JP2024090218A - Zonisamide-containing intraorally rapidly disintegrating tablet with improved disintegration delay - Google Patents

Abstract

[Problem] To provide an intraorally rapidly disintegrating tablet (OD tablet) containing zonisamide, which has improved disintegration delay observed during storage under harsh humidity conditions.Solution: This intraorally rapidly disintegrating tablet contains zonisamide as an active ingredient, and contains 40-70% by weight of an excipient and 5% by weight or less of a lubricant as formulation additives relative to the total weight of the formulation, and uses a combination of multiple disintegrants as disintegrants, in particular carmellose as one component of the disintegrant, and is combined with other disintegrants, preferably crospovidone and corn starch, at 5-45% by weight of the formulation weight, thereby improving the disintegration delay of the tablet. [Selected Drawing] None

Description

The present invention relates to a zonisamide-containing intraorally rapidly disintegrating tablet that contains zonisamide as an active ingredient and has improved disintegration retardation observed when stored under harsh humidity conditions.

Zonisamide (INN), which has the chemical name 1,2-benzisoxazole-3-methanesulfonamide, is a drug used clinically to treat Parkinson's disease (levodopa enhancer).
Generally, many Parkinson's disease patients are elderly patients who have difficulty swallowing, and therefore orally administered therapeutic agents have been developed in the form of orally disintegrating tablets, and for zonisamide, TRERIEF (registered trademark) OD tablets have been developed as orally disintegrating tablets (hereinafter sometimes referred to as OD tablets) (Non-Patent Document 1).

The formulation of Treleaf (registered trademark) OD tablets currently being offered clinically is taken from Non-Patent Document 1 and is an orally disintegrating tablet that contains the excipients D-mannitol, corn starch, and crystalline cellulose as formulation additives, partially saponified polyvinyl alcohol as a binder, and magnesium stearate as a lubricant.

Regarding zonisamide OD tablets, other proposals have also been made by generic drug manufacturers (Patent Documents 1 and 2). Patent Document 1 proposes OD tablets that do not contain the crystalline cellulose and corn starch contained in the original formulation (Trereef OD tablets), as these ingredients are responsible for the hygroscopicity of the tablets, and instead uses crospovidone and low-substituted hydroxypropyl cellulose as additives.
Furthermore, Patent Document 2 proposes an OD tablet using a two-group method in which granules containing zonisamide and fast-disintegrating granules are prepared and then compressed to prepare tablets, as a technique for masking the bitterness of zonisamide after administration.

Patent No. 6271802 Patent No. 5680898

Treleaf OD Tablets Package Insert

When preparing tablets, it is common to add a disintegrant to ensure the tablet's appropriate disintegration properties. However, to make an orally disintegrating tablet, rapid disintegration in the oral cavity (preferably within 30 seconds) is required, so the selection of the disintegrant to be added is important.

The present inventors have prepared zonisamide OD tablets using various disintegrants alone for zonisamide, and have selected and examined the disintegrant. As a result of a disintegration test of the prepared OD tablets stored under severe humidity conditions (25°C/RH 75%), it was found that disintegration was delayed under severe humidity conditions with the disintegrants other than carmellose.
In the case of carmellose, although no delay in disintegration was observed, the disintegration time was 37 seconds, and an even faster disintegration was required for OD tablets (the target disintegration time was 30 seconds or less).
Therefore, the present invention provides a means for avoiding the above problems in OD tablets containing zonisamide as an active ingredient.

As a result of intensive research to solve the above problems, it was found that in the preparation of zonisamide OD tablets, by combining and formulating multiple disintegrants, in particular by combining and formulating multiple disintegrants including carmellose, which is a representative water-conducting disintegrant, no delay in disintegration of the tablets is observed under severe humidity conditions, and a rapid disintegration time can be obtained.
The present invention has been completed based on these findings.

Therefore, the present invention relates to a method for manufacturing a semiconductor device comprising the steps of:
(1) A zonisamide OD tablet containing zonisamide as an active ingredient and rapidly disintegrating in the oral cavity, characterized in that it contains 40 to 70% by weight of an excipient and 5% by weight or less of a lubricant as formulation additives relative to the total weight of the formulation, and is formulated with a combination of multiple disintegrants as disintegrants, and has an improved disintegration delay;
It is.

More specifically, the present invention relates to a method for producing a medicament for use in a method for producing a medicament comprising the
(2) The zonisamide OD tablet according to (1) above, in which the excipient is one or more selected from lactose, glucose, fructose, sucrose, corn starch, potato starch, crystalline cellulose, mannitol, xylitol, sorbitol, erythritol, calcium phosphate, anhydrous calcium phosphate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate, has an improved disintegration delay;
and

In particular, the present invention relates to
(3) The zonisamide OD tablet according to (1) above, in which the disintegrant is two or more selected from partially pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, sodium starch glycolate, and corn starch, has an improved disintegration delay;
It is.

Further, the present invention more specifically relates to
(4) Zonisamide OD tablet according to the above (1) in which carmellose is one of the disintegrants, and which has an improved disintegration delay;
(5) Zonisamide OD tablet according to the above (1), in which the multiple disintegrants are a combination of carmellose, crospovidone and corn starch, and which has an improved disintegration delay;
(6) The zonisamide OD tablet according to (1) above, in which the total amount of the disintegrant is 5 to 45% by weight of the formulation;
It is.

The present invention proposes an OD tablet that improves on the delayed disintegration under harsh humidity conditions observed with previous zonisamide OD tablets, and therefore has a significant clinical effect in that it can provide a pharmaceutical preparation of good quality.

As described above, the present invention is characterized in that when preparing OD tablets containing zonisamide as an active ingredient, multiple types of disintegrants are used in combination as disintegrants to be blended, and in particular, multiple disintegrants including carmellose are combined and blended.
In other words, since zonisamide contained as an active ingredient in the present invention is poorly soluble in water, carmellose, a water-conducting disintegrant, is used as one component of the disintegrant and is combined with other disintegrants.

The content of zonisamide, the active ingredient, in the zonisamide OD tablets provided by the present invention is preferably the same as the content used clinically, and although it depends on the tablet mass, it is preferably 10 to 20% by mass relative to the tablet mass.

The Trereef OD tablets used clinically contain 25 mg and 50 mg of zonisamide, so it is desirable that the zonisamide content in the tablets of the present invention be the same, and the additives that make up the tablets should be selected accordingly, and the amounts of the additives should be determined accordingly.

Additives constituting the OD tablet of the present invention include various additives commonly used in the pharmaceutical field, such as excipients that can include one or more selected from lactose, glucose, fructose, sucrose, corn starch, potato starch, crystalline cellulose, mannitol, xylitol, sorbitol, erythritol, calcium phosphate, anhydrous calcium phosphate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate.

Lubricants include magnesium stearate, talc, calcium stearate, stearic acid, sodium stearyl fumarate, light anhydrous silicic acid, sucrose fatty acid esters, etc.

As described above, in the present invention, multiple disintegrants including carmellose are used in combination as disintegrants, but examples of disintegrants other than carmellose include partially pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose calcium, carmellose sodium, sodium starch glycolate, and corn starch.

Any one or more disintegrants other than carmellose mentioned above may be freely selected and used in combination with carmellose as long as no delay in disintegration time is observed. However, according to the studies of the present inventors, it is preferable to use a combination of three disintegrants: carmellose, crospovidone, and corn starch.

In the preparation of the zonisamide OD tablet of the present invention, the formulation of the above-mentioned pharmaceutical additives is based on the following: excipients account for 40 to 70% by weight, and lubricants account for approximately 5% by weight or less of the total weight of the formulation, and multiple types of disintegrants are used as disintegrants.
In addition, the total amount of disintegrants is preferably 5 to 45% by weight of the formulation.

The zonisamide OD tablets provided by the present invention can be prepared by direct compression, dry granulation, wet granulation, or other methods commonly used in pharmaceutical formulations, and additives appropriate for each manufacturing method can be appropriately selected and prepared.

The shape, mass, hardness, etc. of the zonisamide OD tablet provided by the present invention are not particularly limited, but in order to be suitable for use as an orally disintegrating tablet, it is preferable to provide it as a round tablet usually having a diameter of about 7 to 11 mm, preferably about 8 mm, and a thickness of 3 to 4 mm.
The oral disintegration time of the zonisamide OD tablet of the present invention is preferably within 30 seconds, and more preferably about 20 seconds.

The present invention will be explained below with reference to reference examples, examples, and test examples that the present inventors have investigated, but the present invention is not limited to these.

Reference Examples 1 to 4: Study on the selection and use of disintegrants With reference to the Examples described later, zonisamide OD tablets containing one type of disintegrant were prepared according to the formulation in Table 1 below. Each OD tablet was stored open under severe humidity conditions (25°C/RH 75%) for 1 day, and then the disintegration time was measured using a disintegration tester (Toyama Sangyo Co., Ltd., ZE6000). The results are also shown in Table 1.

Reference Examples 1 to 4 are zonisamide OD tablets containing crospovidone, carmellose, low-substituted hydroxypropyl cellulose, and corn starch, respectively, as disintegrants. However, it was found that the disintegration times of the tablets after storage in the open for 1 day under severe humidity conditions (25°C/RH 75%) were delayed compared to the tablets after preparation, except for carmellose, and these are not preferable.
In the case of carmellose, no delay in disintegration time was observed, but the disintegration time exceeded 30 seconds, which is not a desirable disintegration time for OD tablets.

In light of the above, it is believed that OD tablets with desirable disintegration times can be obtained by using carmellose, which has not been shown to cause disintegration delay, as one of the disintegrant components and combining it with other disintegrants. Based on this, an example of the present invention is described below in comparison with a comparative example in which it is used alone.

Example 1: (Combined use of multiple disintegrants)
Zonisamide, D-mannitol, light anhydrous silicic acid, and sucralose were placed in a fluidized bed granulation dryer (Freund Corporation, FLO-5), and a coating solution prepared by mixing ethylcellulose dissolved in ethanol with talc dispersed in water was sprayed to obtain coated granules. The coated granules were mixed once with D-mannitol, crystalline cellulose, crospovidone, carmellose, corn starch, and light anhydrous silicic acid, and magnesium stearate was added and mixed. The mixture was then placed in a tablet press (Hata Iron Works, Ltd., HT-EX6SS-II) and plain tablets (OD tablets) with a tablet thickness of 4.0 mm were produced using a punch with a diameter of 8 mm.

Comparative Example 1: (Disintegrant: Crospovidone used alone)
Zonisamide, D-mannitol, light anhydrous silicic acid, and sucralose were placed in a fluidized bed granulation dryer (FLO-5, Freund Corporation), and a coating solution prepared by mixing ethyl cellulose dissolved in ethanol with talc dispersed in water was sprayed to obtain coated granules. The coated granules were mixed with D-mannitol, crystalline cellulose, crospovidone, and light anhydrous silicic acid once, and magnesium stearate was added and mixed. The mixture was then placed in a tablet press (HT-EX6SS-II, Hata Iron Works, Ltd.) and a punch with a diameter of 8 mm was used to prepare plain tablets (OD tablets of Comparative Example 1) with a tablet thickness of 4.0 mm.

Comparative Example 2: (Disintegrant: Corn starch used alone)
Zonisamide, D-mannitol, light anhydrous silicic acid, and sucralose were placed in a fluidized bed granulation dryer (FLO-5, Freund Corporation), and a coating solution prepared by mixing ethyl cellulose dissolved in ethanol with talc dispersed in water was sprayed to obtain coated granules. The coated granules were mixed once with D-mannitol, crystalline cellulose, corn starch, and light anhydrous silicic acid, and magnesium stearate was added and mixed. The mixture was then placed in a tablet press (HT-EX6SS-II, Hata Iron Works Co., Ltd.) and a punch with a diameter of 8 mm was used to prepare plain tablets (OD tablets of Comparative Example 2) with a tablet thickness of 4.0 mm.

The compositions of Example 1 and Comparative Example 1 above are shown in Table 2 below.

Test Example 1: Disintegration test The samples (OD tablets) of Example 1 and Comparative Examples 1 and 2 were stored for one week under severe humidity conditions (25°C/RH 75%), and then the disintegration time was measured using a disintegration tester (Toyama Sangyo Co., Ltd., ZE6000). The results are shown in Table 3 below.

From the results of the above disintegration test, it was confirmed that a delay in disintegration was observed in Comparative Example 1 (disintegrant: crospovidone) and Comparative Example 2 (disintegrant: corn starch), in which a disintegrant was used alone, whereas no delay in disintegration was observed in Example 1 (disintegrant: combination of carmellose, crospovidone, and corn starch), in which carmellose, a representative water-conducting disintegrant, was used as one component of the disintegrant in combination with another disintegrant, and a rapid disintegration time (30 seconds or less) was obtained.
Therefore, the specificity of using carmellose, a representative water-conducting disintegrant of the present invention, as one component of the disintegrant in combination with a plurality of other disintegrants can be clearly understood.

The present invention provides zonisamide OD tablets that do not show any delay in disintegration time when stored under harsh humidity conditions, and therefore has great medical benefits.

Claims (6)

Zonisamide OD tablets are orally rapidly disintegrating tablets containing zonisamide as an active ingredient, and are characterized by containing 40-70% by weight of excipients and 5% by weight or less of lubricant as formulation additives relative to the total weight of the formulation, and by incorporating a combination of multiple disintegrants as disintegrants, resulting in improved delayed disintegration of the tablets. A zonisamide OD tablet with improved disintegration delay according to claim 1, wherein the excipient is one or more selected from lactose, glucose, fructose, sucrose, corn starch, potato starch, crystalline cellulose, mannitol, xylitol, sorbitol, erythritol, calcium phosphate, anhydrous calcium phosphate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. A zonisamide OD tablet with improved delayed disintegration of the tablet according to claim 1, wherein the disintegrant is two or more selected from partially pregelatinized starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carmellose, carmellose calcium, carmellose sodium, sodium starch glycolate, and corn starch. A zonisamide OD tablet with improved disintegration delay compared to the tablet described in claim 1, in which carmellose is one of multiple disintegrants. A zonisamide OD tablet with improved disintegration delay according to claim 1, in which the multiple disintegrants are a combination of carmellose, crospovidone and corn starch. A zonisamide OD tablet with improved disintegration delay according to claim 1, in which the total amount of disintegrant is 5 to 45% by weight of the formulation.