KR20160139704A - Formulation for orodispersible film comprising aripirazole, and method of preparing the same - Google Patents
Formulation for orodispersible film comprising aripirazole, and method of preparing the same Download PDFInfo
- Publication number
- KR20160139704A KR20160139704A KR1020150075053A KR20150075053A KR20160139704A KR 20160139704 A KR20160139704 A KR 20160139704A KR 1020150075053 A KR1020150075053 A KR 1020150075053A KR 20150075053 A KR20150075053 A KR 20150075053A KR 20160139704 A KR20160139704 A KR 20160139704A
- Authority
- KR
- South Korea
- Prior art keywords
- film
- aripiprazole
- acid
- drying
- oral
- Prior art date
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 74
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000009472 formulation Methods 0.000 title abstract description 19
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 70
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- 239000002245 particle Substances 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims description 48
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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Abstract
Description
The present invention relates to an oral film for oral use containing aripiprazole and a method for preparing the same, and more particularly, to an oral film for oral use which has a high compliance with dosages, while allowing preparation of aripiprazole original tablets and elution, A preparation, and a process for producing the same.
The aripiprazole can be identified by the IUPAC name (IUPAC name) of "7- {4- [4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy} -3,4- dihydroquinolin- ), And is a pharmaceutical compound having a structure represented by the following formula (1).
Aripiprazole is a dopaminergic neurotransmitter antagonist which is used as an atypical antipsychotic agent used in the treatment of schizophrenia, bipolar disorder, clinical depression, etc. and a carbostyril derivative (carbostyril derivatives) (Patent Document 1 and Patent Document 2).
Aripiprazole is a substance already known through a large number of literatures and the like, and details of the pharmacokinetics, pharmacokinetics, synthesis methods, and side effects thereof can be understood with reference to the contents of known literatures such as the following non-patent document 1 have. Thus, the entire contents of the non-patent document 1 are incorporated into the contents of this document, and the following cited documents are incorporated as part of this document.
Aripiprazole is widely marketed as a tablet form of formulation (Abilify ™, Otsuka Pharmaceutical Co.), but for more successful treatment of schizophrenia, a more convenient dosage form is preferred over swallowing tablets. That is, patients are more likely to prefer oral disintegrating formulations that disintegrate in the oral cavity than formulations such as tablets or oral solutions that must be swallowed (Non-Patent Document 2).
In view of this, antiepileptic drugs based on aripiprazole are also available in the form of oral disintegrating formulations such as chewable tablets or rapidly film, in addition to swallowing tablets. Conventional techniques for the morphology of oral disintegration formulations can be understood with reference to the following Patent Document 3 which discloses a flash-melt oral formulation of aripiprazole.
However, when aripiprazole is provided in the form of a disintegrating tablet for oral use, there is an advantage that the dosage of patients is increased, but there is a problem that the user feels bitterness peculiar to aripiprazole ingredient, resulting in a decrease in dosage 3).
In order to solve such a problem, a technique of encapsulating aripiprazole in a polymer substance or the like (see Non-Patent Document 4) and a technique of forming a hybrid system with a layered clay material or the like to inhibit dissolution in the oral cavity has been developed 4 discloses a technique for constructing a hybrid of aripiprazole-bentonite-AEA (polyvinyl acetal-diethyl-acetate) to shield a gummy tooth), which further lowers the dissolution and bioavailability of aripiprazole Can occur.
Because aripiprazole, as the compound itself, has a very low solubility in water (about 0.00001 w / v% at 25 DEG C), a low solubility of aripiprazole leads to a low dissolution rate, (See Non-Patent Document 5). In addition, when the dissolution of ariprazole in the oral cavity is suppressed for the purpose of gum-screening, the dissolution rate of aripiprazole is greatly lowered, and ultimately the bioavailability The possibility of degradation increases.
As described above, since the low solubility of aripiprazole influences the lowering of the dissolution rate and further leads to the lowering of the bioavailability, the dissolution rate problem of aripiprazole is a very important technical problem in the aripiprazole preparation separately from the problem of the gummy shielding.
In order to prepare an oral film for oral use, it is necessary to evaporate the solvent by applying heat to the intermediate material in which the solid and solvent are mixed to form a film for a certain period of time to make the final film preparation.
The temperature and time for drying are variables that can have a large effect on the properties of the final product. The flexibility of the film depends on the amount of moisture left in the final product, which is an influence on the consumer quality evaluation of the product.
If the film is too dry, it will easily break, which can make it difficult to dispense the correct dose due to breakage during dosing, and if the film is too moist, it may be difficult to remove the product from the inside of the wrapper. That is, the drying temperature is the most important factor for producing a film containing an appropriate amount of water.
However, the present inventors have surprisingly found that the drying temperature of aripiprazole film formulation affects the elution degree of aripiprazole oral fast film, and ultimately affects the efficacy of the drug. Thus, And to provide a high-quality aripiprazole oral fast film with high compliance.
Disclosure of the Invention In order to solve the problems of the prior art described above and to achieve the above-mentioned object, the present invention provides a film for oral cavity film comprising aripiprazole or a pharmaceutically acceptable salt thereof, wherein the aripiprazole or a pharmaceutically acceptable salt thereof is Wherein the film-forming composition for oral cavity is characterized in that it does not substantially contain amorphous particles.
In addition, the present invention provides a fast film preparation for oral use further comprising an organic acid and having a pH within the range of 4.7 to 6.0.
In the present invention, the organic acid is at least one selected from citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, ascorbic acid, adipic acid, succinic acid, and fumaric acid.
In the present invention, the citric acid is contained in an amount of 0.2 to 1.0 part by weight based on the total weight of the composition.
In the present invention, it is preferable that the film-based polymer further comprises a film-based polymer, and the film-based polymer essentially contains hydroxypropylmethylcellulose and further comprises polyvinyl alcohol. to provide.
In addition, the present invention provides a composition for oral cavity film characterized in that the pH during dissolution of the oral cavity film is within the range of 5.7 to 6.8.
Also, a crude liquid process for dissolving a component comprising aripiprazole or a pharmaceutically acceptable salt thereof and a film-based polymer in a solvent;
A softening step of applying the solution with the solution on the support;
And a drying step of drying the flexible solution,
Wherein the median value of the drying temperature in the drying step is less than 80 占 폚 and the drying temperature is in the range of 50 to 80 占 폚.
In the method of the present invention, the drying step may be a hot air drying method or an IR drying method.
Also provided is a fast film formulation for oral use, which is produced by the method of the present invention.
The oral film composition for oral use of the present invention has an excellent dissolution rate as well as an equivalent formulation in a body absorption rate as well as an original tablets and elution of aripiprazole, and has no fear of damaging the oral tissues, and has excellent effect of taking and dosing.
Figs. 1A to 1D are respectively a photograph of a crystal microphotograph of aripiprazole of Example 1, Example 3, Comparative Example 2, and Comparative Example 4 of the present invention.
Figs. 2A to 2I are respectively a DSC parameter graph of aripiprazole raw material, control drug, Examples 1 to 4, Comparative Example 1, Comparative Example 3 and Comparative Example 5 in order.
Figs. 3A to 3C show graphs of comparative dissolution experiments.
Figs. 4A and 4B respectively show a graph of the bioequivalence test result of Example 3 of the present invention and a graph of the bioequivalence test result of Comparative Example 3, respectively.
Hereinafter, the present invention will be described in detail.
An aspect of the present invention is an oral-use film for oral use comprising aripiprazole or a pharmaceutically acceptable salt thereof, wherein the aripiprazole or a pharmaceutically acceptable salt thereof does not substantially contain amorphous particles. It is a film composition for use in a drag.
Here, the expression " substantially not containing amorphous particles " means a content of no influence of the amorphous particles in terms of pharmacokinetics, and the content of at least amorphous particles is 10 mol (or weight) (Or weight)% or less, preferably 5 mole (or weight)% or less, more preferably 3 mole Weight)% or less.
The aripiprazole may be in free form, but may also form a pharmaceutically acceptable acid addition salt with the acid. Such acids include inorganic acids such as 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, malic acid, tartaric acid, citric acid, succinic acid, , Lactic acid, benzoic acid, and the like, but the present invention is not limited thereto.
As shown in FIGS. 3A to 3C, when the major component, aripiprazole, contains amorphous particles, the dissolution rate and pattern are greatly different from the original preparation, and thus the biologically equivalent equivalent can not be guaranteed. A more detailed understanding of this may be made through the following examples and experiments.
The oral film for oral use according to the present invention may further comprise an organic acid in addition to the principal component aripiprazole or a pharmaceutically acceptable salt thereof, and the pH of the film may be within the range of 4.7 to 6.0.
The organic acid lowers the pH and improves the solubility of the aripiprazole to improve the dissolution rate and promotes the salivation of the saliva in the oral cavity as well as imparts sour taste and serves to make the user less susceptible to aripiprazole- do.
The organic acid may be the same as or different from the acid forming the salt with aripiprazole.
The organic acid is preferably derived from food. Examples of the organic acid include at least one selected from citric acid, acetic acid, maleic acid, lactic acid, tartaric acid, ascorbic acid, adipic acid, succinic acid and fumaric acid. More preferably, the organic acid is citric acid or tartaric acid. Food-derived organic acids are highly effective in promoting the saliva secretion in the oral cavity, so that they can not only take oral film for oral use without water, but also prevent oral pH from becoming too low. That is, although the pH of the film is gradually lowered depending on the amount of the organic acid added, the organic acid also has an effect of increasing the salivary gland secretion. As a result, the oral pH does not decrease in proportion to the pH of the film.
The citric acid is preferably contained in an amount of 0.2 to 1.0 part by weight based on the total weight of the composition. When the amount of citric acid is less than 0.2 part by weight, the solubility of the aripiprazole is lowered and the dissolution rate may be lowered and the saliva secretion effect may be deteriorated. If the amount exceeds 1.0 part by weight, Thereby damaging the intraoral tissues such as dental caries.
The composition of the present invention may further comprise a sweetening agent. The sweetener serves as an antiseptic shield.
As a component of the sweetener, sucralose and acesulfam potassium are essential.
The sweetener has a slightly different taste response in the oral cavity depending on the ingredients. Acesulfame potassium has the fastest taste response and is first expressed, followed by sucralose. In this way, it is possible to effectively shield the teeth during the entire period of disintegration of the formulation in the oral cavity.
Suitably, the weight ratio of the sucralose and the acesulfame potassium is 1: 1 to 1: 2 of sucralose: acesulfame potassium.
The sweetener is preferably contained in an amount of 0.5 to 5.0 parts by weight based on the total weight of the composition.
In addition to sucralose and acesulfame potassium as components of the sweetener, other sweetening agents may be further included. Non-limiting examples of this include, but are not limited to, el-menthol, xylitol, aspartame, saccharin salts, neo time, cyclamate salts, tau martin, Nahan and its extract, licorice extract, sugar, glucose, maltose, oligosaccharides, And at least one selected from the group consisting of fructose, lactose, galactose, starch syrup, sorbitol, maltitol, erythritol, hydrogenated starch syrup, mannitol, and trehalose.
Another aspect of the present invention relates to a film composition for oral cavity, which further comprises a film base polymer in the film preparation of the present invention.
The film-based polymer is preferably a water-soluble polymer. This is because the disintegration of the preparation must occur due to saliva in the oral cavity.
The water-soluble polymer may be selected from the group consisting of carboxymethylethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, Polyvinyl alcohol or polyvinyl alcohol-polyethylene glycol block copolymer, xanthan gum, guar gum, starch, modified starch, and starch starch, Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol graft copolymer, more preferably hydroxypropylmethyl cellulose, polyvinyl alcohol, and polyvinyl alcohol- Polyethylene glycol graft copolymer May be used.
It is preferable that the pH of the film for oral cavity film is within the range of 4.7 to 6.0. If the pH is less than 4.7, there is a risk of damaging the oral tissues. If the pH is more than 6.0, the dissolution rate of aripiprazole is lowered.
It is preferable that the film-based polymer essentially contains hydroxypropylmethylcellulose and further includes polyvinyl alcohol. The final pH of the film formulation may vary depending on the type of base film polymer.
The film formulation for aripiprazole in accordance with the present invention can be easily administered to patients suffering from difficulty in swallowing, particularly, the elderly and children, because the film formulation for aripiprazole is rapidly disintegrated and dissolves in oral saliva without oral administration of water. .
Another aspect of the present invention relates to a liquid preparation process for dissolving a pharmaceutical composition containing aripiprazole or a pharmaceutically acceptable salt thereof and a film base polymer in a solvent;
A softening step of applying the solution with the solution on the support;
And a drying step of drying the flexible solution,
Wherein the median value of the drying temperature in the drying step is less than 80 占 폚, and the drying temperature is in the range of 50 to 80 占 폚.
In the drying step, the drying temperature may be kept constant, but it may be difficult to maintain the thermostability practically. Particularly, when the drying process is continuously carried out, such as belt drum feeding, There may be temperature differences.
Therefore, it is possible to consider the median value of the drying temperature in the drying process considering all the temperature differences according to the drying period, and the drying temperature control of the drying process can be more practically performed through the concept of the median value.
If the drying process is carried out as a batch process without a transfer process, the median value between the temperature values changed by the drying time in the hood or the drying chamber must be taken into consideration. As in the embodiment of the present invention, , It can be considered as a median value between temperature values per transporting section. However, when setting the viewpoint or the interval, it is more preferable to keep the interval constant. A more detailed understanding of this may be made through the following examples and experimental examples.
Here, the "median" is a median (MEDIAN), which is a value located in the middle when the statistical data is sorted in order of magnitude, and this is a widely used term in the field of statistics. .
Further, in the present invention, the median drying temperature is required to be less than 80 캜. A range of 80 占 폚 or higher is not preferable since amorphous particles of aripiprazole are produced and may affect elution and bioavailability.
Further, the drying temperature is preferably in the range of 50 to 80 캜. If the temperature is lower than 50 ° C, the drying speed and efficiency are low, and the drying may not be performed well. If the temperature is higher than 80 ° C, the aripiprazole crystal particles may be transformed into amorphous particles. A more detailed understanding of this may be made through the following examples and experimental examples.
The drying step is not particularly limited and those widely used in the related art can be used. Examples of the drying step include a hot air drying method and an IR drying method.
The oral film for oral use of the present invention can be produced by the following step process, but is not necessarily limited thereto.
(1) Liquid processing
- a) Preparation of first solution: Polyvinyl alcohol (PVA), a water-soluble polymer, is completely dissolved in warm water.
- b) Second solution preparation process: Aripiprazole, which is the main component, and citric acid are mixed in ethanol and homogenizer.
- c) Preparation of the third solution: Add to the first solution additives such as hydroxypropylmethylcellulose (HPMC), polyethylene glycol 400, glycerin, dye, and sensing agent, which are water-soluble polymers.
- d) Fourth solution preparing process: The third solution and the second solution are mixed to prepare a fourth solution.
(2) Molding process
The fourth solution is filtered and then introduced into a molding machine to form a film. At this time, the temperature of the molding machine is in the range of 50 to 120 ° C and is produced in the form of a roll through a belt drum dryer.
(3) Aging process
The molded film can be subjected to a maturing process of about 1 to 10 days at a relative humidity of 30 to 70% and can contain moisture suitable for slitting or cutting. The water content at this time is preferably within 5%. As a subsequent step of the above production method, the following steps may be further performed.
(4) Cutting process
The aged rolls are slit into small rolls, cut to the appropriate size and filled into small containers or aluminum wrappers.
(5) Packaging process
Products in packed small containers or aluminum wrappers can be repackaged in small boxes or produced through blisters.
Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood, however, that the following examples are intended to illustrate the present invention in detail, but are not intended to limit the scope of the present invention thereto.
Example
Polyvinyl alcohol (PVA) as a water-soluble polymer, hydroxypropylmethyl cellulose (HPMC) as a polymer, polyethylene glycol 400, glycerin 400 as a main component, and aripiprazole as a main component and citric acid in ethanol were mixed with a homogenizer. , Coloring matter, and a sensitizer were mixed and dissolved to prepare a solution. The content of each component contained in the bath solution was as shown in Table 1 below.
The prepared tank solution was cast on a release paper and then passed through a belt drum dryer to be dried and then dried under different conditions as shown in Tables 2 and 3, The films of Examples 1 to 5 were prepared. The following drying zones 1 to 5 are arbitrarily divided into five equal parts in the longitudinal direction of the drying zone of the belt drum dryer.
Experimental Example 1 - Microscope confirmation
In order to confirm the crystallinity of aripiprazole of Example 1, Example 3, Comparative Example 2 and Comparative Example 4, a crystal form of aripiprazole on the surface of the film was confirmed by a stereomicroscope. The microscope used was VHX-700FE from Keyence (Japan), which was magnified 800 times.
As shown in FIGS. 1A to 1D, in the case of Example 1 and Example 3, aripiprazole remained in a crystalline form without being affected by heat during the manufacturing process, whereas Comparative Example 2 and Comparative Example 4 showed that aripiprazole It was confirmed that the particles changed to amorphous.
Experimental Example 2 - Differential scanning calorimetry ( DSC ) Confirm
Differential scanning calorimetry (DSC) was performed to confirm the crystallinity of aripiprazole of Examples 1 to 4 and Comparative Examples 1 to 5, and aripiprazole raw material (Hetero, India, Lot No.: AR0030514) Otsuka, Lot No.: AT144004B) as a control group. DSC used Q20 from TA Instruments.
The results were as shown in Figs. 2A to 2I.
DSC is a test to determine the presence or absence of a crystalline form by measuring the melting point of a substance. When aripiprazole is kept in a crystalline form in the sample, it will be observed to be melting at a constant temperature (135-140 ° C, 145-150 ° C), and aripiprazole When it becomes amorphous, melting point is not observed.
Comparing the DSCs of Examples 1 to 4 and Comparative Examples 1 to 5 with those of the aripiprazole raw material and the control tablet, in the case of Examples 1 to 4 which were not influenced by heat during the production process, Indicating similar parameters to the reference drug, which means that in Examples 1-4 the aripiprazole crystal form is maintained. On the other hand, in Comparative Examples 1, 3 and 5, the DSC parameter is different from the raw material or the tablet, which means that the aripiprazole is modified by heat.
When the DSC parameters in the following table were confirmed, peaks were observed in the vicinity of 135-140 DEG C and 145-150 DEG C in Examples 1 to 4, similarly to the raw materials and the comparative tablet purification. In Comparative Examples 1, 3 and 5, It was not.
Experimental Example 3 - Comparative dissolution experiment
Examples 1 to 4 and Comparative Examples 1 to 5 thus prepared were subjected to elution in the general test method of Korean Pharmacopoeia using the same aripiprazole-containing tablets as a control (Abilify ™ tablet, Otsuka, Korea, Lot No.: AT144004B) The eluate was eluted with the paddle method of the first method as follows (37 ± 5 ° C, 50 rpm, pH 5.0, pH 6.0 buffer and 900 ml of water), and 5 ml of the eluate filtrate was precisely taken. The absorbance of the sample solution and the standard solution was measured according to the absorbance measurement method in the test method and the dissolution rate was calculated. The eluant was 708-DS, VK8000 manufactured by Agilent, Inc., and Libra S70 manufactured by Biochrom was used for absorbance measurement.
To confirm the discrimination of drug elution of aripiprazole, a comparative dissolution test was carried out in pH 5.0 and pH 6.0 buffer and water. As a result, the dissolution rate of aripiprazole was confirmed in three kinds of eluates.
The results were as shown in Figs. 3A to 3C.
As a result of the test, it was confirmed that Examples 1 to 4 prepared by hot air drying at a drying temperature of 80 ° C or lower had dissolution rates similar to those of the reference drug. On the other hand, in Comparative Examples 1 and 2 prepared by IR drying at a drying temperature of 80 ° C or higher and Comparative Examples 3 through 5 wherein heat was directly transferred to the film at a drying temperature of 80 ° C or higher, And a high dissolution rate. This result implies that the dissolution rate with tablets may vary due to the change of the crystal form depending on the drying process difference, which indirectly predicts that there is a difference in the absorption rate with the reference drug in clinical trials.
Experimental Example 4 - Biological equivalence experiment
To confirm the drug effects of Example 3 and Comparative Example 3, a bioequivalence test was conducted with a comparative drug (Abilify tablet ™, Otsuka, Korea, Lot No.: AT144004B). Aripiprazole concentrations in the blood were measured by LC-MS / MS (Waters, Xevo TQ-S MS) after a total of 21 blood samples were collected for 240 hours after the administration, Respectively. The control drug, Example 3, and the comparative drug and Comparative Example 3 were respectively tested, and the Cmax was compared to confirm the bioequivalence. All experiments were conducted with the approval of MFDS.
The results were as shown in the following Table 4 and Figs. 4A to 4B. Table 4 summarizes the results of the bioequivalence test and shows the upper and lower limits at the 90% confidence interval.
As a result of the bioequivalence test, Comparative Example 3, which was produced by direct transfer of hot air at a temperature of 80 ° C or higher, showed a Cmax (maximum concentration in blood) of 126% or more higher than that of the control drug. In this indirectly delivered Example 3, Cmax (maximum blood concentration) was 100%, indicating drug absorption equivalent to that of the reference drug.
Based on this bioequivalence test, it was confirmed that the absorption of aripiprazole could be varied depending on the drying temperature and conditions. In the comparative dissolution test of Experimental Example 3 described above, the pH value of 5.0, pH 6.0, The comparative dissolution test confirms that drug absorption in the body can be predicted.
Experimental Example 5 - Gomi Confirmation experiment
The taste sensory test was performed with 20 subjects. The sensory test was carried out according to the 20 - person panel, 5 - point scale method, and the score was rounded to the second decimal place.
The evaluation of the bitter taste was made when the bitterness was felt after the film was put into the mouth, when the bitter taste was decreased and when the bitter taste was lost, it was set to 1 when it was very bitter.
※ Scale (1. very good, 2. good, 3. normal, 4. poor, 5. very bad)
The results are shown in Table 5 below.
(good)
(good)
(good)
(good)
(Poor)
(Poor)
(usually)
(Poor)
(Poor)
In Examples 1 to 4, there was almost no bitter taste, but in Comparative Examples 1 to 5, a bitter taste was felt in the tail. It is considered that the change of the crystal form in the preparation of the aripiprazole oral disintegration film affects the taste of the film.
Claims (9)
A softening step of applying the solution with the solution on the support;
And a drying step of drying the flexible solution,
Wherein the median drying temperature in the drying step is less than 80 占 폚, and the drying temperature is in the range of 50 占 폚 to 80 占 폚.
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| PCT/KR2016/005660 WO2016190714A1 (en) | 2015-05-28 | 2016-05-27 | Orally fast dissolving film formulation including aripiprazole and method for producing the same |
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| CN111991373B (en) * | 2020-09-21 | 2022-04-08 | 力品药业(厦门)股份有限公司 | Aripiprazole orally-dissolving film and preparation method thereof |
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| US4734416A (en) | 1978-03-30 | 1988-03-29 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutically useful carbostyril derivatives |
| US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| EP1145711A1 (en) | 2000-04-12 | 2001-10-17 | Bristol-Myers Squibb Company | Flash-melt oral dosage formulation |
| KR101125210B1 (en) | 2009-09-11 | 2012-03-19 | 주식회사 대웅제약 | Aripiprazole-Bentonite-AEA Nanohybrid, Pharmaceutical Composition Containing the Same, and Method for Preparing the Same |
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|---|---|---|---|---|
| KR20040100483A (en) * | 2003-05-23 | 2004-12-02 | 애경산업(주) | Oral film comprising a active component and manufacturing process thereof |
| KR101074271B1 (en) * | 2009-06-25 | 2011-10-17 | (주)차바이오앤디오스텍 | Fast dissolving oral dosage form containing steviosides as a taste masking agent |
| KR20120100683A (en) * | 2011-09-09 | 2012-09-12 | (주)차바이오앤디오스텍 | Stable orodispersible film formulation |
| KR101571670B1 (en) * | 2012-08-08 | 2015-11-25 | 주식회사 씨엠지제약 | Formulation for orodispersible film comprising aripirazole |
| KR101407922B1 (en) * | 2013-11-14 | 2014-06-17 | 주식회사 서울제약 | Porous Orally Disintegrating Film comprising pharmacologically active substance and Precess For Producing thereof |
-
2015
- 2015-05-28 KR KR1020150075053A patent/KR20160139704A/en not_active Application Discontinuation
-
2016
- 2016-05-27 WO PCT/KR2016/005660 patent/WO2016190714A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4734416A (en) | 1978-03-30 | 1988-03-29 | Otsuka Pharmaceutical Co., Ltd. | Pharmaceutically useful carbostyril derivatives |
| US5006528A (en) | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
| EP1145711A1 (en) | 2000-04-12 | 2001-10-17 | Bristol-Myers Squibb Company | Flash-melt oral dosage formulation |
| KR101125210B1 (en) | 2009-09-11 | 2012-03-19 | 주식회사 대웅제약 | Aripiprazole-Bentonite-AEA Nanohybrid, Pharmaceutical Composition Containing the Same, and Method for Preparing the Same |
Non-Patent Citations (4)
| Title |
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| Bhosle M, Benner JS, DeKoven M, Shelton J. Patient Preference Adherence 2009;3:161-171. |
| Wikipedia, 〃Aripiprazole〃, http://en.wikipedia.org/wiki/Aripiprazole#cite_note-patent_5006528-50, 2015년 3월 25일 방문. |
| Yoshida T, Tasaki H, Maeda A, Katsuma M, Sako K, Uchida T. J Control Release 2008;131:47-53. |
| 오연지, 『Inorganic drug delivery system for poorly water-soluble drug and its bioequivalence study』, 석사학위논문, 이화여자대학교, 2011, pp.2-3. |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016190714A1 (en) | 2016-12-01 |
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