KR20210071242A - Pharmaceutical composition - Google Patents

Abstract

The present invention provides a pharmaceutical composition containing esomeprazole, which has excellent stability due to less generation of related substances even in a harsh atmosphere, as well as a low content reduction rate, and a solid preparation comprising the same. The present invention provides the pharmaceutical composition comprising esomeprazole or a pharmaceutically acceptable salt thereof, and magnesium hydroxide.

Description

Pharmaceutical composition {Pharmaceutical composition}

The present invention relates to pharmaceutical compositions containing esomeprazole.

Omeprazole exists in two isomers, the R-isomer and the S-isomer. It is known that the S-isomer is superior to the R-isomer in terms of therapeutic effects and side effects.

Among them, esomeprazole is (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole, indigestion, indigestion It is a representative proton pump inhibitor (PPI) used in the treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome.

Nexium tablets marketed by AstraZeneca Korea are Esomeprazole Magnesium Trihydrate, which is known to improve the stability of Esomeprazole.

Esomeprazole is susceptible to decomposition or transformation in acidic and neutral media, is promoted by acidic compounds, and is also affected by moisture, heat, organic solvents and light.

Accordingly, Korean Patent No. 10-0100996 proposed a method of mixing beta-cyclodextrin as a stabilizing component in esomeprazole, and Korean Patent No. 10-2006777 proposed a method of adding sodium hydrogen carbonate to esomeprazole. . Although it was said that the stability of esomeprazole was improved to some extent in this way, the mixing stability of these substances and esomeprazole was not good, and there was a problem in that the related substances increased when in contact with each other.

Republic of Korea Patent Registration No. 10-0100996 (June 21, 1996.06), method for preparing a core composition for oral omeprazole drug Korean Patent Registration No. 10-2006777 (2019.07.29), pharmaceutical formulation containing esomeprazole and sodium hydrogen carbonate

The present inventors performed an experiment by selecting various candidates capable of increasing the stability of esomeprazole while reducing the content of related substances, and as a result, when magnesium hydroxide, which is one of the substances used as a stabilizer and an alkalizer, is added, the above It was confirmed that it has bioequivalence with the commercially available Nexium tablet along with the stability improvement of esomeprazole.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising esomeprazole and magnesium hydroxide.

Another object of the present invention is to provide a solid preparation comprising the pharmaceutical composition.

The present invention provides a pharmaceutical composition comprising esomeprazole or a pharmaceutically acceptable salt thereof, and magnesium hydroxide.

At this time, the magnesium hydroxide is included in the total composition in an amount of 2 to 10% by weight.

The present invention also provides a solid formulation comprising the pharmaceutical composition.

The solid formulation is a tablet, and the tablet has a humidity of 75% at 45°C and an open state, and the content of the total related substances after 28 days from the initial is 2% by weight or less, and the content reduction rate under the same conditions is 4.5% by weight is below.

The pharmaceutical composition according to the present invention can manufacture a tablet with improved convenience and patient compliance while having bioequivalence compared to the Nexium tablet. In particular, the tablet of the present invention has a low water absorption rate and can improve formulation stability by minimizing the generation and content reduction rate of related substances even under severe conditions, and thus can be used as an alternative drug to the currently marketed Nexium tablet.

The present invention discloses a method in which stability can be improved by limiting the composition and content of a stabilizing agent or an alkalizing agent to esomeprazole in the preparation of a pharmaceutical composition comprising esomeprazole.

Esomeprazole is a compound represented by the following formula (1).

[Formula 1]

Esomeprazole of Formula 1 is named as (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole.

Nexium tablets, which are currently marketed esomeprazole, are formulated into tablets by preparing a pellet containing esomeprazole magnesium salt, enteric coating it, and adding an excipient. The Nexium tablet had an unsatisfactory problem in terms of stability, and in particular, as a result of being left in an atmosphere at 45°C and 75% humidity was maintained, the generation of related substances increased, and the content of esomeprazole in the formulation was severely reduced.

The present invention discloses a method capable of securing excellent stability even in a harsh environment while having bioequivalence compared to the existing Nexium tablet, which is easy to manufacture and has stability. For these effects and effects, an optimal effect can be achieved when magnesium hydroxide used as a stabilizing agent (or alkalizing agent) is used, but the content thereof is limited in the entire composition.

Stabilizer is a substance added to prevent decomposition by acid, moisture, light, etc., magnesium oxide, magnesium hydroxide, sodium hydrogen carbonate, calcium carbonate, magnesium carbonate, calcium silicate, meglumine, sodium carbonate, Various compositions are known, such as sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium citrate, and potassium citrate.

Among them, it was possible to secure the stability improvement of esomeprazole by using magnesium hydroxide, and in particular, it was limited to 2-10 wt%, 2.5-9.5 wt%, 3.0-8.5 wt%, 4.0-8 wt% in the total pharmaceutical composition. When used, it has the effect of lowering the generation rate of related substances even under a harsh experimental atmosphere and at the same time reducing the content reduction rate after tableting.

At this time, the content of esomeprazole is used in the range of 1 to 40% by weight, 5 to 35% by weight, and 10 to 30% by weight based on the total amount of the solid preparation.

The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient.

The pharmaceutically acceptable additive may be at least one selected from a diluent, a disintegrant, a binder, and a lubricant.

The diluent refers to a substance used to increase the total weight of the solid preparation, L-arginine, mannitol, microcrystalline cellulose, lactose, lactose hydrate, lactose anhydride, cellulose and its derivatives, dibasic or tribasic calcium phosphate, erythritol, It may be at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, starch, pregelatinized starch, sorbitol, and xylitol. According to one embodiment, the diluent may be lactose hydrate, lactose anhydride, and low-substituted hydroxypropyl cellulose. The content of the diluent may be 1 to 80% by weight, 5 to 75% by weight, or 10 to 70% by weight based on the total amount of the solid formulation, and outside this range, the desired effect due to the addition of the diluent may not be obtained. . According to one embodiment, L-arginine and microcrystalline cellulose are used together, but each of them is used in the range of 10 to 60% by weight and 20 to 60% by weight.

The disintegrant is a composition that can be easily decomposed to maintain the appropriate hardness of the solid preparation and to absorb the drug when administered orally, croscarmellose sodium, corn starch, crospovidone, low-substituted hydroxypropyl cellulose, and It may be at least one selected from the group consisting of pregelatinized starch. According to one embodiment, the disintegrant may be crospovidone. The content of the disintegrant may be 1 to 40% by weight, 5 to 30% by weight, or 10 to 25% by weight based on the total amount of the solid preparation, and outside this range, the desired effect due to the addition of the disintegrant cannot be obtained. can

A binder is a material capable of improving the productivity, uniformity and dissolution rate of a solid preparation by binding each composition, for example, hydroxypropyl cellulose, copovidone (copovidone, a copolymer of vinylpyrrolidone with other vinyl derivatives) , hydroxypropyl methyl cellulose, polyvinylpyrrolidone (povidone), pregelatinized starch, and at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, hypromellose, pregelatinized starch, and polyvinylacetic acid. have. According to one embodiment, the binder is povidone. The content of the binder may be 0.01 to 10% by weight, 0.1 to 7% by weight, or 0.3 to 5% by weight based on the total amount of the solid formulation, and outside this range, the desired effect may not be obtained due to the addition of the binder. .

Lubricants are used to improve the tableting process, for example, stearic acid, metal salts of stearate (eg, calcium stearate, magnesium stearate, sodium stearate, etc.), talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable It may be at least one selected from the group consisting of oils, waxes, glyceryl fatty acid esters, and glycerol dibehenate. According to one embodiment, the lubricant is sodium stearyl fumarate. The content of the lubricant may be 0.01 to 10% by weight, 0.1 to 7% by weight, or 0.3 to 5% by weight based on the total amount of the solid formulation, and outside this range, the desired effect due to the addition of the lubricant may not be obtained. .

In addition to the above additives, known additives such as a fluidizing agent, a stabilizer, a brightening agent, a surfactant, an antioxidant, a preservative, and a colorant may be further included.

The pharmaceutical composition comprising the composition as described above can be formulated into an orally administrable dosage form.

The orally administrable dosage form is not particularly limited whether it is a solid preparation or a non-solid preparation, but is preferably a solid preparation.

As used herein, "solid formulation" refers to a formulation made by molding or encapsulating a drug in a certain shape. The solid preparation may be any solid preparation for oral use prepared as wet granules or may include wet granules, for example, dry syrup, granules, tablets (including single-layered tablets, double-layered tablets, inner core tablets, etc.), pellets, Or it may be formulated as a capsule, etc., but is not limited thereto. The solid formulation may be one in which wet granules are filled in the form of tablets, pellets, or capsules. The tablets, pellets, and capsules may be those commonly used in the art. The capsule may be a hard capsule or a soft capsule. When the oral solid combination preparation is a capsule, the capsule may be in a form including granules or tablets therein. In one embodiment, the solid formulation may be a tablet including wet granules. In one embodiment, the oral solid formulation is a tablet.

The solid preparation of the present invention can be used as a representative proton pump inhibitor used in the treatment of indigestion, peptic ulcer disease, gastroesophageal reflux disease, Zollinger-Ellison syndrome, and the like.

The dosage of the solid preparation is, for example, in the range of 1 mg to 200 mg for adults, 5 mg to 100 mg, 5 mg to 90 mg, 5 mg to 80 mg, 5 mg to 75 mg, 5 mg to 70 mg. Or 5 mg - 60 mg are preferable, and 15 mg - 60 mg are still more preferable. The administration may be administered once a day, multiple times a day, or once a week, once every 2 weeks, once every 3 weeks, or once every 4 weeks to once a year. In one embodiment, the solid formulation may be administered at 50 mg per day once a day in the morning or dividedly administered at 50 mg per day at 25 mg twice a day twice a day in the morning and in the evening.

The solid preparation according to the present invention may be formulated in a tablet form by mixing esomeprazole and magnesium hydroxide, but by tableting with a pharmaceutical additive.

Tableting is a process of manufacturing tablets by applying a certain level of compression pressure, and is a process of binding particles by creating a bonding force between particles using a tableting machine. Specific steps are not particularly limited in the present invention.

A tableting machine is an equipment for molding powder or granules under strong pressure with punches and dies of various shapes, and may vary depending on the size and shape of the punches and dies.

Tablets may vary in shape, for example oval, triangular, almond, peanut, parallelogram, circular, pentagonal, hexagonal and trapezoidal. Preferred shapes are circular, oval and parallelogram shapes.

A coating process may be further performed after the additionally prepared tableting.

Tablets manufactured after the coating process are called coated tablets, and compressed tablets (eg, uncoated tablets) containing esomeprazole or a pharmaceutically acceptable salt thereof, and magnesium hydroxide are coated in a single layer or multiple layers using a coating base. .

The coating base used in the coating process may include a general coating agent used for tablets, preferably one that is difficult to dissolve in the intestinal pH environment and can promote dissolution of the active ingredient.

Examples of the base include cellulose derivatives such as hypromellose (hydroxypropylmethyl cellulose), hydroxypropyl cellulose, ethyl cellulose and methyl cellulose; polyvinyl compounds such as polyvinyl alcohol, povidone (polyvinylpyrrolidone), polyvinylacetal diethylaminoacetate, and vinyl acetate resin; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS and ethyl acrylate/methyl methacrylate copolymer dispersion; sugars such as sucrose and mannitol used for coating sugar; Polyethylene glycol and the like are possible, and these may be used alone or in combination of two or more. According to one embodiment, the coating agent includes Pharmacoat, Methocel, Sepifilm, Viscontran, Opadry, Etocell, Aquacoat, A coating base having a trade name such as Surelease, Viscontran, Tylopur, or Methocel may be used, but is not limited thereto.

In addition, the tablet of the present invention is a small preparation. The small size is a concept compared to the size of the existing esomeprazole capsules or core granules, which means that the size is small compared to conventionally known pharmaceuticals, and preferably, the weight of the tablet is 400 mg or less. It has a small size compared to the weight of about 540 mg of the conventional Nexium tablet.

Larger tablets reduce ease of dosing and reduce patient compliance as well. Esomeprazole is a prescription frequently used for chronic patients such as gastric ulcer, duodenal ulcer, and gastritis. When formulated in a small size, ease of administration and patient compliance can be increased.

The solid formulation according to the present invention was tested under severe stability conditions among stability conditions, and as a result, the moisture absorption rate was low, the generation of related substances was small, and the content reduction rate was low.

The harsh stability conditions are based on temperature 45°C and humidity 75%, and left in an open state, the content of total related substances after 28 days compared to the initial time is 2% by weight or less, 1.9% by weight or less, 1.8% by weight or less, 1.7% by weight or less, 1.6 wt% or less, 1.5 wt% or less, 1.3 wt% or less.

In addition, as a result of measuring the content reduction rate under the same conditions, they were 4.5 wt% or less, 3.8 wt% or less, 2.5 wt% or less, 2.0 wt% or less, 1.9 wt% or less, and 1.8 wt%.

[Example]

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Examples and Comparative Examples

The compositions of Tables 1 and 2 were mixed, and a lubricant was added and mixed, followed by tableting to prepare uncoated tablets.

Uncooked (wt%) Example 1 Example 2 Example 3 Example 4 Example 5 esomeprazole magnesium 15.03 15.03 15.03 15.03 15.03 L-Arginine 25.34 25.34 25.34 25.34 25.34 stabilizer magnesium hydroxide 1.01 2.53 5.07 7.60 15.20 Microcrystalline Cellulose 44.59 43.07 40.54 38.01 30.41 D-mannitol 1.52 1.52 1.52 1.52 1.52 povidone 5.07 5.07 5.07 5.07 5.07 crospovidone 5.07 5.07 5.07 5.07 5.07 Sodium Stearyl Fumarate 2.36 2.36 2.36 2.36 2.36

Uncooked (wt%) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 esomeprazole magnesium 15.03 15.03 15.03 15.03 15.03 15.03 L-Arginine 25.34 25.34 25.34 25.34 25.34 - stabilizer magnesium oxide 5.07 - - - - - sodium bicarbonate - 5.07 - - - - meglumine - - 5.07 - - - calcium silicate - - - 5.07 - - calcium carbonate - - - - 5.07 - Microcrystalline Cellulose 40.54 40.54 40.54 40.54 40.54 70.95 D-mannitol 1.52 1.52 1.52 1.52 1.52 1.52 povidone 5.07 5.07 5.07 5.07 5.07 5.07 crospovidone 5.07 5.07 5.07 5.07 5.07 5.07 Sodium Stearyl Fumarate 2.36 2.36 2.36 2.36 2.36 2.36

Experimental Example 1: Water absorption stability test

The uncoated tablets of Examples and Comparative Examples were stored at room temperature (30° C., 50 %RH) for 1 day, and the change in weight of the tablets over time was measured and shown in Table 3 below.

Weight change per hour (%) (30℃/50%RH, open condition) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 1 hours 3.6 2.6 0.9 0.9 0.7 0.9 2 hours 4.2 3.1 1.5 1.4 1.3 1.5 4 hours 5.4 4.3 2.5 2.4 2.4 2.6 8 hours 5.3 5.0 3.5 3.2 3.3 4.2 24 hours 5.2 4.8 3.3 3.2 3.2 4.7

Table 3 is a primary evaluation of tablet stability, and the weight of the tablet increased by absorbing moisture in the air over time, but as the content of magnesium oxide increased, the stability to moisture showed a tendency to improve.

In comparison, it can be seen that the tablet of Comparative Example 1 has a large increase in weight, so that the addition of magnesium hydroxide can further improve the stability to moisture during tablet manufacture.

Experimental Example 2: Stability test of related substances

The uncoated tablets of Examples and Comparative Examples were dissolved in Opadry II (85F18422), Opadry Acrylic (93A18597) and Opadry II (85F15458) in purified water and sequentially coated to prepare the tablets of Examples and Comparative Examples. The mass of the unit dosage form of the final manufactured tablet was 380 mg.

In order to confirm the stability of esomeprazole according to the type and content of the stabilizer, 10 tablets of each of the Examples and Comparative Examples were collected, exposed to severe (45°C, 75% humidity) conditions for 2 weeks, and then 50 mL It was placed in a volumetric flask, 20 mL of methanol was added, and ultrasonic extraction was performed for 10 minutes. After cooling, the mark was adjusted with the mobile phase, and the sample solution was filtered through a membrane filter of 0.45 μm or less and high-performance liquid chromatography (HPLC) was performed. The results obtained are shown in the table below.

Changes in the content of related substances according to the type of stabilizer Stabilizer type Related Substances D (Standard 0.2% or less) / Total Related Substances (Standard 2% or less), Early Day 7 Day 14 Day 21 Day 28 Example 3 magnesium hydroxide (D 0.04)
0.24 (D 0.06)
0.61 (D 0.07)
1.13 (D 0.09)
1.40 (D 0.09)
1.92 Comparative Example 1 magnesium oxide (D 0.06)
0.31 (D 0.10)
0.57 (D 0.16)
0.88 (D 0.22)
1.03 (D 0.26)
1.42 Comparative Example 2 sodium bicarbonate (D 0.04)
0.32 (D 0.07)
0.69 (D 0.08
1.23 (D 0.09)
2.05 (D 0.09)
2.93 Comparative Example 3 meglumine (D 0.07)
0.24 - - (D 0.09)
0.62 purified moisture Comparative Example 4 calcium silicate (D 0.08)
0.28 - - (D 0.13)
1.73 purified moisture Comparative Example 5 calcium carbonate (D 0.06)
0.24 - - (D 0.19)
1.66 purified moisture Comparative Example 6 placebo (D 0.03)
0.23 (D 0.04)
1.05 (D 0.05)
1.73 (D 0.07)
2.56 (D 0.07)
3.42 Control Example 1 Nexium Tablet (D 0.06)
0.29 (D 0.16
0.78 (D 0.15)
1.07 (D 0.22)
1.61 D 0.27
2.22

Referring to Table 4, when the magnesium hydroxide according to the present invention was used as a stabilizer, the generation of related substances was low even under severe conditions, which means that significant decomposition of esomeprazole did not occur. In comparison, it was confirmed that commercially available Nexium tablets significantly increased the content of related substances under severe conditions.

Experimental Example 3: Stability test of content reduction rate

The tablets of Examples and Comparative Examples were stored for 28 days under accelerated conditions (40° C., 75 % RH), and the reduction rate of esomeprazole content at the initial, 7th, 14th, 21st, and 28th days was measured. The content of esomeprazole was evaluated by measuring the absorbance at 305 nm with an ultraviolet absorptiometer by dissolving the tablets in 50% methanol for the reduction in the content.

Decrease rate of esomeprazole content according to the type of stabilizer (%) Control Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Example 3 Early 101.95 99.52 105.21 105.21 105.21 103.5 Day 7 102.31 99 104.37 104.37 104.37 101.57 Day 14 104.21 96.86 99.07 99.07 99.07 100.51 Day 21 95.14 100.07 100.61 100.61 100.61 100.28 Day 28 93.05 95.7 96.21 96.21 96.21 101.62 content reduction rate 8.73 3.83 8.55 8.55 8.55 1.81

Referring to Table 5 above, when magnesium hydroxide according to the present invention was used as a stabilizer, the content change was small even under severe conditions for 4 weeks, which means that significant decomposition of esomeprazole did not occur. In comparison, the commercially available Nexium tablet had a severe content decrease under severe conditions.

Decrease rate of esomeprazole content according to stabilizer content (%) Example 1 Example 2 Example 3 Example 4 Example 5 Control Example 1 Early 103.1 103.9 103.5 103.6 103.8 101.95 Day 7 102.83 102.55 101.57 103.2 101.44 102.31 Day 14 101.8 101.51 100.51 101.45 100.29 104.21 Day 21 100.89 100.76 100.28 101.04 100.31 95.14 Day 28 99.58 99.98 101.62 100.99 99.18 93.05 content reduction rate 3.41 3.77 1.81 2.52 4.45 8.73

Referring to Table 6, as a result of changing the content of magnesium hydroxide as a stabilizer, it can be seen that the content reduction rate is changed according to the content of the magnesium hydroxide. In particular, it can be seen that in Examples 3 and 4, the content reduction rate of esomeprazole in the tablet is very small.

Through this, it can be seen that even when magnesium hydroxide is used as a stabilizer, it is necessary to control its content.

Experimental Example 4: Comparison of properties with commercial formulations

Each tablet of Example 3 has a total weight of about 380 mg, and in the case of a commercially available Nexium tablet, about 540 mg, it can be seen that the size of the tablet according to the present invention is small. These small-sized tablets bring excellent results in convenience of administration and patient preference in Experimental Example 5 below.

Experimental Example 5: Convenience of taking and patient preference test

For the tablets of Examples 3 and 4 prepared according to the present invention and the tablets of Control Example 1 (Nexium tablet 40 mg), which are commercially available tablets, administration convenience and patient preference tests were conducted on 30 patients.

The patients were randomly assigned to group 1 as 10 patients, and then each group was instructed to take each tablet. As for the convenience of taking, the degree of ease of swallowing the tablet when swallowing was scored using a scoring method of 1: very hard / 2: hard / 3: normal / 4: easy / 5: very easy. The average value was calculated. The test results are shown in the table below.

Control Example 1 (Nexium Tablet) Example 3 Example 4 Convenience of taking 2.3 4.8 4.7 patient preference 6 people 15 people 9 people

As shown in Table 7, the tablet according to the present invention, Example 3, had the highest score for convenience in taking. It was confirmed that the tablet of Example 3 reduced the unit dosage form (about 540 mg) of Nexium tablet marketed in a unit dosage form of 380 mg by about 30%, thereby improving patient convenience and preference.

Claims (11)

A pharmaceutical composition comprising esomeprazole or a pharmaceutically acceptable salt thereof, and magnesium hydroxide. According to claim 1,
The pharmaceutical composition, wherein the magnesium hydroxide is comprised in an amount of 2 to 10% by weight in the total composition. According to claim 1,
A pharmaceutical composition, further comprising one or more pharmaceutical additives selected from the group consisting of diluents, disintegrants, binders, and lubricants. 4. The method of claim 3,
The diluent is at least one selected from the group consisting of microcrystalline cellulose, L-arginine, lactose, sucrose, crystalline cellulose, cellulose, and siliconized microcrystalline cellulose. 4. The method of claim 3,
The binder is a pharmaceutical composition, characterized in that at least one selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, carboxymethyl cellulose, sodium phosphate, and starch. 4. The method of claim 3, wherein the disintegrant is at least one selected from the group consisting of crospovidone, carboxymethylcellulose calcium, croscarmellose sodium, starch, sodium starch glycolate, and low-substituted hydroxypropyl cellulose. pharmaceutical composition. 4. The method of claim 3,
The lubricant is sodium stearyl fumarate, talc, magnesium stearate, silicon dioxide, stearic acid, a pharmaceutical composition, characterized in that at least one selected from the group consisting of hydrogenated oil. According to claim 1,
The pharmaceutical composition is formulated into a tablet comprising a coated tablet. 9. The method of claim 8,
The coated tablet is a compressed tablet comprising esomeprazole or a pharmaceutically acceptable salt thereof, and magnesium hydroxide, and a coating base is coated in a single layer or in multiple layers, a pharmaceutical composition. 9. The method of claim 8,
The tablet is 45 ° C. humidity 75%, based on standing in an open state, the content of the total related substances after 28 days compared to the initial is 2% by weight or less, and the content reduction rate under the same conditions is 4.5% by weight or less, pharmaceutical composition. 9. The method of claim 8,
The tablet is a pharmaceutical composition wherein the weight of the unit dosage form is 400 mg or less.