JP6050564B2 - Film-form preparation - Google Patents

Description

  The present invention relates to a film-form preparation, and more particularly to a film-form preparation which is rapidly dissolved in the oral cavity for oral administration.

  In recent years, there has been an increasing demand for preparations that facilitate the oral administration of drug components to those who have difficulty swallowing. In particular, as the aging of society tends to increase, the number of people whose swallowing function has declined due to aging tends to increase, so that even those who are easy to disintegrate or dissolve in the oral cavity and are difficult to swallow things are easy to take However, there is a strong demand.

  Meloxicam (generic name) (trade name Movic, Daiichi Sankyo Co., Ltd.) is an oxicam nonsteroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase (COX) -2. Meloxicam exhibits potent anti-inflammatory and bone / cartilage destruction inhibitory effects on rat adjuvant arthritis similar to human rheumatoid arthritis and long-lasting analgesic effects on rat yeast-induced hyperalgesia . On the other hand, gastric mucosal disorders, which are the main side effects of NSAIDs, are less expressed and have a higher therapeutic index than conventional NSAIDs. In addition, at clinical doses, platelet aggregation is not suppressed and bleeding time is not prolonged. In clinical trials, the overall results show that the efficacy is the same as that of conventional NSAIDs and the safety is high, and it is for "Rheumatoid arthritis, Osteoarthritis, Lumbar pain, Shoulder periarthritis, and Neck-shoulder arm syndrome" Indications are recognized. In general, for adults, 10 mg of meloxicam is orally administered once a day after meals.

  Candesartan cilexetil (generic name) (Blopress, Takeda Pharmaceutical Company Limited) is a drug that antagonizes the receptor for angiotensin II and lowers the resistance of peripheral blood vessels to lower blood pressure. Used for treatment. In general, for adults, take 0.5 to 1 tablet (4 to 8 mg of the active ingredient) once a day, and increase to 1.5 tablets (12 mg) once a day as needed.

  Acidic active pharmaceutical ingredients such as meloxicam and candesartan cilexetil are also required to be formulated in a dosage form that anyone can take, including those with low swallowing function. For example, Patent Document 1 discloses a dry-type direct hitting disintegrating tablet containing meloxicam. Patent Documents 2 and 3 disclose an internal solid preparation containing candesartan cilexetil. However, an intraoral fast-dissolving film-form preparation containing an acidic pharmaceutical active ingredient such as candesartan cilexetil or meloxicam has not been developed yet.

  The inventors of the present invention have made various investigations on intraoral fast-dissolving film-form preparations containing acidic active ingredients such as meloxicam and candesartan cilexetil. As a result, it has been found that the conventional production method has a problem that the dissolution property of meloxicam and candesartan cilexetil is remarkably poor, and there is a need for further improvement.

International Publication No. WO2007 / 119792 Japanese Patent No. 3751287 Japanese Patent No. 4284017

  In view of the present situation, the present invention can be swallowed smoothly by rapidly disintegrating or dissolving in the oral cavity, and is easy to take because it is difficult to adhere to and stay in the mucous membrane of the throat and esophagus. It is an object of the present invention to provide a film-form preparation which is excellent in the dissolution property of the ingredients from the preparation and has a good stability of the active pharmaceutical ingredient in the preparation.

  As a result of intensive studies to solve the above problems, the present inventors have found that meloxicam is obtained by blending a basic compound into a film-form preparation containing meloxicam or candesartan cilexetil, which are acidic pharmaceutical active ingredients. And candesartan cilexetil were found to improve the dissolution properties from the preparation. Furthermore, although the stability (thermal stability etc.) of meloxicam in the film-form preparation was also confirmed, no significant decrease in the content was observed. Based on the above findings, the present inventors have further studied and have completed the present invention.

That is, the present invention relates to the following (1) to (9).
(1) A film-form preparation characterized by containing an acidic pharmaceutically active ingredient and a basic compound and improving the dissolution of the pharmaceutically active ingredient.
(2) The film preparation according to (1), which is for oral administration.
(3) The film-form preparation according to (1) or (2), which is rapidly soluble in the oral cavity.
(4) The elution rate of an acidic pharmaceutically active ingredient is 10% or more after 10 minutes when an elution test by a paddle method rotating at 50 rpm per minute using 900 mL of water as a test solution is performed. The film-form preparation according to any one of 3).
(5) The film-form preparation according to any one of (1) to (4), wherein the pH of the 1 w / v% aqueous solution of the film-form preparation is in the range of 6 to 10.
(6) The film-form preparation according to any one of (1) to (5), wherein the acidic pharmaceutically active ingredient is meloxicam or candesartan cilexetil.
(7) The basic compound is (i) at least one selected from the group consisting of sodium bicarbonate, sodium hydroxide and L-arginine, or (ii) from sodium bicarbonate, sodium hydroxide and L-arginine. At least 1 sort (s) selected from the group which consists of, and the film-form formulation in any one of said (1)-(6) which is sodium citrate.
(8) The film-form preparation according to any one of (1) to (7), wherein the film-form preparation has a thickness of 1 to 3000 μm.
(9) The film-form preparation according to any one of (1) to (8), further containing hypromellose and / or hydroxypropylcellulose as a film base.

  According to the present invention, since it has disintegration or solubility with no practical problems with a small amount of saliva in the oral cavity, it can be swallowed smoothly, and it is difficult to adhere to or stay in the mucous membrane of the throat and esophagus. Become. Moreover, since the elution property from the preparation of an acidic pharmaceutically active ingredient is excellent, the efficacy of the active ingredient can be efficiently exhibited. Furthermore, since the film-form preparation has practical strength and the stability of the active ingredient in the preparation is good, handling is easy.

FIG. 1 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 2 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 3 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 4 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 5 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 6 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example and a commercially available tablet. FIG. 7 is a graph showing the residual ratio of meloxicam in the film-form preparation produced in the preparation example. FIG. 8 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 9 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 10 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example. FIG. 11 is a diagram showing the results of a dissolution test of a film-form preparation produced in the preparation example and a commercially available tablet.

The film-form preparation of the present invention contains an acidic pharmaceutically active ingredient and a basic compound.
Each of the acidic pharmaceutically active ingredient and the basic compound may be one kind or two or more kinds.

  The “acidic pharmaceutically active ingredient” may be any pharmaceutically active ingredient having a functional group that can dissociate and supply hydrogen ions (protons). Examples of the acidic pharmaceutically active ingredient in the present invention include meloxicam, piroxicam, indomethacin, ketoprofen, flurbiprofen, diclofenac sodium, aspirin, candesartan cilexetil and the like. The acidic pharmaceutically active ingredient may be one kind or two or more kinds. In particular, meloxicam or candesartan cilexetil is suitable as the active ingredient of the film-form preparation of the present invention.

  The “basic compound” may be an inorganic compound or an organic compound, and may be any basic compound that is generally used in pharmaceutical preparations. Examples of basic organic compounds include salts of weak acids and strong bases such as potassium citrate, sodium citrate, potassium acetate and sodium acetate; carbonates such as sodium bicarbonate and sodium carbonate; basic amino acids such as L-arginine Etc. Moreover, sodium hydroxide, potassium hydroxide, etc. are mentioned as a basic inorganic compound.

  The basic compound is preferably sodium hydrogen carbonate, sodium citrate, sodium hydroxide, L-arginine or the like. A salt of a weak acid such as sodium citrate and a strong base is preferably used in combination with another basic compound, more preferably (i) a group consisting of sodium bicarbonate, sodium hydroxide and L-arginine as the basic compound. Or (ii) at least one selected from the group consisting of sodium bicarbonate, sodium hydroxide and L-arginine, and sodium citrate.

  The film-form preparation of the present invention preferably further contains a film base. The “film base” is a material having a film forming ability and forming a film base in a film-form preparation. In the present invention, as the film substrate, those generally used in the pharmaceutical field can be used, but those having no unpleasant taste are preferably used. By using such a film substrate, it is possible to provide a film-form preparation that does not feel an unpleasant taste even if it dissolves or disintegrates rapidly in the oral cavity. The film substrate is, for example, gelatin, pectin, alginic acid, sodium alginate, carrageenan, xanthan gum, guar gum, pullulan, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carmellose, carmellose sodium, polyvinyl alcohol, povidone, carboxyvinyl polymer, etc. Is preferred. These may be used alone or in combination of two or more. Of these, hypromellose, hydroxypropylcellulose and the like are suitable as the film substrate. Hypromellose and hydroxypropylcellulose are both excellent in film-forming ability, and the formed film is highly water-soluble, so that the effects of the present invention are more fully achieved by including hypromellose and / or hydroxypropylcellulose as a film base material. be able to.

  In addition, the Japanese pharmacopoeia describes that hydroxypropylcellulose is “white to yellowish white powder with no odor and taste”, and hypromellose is “white to yellowish white powder or granules. And no odor, or a slightly unique odor and no taste. "As described, both hydroxypropylcellulose and hypromellose have no taste. For this reason, even if it dissolves or disintegrates rapidly in the oral cavity, it is suitable for the production of a film-form preparation that does not feel an unpleasant taste.

  “Hypromellose” includes 2910, 2906, and 2208 substitution types, and any of those commonly used in the pharmaceutical field can be used. For example, as the substitution degree type 2910, manufactured by Shin-Etsu Chemical Co., Ltd., METOLOSE 60SH-50 (viscosity 50 mPa · s), 60SH-4000 (viscosity 4000 mPa · s), 60SH-10000 (viscosity 10000 mPa · s); TC-5E (viscosity 3.0 mPa · s), TC-5M (viscosity 4.5 mPa · s), TC-5R (viscosity 6.0 mPa · s), TC-5S (viscosity 15.0 mPa · s), etc. (Both are trade names). As the substitution degree type 2906, METOLOSE 65SH-50 (viscosity 50 mPa · s), 65SH-400 (viscosity 400 mPa · s), 65SH-1500 (viscosity 1500 mPa · s), 65SH-4000 (viscosity 4000 mPa · s) manufactured by Shin-Etsu Chemical Co., Ltd. s) (all are trade names). As the substitution degree type 2208, manufactured by Shin-Etsu Chemical Co., Ltd., METOLOSE SR 90SH-100 (viscosity 100 mPa · s), 90SH-4000 (viscosity 4000 mPa · s), 90SH-15000 (viscosity 15000 mPa · s), 90SH-100000 (viscosity 100000 mPa) S); SB-4 (viscosity 4.0 mPa · s) manufactured by Shin-Etsu Chemical Co., Ltd. (both are trade names) can be used. The viscosity is the viscosity of a 2% aqueous solution at 20 ° C. specified by the Japanese Pharmacopoeia, and the same applies hereinafter.

  As the hydroxypropyl cellulose, any of those generally used in the pharmaceutical field can be used. For example, Nippon Soda Co., Ltd., HPC-SSL (viscosity 2.0-2.9 mPa · s), HPC-SL (viscosity 3.0-5.9 mPa · s), HPC-L (viscosity 6.0-10. 0 mPa · s), HPC-M (viscosity 150 to 400 mPa · s), HPC-H (viscosity 1000 to 4000 mPa · s), etc. (all trade names) can be used.

  In addition to the above components, the film-form preparation of the present invention may contain an appropriate amount of additives generally used in pharmaceuticals such as plasticizers, excipients, emulsifiers, colorants, fragrances, and preservatives. For example, as a plasticizer, macrogol, glycerin, propylene glycol and the like can be mentioned. Examples of excipients include saccharides such as mannitol, sorbitol, xylitol, erythritol, lactose, fructose, sucrose, glucose and trehalose; starches such as corn starch, potato starch and wheat starch; cellulose such as crystalline cellulose and powdered cellulose Class: talc, titanium oxide, etc. are raised. Examples of the emulsifier include sodium lauryl sulfate, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol fatty acid ester. Examples of the sweetening agent include aspartame, acesulfame potassium, saccharin, saccharin sodium, stevia, sucralose, dipotassium glycyrrhizinate, thaumatin (thaumatin) and the like. Examples of the corrigent include citric acid, tartaric acid, malic acid, ascorbic acid and the like. Examples of the colorant include edible dyes, edible lake dyes, iron sesquioxide, and yellow iron sesquioxide. Examples of the fragrances include fennel oil, orange oil, chamomile oil, spearmint oil, cinnamon oil, clove oil, bergamot oil, eucalyptus oil, lavender oil, lemon oil, rose oil, roman chamomile oil, mint oil and the like. Examples of the preservative include benzoic acid, sodium benzoate, benzyl benzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, and propyl paraoxybenzoate. These additives may be used alone or in combination of two or more.

  What is necessary is just to set suitably content of each component contained in the film-form preparation of this invention according to the kind of acidic pharmaceutical active ingredient, the kind of basic compound, etc. For example, the acidic pharmaceutically active ingredient is usually preferably 0.1 to 70% by mass, more preferably 1 to 50% by mass with respect to the total solid content in the film-form preparation. More preferably, the content is 40% by mass.

The content of the basic compound may be appropriately set according to the type of the basic compound, but is usually preferably 0.1 to 50% by mass with respect to the total solid content in the film-form preparation. -30 mass% is more preferable. For example, when using carbonates, such as sodium hydrogencarbonate, 2-6 mass% is normally preferable with respect to the total of the solid content in a film-form preparation. When a basic inorganic compound such as sodium hydroxide is used, the basic inorganic compound is generally preferably 0.3 to 3% by mass with respect to the total solid content in the film-form preparation. When using basic amino acids, such as L-arginine, 5-15 mass% is preferable normally with respect to the sum total of the solid content of a basic amino acid in a film-form preparation.
Moreover, you may use together other bases, such as sodium citrate, with the said basic compound. When the content of the basic compound is in the above range, the dissolution property of the acidic pharmaceutically active ingredient from the preparation is further improved, and the stability of the acidic pharmaceutically active ingredient in the film-form preparation is better maintained. Moreover, what is necessary is just to select content of each compound suitably within said range, when using 2 or more types of basic compounds.

  The usage-amount of a film base material is not specifically limited as long as the effect of this invention is produced, For example, it can use in the range normally used for the film-form preparation for oral administration.

  The film-form preparation of the present invention may be a single layer film or a laminated film composed of multiple layers. The film-form preparation of the present invention is preferably a monolayer. When it is set as the laminated film which consists of a multilayer, you may provide a support layer in the single side | surface or both surfaces of the layer containing an acidic pharmaceutical active ingredient and a basic compound, for example. Moreover, the layer containing an acidic pharmaceutical active ingredient and the layer containing a basic compound may be provided separately, and a support layer may be further provided. The component of the support layer is not particularly limited as long as the effects of the present invention are exhibited, and the above-described film base material and the like are preferable.

  Although the thickness of the film-form preparation of the present invention is not particularly limited as long as the effects of the present invention are exhibited, it is usually preferable to set within the range of 1 μm to 3000 μm. For example, it is preferable to set it as 10 micrometers-1000 micrometers from points, such as ease of handling and manufacturing efficiency. For example, in order to further improve the solubility or disintegration property of the film-form preparation in the oral cavity, the thickness is preferably 5 μm to 500 μm. When the thickness is 10 μm to 500 μm, it is preferable because the handling and production efficiency are further improved, and the solubility or disintegration property of the film preparation in the oral cavity is also improved.

  The film-form preparation of the present invention is preferably rapidly soluble in the oral cavity. The fast solubility in the oral cavity is preferably one that dissolves or disintegrates within 60 seconds in the oral cavity, for example. Moreover, it is preferable that it melt | dissolves or disintegrates within 30 second by the disintegration test method as described in the general test method of the Japanese Pharmacopoeia.

  This invention is a film-form preparation which improved the elution property of this pharmaceutical active ingredient by containing a basic compound with an acidic pharmaceutical active ingredient. When the dissolution rate of the acidic active pharmaceutical ingredient is improved, the dissolution rate is usually 10% or more after 10 minutes when the dissolution test is performed by the paddle method rotating at 50 rpm per minute using 900 mL of water as a test solution. Preferably it is 15% or more, More preferably, it is 20% or more, More preferably, it is 30% or more. Thus, by improving the dissolution property, the active pharmaceutical ingredient is efficiently absorbed, and the medicinal effect can be rapidly exhibited. The paddle method in the present invention is the second dissolution test method (paddle method) described in the general test method of the Japanese Pharmacopoeia. The dissolution rate is the mass% of the eluted active ingredient when the total mass of the acidic pharmaceutical active ingredient contained in the preparation before the dissolution test is 100.

  In the present invention, the pH of the 1 w / v% aqueous solution of the film-form preparation is preferably in the range of 6-10. That is, it is preferable to appropriately select the blending amounts of the respective components so that the pH of the 1 w / v% aqueous solution of the film-form preparation is in such a range. More preferably, the pH of the 1 w / v% aqueous solution of the film-form preparation is 7 to 10, and more preferably the pH of the 1 w / v% aqueous solution of the film-form preparation is 7 to 9.

  The film-form preparation of the present invention usually comprises, for example, a mixed liquid preparation step of preparing a mixed liquid containing an acidic pharmaceutically active ingredient and a basic compound, and optionally a film base material, and the mixed liquid on the base film. It is easily manufactured by performing a casting process for casting and a drying process for drying the cast mixed liquid to form a film in this order. In the production of the film-form preparation of the present invention, a peeling process for peeling the film-form preparation formed by the drying process from the base film, a cutting process for cutting the obtained film-form preparation into a predetermined size, etc. Good.

  In the mixed liquid preparation step, acidic pharmaceutically active ingredients such as meloxicam and candesartan cilexetil, a basic compound, and a film base material, and a predetermined amount of additives are mixed or stirred with water or an organic solvent to obtain a solution or Prepare a suspension and defoaming to prepare a mixture. As the organic solvent, alcohols such as ethanol and isopropanol are preferably used.

  In the casting process, the base film is fixed on a smooth plane, and the prepared mixed solution is uniformly coated on the base film. Here, the base film is a film constituting a surface that becomes a prototype for forming a film by casting a mixed solution, which is a stock solution of a film-form preparation, on the upper surface thereof, for example, a mirror-polished stainless steel belt A plastic film such as polyethylene terephthalate or polypropylene fixed on a smooth surface such as a drum can be used, but is not particularly limited. Since the thickness of the film-form preparation depends on the concentration, viscosity, coating speed and the like of the mixed solution, it is appropriately adjusted so as to have a desired thickness.

  In the drying step, for example, the mixed solution is made into a film by drying the cast solution together with the base film by convection of air with adjusted temperature and humidity, irradiation with far infrared rays, etc., and a film-form preparation is obtained. be able to. When performing a peeling process and a cutting process, an order is not specifically limited, After performing a peeling process, you may perform a cutting process, You may perform a peeling process after performing a cutting process. Moreover, a film-form preparation can also be manufactured without performing a peeling process. For example, the film-form preparation can be stored in a state of being attached to the base film, and the film-form preparation can be peeled off from the base film at the time of taking. Such a film-form preparation is also included in the film-form preparation of the present invention.

  The film-form preparation of the present invention is suitable for oral administration. The film-form preparation of the present invention can be taken without drinking water because it dissolves easily with moisture in the oral cavity, but may be taken with water if desired.

  The film-form preparation of the present invention dissolves rapidly (within 60 seconds) in the oral cavity and is therefore easy to take. For example, elderly patients with a small amount of saliva, patients with difficulty in saliva due to illness, side effects of treatment, etc. Even if it is taken without drinking water, it dissolves easily in the oral cavity. Furthermore, since the film-form preparation of the present invention has a good dissolution property of the pharmaceutically active ingredient, the action of the active ingredient is rapidly expressed. Therefore, the film-form preparation of the present invention can exhibit the same pharmacological effects as conventional oral preparations such as tablets and capsules, and can be easily taken without water. It can be safely administered.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, these do not limit this invention at all.

  In Formulation Examples 1 to 28, meloxicam (manufactured by DKSH Japan) was used as a medicinal component. Hydroxypropyl cellulose (trade name HPC-L, manufactured by Nippon Soda Co., Ltd.) and hypromellose (trade name Metroles 60SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) were used as the film base. As additives, Macrogol 6000 (manufactured by Wako Pure Chemical Industries), sodium lauryl sulfate (manufactured by Wako Pure Chemical Industries), L-menthol (manufactured by Nagaoka Jitsugyo Co., Ltd.), D-mannitol (manufactured by Rocket Japan), aspartame ( Ajinomoto Co.) and acesulfame potassium (Maruzen Pharmaceutical Co., Ltd.) were used. As a basic compound, sodium hydrogen carbonate, sodium hydroxide, sodium citrate and L-arginine were used.

  In Preparation Examples 29 to 38, candesartan cilexetil (manufactured by GOLD PHARMA, China) was used as a medicinal ingredient. Hydroxypropyl cellulose (trade name HPC-L, manufactured by Nippon Soda Co., Ltd.) and hypromellose (trade name Metroles 60SH-4000, manufactured by Shin-Etsu Chemical Co., Ltd.) were used as the film base. As additives, sucrose fatty acid ester (Mitsubishi Chemical Foods), D-mannitol (Rocket Japan), aspartame (Ajinomoto Co.), acesulfame potassium (Maruzen Pharmaceutical), thaumatin (Saumatine) FFI) and mint oil (manufactured by Suzuki Hikaru Co., Ltd.) were used. Sodium bicarbonate, sodium hydroxide, and L-arginine were used as basic compounds.

  About each formulation obtained by the formulation example, physical property evaluation and stability evaluation were implemented by the test method shown below.

(1) Physical property evaluation (i) (elution property)
Evaluation is carried out using a dissolution tester (manufactured by Toyama Sangyo Co., Ltd.) according to the dissolution test method method 2 (paddle method), which is a general test method of the Japanese Pharmacopoeia (test solution: water, rotation speed of paddle: 50 rpm, elapsed time: 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes and 120 minutes), and the dissolution amount and dissolution rate of meloxicam or candesartan cilexetil from the preparation were determined.
Specifically, one preparation was taken, and 900 mL of water was used as a test solution, and the test was performed at 50 revolutions per minute by the second dissolution test method (paddle method). After 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes and 120 minutes from the start of the dissolution test, accurately take 10 mL of the eluate and immediately pay attention to the water heated to 37 ± 0.5 ° C. Made up. The eluate was filtered through a membrane filter having a pore size of 0.45 μm or less. Except for 5 mL of the first filtrate, the next filtrate was used as a sample solution. About meloxicam, about 0.05 g of meloxicam for quantification was separately weighed and dissolved in methanol to make exactly 100 mL, then 5 mL of this solution was accurately weighed and water was added to make exactly 50 mL. 5 mL of this solution was accurately weighed and water was added to make exactly 50 mL, which was used as a standard solution. The meloxicam content was determined by measuring the absorbance A _T (n) (absorbance of the sample solution) and A _S (absorbance of the standard solution) of meloxicam at a wavelength of 360 to 364 nm by using a UV-visible absorbance measurement method with water as a control. Asked.

  For candesartan cilexetil, separately weigh approximately 0.01 g of candesartan cilexetil for measurement, dissolve in methanol to make exactly 200 mL, then accurately measure 4 mL of this solution and add water to make exactly 50 mL. A standard solution was used. The candesartan cilexetil content was determined under the following measurement conditions using liquid chromatography.

Test condition detector: UV spectrophotometer (measurement wavelength: 254 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C. Mobile phase: acetonitrile / water / acetic acid (100) mixture (65: 35: 1)
Flow rate: Adjusted so that the retention time of candesartan cilexetil was about 6 minutes.
System performance: When 20 μL of the standard solution is operated under the above-mentioned conditions, the theoretical plate number and symmetry factor of the peak of candesartan cilexetil are 5,000 plates or more and 1.5 or less, respectively.
System repeatability: When the test is repeated 6 times with 20 μL of the standard solution under the above conditions, the relative standard deviation of the peak area of candesartan cilexetil is 1.5% or less.

(2) Physical property evaluation (ii) (pH)
For the evaluation, the pH of the solution of the preparation (1 → 100) was determined according to the pH measurement method, which is a general test method by the Japanese Pharmacopoeia, using a pH meter.

(3) Stability evaluation The preparations were prepared by SP packaging (aluminum foil) individually, then stored in a thermostat set at a storage temperature of 60 ° C., sampled after 4 weeks of storage period, and the content of meloxicam in the preparation was determined. The residual ratio with respect to the initial content was determined by liquid chromatography.
Specifically, one preparation was taken, 5 mL of the internal standard solution was accurately added, 45 mL of methanol was further added, and the mixture was shaken for 30 minutes, and then sonicated for 30 minutes. This liquid was filtered through a membrane filter having a pore size of 0.45 μm or less, and the filtrate was used as a sample solution. Separately, about 10 mg of quantitative meloxicam was accurately weighed and dissolved in methanol to make exactly 50 mL. 25 mL of this solution was accurately weighed, 5 mL of the internal standard solution was accurately added, and methanol was further added to 50 mL to obtain a standard solution. The meloxicam content was determined by measuring the ratios Q _T and Q _S of the peak area of meloxicam to the peak area of the internal standard substance.

Test condition detector: UV spectrophotometer (measurement wavelength: 254 nm)
Column: A stainless tube having an inner diameter of 3.0 mm and a length of 15 cm was filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C. Mobile phase: methanol / water / phosphoric acid mixture (600: 400: 1)
Flow rate: Adjusted so that the retention time of meloxicam was about 6 minutes.
The following conditions were adopted for system suitability.
System performance: When 5 μL of the standard solution is operated under the above conditions, meloxicam and the internal standard substance are eluted in this order, and the resolution is 3 or more.
System reproducibility: When the test is repeated 6 times with 5 μL of the standard solution under the above conditions, the relative standard deviation of the ratio of the peak area of meloxicam to the peak area of the internal standard substance is 1.0% or less.

Formulation Example 1
For preparation of the preparation, prepare a mixed solution in which meloxicam and base shown in Table 1 and additives are dissolved or dispersed in absolute ethanol or purified water, and then apply the mixed solution on a base film (polyethylene terephthalate film). did. After the applied mixed liquid is dried to form a film, the formed film is peeled off from the base film, and the peeled film has a size of about 15 mm × 20 mm per film-form preparation, It cut | disconnected so that mass might become about 35 mg. The thickness of one film-form preparation was adjusted to be about 100 μm. Table 1 shows the formulation of this preparation.

Formulation Example 2
Preparation of the preparation was performed by preparing a mixed solution in which meloxicam, basic compounds and bases, and additives shown in Table 1 were dissolved or dispersed in absolute ethanol or purified water, and then mixing the mixed solution with a base film (polyethylene terephthalate film). ). After the applied mixed solution was dried to form a film, a film-form preparation was produced in the same manner as in Preparation Example 1. Table 1 shows the formulation of this preparation.

Formulation Examples 3 to 28
Film-form preparations were produced by the same method as in Preparation Examples 1 and 2, except that the blending amounts of meloxicam and other components were as shown in Tables 1 to 5. Numerical values other than pH in Tables 1 to 5 represent the solid content (parts by mass), and the totals in Tables 1 to 5 represent the total solids (parts by mass).

About each formulation of the formulation examples 1-28 shown in Table 1-Table 5, the test of said (1)-(3) was done. The pH of the preparation solution (1 → 100) is shown in Tables 1-5. Tables 6 to 10 and FIGS. 1 to 6 show the results of the dissolution test. The numerical values in Tables 6 to 10 are dissolution rates (%) when the meloxicam mass contained in the preparation before the test is 100. 1 to 6, the horizontal axis represents the time from the start of the dissolution test (0 minutes), and the vertical axis represents the dissolution rate.
Separately, for MOVIC tablets (trade name, manufactured by Daiichi Sankyo Co., Ltd.) and meloxicam fast-disintegrating tablets (trade name, manufactured by Nippon Organ Pharmaceutical Co., Ltd.) Although confirmed (Reference Example 1: Movic tablet, Reference Example 2: Meloxicam quick-disintegrating tablet), the range of dissolution behavior of the preparations of Preparation Examples 3-6, 8-17 and 20-28 shown in Tables 1 to 5 (Table 10 and FIG. 6).

  Table 11 and FIG. 7 show the residual ratio (%) of meloxicam in the preparation with respect to the amount of the basic compound in the preparation produced in the preparation example. In FIG. 7, the triangle (▲) is sodium hydroxide, the square (□) is sodium bicarbonate, the cross (×) is L-arginine, and the circle (●) is sodium citrate. is there.

  For each of the preparations in the formulation examples, stability and physical properties were evaluated based on the test methods described above, and the dissolution of meloxicam, which is an acidic pharmaceutical active ingredient, was mass dependent by adding a basic substance. Improved. Furthermore, in all of the preparations of Preparation Examples 4 to 6, 8 to 17, and 23 to 28, elution was confirmed at the first sampling time (5 minutes). Regarding the stability evaluation, in the preparations of all preparation examples, a residual ratio of 90% or more of the meloxicam content in the film-form preparation was observed.

Formulation Example 29
The preparation of the preparation was prepared by preparing a mixed solution in which candesartan cilexetil and base shown in Table 12 and additives were dissolved or dispersed in absolute ethanol or purified water, and then the mixed solution was used as a base film (polyethylene terephthalate film). It was applied on top. After the applied mixed liquid is dried to form a film, the formed film is peeled off from the base film, and the peeled film has a size of about 15 mm × 20 mm per film-form preparation, It cut | disconnected so that mass might become about 35 mg. The thickness of one film-form preparation was adjusted to be about 100 μm. Table 12 shows the formulation of this preparation.

Formulation Example 30
The preparation of the preparation was prepared by preparing a mixed solution in which candesartan cilexetil shown in Table 12, a basic compound and a base, and an additive were dissolved or dispersed in absolute ethanol or purified water. Polyethylene terephthalate film). The applied mixed solution was dried to form a film, and then a film-form preparation was produced in the same manner as in Preparation Example 29. Table 12 shows the formulation of this preparation.

Formulation Examples 31-38
Film-form preparations were produced in the same manner as in Preparation Examples 29 to 30 except that the blending amounts of candesartan cilexetil and other components were as shown in Tables 12 to 13. Numerical values other than pH in Tables 12 to 13 represent the solid content (parts by mass), and the totals in Tables 12 to 13 represent the total solids (parts by mass).

The above tests (1) to (2) were conducted for each of the preparations of Preparation Examples 29 to 38 shown in Tables 12 to 13. The pH of the preparation solution (1 → 100) is shown in Tables 12-13. Tables 14 to 15 and FIGS. 8 to 11 show the results of the dissolution test. Numerical values in Tables 14 to 15 are dissolution rates (%) when the mass of candesartan cilexetil contained in the preparation before the test is 100. 8 to 11, the horizontal axis is the time from the start of the dissolution test (0 minutes), and the vertical axis is the dissolution rate.
Separately, the dissolution property of candesartan cilexetil was also confirmed for bropress tablets (trade name, manufactured by Takeda Pharmaceutical Company Limited) by the above-described method (Reference Example 1: Bropress tablets). The pH of the Blopress tablet solution (1 → 100) was 6.05.

  About each formulation of formulation example 29-38, when stability evaluation and physical-property evaluation were implemented based on the test method shown above, by mix | blending a basic substance, candesartan cilexetil which is an acidic pharmaceutical active ingredient Was improved in a mass-dependent manner. Furthermore, in all of the preparations of Preparation Examples 30 to 38, elution was confirmed at the second sampling time point (10 minutes).

  The present invention is useful in the medical field and the like.

Claims (6)

A film-form preparation for oral administration comprising an acidic pharmaceutically active ingredient and a basic compound in a mixed state, and improved dissolution of the pharmaceutically active ingredient, further comprising a film base The dissolution rate of the active pharmaceutical ingredient that is rapidly soluble in the oral cavity is 10% or more after 10 minutes when the dissolution test is performed by the paddle method rotating at 50 rpm per minute using 900 mL of water as a test solution. Film-form preparation (except when the acidic pharmaceutically active ingredient is ketoprofen).   The film-form preparation according to claim 1, wherein the pH of the 1 w / v% aqueous solution of the film-form preparation is in the range of 6-10.   The film-form preparation according to claim 1 or 2, wherein the acidic pharmaceutically active ingredient is meloxicam or candesartan cilexetil.   The basic compound is (i) at least one selected from the group consisting of sodium bicarbonate, sodium hydroxide and L-arginine, or (ii) from the group consisting of sodium bicarbonate, sodium hydroxide and L-arginine. The film-form preparation according to any one of claims 1 to 3, which is at least one selected from sodium citrate.   The film-form preparation according to any one of claims 1 to 4, wherein the film-form preparation has a thickness of 1 to 3000 µm. Film-form preparation according to claim 1 containing hypromellose and / or hydroxypropyl cellulose as a full Irumu base.

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