WO2016190714A1

WO2016190714A1 - Orally fast dissolving film formulation including aripiprazole and method for producing the same

Info

Publication number: WO2016190714A1
Application number: PCT/KR2016/005660
Authority: WO
Inventors: Yong Soo Kim; Jun Ho Shin
Original assignee: CMG Pharmaceutical Co Ltd
Current assignee: CMG Pharmaceutical Co Ltd
Priority date: 2015-05-28
Filing date: 2016-05-27
Publication date: 2016-12-01
Anticipated expiration: 2017-11-28
Also published as: KR20160139704A

Abstract

The present invention relates to an orally fast dissolving film formulation including aripiprazole. Specifically, the orally fast dissolving film formulation includes aripiprazole or a pharmaceutically acceptable salt thereof that is substantially free of amorphous particles. The orally fast dissolving film formulation is comparable to an original aripiprazole tablet in terms of both dissolution and uptake rate, ensuring high dissolution rate of aripiprazole without any risk of damage to oral tissues. In addition, the orally fast dissolving film formulation is effective in masking a bitter taste of aripiprazole, achieving superior medication compliance. The present invention also relates to a method for producing the orally fast dissolving film formulation.

Description

Title of Invention: ORALLY FAST DISSOLVING FILM FORMULATION INCLUDING ARIPIPRAZOLE AND METHOD FOR

PRODUCING THE SAME

Technical Field

[1] The present invention relates to an orally fast dissolving film formulation including aripiprazole and a method for producing the same. More specifically, the present invention relates to an orally fast dissolving film formulation that is comparable to an original aripiprazole tablet in terms of both dissolution and uptake rate and has improved medication compliance, and a method for producing the film formulation.

Background Art

[3] Aripiprazole is a pharmaceutical compound having the IUPAC name

7- { 4- [4-(2,3-dichlorophenyl)piperazin- 1 -yl] butoxy } -3 ,4-dihydroquinolin-2( 1 H)-one, which is represented by Formula 1:

[6] Aripiprazole is a dopaminergic neurotransmitter antagonist and belongs to a group of carbostyril derivatives that can be used as atypical antipsychotics and antidepressants for schizophrenia, bipolar disorder, clinical depression, and the like (see Patent Documents 1 and 2).

[7] Aripiprazole is already known in the literature and more detailed pharmacological mechanisms, pharmacokinetics, synthesis methods, and side effects thereof can be understood from the disclosures of known references, for example, Non-Patent Document 1, the entire disclosure of which is incorporated herein by reference. The following cited references are also incorporated herein by reference in their entireties.

[8] Aripiprazole formulations in the form of tablets are widely commercially available

(Abilify™, Otsuka Pharmaceutical Co.). For more successful treatment for

schizophrenia, easy-to-take formulations are used in preference to swallowing tablets. That is, patients prefer orally disintegrating formulations to tablets and oral solutions that are difficult to swallow (see Non-Patent Document 2).

[9] In view of this, antipsychotics including aripiprazole as an active ingredient are

presented in the form of orally disintegrating formulations, such as chewable tablets and rapidly dissolving films, as well as swallowing tablets. Conventional orally disin- tegrating formulations can be understood, for example, from Patent Document 3, which discloses a flash-melt oral dosage formulation of aripiprazole.

[10] Orally disintegrating formulations of aripiprazole increase the convenience of administration for patients but cause the patients to feel bitterness peculiar to aripiprazole, resulting in an unfavorable feeling upon taking (Non-Patent Document 3).

[11] To solve such problems, there have been developed, for example, techniques for encapsulating aripiprazole with suitable materials, such as polymeric materials (see Non- Patent Document 4) and techniques for constituting hybrid systems of aripiprazole with layered clay materials to suppress dissolution of the aripiprazole in the oral cavity (for example, Patent Document 4 discloses an aripiprazole-bentonite-AEA (pol vinyl acetal-diethyl-acetate) hybrid for masking a bitter taste of aripiprazole). However, these techniques have the problems of low dissolution rate and bioavailability of aripiprazole.

[12] The problems of the prior art are explained by the fact that aripiprazole per se has a very low solubility in water (about 0.00001 w/v% at 25 °C), which directly leads to low bioavailability (see Non-Patent Document 5). Another reason is that when the dissolution of aripiprazole in the oral cavity is suppressed for the purpose of masking a bitter taste of aripiprazole, the dissolution rate of aripiprazole is considerably reduced, eventually increasing the possibility of poor bioavailability.

[13] The low solubility of aripiprazole affects the dissolution rate of aripiprazole, leading to poor bioavailability. In this regard, an improvement in the solubility of aripiprazole is considered a very important technical solution in aripiprazole formulations, apart from bitterness masking.

[14]

[15] [Prior Art Documents]

[16] [Patent Documents]

[17] (Patent Document 1) US 4734416 B (March 29, 1988)

[ 18] (Patent Document 2) US 5006528 B (April 09, 1991)

[19] (Patent Document 3) EP 114571 1 Al (October 17, 2001)

[20] (Patent Document 4) KR 10-1125210 B l (March 19, 2012)

[21] [Non-Patent Documents]

[22] (Non-Patent Document 1) Wikipedia, "Aripiprazole",

http://en.wikipedia.Org/wiki/Aripiprazole#cite_note-patent_5006528-50, visited on March 25, 2015

[23] (Non-Patent Document 2) Bhosle M, Benner JS, DeKoven M, Shelton J. Patient

Preference Adherence 2009;3: 161-171

[24] (Non-Patent Document 3) O, Yeon-ji, ilnorganic drug delivery system for poorly water-soluble drug and its bioequivalence studyJ , Research paper for master's degree, Ewha Womans University, 2011, pp.2-3

[25] (Non-Document 4) Yoshida T, Tasaki H, Maeda A, Katsuma M, Sako K, Uchida T. J Control Release 2008;131:47-53

[26]

Disclosure of Invention

Technical Problem

[27] A final orally fast dissolving film formulation can be produced by mixing a film- forming solid with a solvent to prepare an intermediate and heating the intermediate for a time sufficient to evaporate the solvent.

[28] The drying temperature and time are variables greatly affecting the physical

properties of the final product. The flexibility of the film varies depending on the amount of water remaining in the final product and is a factor affecting consumers' quality evaluation.

[29] When the film is very dry, it tends to be brittle, making it hard to take an exact dose of the product. Meanwhile, when the film contains a large amount of water, it tends to be attached to a wrapping paper, making it difficult to take the product out of the wrapping paper. That is, the greatest factor in the production of the film containing an appropriate amount of water is to set the drying temperature.

[30] The present inventors have surprisingly found that the drying temperature in the course of the production of an orally fast dissolving film formulation has an influence on the degree of dissolution of aripiprazole from the film formulation, eventually the pharmacological effects of the film formulation. Based on this finding, the present invention is intended to provide a high-quality aripiprazole orally fast dissolving film that exhibits pharmacological effects comparable to and better medication compliance than existing aripiprazole tablets.

[31]

Solution to Problem

[32] In order to solve the problems of the prior art and achieve the above object, the

present invention provides an orally fast dissolving film formulation including aripiprazole or a pharmaceutically acceptable salt thereof wherein the aripiprazole or pharmaceutically acceptable salt thereof is substantially free of amorphous particles.

[33] In the present invention, the orally fast dissolving film formulation further includes an organic acid and has a pH in the range of 4.7 to 6.0.

[34] In the present invention, the organic acid is selected from citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, ascorbic acid, adipic acid, succinic acid, fumaric acid, and mixtures thereof.

[35] In the present invention, the organic acid is citric acid and is included in an amount of 0.2 to 1.0 part by weight, based on 100 parts by weight of the film formulation.

[36] In the present invention, the orally fast dissolving film formulation further includes a film base polymer essentially including hydroxypropyl methylcellulose and optionally polyvinyl alcohol.

[37] In the present invention, the orally fast dissolving film formulation has a pH in the range of 5.7 to 6.8 when dissolved in the oral cavity.

[38] The present invention also provides a method for producing an orally fast dissolving film, including: dissolving aripiprazole or a pharmaceutically acceptable salt thereof and ingredients including a film base polymer in a solvent; casting the solution on a support; and drying the cast solution, wherein the drying temperature has a median of less than 80 °C and is in the range of 50 to 80 °C.

[39] In the method of the present invention, the drying step is carried out by drying with hot air or IR.

[40] The present invention also provides an orally fast dissolving film formulation

produced by the method.

[41]

Advantageous Effects of Invention

[42] The orally fast dissolving film formulation of the present invention is comparable to an original aripiprazole tablet in terms of both dissolution and uptake rate, ensuring high dissolution rate of aripiprazole without any risk of damage to oral tissues. In addition, the orally fast dissolving film formulation of the present invention is effective in masking a bitter taste of aripiprazole, achieving superior medication compliance.

[43]

Brief Description of Drawings

[44] FIGS, la to Id are microscopy images showing crystalline forms of aripiprazole on the surfaces of films produced in Examples 1 and 3 and Comparative Examples 2 and 4, respectively.

[45] FIGS. 2a to 2i are curves showing differential scanning calorimetry (DSC) parameters of aripiprazole as a raw material, a reference drug, and the films produced in Examples 1 to 4 and Comparative Examples 1, 3, and 5, respectively.

[46] FIGS. 3a to 3c are graphs comparing the dissolution rates of aripiprazole from a reference drug and films produced in Examples 1 to 4 and Comparative Examples 1 to 5.

[47] FIGS. 4a and 4b are graphs showing the test results for the biological equivalence of films produced in Example 3 and Comparative Example 3, respectively.

[48]

Mode for the Invention [49] The present invention will now be described in detail.

[50] One aspect of the present invention is directed to an orally fast dissolving film formulation including aripiprazole or a pharmaceutically acceptable salt thereof wherein the aripiprazole or pharmaceutically acceptable salt thereof is substantially free of amorphous particles.

[51] As used herein, the expression "substantially free of amorphous particles" means that the amorphous particles are present in such an amount to have no influence in terms of pharmacokinetics. The content of the amorphous particles is 10 mole% (or % by weight) or less, preferably 5 mole (or % by weight) or less, more preferably 3 mole% (or % by weight) or less, even more preferably 1 mole% (or % by weight) or less, most preferably 0.1 mole% (or % by weight) or less.

[52] The aripiprazole may be in free form or may form an acid addition salt with a pharmaceutically acceptable acid. Examples of such acids include, but are not necessarily limited to, sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, succinic acid, ascorbic acid, adipic acid, lactic acid, and benzoic acid.

[53] As shown in FIGS. 3a to 3c, the presence of amorphous particles of aripiprazole as an active ingredient in orally fast dissolving films formulations makes the dissolution rate and pattern of the film formulations different from those of an original formulation, failing to ensure biological equivalence of the film formulations to the original formulation. Further details will be understood from the following examples section, including experimental examples.

[54] The orally fast dissolving film formulation may further include an organic acid in addition to aripiprazole or a pharmaceutically acceptable salt thereof as an active ingredient and may have a pH in the range of 4.7 to 6.0.

[55] The organic acid lowers the pH of the orally fast dissolving film formulation to

increase the solubility of the aripiprazole, contributing to an improvement in the dissolution rate of the aripiprazole. Other roles of the organic acid are to promote the secretion of saliva in the mouth and to impart a sour taste to the orally fast dissolving film formulation, allowing a taker to be slightly less sensitive to bitterness peculiar to the aripiprazole.

[56] The organic acid may be the same as or different from an acid forming the salt with the aripiprazole.

[57] The organic acid is preferably an acid derived from food and may be, for example, selected from citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, ascorbic acid, adipic acid, succinic acid, fumaric acid, and mixtures thereof. More preferably, the organic acid is citric acid or tartaric acid. The food-derived organic acid is very effective in promoting the secretion of saliva in the mouth of a patient, enabling the patient to take the orally fast dissolving film without water, and serves to prevent the intra-oral pH from being excessively lowered. That is, the pH of the film decreases gradually with increasing amount of the organic acid added but the intra-oral pH is not lowered in proportion to the pH of the film due to the effect of the organic acid to increase the secretion of saliva.

[58] The citric acid is preferably included in an amount of 0.2 to 1.0 part by weight, based on 100 parts by weight of the film formulation. The presence of the citric acid in an amount of less than 0.2 parts by weight leads to a reduction in the solubility of the arip- iprazole, resulting in a low dissolution rate of the aripiprazole, and is unsatisfactory in saliva secretion. Meanwhile, the presence of the citric acid in an amount exceeding 1.0 part by weight reduces the intra-oral pH to less than 5.7, causing undesirable damage to oral tissues, such as dental caries.

[59] The orally fast dissolving film formulation may further include a sweetening agent.

The sweetening agent serves to mask a bitter taste.

[60] The sweetening agent includes sucralose and acesulfame potassium as essential ingredients.

[61] The gustatory response of the sweetening agent in the oral cavity varies slightly

depending on the ingredients of the sweetening agent. The acesulfame potassium is first exhibited due to its faster gustatory response and the effect of the sucralose follows, so that the sweetening agent can effectively mask a bitter taste over the entire period during which the formulation is disintegrated in the mouth.

[62] The sucralose and the acesulfame potassium are preferably in a weight ratio of 1 : 1 to 1:2.

[63] The sweetening agent is preferably included in an amount of 0.5 to 5.0 parts by

weight, based on 100 parts by weight of the film formulation.

[64] The sweetening agent may further include a sweetener in addition to sucralose and potassium acesulfame. Non-limiting examples of such sweeteners include L-menthol, xylitol, aspartame, saccharin salts, neotame, cyclamate salts, thaumatin, Luo han guo extract, licorice extract, sugar, glucose, maltose, oligosaccharides, dextrin, invert sugar, fructose, lactose, galactose, starch syrup, sorbitol, maltitol, erythritol, hy- drogenated starch syrup, mannitol, and trehalose. These sweetening agents may be used alone or as a mixture thereof.

[65] The film formulation of the present invention further includes a film base polymer.

[66] The film base polymer is preferably a water-soluble polymer because the formulation should be disintegrated by saliva in the mouth.

[67] The water-soluble polymer may be selected from carboxymethylethylcellulose, mi- crocrystalline cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol block copolymers, xanthan gum, guar gum, starch, modified starch, gelatinized starch, and mixtures thereof. The water-soluble polymer is preferably selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol block copolymers, and mixtures thereof. The water-soluble polymer is more preferably selected from hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol block copolymers, and mixtures thereof.

[68] The pH of the orally fast dissolving film formulation is preferably in the range of 4.7 to 6.0. Below pH 4.7, there is a risk that oral tissues may be damaged. Meanwhile, above pH 6.0, the dissolution rate of the aripiprazole may deteriorate undesirably.

[69] Preferably, the film base polymer essentially includes hydroxypropyl methylcellulose and optionally polyvinyl alcohol. The final pH of the film formulation may vary depending on the kind of the film base polymer.

[70] The fast dissolving film formulation of the present invention is rapidly disintegrated and dissolved by saliva in the mouth without the need to' drink water. Therefore, the film formulation can be easily administered to patients, particularly the elderly and children, who suffer from difficulty in swallowing tablets, and can be administered to schizophrenic patients for a long period of time.

[71] Another aspect of the present invention is directed to a method for producing an orally fast dissolving film, including: dissolving aripiprazole or a pharmaceutically acceptable salt thereof and ingredients including a film base polymer in a solvent; casting the solution on a support; and drying the cast solution, wherein the drying temperature has a median of less than 80 °C and is in the range of 50 to 80 °C.

[72] In the drying step, it is important to maintain the drying temperature at a constant level. However, it may be substantially difficult to maintain the drying temperature constant. Particularly, when the drying step is continuously carried out, for example, using a transfer belt drum, the temperatures of the drying zones may be different.

[73] Thus, in view of all different temperatures in the drying zones, the median of the drying temperatures can be considered. The concept of the median enables more substantial control over the drying temperature during drying.

[74] When the drying step is carried out in a batch process without transfer, the median of varying temperatures in a hood or drying room over drying time should be taken into consideration. In contrast, when the drying is performed in a continuous process through a belt drum, as in the Examples section that follows, the median of temperatures in different transfer zones would be taken into consideration. At this time, it would be more desirable to set the drying time points and zones at uniform intervals. Further details will be understood from the following examples section, including ex- perimental examples.

[75] As used herein, the term "median" refers to the middle number in variables of a statistical group that are arranged on the basis of size. This term is widely used in the field of statistics and its detailed explanation is thus omitted.

[76] In the present invention, the drying temperature is required to have a median lower than 80 °C. If the median of the drying temperature is higher than 80 °C, amorphous aripiprazole particles may be formed that undesirably affect the degrees of dissolution and uptake of aripiprazole.

[77] Furthermore, the drying temperature is preferably in the range of 50 to 80 °C. If the drying temperature is lower than 50 °C, low drying rate and efficiency may be caused and there is a risk that drying may not be readily performed. Meanwhile, if the drying temperature exceeds 80 °C, there is a risk that crystalline aripiprazole particles may be deformed into amorphous particles. Further details will be understood from the following examples section, including experimental examples.

[78] The drying step is not particularly limited and may be carried out by any suitable process widely used in the art, for example, by drying with hot air or IR.

[79] The method of the present invention may include, but necessarily not limited to, the following specific steps:

[80] (1) Preparation of solutions

[81] - a) Preparation of first solution: Polyvinyl alcohol (PVA) as a water-soluble polymer is completely dissolved in warm water.

[82] - b) Preparation of second solution: Aripiprazole as an active ingredient and citric acid are mixed in ethanol using a homogenizer.

[83] - c) Preparation of third solution: The first solution is mixed with additives, such as hydroxypropyl methylcellulose (HPMC) as a water-soluble polymer, Polyethylene

Glycol 400, glycerin, a colorant, and a sensitizer.

[84] - d) Preparation of fourth solution: the third solution is mixed with the second

solution to prepare a fourth solution.

[85]

[86] (2) Molding

[87] The fourth solution is filtered, fed into a molding machine, and molded into a film.

The temperature of the molding machine is from 50 to 120 °C and the film is passed through a belt drum dryer. The film is produced in the form of a roll.

[88]

[89] (3) Aging

[90] The film is aged at a relative humidity of 30 to 70% for about 1 to about 10 days. As a result, the film contains water in an amount sufficient for slitting or cutting. At this time, the water content is preferably 5% or less. The method may further include the following subsequent steps.

[91]

[92] (4) Cutting

[93] The aged film is slit into smaller ones, cut into desired sizes, and filled in small

containers or aluminum packaging papers.

[94]

[95] (5) Packaging

[96] For commercialization, the filled containers or packaging papers are repackaged in a small box or are blister packed.

[97]

[98] The present invention will be explained in more detail with reference to the following examples. However, it should be understood that these examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[99]

[100] EXAMPLES

[101]

[102] Examples 1-4 and Comparative Examples 1-5

[103] Anpiprazole as an active ingredient and citric acid were mixed in ethanol using a ho- mogenizer. The mixture solution was mixed with a solution of polyvinyl alcohol (PVA) as water-soluble polymer, hydroxypropyl methylcellulose (HPMC) as a polymer, Polyethylene Glycol 400, glycerin, a colorant, a sensitizer, and other additives to prepare a solution. The amounts of the ingredients in the solution are shown in Table 1.

[104]

[105] Table 1

[Table 1]

[106]

[107] The solution was cast on a release paper and dried by passing through a belt drum dryer under different conditions shown in Tables 2 and 3 to produce films. The drying region of the belt drum dryer was divided into five equal zones (Drying zones #1-5) in the lengthwise direction.

[108]

[109] Table 2

[Table 2]

[110]

[111] Table 3

[Table 3]

[112]

[113] Experimental Example 1 - Determination by microscopy

[114] In this example, the crystallinities of the aripiprazole in the films of Examples 1 and 3 and Comparative Examples 2 and 4 were determined. To this end, the crystalline forms of the aripiprazole on the surfaces of the films were observed using a stereoscopic microscope (VHX-700FE, Keyence (Japan)) with a magnification of 800x.

[115] As shown in FIGS, la to Id, the aripiprazole was not affected by heat during film production in Examples 1 and 3, and as a result, its crystalline forms were maintained. In contrast, the crystalline aripiprazole particles were changed to the amorphous state by heat in Comparative Examples 2 and 4.

[116]

[117] Experimental Example 2 - Determination by differential scanning calorimetry (DSC)

[118] The crystalline forms of the aripiprazole in the films of Examples 1-4 and Com- parative Examples 1-5 were determined by DSC (Q20, TA Instruments). Aripiprazole (Hetero, India, Lot No.: AR0030514) as a raw material and a reference drug (Abilify tablet, Korea Otsuka Pharmaceutical Co., Ltd., Lot No.: AT144004B) were used as controls.

[119] The results are shown in FIGS. 2a to 2i.

[120] DSC is an experimental tool for measuring the melting points of materials to

determine the crystalline forms of the materials. When aripiprazole maintains its crystalline form in a sample, its melting is observed at temperatures of 135-140 °C and 145-150 °C, as measured by DSC. When crystalline aripiprazole is changed to the amorphous state, its melting is not observed.

[121] The DSC parameters of the films of Examples 1-4 and Comparative Examples 1, 3, and 5 were compared with those of the raw material aripiprazole and the reference tablet. As a result, the films of Examples 1-4, which had not been affected by heat during production, showed parameters comparable to the raw material and the reference drug, indicating that the aripiprazole maintained its crystalline forms in the films of Examples 1-4. In contrast, the films of Comparative Examples 1, 3, and 5 showed different profiles of DSC parameters from the raw material and the tablet, indicating that the crystalline aripiprazole had been deformed by heat.

[122] As can be seen from the DSC parameters shown in FIGS. 2a to 2i, peaks were

observed at around 135-140 °C and 145-150 °C in the films of Examples 1-4, similarly to in the raw material and the reference drug. None of the peaks were observed in the films of Comparative Examples 1, 3, and 5.

[123]

[124] Experimental Example 3 - Comparative dissolution experiment

[125] In accordance with Method 1 (paddle method) for dissolution testing described in the general test methods of the Korean Pharmacopoeia, the films of Examples 1-4 and Comparative Examples 1-5 and a reference drug (Abilify™ tablet, Korea Otsuka Pharmaceutical Co., Ltd., Lot No.: AT144004B) in the form of a tablet containing the same amount of aripiprazole as the films of Examples 1-4 and Comparative Examples 1-5 were dissolved under the following conditions: 37+5 °C, 50 rpm, pH 5.0, pH 6.0 buffer, and 900 ml water, the solutions were filtered, and 5 ml of each filtrate was exactly sampled. The absorbance values of the sample solution and the standard solution were measured at around 249 nm and 325 nm in accordance with the method for absorbance measurement described in the general test methods of the Korean Pharmacopoeia and dissolution rates were calculated therefrom. Agilent 708-DS with VK8000 autosampler was used as a dissolution apparatus and Biochrom Libra S70 was used to measure the absorbance values.

[126] To determine the discrimination of the films from the tablet for aripiprazole dis- solution, dissolution tests were conducted in buffers at pH 5.0 and 6.0 and water. As a result, different dissolution rates of aripiprazole were observed in the three dissolution solutions.

[127] The results are shown in FIGS. 3a to 3c.

[128] The test results reveal that the films of Examples 1-4, which were produced by hot air drying at a drying temperature of < 80 °C, showed dissolution rates comparable to the reference drug. In contrast, the films of Comparative Examples 1 and 2, which were produced by IR drying at a drying temperature of > 80 °C, and the films of Comparative Examples 3-5, which were produced by direct heat transfer at a drying temperature of > 80 °C, showed higher dissolution rates than the reference tablet under the specific dissolution conditions. These results indicate that the crystalline forms of the aripiprazole in the comparative films were changed depending on the drying process, which is responsible for the dissolution rates different from those of the tablet. Thus, the possibility can be indirectly expected that the uptake rates of the comparative films may be different from those of the reference drug in clinical trials.

[129]

[130] Experimental Example 4 - Biological equivalence experiment

[131] In this example, the pharmacological effects of the films of Example 3 and Comparative Example 3 were determined by comparison with those of a reference drug (Abilify tablet™, Korea Otsuka Pharmaceutical Co., Ltd., Lot No.: AT144004B). To this end, the films and the reference drug were tested for biological equivalence. Each formulation was administered singly in a 2x2 crossover design to 36 subjects. 21 blood samples were drawn from each subject over 240 h after administration. The blood aripiprazole concentrations of the samples were analyzed by LC-MS/MS (Waters, Xevo TQ-S MS). The C_max values were compared to determine the biological equivalence of the reference drug and the films of Example 3 and Comparative Example 3. All experiments were conducted in accordance with the protocol approved by the MFDS.

[132] The results are shown in Table 4 and FIGS. 4a and 4b. Table 4 summarizes the

results of the biological equivalence tests. The numbers in Table 4 indicate upper and lower limits at the 90% confidence interval.

[133]

[134] Table 4

[Table 4]

Example 3 Comparative Example 3 c Upper limit 1.1214 1.2788

Lower limit 0.9069 1.0524

T/R 1.008 1.160 [135]

[136] The results show that the C_max value (highest blood aripiprazole concentration) of the film of Comparative Example 3, which was produced by direct transfer of hot air at > 80 °C, corresponded to at least 126% of that of the reference drug. That is, the comparative film was not biologically equivalent to the reference drug. The C_mM value of the film of Example 3, which was produced by indirect transfer of hot air at < 80 °C, corresponded to 100% of that of the reference drug. That is, the inventive film showed drug uptake comparable to the reference drug.

[137] Based on these biological equivalence test results, it could be confirmed that the uptake of aripiprazole may vary depending on the drying temperature and other conditions. Through the comparative dissolution tests at pH 5.0 and 6.0 and water in Experimental Example 3, it could also be confirmed that the uptake of the drug can be expected.

[138]

[139] Experimental Example 5 - Bitterness evaluation experiment

[140] The films were organoleptically evaluated for taste. 20 panelists were requested to taste the films and the bitter taste was evaluated using a 5-point scale. The scores were rounded off to two decimal places.

[141] At the time when the panelists began to feel a bitter taste in their mouths, the

bitterness was evaluated. The taste was scored as "5" when the panelist felt a very bitter taste and as "1" when the bitter taste disappeared. Specifically, the taste was scored based on the following criteria: 1 - excellent, 2 - good, 3 - fair, 4 - poor, 5 - very poor.

[142] The results are shown in Table 5.

[143]

[144] Table 5

[Table 5]

[145]

[146] The films of Examples 1-4 did not substantially have bitterness but the films of Comparative Examples 1-5 were bitter in aftertaste. From these results, changes in the crystalline form of aripiprazole during production of the aripiprazole orally disintegrating films are believed to affect the tastes of the films.

Claims

[Claim 1] An orally fast dissolving film formulation comprising aripiprazole or a pharmaceutically acceptable salt thereof wherein the aripiprazole or pharmaceutically acceptable salt thereof is substantially free of amorphous particles.

[Claim 2] The orally fast dissolving film formulation according to claim 1, further comprising an organic acid wherein the orally fast dissolving film formulation has a pH in the range of 4.7 to 6.0.

[Claim 3] The orally fast dissolving film formulation according to claim 2,

wherein organic acid is selected from citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, ascorbic acid, adipic acid, succinic acid, fumaric acid, and mixtures thereof.

[Claim 4] The orally fast dissolving film formulation according to claim 3,

wherein the organic acid is citric acid and is present in an amount of 0.2 to 1.0 part by weight, based on 100 parts by weight of the film formulation.

[Claim 5] The orally fast dissolving film formulation according to any one of claims 1 to 4, further comprising a film base polymer essentially comprising hydroxypropyl methylcellulose and optionally polyvinyl alcohol.

[Claim 6] The orally fast dissolving film formulation according to claim 5,

wherein the orally fast dissolving film formulation has a pH in the range of 5.7 to 6.8 when dissolved in the oral cavity.

[Claim 7] A method for producing an orally fast dissolving film, comprising:

dissolving aripiprazole or a pharmaceutically acceptable salt thereof and ingredients comprising a film base polymer in a solvent; casting the solution on a support; and drying the cast solution, wherein the drying temperature has a median of less than 80 °C and is in the range of 50 to 80 °C.

[Claim 8] The method according to claim 7, wherein the drying step is carried out by drying with hot air or IR.

[Claim 9] An orally fast dissolving film formulation produced by the method according to claim 7.