WO2011049122A1

WO2011049122A1 - Pravastatin sodium tablet rapidly disintegrating in oral cavity and method for producing same

Info

Publication number: WO2011049122A1
Application number: PCT/JP2010/068468
Authority: WO
Inventors: 勉今野; 由雄久野; 慎一朗田尻; 充英谷本
Original assignee: 第一三共株式会社
Priority date: 2009-10-21
Filing date: 2010-10-20
Publication date: 2011-04-28
Also published as: JPWO2011049122A1

Abstract

Provided is a pravastatin sodium tablet rapidly disintegrating in the oral cavity, which shows rapid disintegration properties and a high solubility when put into the oral cavity or water, has such a hardness as causing no breakage in the course of production and distribution, has a high storage stability and has an equivalent bioavailability to a pravastatin sodium tablet that is to be taken together with water. The aforesaid pravastatin sodium tablet rapidly disintegrating in the oral cavity comprises anhydrous calcium hydrogen phosphate and pravastatin sodium.

Description

Pravastatin sodium intraoral quick disintegrating tablet and method for producing the same

The present invention is a rapidly disintegrating pravastatin sodium tablet comprising pravastatin sodium as an active ingredient, having rapid disintegration when contained in the mouth or in water and exhibiting pharmacokinetics equivalent to that of a normal tablet. And a manufacturing method thereof.

Tablets, capsules, troches, chewable tablets, granules, powders, etc. are known as dosage forms for oral solid preparations in the fields of pharmaceuticals and foods, but they are also suitable for elderly people, children and patients who have difficulty swallowing Development of a dosage form that is easy to handle and easy to take is desired.

Tablets and capsules require water when taken, and problems such as difficulty in swallowing and use in the pharynx and esophagus when large preparations or large quantities are taken are pointed out.

Especially in elderly people, children, and patients who have difficulty swallowing, this problem is great, and sometimes the throat becomes clogged and suffocates, or it adheres to the esophagus and may be inflamed due to the influence of drugs.

A lozenge is a dosage form that dissolves or disintegrates gradually in the mouth and is applied to the oral cavity, pharynx, etc. It does not require water, but it may clog the pharynx and esophagus if accidentally swallowed.

Chewable tablets are chewable dosage forms that do not require water, but are not suitable for the elderly or children with weak chewing ability.

Granules and powders require water at the time of taking, and also have problems of remaining in the oral cavity, slipping off at the time of taking, and entering between dentures to cause pain.

On the other hand, in recent years, a tube administration method has been implemented in which a drug is administered by inserting a gastric tube catheter orally or nasally to a severe patient who has difficulty swallowing. At present, a method is used in which tablets or granules are pulverized or powdered as they are, suspended in 20 to 30 ml of water and injected into a gastric tube catheter with a syringe. However, there is a problem that the operation is complicated, and sometimes the inner diameter of the catheter is as thin as 2 to 4 mm, so that it is easily clogged.

From these backgrounds, oral disintegrating tablets that rapidly disintegrate or dissolve when contained in the mouth or when placed in water are known as dosage forms suitable for the elderly, children, or patients who have difficulty swallowing. Yes.

On the other hand, when switching from a tablet to be taken with water to a rapidly disintegrating tablet in the oral cavity, if the amount of active ingredient is the same, it is necessary to show the same medicinal effect. It is necessary to be.

Pravastatin sodium is widely used as a therapeutic agent for hyperlipidemia, but is known to change to a lactone form in a low pH region and lose its pharmacological effect (Patent Document 1). Need to prevent. In addition, various analogs are known for pravastatin sodium, and it is necessary to prevent the formation of these analogs during storage.

European Patent Application No. 0336298

The object of the present invention is to quickly disintegrate and dissolve in the oral cavity or in water, has a hardness that does not collapse in the manufacturing process and distribution process, has excellent storage stability, and water. The purpose is to provide pravastatin sodium orally disintegrating tablets that have the same bioavailability as pravastatin sodium tablets taken together.

Another object of the present invention is to produce pravastatin sodium intraoral rapidly disintegrating tablets having the above-mentioned excellent characteristics by the same dry method as a normal tableting method without requiring a complicated process or special equipment. It is to provide a method with excellent industrial productivity.

As a result of intensive studies to solve the above problems, the present inventors have found that pravastatin sodium intraoral rapidly disintegrating tablets containing anhydrous calcium hydrogen phosphate and pravastatin sodium can solve the above problems, and have completed the present invention. It was.

That is, the present invention provides pravastatin sodium intraoral rapidly disintegrating tablets and a method for producing the same, characterized by containing anhydrous calcium hydrogen phosphate and pravastatin sodium.
That is, the present invention
(1) pravastatin sodium oral disintegrating tablet containing pravastatin sodium and anhydrous calcium hydrogen phosphate,
(2) The pravastatin sodium intraoral rapidly disintegrating tablet according to (1), further comprising an alkali metal salt of carbonic acid or an alkali metal salt of an organic acid,
(3) Pravastatin sodium intraoral rapidly disintegrating tablet according to (1), further comprising sodium citrate or sodium tartrate,
(4) Pravastatin sodium oral disintegrating tablet according to (2), characterized by containing an alkali metal salt of carbonic acid,
(5) The pravastatin sodium orally disintegrating tablet according to (2) or (4), wherein the alkali metal salt of carbonic acid is any one selected from the group consisting of sodium hydrogen carbonate, sodium carbonate and calcium carbonate,
(6) Pravastatin sodium intraoral rapidly disintegrating tablet according to any one of (1) to (5), comprising crospovidone as a disintegrant;
(7) Pravastatin sodium intraoral rapidly disintegrating tablet according to any one of (1) to (6), further comprising crystalline cellulose and / or powdered cellulose,
(8) Pravastatin sodium intraoral quick disintegrating tablet according to (7), characterized by containing crystalline cellulose;
(9) Pravastatin sodium oral disintegrating tablet according to any one of (1) to (8), further comprising calcium silicate,
(10) Pravastatin sodium intraoral rapidly disintegrating tablet according to any one of (1) to (9), further comprising magnesium aluminate metasilicate
(11) The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of (1) to (10), further comprising a sweetener, a fragrance, and a lubricant,
(12) A method for producing pravastatin sodium intraoral rapidly disintegrating tablet by mixing and compressing a composition containing pravastatin sodium and anhydrous calcium hydrogen phosphate,
(13) A method for producing pravastatin sodium orally disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium bicarbonate and anhydrous calcium hydrogen phosphate,
(14) A method for producing pravastatin sodium intraoral rapidly disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate and crospovidone,
(15) A method for producing pravastatin sodium orally disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone and crystalline cellulose,
(16) The method for producing pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 12 to 15, wherein the tableting is direct tableting,
Consists of.

According to the present invention, when placed in the oral cavity or in water, it has rapid disintegration and solubility, has hardness that does not collapse in the manufacturing process and distribution process, has excellent storage stability, and has bioavailability. Equivalent pravastatin sodium intraoral quick disintegrating tablets could be provided.

Furthermore, according to the present invention, there is provided a production method for producing an orally rapidly disintegrating tablet having excellent characteristics as described above by a normal tableting method without requiring a complicated process or special equipment. did it.

The figure which shows the influence which the addition of various pH regulators has on the pravastatin density | concentration transition in plasma (n = 5). The horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma. The figure which shows the influence which the addition amount of sodium hydrogencarbonate has on the pravastatin concentration transition in plasma (n = 5, mean ± SD). The horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma. The figure which shows the influence which the presence or absence of the addition of sodium hydrogen carbonate in the anhydrous calcium hydrogen phosphate addition prescription has on the pravastatin concentration transition in plasma (n = 10, mean ± SD). The horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma.

In the present invention, pravastatin sodium orally disintegrating tablet is a preparation containing pravastatin sodium as an active ingredient, and is a compression-molded product having a practically sufficient strength in the preparation process and distribution process of the preparation, and contained in the mouth. It is a compression-molded product that has rapid disintegration and solubility when placed in water or water. As an example, pravastatin sodium oral disintegrating tablet containing pravastatin sodium and anhydrous calcium hydrogen phosphate can be mentioned. As another example, pravastatin sodium, an alkali metal salt of carbonic acid or an alkali metal salt of organic acid, and pravastatin sodium orally disintegrating tablet containing anhydrous calcium hydrogen phosphate can be mentioned. The alkali metal salt of carbonic acid and the alkali metal salt of organic acid are not limited as long as the pH of pravastatin sodium orally disintegrating tablet is maintained alkaline and the pharmacokinetics of pravastatin sodium is equivalent to pravastatin sodium tablet. Examples of the alkali metal salt of carbonic acid include at least one selected from the group consisting of sodium bicarbonate, sodium carbonate, and calcium carbonate. Examples of the alkali metal salt of organic acid include citric acid. Examples thereof include sodium acid and sodium tartrate, and sodium hydrogen carbonate is preferable. As another example, pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate can be mentioned. As another example, pravastatin sodium, sodium bicarbonate, anhydrous calcium hydrogen phosphate, pravastatin sodium orally disintegrating tablet containing disintegrant can be mentioned. As another example, pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone can be mentioned. As yet another example, pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone, and pravastatin sodium orally disintegrating tablet containing crystalline cellulose and / or powdered cellulose can be mentioned. As yet another example, pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone and crystalline cellulose can be mentioned. As yet another example, pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium bicarbonate, anhydrous calcium hydrogen phosphate, crospovidone, crystalline cellulose and calcium silicate can be mentioned. As yet another example, pravastatin sodium orally disintegrating tablet containing sodium pravastatin, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone, crystalline cellulose, calcium silicate and magnesium aluminate metasilicate can be mentioned. .

The amount of pravastatin sodium in pravastatin sodium orally disintegrating tablet is 1 to 70% by weight, preferably 1 to 50% by weight, more preferably 1 to 30% by weight, based on the total amount of solid components.

In the pravastatin sodium intraoral quick disintegrating tablet, the blending amount of each component can be arbitrarily set according to the content ratio of pravastatin sodium as long as it has the effect of the present invention.

For example, in an example of pravastatin sodium intraoral quick disintegrating tablet (pravastatin content: 4% by weight) containing pravastatin sodium 10 mg as a whole, the content ratio of each component is as follows, for example. The content of anhydrous calcium hydrogen phosphate is 10 to 90%, preferably 20 to 85%, more preferably 25 to 85%. The content of crospovidone is 0.5 to 15%, preferably 1 to 5%. The content of crystalline cellulose is 0 to 30%, preferably 5 to 20%. The content of calcium silicate is 0 to 5%, preferably 0.5 to 5%. The content of magnesium aluminate metasilicate is 0 to 5%, preferably 0.3 to 3%.

For example, in an example of pravastatin sodium intraoral rapidly disintegrating tablet (pravastatin content: 5% by weight) including pravastatin sodium 10 mg as a whole, the content ratio of each component is as follows, for example. The content ratio of sodium hydrogen carbonate is 1 to 70% by weight, preferably 3 to 60% by weight, and more preferably 5 to 50% by weight. The content of anhydrous sodium phosphate is 10 to 80%, preferably 20 to 75%, more preferably 25 to 70%. The content of crospovidone is 0.5 to 15%, preferably 1 to 10%. The content of crystalline cellulose is 0 to 30%, preferably 5 to 20%. The content of calcium silicate is 0 to 5%, preferably 0.5 to 5%. The content of magnesium aluminate metasilicate is 0 to 5%, preferably 0.3 to 3%.

Also in pravastatin sodium intraoral quick disintegrating tablet containing 5 mg of pravastatin sodium, the content ratio of each component can be set according to the above.

The pravastatin sodium intraoral quick disintegrating tablet can contain various additives generally used in the manufacture of tablets as long as the effect of the invention is not hindered in addition to the above components.

Examples of the additive include a lubricant, a disintegrant, an excipient, a binder, a coloring agent, a flavoring agent, a sweetening agent, a corrigent, a fluidizing agent, a foaming agent, and a surfactant. .

Examples of the lubricant include one or a combination of two or more selected from magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, talc, sucrose fatty acid ester, polyethylene glycol and hydrogenated oil. Preferably, it is magnesium stearate.

The disintegrant may include one or a combination of two or more selected from crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium alginate, calcium alginate, carmellose and carmellose calcium, corn starch Preferably, crospovidone is used.

Examples of excipients include organic excipients selected from saccharides, starches, and celluloses, and inorganic excipients. Examples of the saccharide include one or a combination of two or more selected from sucrose, glucose and fructose. Examples of the starches include one or a combination of two or more selected from corn starch, potato starch, rice starch, and partially pregelatinized starch. Examples of celluloses include, in addition to crystalline cellulose, one or a combination of two or more selected from powdered cellulose, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, and croscarmellose sodium. Examples of the inorganic excipient include one or a combination of two or more selected from synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminate silicate and magnesium hydroxide. be able to.

As the binder, for example, selected from gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone and macrogol One or a combination of two or more may be mentioned.

The colorant is selected from, for example, edible dyes such as edible yellow No. 5, edible red No. 2 and edible blue No. 2; edible lake dyes, yellow ferric oxide, ferric oxide, titanium oxide, β-carotene and riboflavin One or a combination of two or more can be mentioned.

Examples of the flavoring agent include one or a combination of two or more selected from orange, lemon, mint, menthol, menthol micron, and various flavors.

Examples of the sweetener include one or a combination of two or more selected from saccharin sodium, aspartame, acesulfame potassium, dipotassium glycyrrhizinate and steviathomatin.

Examples of the corrigent include one or a combination of two or more selected from sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

Examples of the surfactant include one or a combination of two or more selected from polyoxyl 40 stearate, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate and sodium lauryl sulfate. it can.

Examples of the foaming agent include tartaric acid and / or anhydrous citric acid.

Examples of the fluidizing agent include one or a combination of two or more selected from hydrous silicon dioxide, light anhydrous silicic acid, and talc.

As the method for producing the preparation, wet granulation method, dry granulation method, direct tableting method and the like are known, and in the production of pravastatin sodium intraoral rapidly disintegrating tablet of the present invention, as long as it has the effect of the present invention. Although not limited, the direct compression method is preferred.

The pravastatin sodium intraoral quick disintegrating tablet of the present invention is produced by, for example, mixing anhydrous calcium hydrogen phosphate, crystalline cellulose, crospovidone, pravastatin sodium and the above-mentioned additives and then directly compressing them with a tableting machine.

The molding pressure by the tableting machine may be about the same as that of ordinary tablets, and is about 50 to 2000 kg / cm ² , preferably 100 to 1800 kg / cm ² , more preferably about 200 to 1600 kg / cm ² .

The thus-obtained pravastatin sodium intraoral rapidly disintegrating tablet is excellent in disintegration and solubility when placed in the oral cavity or in water, and is excellent in physical and chemical stability.

Disintegration or dissolution of pravastatin sodium intraoral quick disintegrating tablet is the disintegration or dissolution time in the oral cavity (the time until the tablet is completely dissolved in the mouth of a healthy adult male without water and with only saliva. ) Is usually 5 to 120 seconds, preferably 5 to 60 seconds, more preferably about 5 to 30 seconds.

Pravastatin sodium intraoral rapidly disintegrating tablets gradually disintegrate or dissolve by saliva when contained in the mouth, but by oral pressure, that is, pressure by the upper jaw and tongue, or friction by the tongue, that is, "licking" action, etc. Disintegrate or dissolve in a shorter time.
For people who are dry in the mouth or who have little saliva, they can be disintegrated and dissolved in the mouth using water or hot water, or they can be taken with water just like normal tablets. .

It should be noted that pravastatin sodium intraoral quick disintegrating tablet does not disintegrate or dissolve instantly (for example, within 1 second), so that it can be included in the mouth and tasted, and can be exhaled if necessary.

The pravastatin sodium intraoral quick disintegrating tablet of the present invention has bioavailability equivalent to that of pravastatin sodium tablet taken with water. For example, when administered directly to dogs or dissolved in a small amount of saliva of about 2 ml, the equivalent AUC (area under the blood content time curve: area under the drug blood concentration-time curve) and Cmax (maximum blood concentration) Concentration).

On the other hand, the hardness (measured by a tablet hardness meter) of pravastatin sodium intraoral rapidly disintegrating tablet of the present invention is a stability test under temperature and humidity (40 ° C., humidity 75%, open system, 1 week) or room temperature conditions (25 Even after the stability test at 0 ° C., humidity 60%, open system, 1 week), it shows 2.0 kp or more. This hardness is a hardness that does not collapse in the manufacturing process and the distribution process.

In addition, the pravastatin sodium intraoral rapidly disintegrating tablet of the present invention does not show an increase in pravastatin related substances that are problematic as pharmaceuticals in the stability test under the above temperature and humidity conditions.

Therefore, pravastatin sodium intraoral rapidly disintegrating tablet has a hardness that does not collapse in the manufacturing process and distribution process of the preparation, has a practical hardness even in storage under temperature and humidity, and has excellent storage stability. .

In addition, pravastatin sodium intraoral quick disintegrating tablet of the present invention is pravastatin sodium current tablet (mevalotin (registered trademark): manufactured by Daiichi Sankyo Co., Ltd .; pravastatin sodium, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, aluminum metasilicate It contains the same pharmacokinetics as magnesium oxide, lactose hydrate and magnesium stearate.) It is easy to take for the elderly and children, and is safe for general adults. It can be used for the treatment and prevention of various diseases.

Hereinafter, the present invention will be described in more detail with reference to examples, but these examples do not limit the present invention.

1. Test method The following tests were conducted on tablets of each formulation obtained in the examples.

1-1. Dog evaluation test The dog test was conducted as follows.

1-1-1. Dog type: Beagle, male, over 20 weeks of age 1-1-2. Dog treatment method: Tetragastrin (60 mg / body) was intramuscularly administered 30 minutes before administration of the preparation, immediately before administration, and 30 minutes after administration.

1-1-3. Administration method: 10 mg pravastatin sodium tablet (Mevalotin (registered trademark) tablet 10: manufactured by Daiichi Sankyo Co., Ltd .; referred to as “current tablet”) was taken to dogs with 40 mL of water. Pravastatin sodium intraoral quick disintegrating tablet was taken without water.

1-1-4. Blood collection time: 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours and 8 hours after administration 1-2. Appearance One tablet was placed on a white paper and the appearance was observed.

1-3. Color tone The color tone of each tablet was measured using a color difference meter (model number: manufactured by Nippon Denshoku Industries Co., Ltd.) against a white plate. For stored products for the stability test, the ΔE value with the tablet (initial product) at the start of the test was also determined.

Here, ΔE was calculated from the color difference from the storage start product by the following formula.

1-4. Hardness test method The breaking strength in the diameter direction of the tablet was measured using a tablet hardness meter (TBH28: manufactured by L Baker).

1-4. Oral Disintegration Test A tablet was included in the oral cavity of a healthy adult male without water, and the time until the tablet disintegrated and dissolved from the oral cavity was measured.

1-5. Analysis of pravastatin analogues 1-5-1.
One pravastatin sodium intraoral rapidly disintegrating tablet was added to and suspended in about 8 mL of a water / methanol (1: 1) mixed solution, and a water / methanol (1: 1) mixed solution was further added to make the volume 10 mL. This solution was filtered with a membrane filter (Millex-LH, pore size 0.45 μm, manufactured by Millipore), and the filtrate after removing 5 mL of the first filtrate was used as a sample solution.

1-5-2
50 mg of pravastatin sodium (Daiichi Sankyo Propharma Co., Ltd.) is dissolved by adding about 40 mL of a water / methanol (1: 1) mixed solution, and further a water / methanol (1: 1) mixed solution is added to adjust the volume to 50 mL. It was. 1 mL of this solution was added to a water / methanol (1: 1) mixed solution to make exactly 100 mL, and this solution was filtered with a membrane filter (Millex-LH, pore size: 0.45 μm) to remove the first 5 mL of the filtrate. The later filtrate was used as a standard solution.

The sample solution and 20 μL of the standard solution were tested by liquid chromatography under the following conditions, each peak area of each solution was measured by an automatic integration method, and the amount of each related substance was determined according to the following formula. The related substances were specified by relative retention times with respect to pravastatin sodium and expressed as Compound A, Compound B, and Compound C.

Calculation formula Amount of individual related substances (%) = Ws × A _T / A _S × 1 / R _T × 1/500 × 1/10 × 100

W _S : Weighed amount of pravastatin sodium (mg)
A _T : Peak area of each related substance in sample solution A _S : Peak area of pravastatin in standard solution 1/500: Dilution conversion factor 10: Theoretical amount of pravastatin in 1 tablet of this product (mg)
R _T : Relative sensitivity ratio to pravastatin sodium Compound A: 0.58
Compound B: 1.00
Compound C: 1.00
Other related substances: 1.00

<Test conditions>
Detector: UV absorptiometer (measurement wavelength: 238 nm)
Column: Column, Ultrasphere ODS, Analytical, 4.6 mm ID, 150 mm length (manufactured by BECKMAN COULTER)
Mobile phase A: water / methanol / acetic acid (100) / triethylamine mixture (750: 250: 1: 1)
Mobile phase B: methanol / water / acetic acid (100) / triethylamine mixed solution (650: 350: 1: 1)
Transfer of mobile phase: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 1.

Flow rate: The pravastatin peak was adjusted to about 21 minutes (a constant amount of 1.3 mL / min per minute).

Injection volume: 20 μL
Injector cleaning solution: water / methanol mixture (1: 1)
Needle cleaning solution: water / methanol mixture (2: 8)
Column temperature: 25 ° C
Sample cooler temperature: 5 ° C
Area measurement range: About 3.5 times the retention time of pravastatin (about 75 minutes)
Example 1. Effect of pH adjuster Pravastatin sodium intraoral rapidly disintegrating tablets using sodium bicarbonate, magnesium oxide and synthetic hydrotalcite as pH adjusters were prepared, and the pharmacokinetics were examined. Components shown in Table 2 were mixed in a V-type mixer (Patterson-Kelly Co.) to obtain a mixed powder. The obtained mixed powder was tableted using a single tableting machine (N-30E: manufactured by Okada Seiko Co., Ltd.) in which a small amount of magnesium stearate was applied to a mortar and a punch. Table 1 shows the formulations of the obtained tablets (Prescription Example 1, Comparative Example 1, Comparative Example 2).

FIG. 1 shows changes in blood drug concentration when the obtained tablets (Prescription Example 1, Comparative Example 1 and Comparative Example 2) were administered to dogs according to the method described in “1. Test Method” without water. Is shown in Table 3. For reference, the blood drug concentration transition when the current tablet is administered to dogs with water is also shown.

When a tablet containing sodium bicarbonate as a pH regulator is administered without water, the area under the AUC (area under the concentration concentration curve: time under the drug blood concentration-time curve) is the same as when the current tablet is administered with water. ) And Cmax (maximum blood concentration). On the other hand, in the tablet of Comparative Example 1 using magnesium oxide as a pH adjuster, AUC and Cmax are about 60-70% as compared with the current tablet, and in Comparative Example 2 using synthetic hydrotalcite as a pH adjuster. In the tablets, AUC and Cmax were about 50%, and both tablets showed lower blood drug concentration transitions than the current tablets.

Example 2 Effect of sodium bicarbonate addition amount In order to examine the effect of sodium bicarbonate addition amount, tablets (Prescription Example 2, Formulation Example 3 and Comparative Example 3) shown in Table 4 were obtained in the same manner as in Example 1. It was.

FIG. 2 shows the changes in blood drug concentration when the obtained tablets were administered to dogs without water, and Table 5 shows the pK parameters. For reference, the blood drug concentration transition when the current tablet is administered to dogs with water is also shown.

When the tablet of Formulation Example 2 containing 10 mg of sodium bicarbonate and the tablet of Formulation Example 3 containing 50 mg of sodium bicarbonate were administered without water, the AUC was compared with the case where the current tablet was administered with water. And Cmax was about 90-100%, which was shown to show a similar blood drug profile. On the other hand, in Comparative Example 3 containing 350 mg of sodium hydrogen carbonate, AUC and Cmax were as high as about 150% compared to the case where the current tablet was administered, indicating a higher blood drug concentration transition than the current tablet.

Example 3 Stability test In order to examine the stability of the tablets, the tablets shown in Table 6 (formulation example 4, formulation example 5, comparison example 4, comparison example 5, comparison example 6, comparison example 7) were prepared in the same manner as in Example 1. Comparative Example 8 and Comparative Example 9) were obtained.

Measure the appearance, hardness and disintegration time of the initial product (Initial) at the start of the experiment of the obtained tablets, and the appearance and hardness of the stored product under temperature and humidity (40 ° C, humidity 75%, open system, 1 week) The physical stability under temperature and humidity was evaluated. The results are shown in Table 7.

In lactose-containing tablets (Comparative Example 4), erythritol-containing tablets (Comparative Example 6) and xylitol-containing tablets (Comparative Example 7), a significant change in appearance was observed with a ΔE value of 10 or more when stored under temperature and humidity. It decreased to the extent that it could not be measured by the device. Further, in the D-mannitol-containing tablet (Comparative Example 5), the appearance change under temperature and humidity hardly occurred, but the hardness decreased to less than 2 kp.

On the other hand, the calcium hydrogen phosphate-containing tablets (Comparative Example 8 and Comparative Example 9) and the anhydrous calcium hydrogen phosphate-containing tablets (Prescription Example 4 and Formulation Example 5) hardly change in appearance under temperature and humidity, and the hardness is also high. It was 2 kp or more. Therefore, it has been found that tablets containing calcium hydrogen phosphate and anhydrous calcium hydrogen phosphate can be obtained with sufficient hardness even when stored under temperature and humidity.

Next, in order to evaluate the chemical stability of the calcium hydrogen phosphate-containing tablet (Comparative Example 9) and the anhydrous calcium hydrogen phosphate-containing tablet (Formulation Example 5) under the temperature and humidity, the initial product and the temperature and humidity The change in the amount of pravastatin related substances in the preserved product was measured. Table 8 shows the relative retention times and relative sensitivities of major pravastatin analogues (represented as compounds A, B, and C), which showed a difference between Comparative Example 9 and Formulation Example 5, for use in liquid chromatography. . Further, Table 9 shows the results of changes in the total amount of pravastatin analogues obtained by adding these pravastatin analogues and other pravastatin analogues to these pravastatin analogues.

As shown in Table 9, in the calcium hydrogen phosphate-containing tablet (Comparative Example 9), the ratio of Compound A, Compound B and Compound C increased under the temperature and humidity, and the total amount of pravastatin-related substances also increased. On the other hand, in the anhydrous calcium hydrogen phosphate-containing tablets (Formulation Example 5), there was almost no change in the amount of related substances under temperature and humidity.

From the above results, it was revealed that the anhydrous calcium hydrogen phosphate-containing tablets (Formulation Example 5) are physically and chemically stable under temperature and humidity.

Example 4 Effect of the amount of sodium hydrogen carbonate added in the anhydrous calcium hydrogen phosphate formulation The ingredients shown in Table 10, except for magnesium stearate, were placed in a V-type mixer (Tsutsuri Chemical Instruments Co., Ltd.) and mixed. Obtained. The obtained mixed powder was tableted using a tablet machine and an external lubricant spray device (both manufactured by Kikusui Seisakusho Co., Ltd.) while spraying a small amount of magnesium stearate on a mortar and pestle. Example 6 and formulation example 7) were obtained.

In order to mimic the actual method of taking orally disintegrating tablets, among the methods described in “1. Test methods” above, “1-1-3. Administration method” is a pravastatin sodium orally rapidly disintegrating tablet. The tablets of Formulation Example 6 and Formulation Example 7 were modified to be suspended in a small amount of saliva and administered to dogs. The changes in blood drug concentration are shown in FIG. 3, and the pK parameters are shown in Table 11. For reference, the blood drug concentration transition when the current tablet is administered to dogs with water is also shown.

In the tablet of Formulation Example 6 containing anhydrous calcium hydrogen phosphate, even when sodium hydrogencarbonate is not added, AUC is about 110% and Cmax is about 130%, compared with the case where the current tablet is administered with water. (Table 11). As shown in the results of Formulation Example 7, even when sodium bicarbonate was added, AUC was about 110%, and Cmax was about 105%, indicating good absorption (Table 11).

Embodiment 5 FIG. Stability test In order to examine the stability of the tablet, the appearance, hardness and disintegration time of the initial product (Initial) at the start of the experiment of the tablet of the bleb example 6 and room temperature conditions (25 ° C, humidity 60%, Open system, 1 week) Appearance and hardness of stored products were measured, and physical stability during normal use was evaluated. The results are shown in Table 12. In Formulation Example 6, there was no significant change in the appearance and hardness that would affect the stability as a pharmaceutical product (Table 12).

The pravastatin sodium intraoral rapidly disintegrating tablet of the present invention has rapid disintegration and solubility when placed in the oral cavity or in water, so it is easy to take and in the manufacturing process and distribution process. Excellent storage stability. Moreover, even if it is taken without water, it shows the same pharmacokinetics as the current tablet taken with water.

Therefore, it can be widely used for the treatment of hyperlipidemia.

Claims

Pravastatin sodium orally disintegrating tablet containing pravastatin sodium and anhydrous calcium hydrogen phosphate.
The pravastatin sodium intraoral rapidly disintegrating tablet according to claim 1, further comprising an alkali metal salt of carbonic acid or an alkali metal salt of an organic acid.
The pravastatin sodium intraoral rapidly disintegrating tablet according to claim 1, further comprising sodium citrate or sodium tartrate.
The pravastatin sodium intraoral rapidly disintegrating tablet according to claim 2, comprising an alkali metal salt of carbonic acid.
The pravastatin sodium orally disintegrating tablet according to claim 2 or 4, wherein the alkali metal salt of carbonic acid is any one selected from the group consisting of sodium bicarbonate, sodium carbonate and calcium carbonate.
The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 1 to 5, comprising crospovidone as a disintegrant.
The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 1 to 6, further comprising crystalline cellulose and / or powdered cellulose.
The pravastatin sodium intraoral rapidly disintegrating tablet according to claim 7, further comprising crystalline cellulose.
The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 1 to 8, further comprising calcium silicate.
The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 1 to 9, further comprising magnesium aluminate metasilicate.
The pravastatin sodium intraoral rapidly disintegrating tablet according to any one of claims 1 to 10, further comprising a sweetener, a fragrance, and a lubricant.
A method for producing pravastatin sodium intraoral quick disintegrating tablet by mixing and compressing a composition containing pravastatin sodium and anhydrous calcium hydrogen phosphate.
A method for producing pravastatin sodium intraoral rapidly disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium hydrogen carbonate and anhydrous calcium hydrogen phosphate.
A method for producing pravastatin sodium oral disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate and crospovidone.
A method for producing pravastatin sodium intraoral quick disintegrating tablet by mixing and compressing a composition containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone and crystalline cellulose.
The method for producing pravastatin sodium intraoral quick disintegrating tablet according to any one of claims 12 to 15, wherein the tableting is direct tableting.