividing line, both sides are applied the same. When the tablet of each of the tablets or the type of the dividing line of the type is used, only one side or a tablet of the dividing line of the type 4. and type 2. or the type is applied, it is judged that the tablet has a good separating property. An elliptical tablet having a long diameter of 16.2 mm and a long diameter to short diameter ratio of about 2.05. When the tablet of the formula 2 is used, even if only a tablet of a type of dividing line is applied on one side, the splitting performance is determined. good.

The segmentation performance shown above is based on the results of human functional tests. That is, the tablet which is applied with various dividing lines is actually divided by a hand, and the result of being easily broken or not easily broken is evaluated. For this evaluation, set the scores of 6 stages [5: almost no effort can be divided; 4: a little effort can be divided Cut; 3: can be divided by a little force; 2: can be divided by force; 1: must be very hard to divide; 0: the force can not be divided], based on this score, the evaluation of the segmentation characteristics.

Focusing on the state of the division performance of each of the tablets, the relationship between the type of the dividing line and the necessary force applied to the tablet to which the dividing line is applied is measured for the necessary urging force for dividing the dividing line portion. , to conduct a review. In order to measure the required urging strength (hereinafter referred to as "dividing line strength") for dividing the dividing line portion, an automatic tester (manufactured by SHIMADZU) of the test force measuring device is used as the urging means. In the measurement, the situation in which the person can be divided is set, and two opposing pedestals are placed at a certain distance. The distance between the two pedestals is such that the edge of the long diameter of the tablet is placed 1 mm or 1.5 mm from the edge of the pedestal. The tablet was placed across the two susceptors provided in this operation, and the load was applied by a crucible of an autograph to measure the strength of the rupture at the time of the break. According to this method, the strength can be measured based on the dividing line applied to the contact surface and the reverse surface of the bar on the tablet, and the dividing line which is not in contact with the crowbar when there are a plurality of dividing lines. The unit of the intensity value measured by the test force measuring device is Newton (N).

From the data of the strength of the dividing line obtained in this way, the tablet of Example 9, that is, the dividing line strength of the tablet having insufficient splitting performance was 54.2 N. On the other hand, each tablet of the present invention having a good division performance indicates a value of a dividing line strength of 30.9 N to 44.0 N. In other words, the tablet may be a tablet having a value of about 46 N or less in the strength of the dividing line. Further, it is particularly preferable that the dividing line strength is 42 N or less.

For the strength of the dividing line to be in the above range, because the hardness of the tablet itself When the temperature is low, the overall strength of the tablet is lowered, so the splitting performance sometimes increases. However, in the case of a tablet having a low hardness, the tablet is easily broken or damaged during the production or handling, and the manufacturing efficiency is lowered, which may result in a decrease in the shape stability of the product. Therefore, the tablet of the present invention must have sufficient hardness. In general, when the hardness of the tablet is 30 N or more, such a problem is unlikely to occur, and it is preferably 50 N or more. The hardness of the tablet is generally measured by a tablet hardness tester, but the hardness of the tablet of the present invention may be 30 N or more, preferably 50 N or more, particularly preferably 30 to 300 N, and further 50 to 280 N. it is good. In this range, 70 to 250 N is particularly preferred.

In view of the above, the strength of the dividing line in the tablet of the present invention is set together with the hardness of the tablet. However, when the above range is selected as the hardness of the tablet, the dividing line strength is preferably 20 N or more, and the suitable range is 20 to 46 N. It is especially good in the range of 20~42N.

The combination of the split line strength and the tablet hardness may be, for example, a combination of a split line strength of 20 N or more, a tablet hardness of 30 N or more, a split line strength of 20 N or more, and a tablet hardness of 30 to 300 N. The range is preferably, and the dividing line strength is 20 N or more, and the tablet hardness is in the range of 50 to 280 N, and then the dividing line strength is 20 N or more, and the tablet hardness is in the range of 70 to 250 N; The range of 20 to 46 N, and the range of the tablet hardness of 30 to 300 N is particularly preferable. Further, the dividing line strength is in the range of 20 to 46 N, and the tablet hardness is in the range of 50 to 280 N, and further, the dividing line strength is in the range of 20 to 46 N, and the tablet hardness is in the range of 70 to 250 N; The line strength is in the range of 20 to 42 N, and the range of the tablet hardness is preferably 30 to 300 N. Further, the dividing line strength is in the range of 20 to 42 N, and the tablet hardness is in the range of 50 to 280 N, and further, the dividing line strength It is in the range of 20 to 42 N, and the tablet hardness is in the range of 70 to 250 N, but is not limited thereto.

Further, the dividing line strength of the tablet is considered to be important in the area of the fracture surface (hereinafter referred to as "fracture area") when dividing along the dividing line. This fracture surface combines the portions of the two divided sheets, and when the area is at a specific value, excellent division performance can be obtained. The fracture area of the tablet of the present invention which imparts good splitting properties is, for example, 15 to 33 mm ² , and particularly preferably the area of the fracture surface is in the range of 20 to 33 mm ² . Dividing the area of poor performance of the fracture surface of the Example 9, lozenges 35.40mm ^2. The area of the fracture surface is calculated based on the measured dimensions of the divided tablets, and the fracture surface is formed by CAD (Computer Aided Design), and the area is measured by a microscope input to a computer.

On the other hand, a tablet having no split line shape, that is, an oval tablet having a long diameter of 16.2 mm and a long diameter/short diameter ratio of about 2.05, and a tablet having a composition of 1 is not divided into a tablet. The cross-sectional area of the short-diameter center point in the short-diameter direction is about 36.7 mm ² . Therefore, the fracture area is about 55% to 89% with respect to the cross-sectional area of the undivided strand tablet. That is, the fracture area of the split-line tablet may be in the range of 50 to 90% of the sectional area of the undivided strand tablet of the same shape. When this is expressed by the reduction rate of the sectional area, it is in the range of 10 to 50%.

When seeking the score of the split line and the score in the functional test, and then the correlation between the fracture area and the strength of the split line, it is considered that there is a good correlation. Therefore, in order to provide the tablet of the present invention having the good splitting property, it is set to divide by the dividing line. The breaking area of the tablet may be in the above range. Therefore, regarding the dividing line applied to obtain the fracture area in this range, there is no need to specifically consider the limitation regarding the so-called cross-sectional shape or length, or the shape of the dividing line of the dividing line applied to either side of the tablet. . That is to say, regarding the design of the dividing line, the degree of freedom is high, and various dividing lines can be employed.

For example, the dividing line shown in Table 3, the design pattern of the dividing line is classified by the American Pharmacists Association (TABLETING SPECIFICATION MANUAL, 2006, 7th edition, p.69; issued by the American Pharmacists Association) In the design pattern classified into E type or D type. The state of the dividing line is such that the angle at which the faces constituting the dividing line intersect is 90°, and the depth of the dividing line is a value shown in the figure from the edge face of the tablet, as shown in Table 3. Further, the angle of the dividing line is determined in the range of 30° to 120° in the range of 30° to 120°, but it is preferably in the range of 30° to 90°. Further, the depth of the dividing line may be in the range of 0.4 mm to 2 mm. It is preferably in the range of 0.7 mm to 1.5 mm.

The specific shape of the dividing lines, that is, the design pattern, the angle, and the depth affect the segmentation performance of the tablet, but it is also necessary to consider the factors for the manufacture of the tablet other than the segmentation performance.

The composition of Formulation 1 having Table 1 of the present invention has an elliptical shape, a long diameter of about 16.2 mm, a short diameter of about 7.9 mm, and an ingot thickness of about 5.6 mm, for example, a two-sided dividing line and a fracture area. It is preferably about 24 mm ² . One of such tablets is shown, for example, in Table 4 below. Regarding the tablet, the projected area of the elliptical plan has a projected area of about 111.2 mm ² ; the dividing line has a triangular shape with an angle of 90° (a right-angled equilateral triangle), and the depth of the dividing line on both sides is about 1.2 mm. Further, the tablet hardness was 225 N, the dividing line strength was 40.7 N, and the breaking area was about 23.97 mm ² .

In addition, the various sizes mentioned in the present specification, especially regarding the size of the tablet, are generally required to be small in size for the manufactured tablet, depending on the size of the tablet used. The error is about 0.1 to 0.2 mm, preferably 0.1 mm or less, and preferably 0.05 mm or less.

Example

The invention will be described in more detail in the following examples, but the invention is not limited thereto.

[Evaluation of Functionality of 500mg Ingot Take-up]

(1) Preparing a soothing ingot of 500 mg ingot: Regarding the Levofloxacin 500 mg ingot, the shape of the traditional product was prepared by the same formulation and manufacturing method, except that the lactose hydrate (512.5 mg) was blended to replace the active ingredient of levofloxacin hydrate (512.5 mg). Diameter: 18.2 mm, short diameter: 8.2 mm, ingot thickness: about 5.0 mm) and a suitable shape in the tablet of the present invention (long diameter: 16.2 mm, short diameter: 7.9 mm, ingot thickness: about 5.6 mm) Kind of comfort ingot.

(2) The tester of each of the four males and the two females took the above two types of soothing tablets, and the ingestion of each of the tablets was investigated in accordance with any of the following scores. The numbers represented in parentheses are scores.

Evaluation criteria:

Can be taken without problems [3]

It is slightly difficult to take, but can be taken [2]

It is quite difficult to take, but it can be taken [1]

Can't take [0]

As a result, the result of the lozenge shape of the comforting ingot is that it can be taken without problems: 3 people

It is slightly difficult to take, but it can be taken: 2 people

It is quite difficult to take, but it can be taken: 1 person

On the other hand, the result of the traditional shape of the comforting ingot is that it can be taken without problems: 1 person

It is slightly difficult to take, but can be taken: 4 people

It is quite difficult to take, but it can be taken: 1 person

That is to say, the evaluations of "taking a little difficult but taking it" are all the same number of 5 people. On the other hand, the evaluator of the highest-stage evaluation of "can be taken without problems" was one of the traditional shape-shaped comfort tablets, but the shape of the lozenge was greatly increased to three. Further, the "sitting is slightly difficult, but it can be taken" is a traditional type of comforting ingots of 4 people, but the shape of the lozenge is reduced to 2 people, and the evaluation of "difficult to take" is reduced.

From the above results, it was revealed that the tablet of the present invention has good applicability.

Further, the average value of the score is the "2.0" of the conventional product, and the shape of the tablet of the present invention is "2.4", which is a high score.

[Examples 1~7]

Based on the formulations of Examples 1 to 7 shown in Table 5, a lozenge containing 500 mg of levofloxacin having the dividing line shown in Table 6 was prepared. That is, Levofloxacin hydrate (first three co-products), crystalline cellulose (CEOLUS PH-101, Asahi Kasei chemicals), carboxymethyl cellulose (carmellose) (NS-300, Nichirin) Chemical industry) in the fluid layer A granulation dryer (FLO-120, Freund Industries) was sprayed with an aqueous solution of 6% hydroxypropylcellulose (Japan Soda) prepared separately for granulation. After granulation, it was sufficiently dried, and the obtained dried product was granulated by Sanitary Dresser (Asakusa Iron Works) to produce granules. To the pellet, sodium fumarate (Nippon Chemical Industry Co., Ltd.) was added, and the mixture was mixed with a V-type mixer (V-600) to prepare pellets for ingots. Thereafter, the ingot was ingots in a rotary tableting machine having a crowbar having the dividing line shown in Table 6, and a tablet was produced. The obtained tablet was coated with a dispersion of OPADRY 01F43013 (Japan colorcon) using Hicoater-mini (Freund Industries) to prepare tablets of Examples 1 to 7. The tablet of Example 7 had the same shape as the tablet of the conventional product shown in Table 2.

[Example 8]

According to the formulation of Example 8 of Table 5, in the same manner as in Examples 1 to 7, the ingot was produced by a pry bar having the dividing line shown in Table 6, and a tablet was produced. The obtained tablet was coated with a dispersion of OPADRY 01F430001 (Japan colorcon) using Hicoater-mini (Freund Industries) to prepare a tablet of Example 8.

[Example 9]

According to the formulation of Example 9 of Table 5, in the same manner as in Examples 1 to 7, the ingot was prepared by using the crucible bar shown in Table 6, and a tablet was produced. The obtained tablet was coated with a dispersion of OPADRY 01F43013 (Japan colorcon) using Hicoater-mini (Freund Industries), and a preparation example was prepared. 9 lozenges.

The shape of the dividing line used in the review is shown in Table 6. Separate rods (Shiqiao Seiki Co., Ltd.) in the shape of the dividing line shown in this table were produced, and various kinds of upper and lower crowbars were combined to prepare tablets having different fracture areas.

[Measurement Example 1] Measurement of fracture area

The prepared tablet is divided along the dividing line, and the area of the obtained section is defined as the fracture area. For the divided tablets, the fracture surface is formed by CAD based on the measured dimensions of each part, and the fracture surface is input into a computer by a microscope to measure the area. The results of measurement of the fracture area at the time of division of the divided line portions for each of the tablets having the divisional line shape combination shown in Table 6 are shown in Tables 1 and 8 and Table 9 as shown in Table 8.

[Measurement Example 2] Segmentation (human functional test)

The segmentation tester presses the dividing line on the opposite side of the dividing line with the thumb to separate, and the easy division degree at the time of division is evaluated based on the reference (scoring) selection as shown below. When there are dividing lines on both sides of the tablet, the two sides are reviewed, and the segmentation property is evaluated according to the difference in the shape of the dividing line. In addition, when the same dividing line is applied to both sides, only one side is evaluated. The test subjects were 5 males (testers No. A to E) and 5 females (tester No. F~J), and 10 were judged.

Evaluation basis

5: It can be divided almost without force

4: You can split it with a little effort

3: Split by a little harder

2: Split by force

1: Must be very hard to split

0: the force cannot be divided

The segmentation results measured in the functional test are shown in Tables 9 to 7 and Table 9 as shown in Table 10.

[Measurement Example 3] Separation line strength using an intensity tester (autograph)

As shown in Fig. 1, a load was applied at a compression speed of 10 mm/min using an autograph (manufactured by SHIMADZU), and the maximum load at the time of breakage of the tablet was the dividing line strength (average of three ingots). The distance from the edge of the tablet to the edge of the base is 1 mm, the case 8 and the case 9 are 1 mm, and the case 7 is 1.5 mm (this distance is determined according to the stability of the tablet during the measurement, and the tablet can be stably used. The shortest distance fixed.). Further, when the shape of the dividing line in the tablet table is different, the evaluation target dividing line surface is placed below, and the measurement is performed on both sides. The results are shown in Table 11.

[Measurement Example 4] Lozenge hardness

Tablet hardness is determined by tablet hardness tester (ERWEKA TBH20) (average of 3 ingots). The measurement was carried out by applying a compressive force to the long diameter (long axis) direction of the tablet. The results of the tablets of Examples 1 to 8 of the present invention are shown in Table 11. In addition, the results for Example 9 are shown in Table 12. The hardness of the preparation of the present invention is 206 to 235 N, and it is confirmed that any of the tablets has a hardness which is not problematic in circulation.

[Relationship between the strength of the dividing line and the segmentation of the functional test]

The relationship between the dividing line strength of the tablets of Examples 1 to 7 and Example 9 and the segmentation property of the functional test is shown in Fig. 2 . It is considered that the two have a good correlation, and if the dividing line strength is 46 N or less, it is shown as a separable tablet.

[Fracture area and dividing line strength]

Next, the dividing line intensity is plotted against the fracture area, and the result is shown in FIG. When the fracture area is 33 mm ² or less, the division line strength is lower than 46 N, and the division property is good.

[The ratio of the fracture area of the split line tablet to the undivided line tablet]

The tablet of Examples 1 to 8 does not have such a split-line shape tablet, that is, an oval tablet having a long diameter of 16.2 mm and a long diameter/short diameter ratio of about 2.05, and a tablet composed of Formulation 1 In the case of the undivided wire lozenge, when calculating the cross-sectional area in the short-diameter direction of the long-diameter center point by the computer, it is about 36.73 mm ² . Based on this, the ratio of the fracture area of the tablet of Examples 1 to 8 to the fracture area of the split-line tablet to the cross-sectional area of the undivided wire tablet is shown in Table 13.

Industrial use

Even if the lozenge of the present invention is a high-content large lozenge, it is visually miniaturized as compared with the conventional lozenge, and does not cause visual uneasiness for the patient to take difficulty, because it is actually easy to swallow, so it can be improved The patient is medically compliant. Further, since the tablet can be easily divided, the amount of the tablet can be easily adjusted. On the other hand, since it has sufficient hardness and does not cause cracking or chipping during production or handling, it is possible to avoid problems in manufacturing.

Claims (17)

A tablet which can be easily divided, characterized in that it contains 500 mg of levofloxacin, the mass is 570 mg to 700 mg, and the projected area on the plan view is 90 to 125 mm ² , and has a hardness of 30 to 300 N. A lozenge according to item 1 of the patent application, which is elliptical. A lozenge of claim 1 or 2, which is a lozenge having a dividing line. The lozenge according to any one of claims 1 to 3, wherein the long diameter/short diameter ratio of the tablet is in the range of 2.00 to 2.50, and the long diameter is 14 to 18 mm. The lozenge according to any one of claims 1 to 3, wherein the long diameter/short diameter ratio of the tablet is in the range of 2.00 to 2.20, and the long diameter is 14 to 18 mm. For example, the tablet of claim 4 or 5, wherein the long diameter is in the range of 15.0 to 18.0 mm. The lozenge according to any one of claims 1 to 6, wherein the lozenge has a fracture surface area of 15 to 33 mm ² when divided by a dividing line. The lozenge according to any one of claims 1 to 6, wherein the lozenge has a fracture surface area of 20 to 33 mm ² when divided by a dividing line. A lozenge according to any one of claims 1 to 8, wherein the dividing line strength is 46 N or less. The lozenge according to any one of claims 1 to 8, wherein the dividing line strength is 42 N or less. The lozenge according to any one of claims 1 to 8, wherein the dividing line strength is in the range of 20 to 46 N. The lozenge according to any one of claims 1 to 8, wherein the dividing line strength is in the range of 20 to 42N. A lozenge according to any one of claims 1 to 12, wherein the lozenge has a hardness of 50 to 280 N. The lozenge of any one of clauses 1 to 12, wherein the tablet has a hardness of 70 to 250 N. A lozenge is an elliptical tablet containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, characterized by a long diameter/short diameter ratio in the range of 2.00 to 2.50, a long diameter of 14 to 18 mm, and a hardness of the tablet. It is 30 to 300 N, and has a dividing line for division, and the dividing line strength is 46 N or less. A lozenge is an oval lozenge containing 500 mg of levofloxacin and having a mass of 570 mg to 700 mg, characterized by a long diameter/short diameter ratio in the range of 2.00 to 2.20, a long diameter of 14 to 18 mm, and a hardness of the tablet. It is 50~280N, and has a dividing line for division, and the dividing line strength is in the range of 20~42N. A tablet according to any one of claims 1 to 16, wherein a pellet containing levofloxacin is prepared, a slip agent is added to the pellet, and ingot is applied, and the obtained ingot is subjected to a film. Covered.