WO2011049122A1 - Comprimé de pravastatine sodique à désintégration rapide dans la cavité orale et son procédé de fabrication - Google Patents

Comprimé de pravastatine sodique à désintégration rapide dans la cavité orale et son procédé de fabrication Download PDF

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WO2011049122A1
WO2011049122A1 PCT/JP2010/068468 JP2010068468W WO2011049122A1 WO 2011049122 A1 WO2011049122 A1 WO 2011049122A1 JP 2010068468 W JP2010068468 W JP 2010068468W WO 2011049122 A1 WO2011049122 A1 WO 2011049122A1
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Prior art keywords
pravastatin sodium
sodium
disintegrating tablet
pravastatin
rapidly disintegrating
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PCT/JP2010/068468
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English (en)
Japanese (ja)
Inventor
勉 今野
由雄 久野
慎一朗 田尻
充英 谷本
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第一三共株式会社
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Priority to JP2011537278A priority Critical patent/JPWO2011049122A1/ja
Publication of WO2011049122A1 publication Critical patent/WO2011049122A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • various analogs are known for pravastatin sodium, and it is necessary to prevent the formation of these analogs during storage.
  • 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.
  • 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.
  • 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 (1)
  • the horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma.
  • the horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma.
  • the horizontal axis of the graph shows the elapsed time after taking, and the vertical axis shows the amount of pravastatin in plasma.
  • 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.
  • pravastatin sodium oral disintegrating tablet containing pravastatin sodium and anhydrous calcium hydrogen phosphate can be mentioned.
  • 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.
  • the alkali metal salt of carbonic acid include at least one selected from the group consisting of sodium bicarbonate, sodium carbonate, and calcium carbonate.
  • the alkali metal salt of organic acid include citric acid. Examples thereof include sodium acid and sodium tartrate, and sodium hydrogen carbonate is preferable.
  • pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate can be mentioned.
  • pravastatin sodium, sodium bicarbonate, anhydrous calcium hydrogen phosphate, pravastatin sodium orally disintegrating tablet containing disintegrant can be mentioned.
  • pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone can be mentioned.
  • 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.
  • pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium hydrogen carbonate, anhydrous calcium hydrogen phosphate, crospovidone and crystalline cellulose can be mentioned.
  • pravastatin sodium oral disintegrating tablet containing pravastatin sodium, sodium bicarbonate, anhydrous calcium hydrogen phosphate, crospovidone, crystalline cellulose and calcium silicate can be mentioned.
  • 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.
  • 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.
  • pravastatin sodium intraoral quick disintegrating tablet 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%.
  • 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%.
  • 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.
  • the additive examples 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.
  • the lubricant examples 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.
  • 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.
  • excipients include organic excipients selected from saccharides, starches, and celluloses, and inorganic excipients.
  • saccharide include one or a combination of two or more selected from sucrose, glucose and fructose.
  • starches include one or a combination of two or more selected from corn starch, potato starch, rice starch, and partially pregelatinized starch.
  • 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.
  • 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, ⁇ -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.
  • sweetener examples 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.
  • surfactant examples 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.
  • foaming agent examples 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.
  • 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.
  • 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. .
  • 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.
  • AUC area under the blood content time curve: area under the drug blood concentration-time curve
  • Cmax maximum blood concentration
  • 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.
  • 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.
  • 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. .
  • 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.
  • Test method The following tests were conducted on tablets of each formulation obtained in the examples.
  • Dog evaluation test The dog test was conducted as follows.
  • 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.
  • pravastatin sodium tablet 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.
  • 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.
  • ⁇ E was calculated from the color difference from the storage start product by the following formula.
  • 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.
  • 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 ⁇ m, manufactured by Millipore), and the filtrate after removing 5 mL of the first filtrate was used as a sample solution.
  • 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 ⁇ m) to remove the first 5 mL of the filtrate. The later filtrate was used as a standard solution.
  • the sample solution and 20 ⁇ L 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.
  • Flow rate The pravastatin peak was adjusted to about 21 minutes (a constant amount of 1.3 mL / min per minute).
  • Injection volume 20 ⁇ L
  • Injector cleaning solution water / methanol mixture (1: 1)
  • Needle cleaning solution water / methanol mixture (2: 8)
  • 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.
  • Example 2 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
  • Table 5 shows the pK parameters.
  • the blood drug concentration transition when the current tablet is administered to dogs with water is also shown.
  • 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.
  • 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.
  • Example 4 Effect of the amount of sodium hydrogen carbonate added in the anhydrous calcium hydrogen phosphate formulation
  • 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.
  • “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.
  • the blood drug concentration transition when the current tablet is administered to dogs with water is also shown.
  • Embodiment 5 FIG. Stability test
  • 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.
  • 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.

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Abstract

La présente invention concerne un comprimé de pravastatine sodique à désintégration rapide dans la cavité orale présentant des propriétés de désintégration rapide et solubilité élevée lorsqu'il est placé dans la cavité orale ou dans de l'eau, présentant une dureté telle qu'il ne se brise pas au cours de la production et de la distribution, présentant une stabilité au stockage élevée et présentant une biodisponibilité équivalente à celle d'un comprimé de pravastatine sodique s'avalant avec de l'eau. Le comprimé de pravastatine sodique à désintégration rapide dans la cavité orale précédemment cité comprend de l'hydrogénophosphate de calcium anhydre et de la pravastatine sodique.
PCT/JP2010/068468 2009-10-21 2010-10-20 Comprimé de pravastatine sodique à désintégration rapide dans la cavité orale et son procédé de fabrication WO2011049122A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013087061A (ja) * 2011-10-14 2013-05-13 Lion Corp 積層錠
WO2013115171A1 (fr) * 2012-02-03 2013-08-08 旭化成ケミカルズ株式会社 Comprimé à désintégration par voie orale contenant des granules masquant l'amertume
JP2020169143A (ja) * 2019-04-04 2020-10-15 ニプロ株式会社 アジルサルタンを含有する錠剤

Citations (6)

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