Novel intraoral dispersible powder composition

Abstract

An orally disintegrating powder composition containing donepezil or a pharmaceutically acceptable salt thereof as a main component, comprising a diluent consisting of sugar or sugar alcohol, donepezil or a pharmaceutically acceptable salt thereof included in cyclodextrin or a derivative thereof, an ionic additive, and a first coating layer containing a pharmaceutically acceptable additive, and a second coating layer containing a poorly water-soluble polymer, a plasticizer, and a pharmaceutically acceptable additive. An orally disintegrating powder composition is provided.

Description

Technical Field

[0001] The present invention relates to a novel orally disintegrating powder composition for drugs exhibiting bitterness (hereinafter referred to as "bitter drugs"). Specifically, the present invention relates to an orally disintegrating powder composition as a novel formulation for facilitating administration to patients who have difficulty taking tablets or capsules. More specifically, an object of the present invention is to provide a novel orally disintegrating powder composition that can exhibit a function of masking bitterness when a bitter drug is administered as a powder and can maximize the swallowing ability.

Background Art

[0002] Typical oral dosage forms include tablets and capsules. These dosage forms have the inconvenience that they are difficult to administer without taking them with water. In particular, in the case of patients who are difficult to manage for physical or mental reasons such as dementia and Parkinson's disease, or patients with swallowing disorders, the administration of tablets or capsules is very inconvenient. Patients with swallowing disorders may cause other medical conditions or injuries such as shortness of breath and pneumonia during the process of taking a single tablet or capsule. In fact, it is estimated that approximately 10,000 patients die of asphyxiation due to swallowing disorders every year.

[0003] As an alternative to overcome this, there are dosage forms such as aqueous solutions, orally disintegrating tablets, and orodispersible films. However, aqueous solutions are not a dosage form preferred by patients because of the instability peculiar to aqueous solutions and the difficulty of administering an accurate amount of the active ingredient, and further, in the case of bitter drugs, bitterness still remains even when bitterness masking means are introduced.

[0004] In the case of orally disintegrating tablets, it is a dosage form that easily disintegrates in the oral cavity by saliva and has the advantage of being able to be taken without water (or sometimes taken together with water). However, it has the disadvantages of using expensive disintegration accelerators for rapid disintegration in the oral cavity and leaving a foreign body sensation in the oral cavity after taking when using insoluble substances. Furthermore, in the actual dosing site, since a part of the active ingredient often fails to disintegrate, water is often sought again. In fact, according to a summary report on the characteristics of a representative commercial product of orally disintegrating tablets, Zofran ODT (registered trademark), it is recommended to dissolve and take it in the form of water or syrup for children under 6 years old because there is a risk when taking it in tablet form. As a result, orally disintegrating tablets are frequently damaged in terms of their contents due to impacts occurring during storage, transportation, and product distribution processes.

[0005] In the case of orally disintegrating films, due to their formulation characteristics, polymers forming the film must be used, so there is inevitably a residual feeling in the oral cavity, and there is a fundamental limit to the content of the active ingredient that can be loaded on the film. Furthermore, in the case of bitter drugs, it is difficult to apply appropriate bitter masking means due to the limitations of the film dosage form, and even if applied, the bitterness remains in the oral cavity as it is, so it is difficult to solve the problems of residual feeling and foreign body sensation.

[0006] In order to solve the problems of orally disintegrating tablets and orally disintegrating films, the present inventors have disclosed fine particles in Korean Registered Patent No. 10-1352689. The fine particles disclosed in the patent document are characterized in that, as a technical means for making a bitter drug into a powder form with relatively simple steps and excellent bitter masking effect, they are composed of an aggregation unit that forms a discontinuous phase containing a bitter drug and a continuous phase containing sugar or sugar alcohol. The fine particles are a novel dosage form with an extremely short oral disintegration time and no foreign body sensation or residual feeling in the oral cavity.

[0007] The present invention relates to a novel orally disintegrating powder composition with improved fine granules. Specifically, the present invention relates to a novel orally disintegrating powder composition containing a bitter drug as an active ingredient, which comprises a first coating layer containing an encapsulated bitter drug, an ionic additive, and a pharmaceutically acceptable additive in a diluent composed of sugar or sugar alcohol, and a second coating layer containing a poorly water-soluble polymer compound, a plasticizer, and a pharmaceutically acceptable additive. The present invention provides an orally disintegrating powder composition characterized by applying the above layers and a method for producing the same.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0009] The problem to be solved by the present invention is to provide a means for achieving a bitter taste masking ability and for facilitating swallowing, that is, a means capable of maximizing the swallowing ability, when formulating a bitter drug into an orally disintegrating powder. As used herein, the swallowing ability means the smoothness when swallowing the administered formulation when an orally disintegrating powder is administered, and is used as a concept including a foreign body sensation in the oral cavity.

[0010] To some extent, the means for masking the bitter taste of bitter drugs and the principle of bitter taste masking are clear. However, in the case of orally disintegrating powders, simply applying known bitter taste masking means does not completely achieve bitter taste masking. Moreover, focusing only on the bitter taste masking function will impair the original purpose of the orally disintegrating powder, that is, the original purpose of facilitating administration to patients with poor swallowing ability. Therefore, in the present invention, as a means to simultaneously satisfy bitter taste masking and improvement of swallowing ability, the development of a core technology platform applicable to orally disintegrating powders is the problem to be solved.

Means for Solving the Problems

[0011] In order to solve the above problems, the present invention provides an orally disintegrating powder composition comprising a first coating layer containing a diluent composed of a sugar or a sugar alcohol and an inclusion-complexed bitter drug, an ionic additive, and a pharmaceutically acceptable additive, and a second coating layer containing a poorly water-soluble polymer compound, a plasticizer, and a pharmaceutically acceptable additive, and a method for producing the same.

Advantages of the Invention

[0012] The orally disintegrating powder composition according to the present invention has the effects of improved bioavailability, masking of the bitterness of the bitter drug, and excellent swallowability. Since the orally disintegrating powder composition of the present invention masks the specific bitterness of donepezil, it can greatly increase the medication compliance of elderly patients who have insufficient saliva and dry mouth as they age. In addition, as side effects of donepezil, vomiting and nausea symptoms occur frequently after administration, so in view of the situation where taking it before bedtime is recommended, the orally disintegrating powder composition of the present invention that can be taken without water before bedtime while lying in bed can greatly enhance the medication compliance of elderly patients suffering from severe Alzheimer's disease who live lying in bed and nocturia patients who go to the toilet many times during sleep.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Best Mode for Carrying Out the Invention

[0014] In the case of dementia patients, there are great difficulties in drug administration. Such patients may reject taking medications in ordinary dosage forms such as tablets and capsules, or their swallowing ability may be reduced. In the case of donepezil, which is one of the most commonly used drugs for treating dementia, the dosage of the drug is as low as 5 - 10 mg, and due to problems such as the occurrence of side effects like nausea and vomiting, it has the characteristic that it must be taken before going to bed. When considering such drug characteristics, many attempts have been made to develop donepezil into an oral dosage form such as an orally disintegrating tablet or an orally disintegrating film. However, in the case of the bitter taste of donepezil, it is not just a bitter taste but an eggy taste that causes extremely discomfort to patients and is very difficult to mask. Therefore, the primary technical barrier to be solved for making donepezil into an oral administration preparation is the masking of the bitter taste. In relation to the bitter taste masking technology, methods such as introducing a coating layer to create a physical barrier, giving a chemical structural change to donepezil to reduce its solubility, and using sweeteners and fragrances have been proposed. However, no technology that can be generally applied to all oral administration preparations such as orally disintegrating tablets, orally disintegrating films, and orally disintegrating powders is known. As a result, specific actual application means must differ according to each preparation. In the case of donepezil, due to its overly strong bitter taste, there is a difficulty that specific and complex methods must be taken separately for each dosage form, and the satisfaction of the technologies developed so far is not very high. Because if a powerful bitter taste masking means is adopted to completely mask the bitter taste, the inherent characteristics (removal of foreign body sensation, residual sensation, and excellent swallowing function) that the orally disintegrating agent itself should have will be impaired, and for this reason, it is not selected by patients at the actual medication site. In fact, Eisai Co., Ltd., the original development company of donepezil, has developed and marketed an orally disintegrating tablet called Aricept Evess tablets, but the demand in the pharmaceutical market is low.

[0015] In the present invention, in formulating donepezil, which is a typical bitter drug and difficult to mask due to its strong bitterness, into an orally disintegrating powder dosage form, in order to achieve an excellent bitter masking effect and a smooth swallowability (swallowing ability) that is essential for an orally disintegrating powder, a diluent composed of sugar or sugar alcohol, donepezil or a pharmaceutically acceptable salt thereof included in cyclodextrin or its derivative, an ionic additive, and a first coating layer containing a pharmaceutically acceptable additive, and a second coating layer containing a poorly water-soluble polymer, a plasticizer, and a pharmaceutically acceptable additive are provided to form an orally disintegrating powder composition.

[0016] "Donepezil" in the present invention refers to "donepezil or a pharmaceutically acceptable salt thereof". The pharmaceutically acceptable salts are not particularly limited, but may preferably be acid addition salts. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc. can be used, and as the organic acid, acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. can be used. A preferred salt as the pharmaceutically acceptable salt of donepezil that can be used in the present invention can be hydrochloride. The donepezil of the present invention can include not only pharmaceutically acceptable salts but also all hydrates and solvates. The hydrate or solvate can be crystallized or recrystallized after dissolving the donepezil in a water-miscible solvent such as methanol, ethanol, acetone, 1,4-dioxane, and then adding a free acid or free base. In that case, a solvate (especially a hydrate) can be formed. Therefore, in addition to various amounts of hydrates that can be produced by methods such as lyophilization as the compound of the present invention, stoichiometric solvates including hydrates can also be included.

[0017] In the present invention, the "sugar or sugar alcohol" as a diluent can be xylitol, mannitol, isomalt, sorbitol, maltitol, refined white sugar, lactose, inositol, erythritol, crystalline fructose, trehalose, ribitol, arabitol, galactitol, lactitol and maltotriitol and mixtures thereof, and xylitol is preferred. In the case of xylitol, it has the effect of promoting saliva secretion, and thus when the orally disintegrating powder composition of the present invention is administered, it smooths the swallowing by the promoted saliva. The sugar or sugar alcohol may be contained in an amount of 50 to 95% by weight based on the total amount of the composition.

[0018] The bitter drug contained in the orally disintegrating powder of the present invention is used in an encapsulated state. Usually, in the case of donepezil, it is known that it is encapsulated with cyclodextrin to mask the bitterness, but in the present invention, the effect of improving the bioavailability is also achieved by encapsulating donepezil with cyclodextrin. The present invention uses sugar or sugar alcohol as a diluent, but this may cause a decrease in the bioavailability of the drug due to the osmotic pressure phenomenon in the stomach. In the present invention, this is complemented by the use of cyclodextrin. The cyclodextrin or its derivative may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutyl ether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin. The cyclodextrin or its derivative can be contained in an amount of 1.0 to 10.0% by weight based on the total amount of the composition, and the weight ratio of donepezil to cyclodextrin can be 1:0.5 to 1:16, preferably 1:1 to 1:8, more preferably 1:1.15 to 1:8.

[0019] As used in the present invention, the "ionic additive" refers to an additive capable of suppressing the bitterness of bitter drugs and means an additive contained in the first coating layer. Examples of the ionic additive include sodium saccharin, sodium citrate, sodium propionate, sodium metabisulfite, sodium acetate, sodium benzoate, sodium ascorbate, sodium hydrogen carbonate, sodium borate, sodium carbonate, and sodium sulfite. The ionic additive may be contained in an amount of 0.01 to 0.5% by weight based on the total amount of the composition.

[0020] The "water-insoluble polymer" in the present invention is contained in the second coating layer and may be any one or more selected from the group consisting of ethyl cellulose, carbomer, and polyvinyl acetate, and can be contained in an amount of 1.0 to 10.0% by weight based on the total amount of the composition. The water-insoluble polymer contained in the second coating layer functions to delay the disintegration of the encapsulated donepezil in the oral cavity. In this case, there is an effect of more firmly masking the bitterness of donepezil. However, when the disintegration and dissolution of the orally disintegrating powder composition are delayed, inconvenience is felt when swallowing the preparation in the oral cavity into the throat. The present inventor has found that such problems can be solved by adding a plasticizer to the second coating layer.

[0021] The "plasticizer" in the present invention is contained in the second coating layer and plays a role in enhancing the swallowing function. The orally disintegrating powder of the present invention uses the bitter medicine in an encapsulated state, and at the same time, the bitterness of donepezil is suppressed by the ionic additive. However, according to the research of the present inventor, although the masking effect of bitterness is sufficient, it has been found that the swallowing ability, which is a basic function as an orally disintegrating powder, is insufficient. Thus, by introducing a poorly water-soluble polymer substance into the second coating layer, while slightly reducing the solubility and disintegration property of the preparation, a novel finding has been made that by further including a plasticizer, the preparation administered in the oral cavity can be smoothly swallowed by saliva. In particular, when xylitol is used as the sugar or sugar alcohol, such a phenomenon acts synergistically with the saliva secretion promoting function of xylitol, enabling smooth swallowing.

[0022] Examples of the plasticizer that can be used in the present invention include triethyl citrate, triethyl citrate, medium-chain triglyceride, polyethylene glycol, diacetylated monoglyceride, etc., and triethyl citrate is preferred. The plasticizer can be contained in an amount of 0.5 to 5.0% by weight based on the total amount of the composition.

[0023] The method for producing the orally disintegrating powder composition of the present invention includes: (1) encapsulating donepezil or a pharmaceutically acceptable salt thereof with cyclodextrin or a derivative thereof in water or a mixed solution of water and alcohol; (2) adding an ionic additive and a pharmaceutically acceptable additive to the solution obtained in step (1) to produce a first coating solution; (3) coating sugar or sugar alcohol with the first coating solution; (4) adding a poorly water-soluble polymer, a plasticizer, and a pharmaceutically acceptable additive to water or a mixed solvent of water and alcohol to produce a second coating solution; and (5) coating the product of step (3) with the second coating solution.

[0024] Examples of the pharmaceutically acceptable additives include antioxidants such as BHT and ascorbic acid, binders such as hydroxypropyl cellulose, ethyl cellulose, and hypromellose, lubricants such as talc and magnesium stearate, anti-caking agents such as silicon dioxide and colloidal silicon dioxide, and sweeteners such as sucralose, aspartame, enzymatically treated stevia, and acesulfame potassium.

[0025] To the orally disintegrating powder composition of the present invention produced as described above, sugar or sugar alcohol can be further post-mixed. At this time, the sugar or sugar alcohol to be post-mixed is mixed for the purpose of further promoting saliva secretion. Also, pharmaceutically acceptable sweeteners, lubricants, and glidants may be included by post-mixing.

Mode for Carrying Out the Invention

[0026] Hereinafter, the present invention will be described by way of examples. The following examples are presented for illustrative purposes and should not be construed as limiting the scope of the present invention. Those skilled in the art can implement various modified examples with reference to the following examples within the scope of the technical idea described in the claims of this specification.

[0027] Example 1: Production of the orally disintegrating powder composition of the present invention The production of 2,000 packages of medicine was carried out to reflect the optimal operating capacity of the fluidized bed coater. 600.0 g of xylitol was sieved through a #35 mesh sieve and put into a fluidized bed coater preheated to 35 - 40 °C in advance, and coating was carried out while fluidizing. 200 g of purified water and 200 g of ethanol were put into a dispensing tank, 20.86 g of donepezil hydrochloride and 80.0 g of hydroxypropyl-β-cyclodextrin were added, and they were stirred for 12 hours for inclusion. After the end of the inclusion stirring of the coating solution, 2.0 g of BHT, 1.24 g of sodium saccharin, and 40.0 g of hydroxypropyl cellulose were added and dissolved, and then 6.0 g of talc was dispersed to complete the production of the coating solution. The injection rate of the coating solution was set at 5.0 - 10.0 rpm, the temperature of the product was maintained between 32 - 40 °C, and injection and coating were carried out by the bottom spray method. After the injection of the coating solution was completed, 50% ethanol was used to rinse the coating tube with the medicine remaining and put it in. After drying for 5 - 10 minutes, the injection of the prepared secondary coating solution was continued. The secondary coating solution was prepared by dissolving 30 g of ethyl cellulose, 10 g of triethyl citrate, and 6 g of talc in 200 g of ethanol and then adding it to the process. The injection rate of the coating solution was set at 8.0 - 13.0 rpm, the temperature of the product was maintained between 32 - 40 °C, and injection and coating were carried out by the bottom spray method. After drying for 5 - 10 minutes, the granules were taken out and sieved through a #35 mesh sieve, and the final mixture was made with 1,791.88 g of xylitol, 6.0 g of Aerosil 200, and 6.0 g of talc to produce a solid preparation in the form of a powder (oral disintegrating powder).

[0028] Examples 2 to 10: Production of the orally disintegrating powder compositions of the present invention with different contents As shown in Table 1 below, a solid preparation in the form of a powder (oral disintegrating powder) was produced in the same manner as in Example 1 except that each constituent component or its content was different.

[0029]

Table 1

[0030] Comparative Example 1: Simple mixture As shown in Table 2 below, although the content of the components is the same as that of Example 1, it was prepared by putting the amount obtained by subtracting ethanol and purified water into a plastic bag and simply mixing them.

[0031]

Table 2

[0032] Comparative Examples 2 to 4: Production of orally disintegrating powder compositions with different types of cyclodextrin As shown in Table 3 below, except that each component or its content was different, an oral solid preparation in powder form was prepared in the same manner as Example 1 above.

[0033]

Table 3

[0034] Experimental Example 1. Sensory Evaluation of the Bitterness of Oral Solid Preparations For the orally disintegrating powder compositions produced in Examples 1 to 10 and Comparative Examples 1 to 4, a sensory evaluation of bitterness was conducted on 20 adults, and the results are shown in Tables 4 to 6 and Figure 1.

[0035]

Table 4

[0036]

Table 5

[0037]

Table 6

[0038] When evaluating the bitter taste of the orally disintegrating powder compositions of Examples 1 to 10 and Comparative Examples 1 to 4, in Comparative Examples 1 to 4 that did not form inclusion complexes with cyclodextrin and its derivatives, the bitter taste peculiar to donepezil hydrochloride was strongly manifested. In particular, in the case of hydroxypropyl-β-cyclodextrin, which has a high solubility in water, the best results were shown in masking bitter taste, and the best bitter taste masking ability was shown at a weight ratio of 1:1.9 to 1:7.7 with donepezil hydrochloride. In the case of Example 6 that did not contain sodium saccharin, there was no difference in the initial taste from Example 1, but a tendency to feel bitter aftertaste appeared.

[0039] Experimental Example 2. Sensory evaluation of the foreign body sensation in the oral cavity of solid oral preparations For the orally disintegrating powder compositions produced in Examples 1 to 10 and Comparative Examples 1 to 4, a sensory evaluation of the foreign body sensation in the oral cavity was conducted on 20 adults, and the results are shown in Tables 7 to 9 and Figure 2.

[0040] [Table 7]

[0041] [Table 8]

[0042] [Table 9]

[0043] When evaluating the foreign body sensation of the orally disintegrating powder compositions of Examples 1 to 10 and Comparative Examples 1 to 4, when manufacturing by adding hypromellose according to Example 8 to the secondary coating solution, a slimy feeling and a sticky feeling peculiar to water-soluble polymers occurred in the oral cavity, and a large foreign body sensation was felt during taking. In Examples 7 and 9 that did not use a plasticizer, the effective dissolution of the ethylcellulose coating part could not be assisted, and a foreign body sensation that the particles felt hard occurred.

[0044] Experimental Example 3. Evaluation of an electronic tongue for solid oral preparations The bitterness masking degree of donepezil hydrochloride in the oral compositions produced in Examples 1 to 10 and Comparative Examples 1 to 4 was analyzed using a taste analyzer (Astree V). Donepezil hydrochloride was diluted in 100 mL of purified water to a concentration of 25 ppm for electronic tongue analysis, and the raw material of donepezil hydrochloride was used as the bitterness standard. Sampling analysis was repeated 5 times and the average value was measured, and the results are shown in Figure 3.

[0045] As shown in Figure 3, this electronic tongue evaluation also showed values similar to those in the results of Experimental Example 1. Specifically, as a result of the electronic tongue evaluation, among the samples of the orally disintegrating powder compositions of the examples containing hydroxypropyl-β-cyclodextrin on the coordinate plane, the samples according to Comparative Examples 1 to 4, the sample of Example 5 using β-cyclodextrin, and the sample of Example 6 not containing sodium saccharin, it was confirmed that the taste of donepezil hydrochloride could be effectively masked.

[0046] Experimental Example 4. Evaluation of the dissolution rate of oral solid preparations Using the control drug Aricept tablets 10 mg and the orally disintegrating powder composition of Example 1 as test drugs, HPLC analysis was performed under the condition of 0.1 N HCl solution with the number of samples n = 6. The dissolution method and analysis method were carried out as follows, and the results are shown in Figure 4.

[0047] Volume of dissolution medium: 900 mL Paddle speed: 50 rpm Dissolution method: Paddle II method Dissolution temperature: 37 °C Column: A column filled with C18 silica gel for liquid chromatography (150×4.6 mm, 5.0 μm) or a column equivalent thereto Flow rate: 1.0 mL / min Wavelength: 271 nm Column temperature: 35 °C Injection volume: 50 μL Mobile phase: Acetonitrile: Purified water: Perchloric acid = 350:650:1 (v / v / v) Diluent: Methanol: 0.1 N hydrochloric acid = 3:1

[0048] Referring to Fig. 4, compared with Aricept tablets which are tablets, due to the characteristics of the powder, the disintegration rate of the orally disintegrating powder composition of Example 1 was fast, and thus the initial dissolution rate tended to be high. The final dissolution rate showed a dissolution rate equivalent to that of the control drug.

[0049] Experimental Example 5. Evaluation of the First Pharmacokinetics Test Using Beagle Dogs Using the composition of Comparative Example 2 that used only sugar alcohol, a pharmacokinetics test evaluation was conducted using 6 Beagle dogs. This test aimed to collect blood for pharmacokinetics comparison and analysis after orally (P.O.) administering the test substance to Beagle dogs. The groups were randomly composed of 2 groups with 3 animals in each group. During the experimental period, no dead animals were observed, and no specific symptoms or changes were observed in clinical symptoms and body weight. The analysis of biological samples using LC / MS / MS was smoothly carried out without reanalysis. As a result of statistics, the Cmax of the control group was 14.69 ± 7.91 ng / mL, the AUC(0-24) was measured to be 57.01 ± 25.12 ng·hr / mL, the half-life was 3.74 ± 1.10 hr, and the AUC∞ was measured to be 60.37 ± 24.28 ng·hr / mL. The Cmax of the test group was 9.48 ± 1.28 ng / mL, the AUC(0-24) was measured to be 29.09 ± 6.84 ng·hr / mL, the half-life was 2.78 ± 0.98 hr, and the AUC∞ was measured to be 30.76 ± 7.08 ng·hr / mL.

[0050] Regarding the evaluation results of bioavailability, the AUC(0-24) and Cmax of the control substance were higher. It was confirmed that the osmotic pressure phenomenon caused by the excessive use of sugar alcohol affected the in vivo absorption of the drug. The results of the first pharmacokinetics test are shown in Fig. 5.

[0051] Experimental Example 6. Evaluation of the Second In Vivo Pharmacokinetics Test Using Beagle Dogs Based on the results of Experiment Example 5 conducted previously, as a solution to improve the phenomenon of reduced bioavailability caused by the use of sugar alcohols, the improvement function of the bioavailability of cyclodextrin was used, and with the composition of Example 1 manufactured accordingly, a secondary in vivo pharmacokinetic test was conducted using beagle dogs. Due to the characteristics of the powder, even when a fixed amount was administered sublingually to beagle dogs, drug administration tended not to be properly carried out due to rejection of the test sample or tongue movement. For setting an appropriate experimental protocol, a group with water added after administration and a group directly administered into the stomach after completely dissolving in water were further selected, and a total of 4 groups were used.

[0052] This test was aimed at collecting blood for pharmacokinetic comparison and analysis after oral (P.O.) administration of the test substance to beagle dogs. The groups were randomly composed of 4 groups with 3 animals in each group. During the experimental period, no dead animals were observed, and no specific symptoms or changes were observed in clinical symptoms or body weight. The analysis of biological samples using LC / MS / MS was carried out smoothly without reanalysis. As a result of the statistics, the Cmax of the control group was measured to be 10.28 ng / mL, the AUC(0 - 24) was 30.09 ng·hour / mL, the half-life was 1.33 hours, and the AUC∞ was measured to be 32.10 ng·hour / mL. The Cmax of the test group was 11.65 ng / mL, the AUC(0 - 24) was measured to be 35.46 ng·hour / mL, the half-life was 1.00 hour, and the AUC∞ was measured to be 39.08 ng·hour / mL.

[0053] Regarding the evaluation results of bioavailability, the AUC(0 - 24) and Cmax showed results equivalent to those of the control substance. Surprisingly, since it showed a significantly higher blood drug concentration compared to Comparative Example 1, it was found that a composition with much higher bioavailability of donepezil hydrochloride can be obtained when complexed with cyclodextrin. The results of the secondary pharmacokinetic test are shown in Figure 6.

Industrial Applicability

[0054] The present invention relates to an orally disintegrating powder composition for the prevention, improvement and treatment of Alzheimer's disease. By using cyclodextrin, sugar or sugar alcohol, and an ionic additive to mask the bitter taste specific to donepezil hydrochloride, the compliance of patients has been improved. A poorly water-soluble polymer compound and a plasticizer are used for secondary coating on the primary coating granules. The decrease in the bioavailability of the drug due to the osmotic pressure phenomenon in the stomach caused by the use of sugar or sugar alcohol is offset by improving the bioavailability by utilizing the inclusion complex with cyclodextrin.

Claims

1. An orally disintegrating powder composition containing donepezil or a pharmaceutically acceptable salt thereof as a main component, a diluent composed of sugar or sugar alcohol, a first coating layer containing donepezil or a pharmaceutically acceptable salt thereof, an ionic additive, and a pharmaceutically acceptable additive, which is included in cyclodextrin or a derivative thereof, a second coating layer containing a poorly water-soluble polymer, a plasticizer, and a pharmaceutically acceptable additive, and characterized by including the above, the orally disintegrating powder composition.

2. The orally disintegrating powder composition according to Claim 1, wherein the sugar or sugar alcohol is contained in an amount of 50 to 95% based on the total amount of the composition.

3. The orally disintegrating powder composition according to Claim 1 or 2, wherein the sugar or sugar alcohol is xylitol, sorbitol, erythritol, isomalt, sucrose, or mannitol.

4. The orally disintegrating powder composition according to Claim 3, wherein the sugar or sugar alcohol is xylitol.

5. The orally disintegrating powder composition according to Claim 1, wherein the cyclodextrin or a derivative thereof is contained in an amount of 1.0 to 10.0% based on the total amount of the composition.

6. The orally disintegrating powder composition according to Claim 1 or 5, wherein the cyclodextrin or a derivative thereof is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutyl ether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, or 2-hydroxypropyl-γ-cyclodextrin.

7. The orally disintegrating powder composition according to Claim 6, wherein the cyclodextrin or a derivative thereof is 2-hydroxypropyl-β-cyclodextrin.

8. The orally disintegrating powder composition according to Claim 1, wherein the ionic additive is contained in an amount of 0.01 to 0.5% based on the total amount of the composition.

9. The ion additive is sodium saccharin, sodium citrate, sodium propionate, sodium metabisulfite, sodium acetate, sodium benzoate, sodium ascorbate, sodium bicarbonate, sodium borate, sodium carbonate, or sodium sulfite, and the orally disintegrating powder composition according to claim 1 or 8 is characterized in that.

10. The orally disintegrating powder composition according to claim 9, wherein the ion additive is sodium saccharin.

11. A method for producing the orally disintegrating powder composition according to claim 1, comprising: (1) a step of inclusion-complexing donepezil or a pharmaceutically acceptable salt thereof with cyclodextrin or a derivative thereof in water or a mixed solution of water and alcohol; (2) a step of adding an ionic additive and a pharmaceutically acceptable additive to the solution obtained in the step (1) to produce a first coating solution; (3) a step of coating sugar or sugar alcohol with the first coating solution; (4) a step of adding a poorly water-soluble polymer, a plasticizer, and a pharmaceutically acceptable additive to water or a mixed solvent of water and alcohol to produce a second coating solution; (5) a step of coating the product of (3) with the second coating solution; A production method characterized by including.

12. The production method according to claim 11, wherein the weight ratio of donepezil or a pharmaceutically acceptable salt thereof to cyclodextrin or a derivative thereof is 1:0.5 to 1:

16.

13. The production method according to claim 12, wherein the weight ratio of donepezil or a pharmaceutically acceptable salt thereof to cyclodextrin or a derivative thereof is 1:1 to 1:

8.

14. The production method according to claim 11, wherein the pharmaceutically acceptable additive is selected from the group consisting of a sweetening agent, a binder, and a lubricant.

15. The production method according to claim 11, wherein the coating step is produced by fluidized bed coating.

16. The composition according to claim 1, wherein the poorly water-soluble polymer is contained in an amount of 1.0 to 10.0% based on the total amount of the composition.

17. The composition according to claim 1, wherein the poorly water-soluble polymer is ethyl cellulose.

18. The composition according to claim 1, wherein the plasticizer is contained in an amount of 0.5 to 5.0% based on the total amount of the composition.

19. The composition according to claim 1, wherein the plasticizer is triethyl citrate.

20. The composition according to claim 1, wherein the bioavailability of donepezil or a pharmaceutically acceptable salt thereof is improved by the addition of cyclodextrin or a derivative thereof.

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