JP2012188383A - Fluid medicine for internal use of donepezil hydrochloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a fluid medicine for internal use of donepezil hydrochloride which is easy to manufacture, in which the taking is easy, and which is safe.SOLUTION: The fluid medicine for internal use of donepezil hydrochloride includes: donepezil hydrochloride; D-sorbitol; edetic acid calcium salt; and propylene glycol. The concentration of donepezil hydrochloride is at least 1.0 mg/mL and at most 5.0 mg/mL. The concentration of D-sorbitol is at least 20 w/v% and at most 60w/v%. The concentration of propylene glycol is at least 5w/v% and at most 30w/v%. Moreover, the fluid medicine for internal use of donepezil hydrochloride has at least 3.0 and at most 6.0 of a pH.

Description

  The present invention generally relates to a liquid preparation for internal use that is an ethical drug containing mainly donepezil hydrochloride as a main component, and specifically, donepezil hydrochloride in which a convenient single dose is packaged and filled in a container. The present invention relates to a liquid for medical use.

  Donepezil hydrochloride is a therapeutic agent for Alzheimer's disease and is orally administered to patients. Patients with Alzheimer's disease who are subjects of this drug are often elderly. In elderly people, in addition to the progression of Alzheimer's disease and Alzheimer's disease, swallowing function is often reduced due to the effects of aging and various other diseases. A decrease in swallowing function is often referred to as dysphagia. For patients with dysphagia, it is difficult to swallow normal tablets and capsules that are solids as well as normal food. Therefore, with regard to donepezil hydrochloride, in addition to ordinary tablets and fine granules, there is already an easily disintegrating orally disintegrating tablet that is easily disintegrated by saliva in the oral cavity and converted into a fluid, thereby facilitating swallowing. Has been developed.

  However, the degree of dysphagia varies greatly depending on the condition and the progress of aging. Some patients find it difficult to take even fine granules and easily disintegrating preparations. Especially in the elderly, the amount of saliva is reduced and the oral cavity is often dry, even in the oral disintegrating tablets, it does not disintegrate easily in the oral cavity and often remains in the oral cavity for a long time, Experienced. Fine granules need to be taken with water, but taking with water can cause aspiration. In addition, after taking the medicine, a part of the fine granules may remain in the mouth forever and complain of a foreign body sensation.

  Therefore, there is a need for a donepezil hydrochloride formulation that is easier to take. Recently, a jelly preparation of donepezil hydrochloride has been developed. A jelly agent exhibits physical properties similar to those of food jelly, contains a large amount of water, and can be easily swallowed in small amounts.

  On the other hand, in patients with dysphagia that have become more difficult to ingest food orally, a nasogastric tube that inserts a thin tube from the nose into the stomach, or a tube that is drilled directly into the stomach from outside the body is inserted. A tube feeding method is used in which liquid food is fed from the “gastric fistula” into the stomach. When a solid internal medicine is administered to such a patient, a method in which tablets are pulverized and administered orally in small amounts is also employed. Furthermore, the contents taken out from the pulverized tablets and capsules are dissolved and suspended in water, or the tablets and capsules are suspended in warm water as they are and administered from a nasogastric tube or a gastric fistula tube.

  The above-mentioned donepezil hydrochloride jelly is convenient for oral administration to patients with dysphagia. However, in the case of administration using a thin tube, there is a problem that the tube is clogged or adhered to the inner wall of the tube. Therefore, it was not a satisfactory formulation for administration from a tube for patients with nasogastric tube or gastric fistula.

  Thus, it is desired to develop a donepezil hydrochloride preparation that can be easily taken orally even by patients with dysphagia and can also be administered through a nasogastric tube or a gastric fistula tube.

  In view of the above situation, a liquid preparation of donepezil hydrochloride is considered useful. However, it is known that when a liquid preparation having a low viscosity such as water is given to a patient with dysphagia, the liquid preparation is accidentally swallowed into the trachea and bronchus. In some cases, it may cause aspiration pneumonia. On the other hand, if the viscosity is too high, the resistance increases and is not suitable for administration from a tube. Therefore, it must be a liquid preparation having an appropriate viscosity for the dysphagic person.

  Furthermore, long-term storage stability and photostability must be ensured in order to obtain an ethical drug.

  For example, JP-A-11-106353 (Patent Document 1) describes a light-stabilized anti-dementia drug composition comprising donepezil hydrochloride and an organic acid.

  Japanese Patent Application Laid-Open No. 2000-136134 (Patent Document 2) discloses donepezil hydrochloride, polyvinylpyrrolidone and / or copolyvidone, propylene for the purpose of reducing the unpleasant taste of drugs and further suppressing the formation of precipitates and decomposition products. A solution consisting of glycol and / or D-sorbitol is described.

  JP 2008-195714 A (Patent Document 3) provides a pharmaceutical composition containing donepezil or a pharmacologically acceptable salt thereof, which has improved storage stability. For this purpose, there is described a pharmaceutical composition further comprising donepezil or a pharmacologically acceptable salt thereof, a natural polymer substance, and edetate in the pharmaceutical composition.

  Moreover, it is necessary to relieve the peculiar bitterness and numbness (hereinafter referred to as bitterness) of the donepezil hydrochloride preparation. Examples of methods for improving taste in the donepezil hydrochloride liquid preparation include a method of adding an anionic polymer and a method of using silicic anhydride.

  For example, JP 2005-41887 A (Patent Document 4) and JP 11-228450 A (Patent Document 5) describe a syrup or jelly agent of donepezil hydrochloride containing an anionic polymer substance. Yes.

  JP-A-11-92402 (Patent Document 6) describes a pharmaceutical composition containing donepezil hydrochloride, a hydrophilic substance having a positive charge, and an anionic polymer substance. Further, it is described that a sweetener such as sorbitol can be added to obtain a syrup as a pharmaceutical composition.

  Japanese Patent Application Laid-Open No. 11-106354 (Patent Document 7) describes a liquid preparation in which anhydrous silicic acid is added to donepezil hydrochloride. Moreover, it describes that sweeteners, such as sorbitol, can be added to a liquid agent.

  International Publication No. 2005/097124 (Patent Document 8) describes an oral solution of donepezil hydrochloride containing sorbitol and propylene glycol.

JP-A-11-106353 JP 2000-136134 A JP 2008-195714 A JP 2005-41887 A JP 11-228450 A JP-A-11-92402 JP-A-11-106354 International Publication No. 2005/097124

  However, the solutions and pharmaceutical compositions described in Patent Documents 1 to 3 and Patent Document 8 have both an appropriate viscosity, a long-term stability, and a liquid that does not exhibit a bitter taste. difficult.

  Moreover, there exists the following problems about the liquid agent containing an anionic polymer substance as described in patent documents 4-6. That is, in general, anionic polymer substances are in the form of powder, and therefore, in the production of liquid preparations, it often takes time in the dissolution step. This complicates the manufacturing process and is not desirable in terms of work efficiency.

  On the other hand, the liquid agent described in Patent Document 7 contains anhydrous silicic acid, but anhydrous silicic acid is insoluble in water and causes precipitation when formulated into a uniform internal liquid agent, which is an additive to be avoided. .

  Therefore, an object of the present invention is to provide a safe internal solution of donepezil hydrochloride that is easier to manufacture, easier to take, and safer than conventional fine granules, orally disintegrating tablets, and jelly preparations.

  In order to provide a liquid donepezil hydrochloride preparation that has an appropriate viscosity, is stable for a long time, and does not exhibit a bitter taste, the present inventors have intensively studied. As a result, the pH of the aqueous solution containing 1.0 mg / mL or more and 5.0 mg / mL or less donepezil hydrochloride, D-sorbitol, propylene glycol, calcium edetate, and a preservative is adjusted to 3.0 to 6. We have found that formulations adjusted to 0 are useful.

  In particular, when the donepezil hydrochloride concentration is 1.0 mg / mL or more, the amount of liquid to be taken clinically becomes small, and it is convenient for patients with dysphagia to feel less difficult to take. On the other hand, when the donepezil hydrochloride concentration is 5.0 mg / mL or more, when taking 3 mg, which is the minimum clinical dose, 0.6 mL or less of liquid is taken out from the container and taken. However, it is generally not easy to handle such a small amount of liquid accurately.

  By the way, there is a test method for drinking 3 mL of water as one of the clinical test methods for determining the presence or absence and degree of dysphagia in a patient. As can be easily inferred from this, even if there is a dysphagia, it is considered that there is no serious risk if a liquid of about 3 mL is accidentally swallowed. For this reason, it is considered that the dosage of the internal solution taken by the patient at one time is preferably about 0.6 mL to 3.0 mL, which is a liquid volume that is easy to handle and has few safety problems. Based on this fact, the present inventors made the following examination.

(Concentration of donepezil hydrochloride)
The clinical dosage and administration of donepezil hydrochloride is 3 mg to 10 mg once a day. Therefore, when the donepezil hydrochloride concentration is 1.0 mg / mL or less, it is necessary to take 10 mL or more of the internal solution in order to take the drug amount corresponding to the clinical use amount of 10 mg / time. However, it is not easy for patients with advanced dysphagia to safely take 10 mL of liquid.

  On the other hand, if the donepezil hydrochloride concentration is 5.0 mg / mL or more, in order to take a drug amount corresponding to the clinical use amount of 3 mg / dose, an internal solution of 0.6 mL or less must be taken. However, it is not easy even for a healthy person to take such a small amount of liquid accurately. In particular, Alzheimer's disease patients are many elderly people, and even if the product is packaged in a single dose, there may be a small amount of remaining in the package, or it may spill at the time of administration. It is difficult to take less than 0.6 mL of liquid.

  As mentioned above, 1.0 mg / mL or more and 5 mg / mL or less is appropriate as the donepezil hydrochloride concentration of the internal solution. Furthermore, if donepezil hydrochloride concentration is 2.0 mg / mL or more and 4.0 mg / mL or less, when taking 5 mg / dose of donepezil hydrochloride which is a clinical general-purpose amount, 1.25 mL or more and 2.5 mL or less The donepezil hydrochloride concentration internal solution may be taken. Thus, the donepezil hydrochloride internal solution having a donepezil hydrochloride concentration of 2.0 mg / mL or more and 4.0 mg / mL or less is considered to be a preparation that is easy to take even for patients with dysphagia because a single dose is small. It is done.

  In addition, if the donepezil hydrochloride concentration is 2.0 mg / mL, when taking 10 mg / dosepezil hydrochloride, the single dose is 5 mL. Patients taking 10 mg / dose donepezil hydrochloride are limited to severe Alzheimer's patients. Such a patient would be accompanied by a caregiver. Therefore, if it is about 5 mL that can be taken using a large spoon in any household, it can be said that it is a highly convenient preparation with low risk of aspiration.

(Solubility of donepezil hydrochloride)
Saturated solutions of donepezil hydrochloride were prepared using diluted McIlvine buffers at various pHs, stirred in a room at 25 ° C. for 24 hours, and then filtered through a 0.2 μm filter. The concentration of donepezil hydrochloride in the filtrate was quantified by ultra high performance liquid chromatography, and the pH-solubility curve of donepezil hydrochloride was examined.

  FIG. 1 is a diagram showing the pH-solubility curve of donepezil hydrochloride. As shown in FIG. 1, donepezil hydrochloride showed high solubility around pH 2-6, and extremely low solubility from neutral to alkaline.

(Stability of donepezil hydrochloride)
Next, the thermal stability and light stability of donepezil hydrochloride were investigated about the donepezil hydrochloride solution of various pH. In order to investigate the thermal stability of donepezil hydrochloride, a donepezil hydrochloride solution dissolved at various pHs was filled into a white glass ampoule and stored at 40 ° C. for 6 months. It measured by the chromatography method (UPLC method). In addition, in order to investigate the photostability, donepezil hydrochloride solution dissolved at various pH was filled in a white glass ampule and stored for 2 weeks under 1800 lx light irradiation, and then the residual rate of donepezil hydrochloride was measured at ultra high speed. It measured by the liquid chromatography method (UPLC method).

  Donepezil hydrochloride residual ratio was measured by ultra high performance liquid chromatography (UPLC). As the detector, an ultraviolet absorptiometer detector (measurement wavelength: 271 nm) was used. As the column, a stainless tube having an inner diameter of 3.0 mm and a length of 100 mm packed with 2.2 μm of octadecylsilylated silica gel for liquid chromatography was used. The column temperature was a constant temperature around 40 ° C. The flow rate was 0.5 mL / min. As the mobile phase, an aqueous phosphate solution mixture (76:24) adjusted to pH 3.0 with acetonitrile / triethylamine was used. As a diluent, a mixed solution of acetonitrile and water (1: 4) was used. The injection volume was 10 μL.

  FIG. 2 shows donepezil hydrochloride remaining rate after 6 months storage at 40 ° C. and donepezil hydrochloride after 2 weeks storage at 1800 lx light irradiation for various pH solutions of donepezil hydrochloride FIG.

  As shown in FIG. 2, the donepezil hydrochloride solution showed a high residual rate of donepezil hydrochloride at a pH of 6 or less with respect to heat. On the other hand, when stored for 2 weeks under irradiation with light of 1800 lx, a solution having a pH of 4 or more and 6 or less was relatively stable. On the other hand, in other pH solutions, the residual rate of donepezil hydrochloride was low, suggesting that it was unstable to light.

  Regarding the status of related substances, the total amount of related substances produced when stored at 40 ° C. for 6 months was measured by the UPLC method.

  The amount of related substances produced was measured by ultra high performance liquid chromatography (UPLC). As the detector, an ultraviolet absorptiometer detector (measurement wavelength: 286 nm) was used. The column used was a stainless tube having an inner diameter of 2.1 mm and a length of 100 mm packed with 1.7 μm of octadecylsilylated silica gel for liquid chromatography. The column temperature was a constant temperature around 50 ° C. The flow rate was 0.5 mL / min. As the mobile phase A, a 0.1% aqueous phosphoric acid solution adjusted to pH 6.5 with triethylamine was used. As mobile phase B, acetonitrile was used. As a diluting solution, a mixture of acetonitrile and water (1: 1) was used. The injection volume was 5 μL.

  Gradient conditions were: initial concentration A90%, B10%, A 90% to 50% in the first 6 minutes, B 10% to 50%, A for the next 4 minutes, ie 6 minutes to 10 minutes. From 50% to 20%, B from 50% to 80%, followed by 10 to 10.1 minutes, A from 20% to 90%, B from 80% to 10%, and finally from 10.1 minutes to 12 A gradient of 90% for A and 10% for B during 5 minutes was used.

  The content of the related substance was calculated from the ratio of the peak area of donepezil and the peak area of the related substance.

  FIG. 3 is a diagram showing the amount of a related substance produced when the donepezil hydrochloride solution having various pH values is stored at 50 ° C. for 2 weeks.

  As shown in FIG. 3, it was found that the donepezil hydrochloride solution is preferably in the range of pH 3 or more and pH 6 or less in order to reduce related substances generated by heating. In particular, in the pH range of 4 to 5, production of related substances was small.

  As described above, the results shown in FIG. 1 indicate that the pH of 6 or less is suitable for the donepezil hydrochloride solution for the solubility of the active ingredient. Further, from the results of the residual ratio in FIG. 2, it was found that the range of pH 3 to pH 6 is suitable for the donepezil hydrochloride solution when not exposed to light for the stability of the active ingredient. Further, from the results of FIG. 3, it was found that pH 3 to pH 6 is suitable for the donepezil hydrochloride solution in order to suppress the formation of related substances.

  From the above results, it was concluded that the pH of the donepezil hydrochloride internal solution is 3 or more and 6 or less, and that the light shielding packaging is most suitable at pH 4 or more and pH 5 or less.

(Screening for stabilizers)
Screening for stabilizers was performed using an inorganic acid buffer system (phosphate) as a base formulation.

  A 0.2 w / v% donepezil solution (pH 3.5 hydrochloric acid adjustment) was prepared using a phosphate buffer. As additives, sorbitol, ethanol, propylene glycol, calcium edetate, specifically, disodium calcium edetate (hereinafter referred to as EDTA · Ca), and Macrogol 400 were used. When additives were added, EDTA · Ca was excluded, and the final concentration of each additive was 10 w / v% (EDTA · Ca was 0.1 w / v%). Thereafter, it was stored at 50 ° C. for 3 weeks. Three weeks later, the related substances were quantified, and the total amount of related substances produced was compared. The results are shown in Table 1. In Table 1, “◯” indicates an additive that has been added, and “−” indicates an additive that has not been added. For example, as a control No. In sample 1, only the donepezil solution was dissolved in water, and no additive was added. No. In sample 2, only sorbitol was added as an additive. No. In 10 samples, sorbitol, ethanol, and propylene glycol were added as additives.

  As shown in Table 1, when sorbitol, ethanol and propylene glycol were used alone, the total related substances content was relatively small, and the effect of improving the stability was confirmed. In addition, even when EDTA · Ca was used alone, the thermal stability was improved. On the other hand, when the macrogol 400 was added, conversely, it was suggested that thermal stability was reduced.

  Moreover, the effect which improves stabilization by combining an additive was suggested. No. Samples 7-11 showed good stability. In particular, EDTA · Ca was added in combination with sorbitol and propylene glycol. For the 11 formulation, a significant stability improvement effect was observed compared to the control (No. 1 sample).

  Furthermore, considering the factors of viscosity and taste, the effect of stability by additives including preservatives was examined.

(D-sorbitol concentration)
For patients with dysphagia, it is known that it is not easy to drink a low-viscosity liquid such as water, and it is often swallowed into the trachea. Therefore, the viscosity of commercially available liquid foods intended for those patients is set to 2 to 20000 mPa · s, and in particular, many are 5 to 100 mPa · s. Regarding the donepezil hydrochloride internal solution, 5-100 mPa · s, which is the same viscosity as liquid food, is suitable considering that it is mainly taken by patients with dysphagia. On the other hand, considering the case of tube administration by gastric fistula or nasogastric tube, extremely viscous liquids may clog in the tube, so that a thin tube should be as low as possible so that it can easily pass through. Desirably, 5 to 20 mPa · s is suitable overall.

  Further, donepezil hydrochloride exhibits a characteristic bitter taste, so that taste-masking by adding a sweetener or the like is necessary. Formulation test to examine the total amount of related substances produced when stored at 60 ° C for 10 days for the stability of the active ingredient when various sweeteners, etc. are blended with 0.1-10 w / v% or a small amount of parabens Carried out.

  FIG. 4 is a diagram showing the total related substance content when a donepezil hydrochloride solution containing various additives is stored at 60 ° C. for 10 days.

  As shown in FIG. 4, it was recognized that D-sorbitol, ethanol, propylene glycol, parabenmethyl and parabenpropyl produced a small amount of related substances and did not adversely affect the stability. Among them, the taste-masking action of D-sorbitol was good. As for ethanol, there is a patient who is physically resistant to alcohol, and propylene glycol exhibits a specific bitterness when the blending amount is high. Therefore, it was considered that D-sorbitol was most suitable as a flavoring agent.

  Furthermore, since the viscosity of 5 to 20 mPa · s was considered to be the most preferable as described above, studies for imparting the viscosity were performed. The viscosity was measured at room temperature of 25 ° C. using a B-type viscometer. The results are shown in Table 2.

  When povidone and D-sorbitol were studied as thickeners, when povidone and D-sorbitol were blended, the desired viscosities were obtained in both formulations 1 and 3. However, since povidone is difficult to dissolve in water and it takes time to dissolve, it was considered preferable not to use povidone in actual production.

  On the other hand, even when povidone was not used and D-sorbitol was increased to 40% (prescription 2), a viscosity of 8.0 mPa · s was obtained. From this, it was clarified that the target viscosity can be obtained without using povidone.

  Based on the above knowledge, the internal use liquid agent of donepezil hydrochloride according to this invention is comprised as follows.

  The internal solution for donepezil hydrochloride according to the present invention contains donepezil hydrochloride, D-sorbitol, calcium edetate, and propylene glycol. The concentration of donepezil hydrochloride is 1.0 mg / mL or more and 5.0 mg / mL or less. The concentration of D-sorbitol is 20 w / v% or more and 60 w / v% or less. The concentration of propylene glycol is 5 w / v% or more and 30 w / v% or less. Moreover, the pH of the internal use liquid agent of donepezil hydrochloride is 3.0 or more and 6.0 or less.

  Since D-sorbitol has a sweetening action, it is desirable that the concentration of donepezil hydrochloride be as high as possible in the internal solution of donepezil hydrochloride. However, when the concentration of D-sorbitol in the internal solution of donepezil hydrochloride is 60 w / v% or more, crystals are likely to precipitate when opened and left indoors. Moreover, if the density | concentration of D-sorbitol in the internal solution of donepezil hydrochloride is less than 20 w / v%, the bitter taste of donepezil hydrochloride cannot be tasted. Considering these, the concentration of D-sorbitol in the internal solution of donepezil hydrochloride is 20 w / v% or more and 60 w / v% or less.

  It is desirable to add a preservative to the internal use solution of donepezil hydrochloride. As preservatives, it is desirable to add effective concentrations of methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate (hereinafter referred to as parabens), and the like. On the other hand, parabens are difficult to dissolve in water. For this reason, dissolving parabens in water during actual production is a laborious operation. Therefore, first, the parabens are dissolved in a readily soluble solvent other than water. By doing in this way, manufacture of the internal solution for donepezil hydrochloride becomes easy. As a result of the compoundability test, it was determined that propylene glycol that does not affect the stability of donepezil hydrochloride is suitable as the easily soluble solvent for parabens used in the internal use liquid preparation according to the present invention. However, propylene glycol gives an astringent stimulus to the tongue at a high concentration of 30 w / v% or more. Therefore, the concentration of propylene glycol in the internal solution of donepezil hydrochloride is 5 w / v% or more and 30 w / v% or less as a concentration that is sufficient to dissolve parabens and does not adversely affect the taste. .

  As described above, the pH of the donepezil hydrochloride solution is suitable for the solubility of the active ingredient. Regarding the stability of the active ingredient, the donepezil hydrochloride solution is suitable in the range of pH 3 to pH 6 when not exposed to light. Furthermore, pH 3 to pH 6 is suitable for the donepezil hydrochloride solution in order to suppress the formation of related substances. Then, the pH of the internal solution for donepezil hydrochloride is 3.0 or more and 6.0 or less.

  In the internal use solution of donepezil hydrochloride according to the present invention, the concentration of calcium edetate is preferably 0.04 mg / mL or more and 4.0 mg / mL or less.

  It is desirable to add a preservative to the internal use solution of donepezil hydrochloride for preservation. The concentration of the preservative in the internal use solution of donepezil hydrochloride is desirably in a range generally used as a preservative for pharmaceuticals from the viewpoint of effectiveness and safety. That is, it is preferable that the density | concentration of the calcium edetate in the internal solution of donepezil hydrochloride is 0.04 mg / mL or more and 4.0 mg / mL or less.

  The internal solution of donepezil hydrochloride according to the present invention preferably contains at least one of methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, and butyl paraoxybenzoate. .

  It is desirable to add a preservative to the internal use solution of donepezil hydrochloride in order to prevent generation of mold and the like for a long period of time. As the preservative, a preservative that does not affect the stability of donepezil hydrochloride, does not adversely affect the taste, and is widely used as a preservative for pharmaceuticals is desirable. Therefore, as a preservative, it is preferable to contain at least one of the above-mentioned parabens that have a precedent for use in pharmaceutical products.

  The internal liquid preparation of donepezil hydrochloride according to the present invention preferably has a viscosity at 25 ° C. of 5 mPa · s to 100 mPa · s.

  It aims to be prescribed to patients who have difficulty swallowing. Although there is no established theory about the viscosity of liquids that are easily taken by patients with dysphagia, it is said that water (1 mPa · s) is easy to drain and tea with a tromi is less likely to suffer. Many commercially available liquid foods have a viscosity at 25 ° C. of 5 mPa · s to 100 mPa · s. In view of the fact that these commercially available liquid foods are accepted by patients with dysphagia, it is considered useful that their viscosity is close. Therefore, it is preferably 5 mPa · s or more and 100 mPa · s or less.

  It is preferable that the internal use liquid agent of donepezil hydrochloride according to this invention is accommodated in the package formed of the metal foil laminated plastic film or the light-shielding metal-deposited plastic film.

  As described above, according to the present invention, it is possible to provide an internal solution of donepezil hydrochloride that is easy to manufacture, easy to take, and safe.

It is a figure which shows the pH-solubility curve of donepezil hydrochloride. The figure which shows the residual rate of donepezil hydrochloride after storing for 6 months at 40 degreeC about the donepezil hydrochloride solution of various pH, and the residual rate of donepezil hydrochloride after storing for 2 weeks under 1800 lx light irradiation. is there. It is a figure which shows the production amount of a related substance about the donepezil hydrochloride solution of various pH. It is a figure which shows total related substance content when the donepezil hydrochloride solution which added the sweetener etc. is preserve | saved at 60 degreeC for 10 days.

  Embodiments of the present invention will be described below.

  The internal solution for donepezil hydrochloride according to one embodiment of the present invention contains donepezil hydrochloride, D-sorbitol, calcium edetate, and propylene glycol. The concentration of donepezil hydrochloride is 1.0 mg / mL or more and 5.0 mg / mL or less. The concentration of D-sorbitol is 20 w / v% or more and 60 w / v% or less. The concentration of propylene glycol is 5 w / v% or more and 30 w / v% or less. Moreover, the pH of the internal use liquid agent of donepezil hydrochloride is 3.0 or more and 6.0 or less.

  In the internal use solution of donepezil hydrochloride according to the present invention, the concentration of calcium edetate is preferably 0.04 mg / mL or more and 4.0 mg / mL or less.

  The internal solution of donepezil hydrochloride according to the present invention preferably contains at least one of methyl parahydroxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, and butyl paraoxybenzoate. .

  The internal liquid preparation of donepezil hydrochloride according to the present invention preferably has a viscosity at 25 ° C. of 5 mPa · s to 100 mPa · s.

  It is preferable that the internal use liquid agent of donepezil hydrochloride according to this invention is accommodated in the package formed of the metal foil laminated plastic film or the light-shielding metal-deposited plastic film. As the metal foil laminated plastic film, for example, an aluminum laminated polyethylene film is used. Moreover, as a light-shielding metal vapor deposition plastic film, the plastic film which vapor-deposited aluminum is used, for example. As the plastic film, for example, a film made of a plastic material such as polyethylene or polypropylene is used.

  As described above, according to the present invention, it is possible to provide an internal solution of donepezil hydrochloride that is easy to manufacture, easy to take, and safe.

  The present inventors examined the optimal prescription by using as an index three factors such as the physicochemical stability of the main drug, whether it is a taste that can be taken or whether it has an appropriate viscosity. The physicochemical stability was examined by ultra high performance liquid chromatography using the remaining amount of the active ingredient and the formation of related substances as indicators. Each measurement condition is as described above. At the same time, the presence or absence of precipitates / precipitation was visually observed. The taste was sensory evaluated as described below. The viscosity was examined with a B-type rotational viscometer. Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Example 1
An internal solution of donepezil hydrochloride was prepared according to the formulation shown in Table 3. That is, methyl paraoxybenzoate and propyl paraoxybenzoate were dissolved in propylene glycol to prepare Preparation Solution I. Separately, sodium dihydrogen phosphate dihydrate, calcium edetate disodium salt, sucralose and donepezil hydrochloride were dissolved in about 250 mL of purified water, and further D-sorbitol solution was added to prepare Preparation Solution II. After adding Preparation I to Preparation II, phosphoric acid was added while measuring pH to adjust to pH 4.0. Then purified water was added to make the total volume 1L. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Example 1 was 40 w / v%, and the concentration of propylene glycol was 10 w / v%.

  The internal solution had a viscosity of 8.1 mPa · s. When 3 healthy adults took 2.5 mL of this product orally, there was no bitterness and they could be easily swallowed. Furthermore, this product was filled in a stick package composed of an aluminum laminated polyethylene film, stored at 40 ° C. for 4 months, and then the content of donepezil hydrochloride and related substances was measured. Donepezil hydrochloride content was 98.7% and total related substances were 0.5%.

  Therefore, the solution for donepezil hydrochloride stick packaging obtained in Example 1 was considered to be a highly medically useful preparation.

(Comparative Example 1)
In the formulation described in Example 1, the D-sorbitol solution was changed to 200 g (140 g as D-sorbitol), and the formulation shown in Table 4 was used for sticking the donepezil hydrochloride in the same manner as in Example 1. A solution was prepared. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 1 was 14 w / v%, and the concentration of propylene glycol was 10 w / v%.

  As a result, the obtained liquid preparation for internal use exhibited a bitter taste and a viscosity as low as 3.4 mPa · s, and it was not always a preparation that could be easily taken for patients with dysphagia.

(Comparative Example 2)
As shown in Table 5, a liquid formulation for donepezil hydrochloride in stick packaging was prepared using the same manufacturing method as in Example 1 with the formulation described in Example 1. A 10% sodium hydroxide solution was used and the pH was adjusted to 7.0. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 2 was 40 w / v%, and the concentration of propylene glycol was 10 w / v%.

  Although this product did not exhibit bitterness, etc., the product was stored at 40 ° C. for 3 months. As a result, the donepezil hydrochloride content was 95.3%, and the total related substances were 3.4%. It was suggested that there was a problem.

(Comparative Example 3)
As shown in Table 6, an internal solution of donepezil hydrochloride was prepared with the formulation described in Example 1 and using the same production method as in Example 1. However, only pH was set to 2.0 using phosphoric acid. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 3 was 40 w / v%, and the concentration of propylene glycol was 10 w / v%.

  As a result of storing this product at 40 ° C. for 3 months, the donepezil hydrochloride content was 95.1%, and the total related substances were 2.9%, which was not a stable preparation.

(Comparative Example 4)
As shown in Table 7, in the formulation described in Example 1, 40 g of propylene glycol was used to prepare a donepezil hydrochloride stick packaging solution in the same manner as in Example 1. However, in the preparation of Preparation Liquid I, it was difficult to dissolve methyl paraoxybenzoate and propyl paraoxybenzoate, and they were dissolved by heating to 45 ° C. and stirring during mixing with Preparation Liquid II. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 4 was 40 w / v%, and the concentration of propylene glycol was 4 w / v%.

  The obtained internal solution was stored at 40 ° C. for 1 month, and the amount of related substances produced was examined. As a result, the total related substances were 1.9%, and it was suggested that there was a problem in storage stability.

(Comparative Example 5)
As shown in Table 8, in the formulation described in Example 1, propylene glycol was 350 g, and donepezil hydrochloride internal solution was prepared in the same manner as in Example 1. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 5 was 40 w / v%, and the concentration of propylene glycol was 35 w / v%.

  As a result, the resulting internal solution of donepezil hydrochloride had a strong bitter taste and was considered inappropriate for oral administration.

(Example 2)
In the formulation described in Table 3, propylene glycol was 150 g, and the formulation shown in Table 9 was changed to a D-sorbitol solution, methyl paraoxybenzoate, and propyl paraoxybenzoate in a pH of 5.0 as in Example 1. An internal solution of donepezil hydrochloride was prepared. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Example 2 was 35 w / v%, and the concentration of propylene glycol was 15 w / v%.

  The viscosity of the obtained liquid for internal use was 7.4 mPa · s. A slight bitter taste was felt when 2.5 mL of this product was taken orally by healthy adults, but it could be easily swallowed.

  Furthermore, as a result of storing this product at room temperature for 1 year, the content of donepezil hydrochloride was 98.3%, and the total related substances were 0.7%, which was considered to be a highly medically useful preparation.

(Comparative Example 6)
As shown in Table 10, an internal solution of donepezil hydrochloride having a pH of 4.0 was prepared in the same manner as in Example 1, except that 150 g of propylene glycol was replaced with Macrogol 400 in the formulation described in Example 1. . The concentration of D-sorbitol in the internal use solution of donepezil hydrochloride of Comparative Example 6 was 40 w / v%.

  The stability of the obtained donepezil hydrochloride stick packaging solution was examined. As a result, the content was 93.7% after storage at 40 ° C. for 3 months, the total related substances increased to 4.5%, and the preparation was not stable as a pharmaceutical product.

(Example 3)
As shown in Table 11, an internal solution of donepezil hydrochloride adjusted to only 3.0 with the formulation described in Table 3 in the same manner as in Example 1 was prepared. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Example 3 was 40 w / v%, and the concentration of propylene glycol was 10 w / v%.

  The viscosity of the obtained liquid for internal use was 8.0 mPa · s. When 3 healthy adults took 2.5 mL of this product orally, there was no bitterness and they could be easily swallowed. Furthermore, this product was filled in a stick package composed of an aluminum laminated polyethylene film and stored at 40 ° C for 4 months. As a result, the donepezil hydrochloride content was 97.7% and the total related substances were 0.9%. It was. Therefore, it was considered that the solution for donepezil hydrochloride stick packaging obtained in Example 3 is a highly medically useful preparation.

(Comparative Example 7)
As shown in Table 12, an internal solution of donepezil hydrochloride having a pH of 4.0 was prepared by preparing a preparation in which only EDTA · Ca was removed from the formulation of Example 1 in the same manner as in Example 1. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Comparative Example 7 was 40 w / v%, and the concentration of propylene glycol was 10 w / v%.

  The stability of the obtained donepezil hydrochloride stick packaging solution was examined. As a result, the total related substances increased to 4.5% after storage at 40 ° C. for 3 months, and the preparation was not stable as a pharmaceutical product.

Example 4
An internal solution of donepezil hydrochloride was prepared in the same manner as in Example 1 with the formulation described in Table 13. The concentration of D-sorbitol in the internal use solution of donepezil hydrochloride of Example 4 was 35 w / v%, and the concentration of propylene glycol was 15 w / v%.

  The viscosity of the obtained liquid for internal use was 18.5 mPa · s. When 2.5 mL of this product was taken orally by healthy adults, there was no bitterness and it was easy to swallow. Furthermore, this product was stored at 40 ° C. for 2 months. As a result, the donepezil hydrochloride content was 98.7% and the total related substances were 0.4%, which was considered to be a highly medically useful preparation.

(Example 5)
As shown in Table 14, specimens were similarly prepared using a formulation in which 8.0 g of povidone was replaced with 4.0 g of xanthan gum. The concentration of D-sorbitol in the internal solution of donepezil hydrochloride of Example 5 was 35 w / v%, and the concentration of propylene glycol was 15 w / v%. In this case, it was considered that the preparation was highly medically useful as in Example 4 using povidone.

  As described above, according to the present invention, it was found that it is possible to prepare a stick-packed donepezil hydrochloride internal liquid that is easy to take even for patients with dysphagia and has excellent stability.

  Even when a light-shielding container is used as a container for the internal liquid preparation of donepezil hydrochloride, it can be considered that it is moved to a large container in actual handling.

  The internal solution of donepezil hydrochloride of Examples 1 to 5 was filled in a transparent white glass ampoule and stored under direct sunlight and 1800 lx ultraviolet irradiation. After 48 hours under direct sunlight, 14 days under ultraviolet irradiation. Later, a yellowish white precipitate was observed.

  From this result, it was found that the dose of donepezil hydrochloride was preferably contained in a package formed of an aluminum laminated polyethylene film or a plastic film on which aluminum was deposited.

  It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is shown not by the above embodiments and examples but by the scope of the claims, and includes all modifications and variations within the meaning and scope equivalent to the scope of the claims.

Claims (5)

Donepezil hydrochloride,
D-sorbitol,
Edetate calcium salt,
Containing propylene glycol,
The concentration of the donepezil hydrochloride is 1.0 mg / mL or more and 5.0 mg / mL or less,
The concentration of the D-sorbitol is 20 w / v% or more and 60 w / v% or less,
The propylene glycol concentration is 5 w / v% or more and 30 w / v% or less,
An internal solution of donepezil hydrochloride having a pH of 3.0 or more and 6.0 or less.   The internal use liquid agent of donepezil hydrochloride of Claim 1 whose density | concentration of the said calcium edetate is 0.04 mg / mL or more and 4.0 mg / mL or less.   The internal use of donepezil hydrochloride according to claim 1 or 2, comprising at least one of methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, isopropyl paraoxybenzoate, and butyl paraoxybenzoate. Liquid drug.   The internal use liquid agent of donepezil hydrochloride of any one of Claim 1- Claim 3 whose viscosity in 25 degreeC is 5 mPa * s or more and 100 mPa * s.   The donepezil hydrochloride according to any one of claims 1 to 4, wherein a single dose is contained in a package formed by a metal foil laminated plastic film or a light-shielding metal-deposited plastic film. Liquid for internal use.

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