JP5123471B2 - Easy to adjust dosage - Google Patents

Description

  The present invention relates to a scored tablet in which a fragment having a different drug content is obtained depending on how it is divided, although it is a single tablet, and a scored tablet whose drug release characteristics vary depending on the part to be divided.

The secant tablet is a tablet that is divided by the pharmacist or patient according to the dose, and was developed to optimize dose management and increase flexibility in prescribing. Furthermore, recently, preparations capable of being divided into four or more parts have been devised due to the problem of preparation of optimal dose and storage inventory space. For example, Patent Document 1 discloses 6-divided tablets and Patent Document 2 discloses 8-divided tablets as disk-shaped ones. Further, a rod-shaped four-part tablet is disclosed in Patent Document 3 and Patent Document 4.
However, all of these conventional scored tablets have the same amount of drug in each fragment.
On the other hand, there are no known secant locks having a plurality of secant lines whose characteristics vary depending on the divided part.

U.S. Pat. No. 4,503,131 US Pat. No. 5,756,124 International Publication WO89 / 05624 Specification International Publication WO01 / 00176 Specification

The first object of the present invention is to provide a scored tablet which has two score lines and is designed so that the combination of drug contents in the fragments obtained by dividing at each score line is different.
The second object of the present invention is to provide a scored tablet having two scored lines and having different drug release characteristics of fragments obtained by dividing at each scored line.

The present invention comprises a plurality of drug-containing parts that may contain a pharmaceutical additive,
Concatenated with them, consisting of one linking part composed of pharmaceutically acceptable ingredients,
All drug-containing parts contain the same type of drug,
The connecting portion has two intersecting score lines that can divide the whole tablet, and is a tablet that can be divided into four,
If divided by one secant, two fragments with equal drug content are obtained, and if divided by the other secant, two fragments with non-equal drug content are obtained (first invention).

The present invention also includes a plurality of drug-containing parts that may contain a pharmaceutical additive,
Concatenated with them, consisting of one connecting part composed of pharmaceutically acceptable ingredients, all drug-containing parts contain the same kind of drug,
The connecting portion has two intersecting score lines that can divide the whole tablet, and is a tablet that can be divided into four,
It is entirely covered with a coating layer that is insoluble in the digestive tract, or a soluble coating layer that has a drug release control function (fast dissolution, fast disintegration, enteric, sustained release, timed release, etc.)
When divided by two dividing lines, the tablet has a connecting part that is engraved with a dividing line so that the cross-sections with different drug release control functions are exposed (second invention).

By dividing the tablet of the first invention, a plurality of fragments having different drug contents can be obtained accurately.
The tablet of the second invention has an effect of changing the characteristics of the obtained fragment by selecting the dividing line to be divided.

The first invention comprises a plurality of drug-containing parts that may contain a pharmaceutical additive,
Concatenated with them, consisting of one linking part composed of pharmaceutically acceptable ingredients,
All drug-containing parts contain the same type of drug,
The connecting portion has two intersecting score lines that can divide the whole tablet, and is a tablet that can be divided into four,
If it is divided by one secant, two fragments with an equal drug content are obtained, and if it is divided by the other secant, a tablet with an uneven drug content is obtained.

  The size of the whole tablet of the first invention is not particularly limited as long as it is not so small as to be unsuitable for dividing as a scored tablet and is not so large as to be inconvenient for taking as a tablet. The thickness should not be so high as to prevent division. The shape is not particularly limited as long as it can be produced without difficulty by an ordinary production apparatus or a production apparatus that has been modified, but a typical example of a general tablet concept is a disk-like shape. it can. In addition, three or hexagonal pillars with a low height and rectangular parallelepipeds can be given as typical examples, but the shape is not particularly problematic as long as the basic functions of each part layer as described below are not impaired. .

  As for the shape of the connecting part, it is desirable that the upper and lower surfaces are basically flat, but as long as it is in a form that can hold the drug-containing part, and only at the intended secant part of the two cuts As long as there is no hindrance, there may be undulations and irregularities.

  The drug-containing part in the present invention may be composed of only the drug as the active ingredient or may contain a pharmaceutical additive, but forms part of the tablet of the present invention and is a solid that maintains a certain shape. Must be a thing. Even when a pharmaceutical additive is contained, it is desirable that the drug is uniformly dispersed. The shape of the portion other than the joint surface of the drug-containing portion with the connecting portion may be completely free as long as there is no hindrance to production and the division at the secant line is not hindered. The shapes of the plurality of drug-containing portions do not need to match.

  The dividing line in the first invention is two intersecting lines, and there is one connecting portion. Since the two secant lines are engraved in one connecting portion, the shape of the connecting portion inevitably approximates that of two intersecting bands. Typically, they intersect at right angles.

  The plurality of drug-containing portions are preferably in the same shape, and in particular, the whole tablet preferably has a point-symmetrical, line-symmetrical, or plane-symmetrical shape. Therefore, as shown in FIG. 1, the typical shape of the first invention is a quadrant when viewed from above. In addition, a shape in which the connecting portion is a disc shape or a quadrangular prism shape, and four drug-containing portions are connected to the outer periphery or the four sides of the connecting portion, respectively.

  The drug as the active ingredient is not particularly limited as long as it can be made into the tablet of the present invention by a usual production method. For example, a drug for the central nervous system, a drug for the peripheral nervous system, a drug for the circulatory organ, a drug for the digestive organs Drugs, hormonal drugs, urogenital drugs, blood and body fluid drugs, metabolic drugs, gout treatment drugs, oncology drugs, allergy drugs, bronchodilators, antibiotics, antibacterial drugs, antiviral drugs, wound healing Substance, antispasmodic agent, anticholinergic agent, antihistamine, anti-inflammatory agent, anticholesterolemia, antilipidemic agent, appetite suppressant, stimulant, coagulant, antacid, chemotherapeutic agent, nutritional supplement, diagnostic agent, narcotic -1 type, or 2 or more types of active ingredients chosen from a stimulant, an analgesic, an antitussive, a glaze etc. are mentioned. More specifically, for example, ascorbic acid, acetaminophen, etenzaamide, ambroxol hydrochloride, alendronate, febuxostat, clenbuterol hydrochloride, ethyl icosapentate, tacalcitol, picosulfate, alphacalcidol, international publication WO99 One or two or more kinds of active ingredients selected from the group consisting of compounds described in Japanese Patent No./26918, compounds described in International Publication WO01 / 53291, compounds described in International Publication WO99 / 25686, and salts and / or hydrates thereof Is mentioned. Here, the drug in the drug-containing part and the drug in the connecting part when the connecting part contains a drug are desirably a combination that does not cause any inconvenience even if they are in contact with each other. Typically, the connecting portion does not contain a drug.

  In the present invention, the pharmaceutical additive contained in the connecting part and the pharmaceutical additive that may be contained in the drug-containing part are pharmaceutically acceptable and do not prevent the tablet shape from being kept stable. As long as it is, it is not particularly limited. Specifically, for masking purposes such as bitterness and irritation, for example, crystalline cellulose, lactose, hydroxypropylcellulose, hydroxypropylmethylcellulose, partially pregelatinized starch, starch, erythritol, mannitol, sorbitol, trehalose, light anhydrous Silicic acid or a mixture or granulated product thereof is used, and may further contain a lubricant, a disintegrant, a fluidizing agent, etc. for the purpose of improving the manufacturability, moldability and formulation function. For the purpose of maintaining or developing enteric function, a plasticizer may be added to methacrylic acid copolymer, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose or mixtures thereof. In order to maintain or develop the sustained release function, a plasticizer is added to hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxyvinyl polymer or a mixture thereof. Is used. Further, for the purpose of maintaining the light stability after the division, titanium oxide or the like may be added to the components of the connecting portion.

  1st invention is a tablet which can be divided into 4 which has two dividing lines in the connecting part. Although the dividing line may be expressed as a dividing groove, in this specification, the dividing line and the dividing line are collectively referred to as a “dividing line”. Making a score line on a tablet and its general shape are already common technical knowledge in this field. Therefore, as long as patients and pharmacists can divide the whole tablet without difficulty, the shape of the secant in the present invention is not particularly limited, and those skilled in the art can easily form it based on common technical knowledge. Specifically, the shape of the secant disclosed in the above patent document can be exemplified. For example, if the shape of the connecting portion is planar, the dividing line may be on both sides or only on one side.

  In the first invention, all drug-containing parts contain the same kind of drug, there is one connecting part, and the drug content in at least one drug-containing part is different from the drug content in other drug-containing parts. ing. Therefore, it is preferable to change the drug content by changing the drug amount per unit volume without changing the shape of each drug-containing part.

  In particular, two fragments with equal drug content if divided by one secant line, and two fragments with non-equal drug content if divided by another secant line, eg, drug content difference is doubled or tripled. Or, a scored tablet in which the drug content and arrangement of each drug-containing part are determined so that a fragment that is four times as large is obtained is preferable.

  As a specific example of the first invention, a tablet as shown in FIG. 2 can be exemplified. In this example, if the tablet is not divided, the dose is 20 mg, but if divided according to the horizontal secant in the drawing, two 10 mg fragments are obtained. On the other hand, when divided according to the secant line in the vertical direction of the drawing, 15 mg fragments and 5 mg fragments are obtained. Further, dividing the 15 mg fragment into two gives two 7.5 mg fragments, and dividing the 5 mg fragment gives two 2.5 mg fragments. That is, considering that a plurality of fragments are used in combination, there are 8 types of 20 mg, 17.5 mg, 15 mg, 12.5 mg, 10 mg, 7.5 mg, 5 mg, and 2.5 mg, although they are one tablet. The dose can be taken.

  Furthermore, the tablet of the first invention may have a coating layer. Such a covering layer has a function of avoiding a disadvantage of the patient from contacting the drug in the oral cavity or the esophagus, for example. Such patient disadvantages include, for example, unpleasant tastes and unpleasant odors such as bitterness, irritation, side effects due to unintentional drug absorption in the oral cavity, or side effects due to dissolution of the drug in the oral cavity or esophagus. In addition, the coating is insoluble, fast-dissolving, fast-disintegrating, enteric, sustained-release, timed-release drug release control function, stabilization against moisture and moisture, in vivo components such as gastric juice and enzymes that come into contact after administration It is also applied for the purpose of stabilization against light or light stability. For masking unpleasant taste and unpleasant odor, for example, hydroxypropyl cellulose and hydroxypropyl methylcellulose are used, and for providing enteric properties, for example, methacrylic acid copolymer, cellulose acetate phthalate, carboxymethylethyl cellulose, hydroxypropyl methylcellulose. For example, hydroxyethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose, which is obtained by adding a plasticizer to phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, or a mixture thereof. A plasticizer added to acetate succinate, carboxyvinyl polymer or a mixture thereof, Ethylcellulose For stabilization against minute, etc., methacrylic acid copolymer, shellac, polyvinyl acetal diethylamino acetate is used. In addition, pharmaceutical additives with masking, enteric, and sustained-release functions can be used alone or in combination for stabilization of in vivo components such as gastric juice and enzymes, and for the purpose of photostability, these additives can be used. Titanium oxide or the like is added into the coating substrate. Such a coating layer may be a plurality of different types of layers.

  In the case of having a coating layer, in order to maintain the effect of the coating layer even after the division, the width of the coupling portion is set so that the coating layer remains on the coupling portion after the division and the drug-containing portion is not exposed. It is desirable to decide.

The second invention comprises a plurality of drug-containing parts that may contain a pharmaceutical additive,
Concatenated with them, consisting of one connecting part composed of pharmaceutically acceptable ingredients, all drug-containing parts contain the same kind of drug,
The connecting portion has two intersecting score lines that can divide the whole tablet, and is a tablet that can be divided into four,
The whole is coated with a coating layer that is insoluble in the digestive tract of the living body or a soluble coating layer that has a drug release control function (fast dissolution, fast disintegration, enteric, sustained release, timed release, etc.)
When the tablet is divided by two dividing lines, it is a tablet in which a connecting part is formed so that a section having different drug release control functions is exposed.

  Examples of the drug release control function of the cross section of the connecting portion include insolubility, fast solubility, fast disintegration, enteric properties, sustained release, and timed release. As an example of the second invention, for example, if a tablet is divided according to one dividing line, a fast-dissolving or fast-disintegrating cross section is exposed, and if a tablet is divided according to another dividing line, sustained release, enteric or time-released It is a tablet with a sex cross section exposed.

  The size and shape of the whole tablet in the second invention, the drug-containing part, the connecting part, and the shape of the secant are also the same as those in the first invention, and the same can be mentioned as preferred.

  By the way, in the second invention, for example, if a tablet is divided according to one dividing line, a fast-dissolving or rapidly disintegrating cross section is exposed, and if a tablet is divided according to another dividing line, it is controlled release, enteric or time-released. Although the connecting portion is configured so that the cross section is exposed, it is not necessary to strictly follow this from the viewpoint of manufacturing in the vicinity of the portion where the two secant lines intersect. That is, in this example, a sustained-release or enteric material may be used near the intersection of the two secant lines. That is, the fast-dissolving, fast-disintegrating, or time-releasing part may be divided at the part where the secant line intersects. This is because the effect of changing the drug release characteristic of the obtained fragment can be substantially achieved by selecting the dividing line to be divided, which the second invention has.

  In order to make the connecting part rapidly soluble, for example, at least one of lactose, crystalline cellulose, partially pregelatinized starch, starch, mannitol, xylitol, erythritol, sorbitol, croscarmellose sodium, carmellose calcium, crospovidone, etc. In order to give disintegration, a mixture or granulated product containing the above is used, and in order to give disintegration, starches of the above additives, crushed carmellose sodium, carmellose calcium, crospovidone, partially pregelatinized starch, starch and easily soluble The content of mannitol, erythritol, etc., which are polysaccharides, may be increased.

In the second invention, the amount of the drug contained in the plurality of drug-containing parts may be different, but the same is generally the same.
The tablet of FIG. 3 which is an example of the second invention has the same shape as the tablet of FIG. 1, but is not limited to this shape as long as the function of the second invention described above can be expressed. For example, in the tablet of FIG. 3, there may be mentioned one in which the arc portion of the outer peripheral portion of the drug-containing portion is linear.

  EXAMPLES Next, although this invention is demonstrated using an Example, this invention is not limited by these.

Example 1: (Compact tablet filling method 1) Lower layer filling → Compact tablet filling → Compression molding A 10 mm flat type mortar (with upper and lower score lines) was attached to a tableting machine (HT-AP6SS-U manufactured by Hata Seiko). 100 mg of this mortar mixed with 0.5% magnesium stearate mixed with Dilactos R (Freund) was used as the lower layer. This lower layer was filled with R tablets each containing 2.5 mg and 5.0 mg febuxostat with a diameter of 3 mm and a weight of 25 mg so as to sandwich the score, and compression molded.

Example 2: Small tablet filling method 1) Lower layer filling-> small tablet filling-> compression molding A 10 mm flat type mortar (with upper and lower secant lines) was attached to a tableting machine (HT-AP6SS-U manufactured by Hata Seiko). 100 mg of this mortar mixed with 0.5% magnesium stearate mixed with Dilactos R (Freund) was used as the lower layer. This lower layer was filled with two R tablets each containing 3 mg in diameter and 25 mg in weight containing 5.0 mg and 10.0 mg ascorbic acid so as to sandwich the score, and compression molded.

Example 3 Small Tablet Filling Method 1) Lower layer filling → small tablet filling → compression molding A 10 mm flat type mortar (with upper and lower scored lines) was attached to a tableting machine (HT-AP6SS-U manufactured by Hata Seiko). 100 mg of this mortar mixed with 0.5% magnesium stearate mixed with Dilactos R (Freund) was used as the lower layer. In this lower layer, 5.0 mg, 10.0 mg of 3- (amidinophenyl) -5-[({[1- (iminoethyl) (4-piperidyl)] methyl} amino) methyl] benzoic acid dihydrochloride trihydrate Two R tablets each having a diameter of 3 mm and a weight of 25 mg were filled so as to sandwich the score, and compression molded.

  The present invention is used for pharmaceutical manufacture.

A specific example of the first invention. A specific example of the first invention. The part where the numerical value is described is the drug containing part. A specific example of the second invention. The surrounding broken line represents the coating layer.

Claims (6)

A plurality of drug-containing portions that may contain pharmaceutical additives;
Concatenated with them, consisting of one connecting part composed of pharmaceutically acceptable ingredients, all drug-containing parts contain the same kind of drug,
The drug content in at least one drug-containing part is different from the drug content in other drug-containing parts,
The connecting portion has two intersecting score lines that can divide the whole tablet, and is a tablet that can be divided into four,
Tablets that yield two fragments with equal drug content if divided at one secant line, and two fragments whose drug content difference is doubled, tripled, or quadrupled when divided at the other secant line .   The tablet according to claim 1, which is entirely coated with a coating layer.   The tablet according to claim 2, wherein the coating layer has a function of preventing the contact of the drug in the oral cavity or the esophagus from being a disadvantage for the patient.   The tablet according to claim 2, wherein the coating layer has some drug release control function.   The tablet according to claim 4, wherein the drug release controlling function is fast-dissolving, fast-disintegrating, enteric, sustained-release, or time-release.   The tablet according to any one of claims 3 to 5, wherein, when divided by two dividing lines, a connecting part is formed so that a section having different drug release control functions is exposed.

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