KR102525213B1 - Identifiable quick response(qr)-coded orodispersible films, and preparation method thereof using 3d printer - Google Patents

Abstract

The present invention relates to an oral disintegrating film to which a QR code is applied and a method for manufacturing the same using 3D printing technology, and in detail, selected from aripiprazole, paliperidone or paliperidone palmitate Contains an antipsychotic drug, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator, including patient information, drug information, or a file address (URL) on the Internet containing the information It provides an oral disintegrating film to which a QR code is applied, characterized in that the QR code is marked, and a manufacturing method thereof.
The oral disintegrating film to which the QR code is applied according to the present invention can be easily and simply manufactured using a 3D printer, and information on patients and drugs can be obtained by scanning the QR code applied to the orally disintegrating film through a smartphone or the like. Easy to figure out.

Description

Oral disintegrating film with QR code and manufacturing method using 3D printing technology {IDENTIFIABLE QUICK RESPONSE (QR)-CODED ORODISPERSIBLE FILMS, AND PREPARATION METHOD THEREOF USING 3D PRINTER

The present invention relates to an oral disintegrating film to which a QR code is applied and a method for manufacturing the same using 3D printing technology.

A three-dimensional (3D) printer is an equipment that manufactures three-dimensional objects by stacking materials such as liquid or powdery polymers (resin) and metals in a layer-by-layer manner according to design data. This is derived from RP (rapid prototyping), which refers to a technology of rapid prototyping using laser and powder materials to produce shapes according to 3D graphics applications. It is the opposite concept of subtractive manufacturing, which produces three-dimensional objects by cutting or shaving three-dimensional materials using mechanical processing or lasers.

In general, 3D printers that make a product three-dimensional through printing are liquid-based, SLA (stereolithography), powder-based, SLS (selective laser sintering), and solid-based, FDM (fused deposition modeling), depending on the method. modeling method).

Aripiprazole is 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one (7-{ It is a pharmaceutical compound named by the IUPAC name of 4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy}-3,4-dihydroquinolin-2(1H)-one). Aripiprazole is a dopaminergic neurotransmitter antagonist, a carbostril derivative that can be used as an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, clinical depression, etc. (carbostyril derivatives).

Aripiprazole is widely marketed as a formulation in tablet form (Abilify™, Otsuka Pharmaceutical Co), but for more successful treatment of schizophrenia, a more convenient dosage form is preferred over formulations such as swallowed tablets or oral solutions. there is.

In addition, in the case of general medicines, information about the patient, usage, dosage, and various information about the drug are written on the packaging to provide information to the patient. And, from the patient's point of view, it is important to take medications, and information exchange between doctors, pharmacists, and patients is also important in order to manage the patient's medication compliance, so a method for managing this more effectively is needed.

Republic of Korea Patent Publication No. 10-2009-0065514 (2009.06.22. Publication)

An object of the present invention is to provide a drug formulation containing an antipsychotic drug and effective in managing information on patients and drugs, and a method for preparing the same.

The present invention is an antipsychotic drug selected from aripiprazole, paliperidone or paliperidone palmitate, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator. Including, provides an oral disintegrating film to which the QR code is applied, characterized in that the QR code containing patient information, drug information or a file address (URL) on the Internet containing the information is marked.

The present invention is an antipsychotic drug selected from aripiprazole, paliperidone or paliperidone palmitate, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator. mixing to prepare a mixture; And the prepared mixture is loaded into a 3D printer extruder and melted and extruded to form an oral disintegrating film, and at the same time, a QR code including patient information, drug information, or a file address (URL) on the Internet containing the information A method for manufacturing an oral disintegrating film to which a QR code is applied and an oral disintegrating film to which a QR code manufactured according to the method is applied are provided.

The oral disintegrating film to which the QR code is applied according to the present invention can be easily and simply manufactured using a 3D printer, and is manufactured according to the optimal content and optimal manufacturing conditions of the film forming agent, solubilizer and acidity regulator, thereby achieving the oral disintegration The film has excellent oral disintegration rate and improved solubility, so it is effective for drug delivery with rapid dissolution.

In addition, by scanning the QR code applied to the oral disintegrating film through a smartphone, etc., information on patients and drugs can be easily grasped, and medication compliance and reliability can be effectively treated by appropriate intake accordingly, Drugs that require separate management can be systematically managed.

1 schematically shows a method of manufacturing an oral disintegrating film (QRODF) to which a QR code is applied and a form of use thereof according to an embodiment of the present invention.
2 is a scanning electron microscope image of the surface of a film according to an experimental example of the present invention.
Figure 3 is a graph of the results of measuring the tensile strength of the film according to an experimental example of the present invention.
4 is a differential scanning calorimetry analysis result performed according to an experimental example of the present invention.
5 is an X-ray diffraction analysis result performed according to an experimental example of the present invention.
6 is a result of evaluating the degree of drug release of an oral disintegrating film according to an experimental example of the present invention.
7 is a QRODF image manufactured according to an embodiment of the present invention, (A) is a QRODF, (B) is a folding of a QRODF, and (C) shows a screen shot of a smartphone scanning a QR code.
8 is a QRODF image manufactured according to an embodiment of the present invention, (A) is a QR code recognition using a QRODF and a smartphone camera, and (B) is a screenshot of a smartphone showing information contained in a QR code. it is shown
9 is a QRODF image manufactured according to an embodiment of the present invention, (A) is a screenshot of a smartphone showing QR code recognition using QRODF and a smartphone camera, and (B) is URL information contained in a QR code. , (C) shows a smartphone screen shot of the webpage accessed after touching the corresponding link.

Hereinafter, the present invention will be described in detail.

The present invention includes an antipsychotic drug, a film former, a solubilizer, and an acidity regulator, and is marked with a QR code including patient information, drug information, or a file address (URL) on the Internet containing the information. To provide an oral disintegrating film to which a QR code is applied.

The antipsychotic drug is a type of psychotropic drug used for the treatment of psychosis, and includes aripiprazole, paliperidone, paliperidone palmitate, risperidone, brexpiprazole, may include haloperidol, clozapine, quetiapine, olanzapine, etc., preferably aripiprazole, paliperidone, or paliperidone palmitate palmitate), but is not limited thereto.

In addition to this, various peptide or protein drugs may be included.

Table 1 below shows the physicochemical properties of aripiprazole, an antipsychotic drug used in an embodiment of the present invention.

The film-forming agent is a water-soluble polymer, and the disintegration of the formulation occurs by saliva in the oral cavity, and a formulation capable of forming a film by hot-melt 3D printing may be selected.

Preferably, it may be polyethylene oxide (PEO), and more preferably, polyethylene oxide N10 having a molecular weight of 100,000 Da or more and a melting point of 65-68 ° C can be usefully used as a film forming agent.

In addition to this, cellulose derivatives such as hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, PVP) may be included, but is not limited thereto, and all polymers capable of forming a film by hot melt 3D printing may be included.

As the solubilizing agent, a surfactant may be selected as an agent used to improve the solubility of the drug, such as aripiprazole, which is poorly soluble.

Preferably, a non-ionic surfactant such as a poloxamer, for example, poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403, poloxamer 407, etc. It may be, more preferably poloxamer 188, but is not limited thereto.

The poloxamer may be included in 10 parts by weight based on 100 parts by weight of the polyethylene oxide. When the content of the poloxamer exceeds 10 parts by weight, the viscosity is excessively lowered, thereby inhibiting film formation and deteriorating physical properties of the produced film. In addition, when the content of poloxamer is less than 10 parts by weight, there is a problem in that the oral disintegrating film intended in the present invention cannot be prepared.

According to an experimental example of the present invention, when 10 parts by weight of poloxamer 188 is included in 100 parts by weight of polyethylene oxide N10, it can be confirmed that the surface of the film is formed uniformly and smoothly, and exhibits high tensile strength.

In addition, an appropriate amount of poloxamer can impart flexibility to the oral disintegrating film.

In addition, as a suitable auxiliary solubilizer, soluplus, polysorbate, vitamin E TPGS (d-α-tocopheryl polyethylene glycol succinate; BASF), Gelucire 50/13 (Gelucire 50/13; Gattefosse) ), Kolliphor HS 15 (BASF), PEG6000 (SAMCHUN), Kollidon 30 (BASF), and the like can be used.

Table 2 below shows the physical and chemical properties of polyethylene oxide as a film forming agent and poloxamer 188 as a solubilizing agent used in one embodiment of the present invention.

The acidity regulator is an agent capable of increasing drug solubility by adjusting the pH of the film to an appropriate range, and includes citric acid, acetic acid, lactic acid, and tartaric acid. acid, fumaric acid, etc. may be selected, preferably citric acid, but is not limited thereto.

The citric acid is included in an amount of 1 to 2 parts by weight, preferably 1.1 to 1.3 parts by weight, more preferably 1.2 parts by weight, based on 100 parts by weight of the total film, and has a pH of 5 to 7, preferably pH 5.24 to 6.41. It is possible to make an orally disintegrating film having

If the content of the acidity regulator exceeds the above range, the acidity of the oral dispersible film may be lowered to a range that can damage the oral cavity. Since it can affect, the above range is preferable.

In the oral disintegrating film to which the QR code is applied according to the present invention, the drug, polyethylene oxide, poloxamer, and citric acid may be included in a weight ratio of 1: 10: 1: (0.1 to 0.2).

According to an experimental example of the present invention, when 20 mg of aripiprazole, 200 mg of polyethylene oxide N10, 20 mg of poloxamer 188, and 3 mg of citric acid, the physical properties such as flexibility, tensile strength, and thickness of the film are suitable, and the oral disintegration rate , drug solubility, etc. were also confirmed to be excellent.

The oral disintegrating film may have a thickness of 200 to 230 μm, preferably 210 to 220 μm. In general, since a film formulation in the range of 150 μm to 250 μm is suitable for patients, the oral disintegrating film according to the present invention may also have a thickness in a range suitable for patients.

The oral disintegrating film has an excellent tensile strength of 4 to 6 MPa, which can reduce the risk of breakage during storage.

In addition, the oral disintegrating film can be rapidly disintegrated in the oral cavity within 15 to 25 seconds, and accordingly, the drug uniformly contained in the film can be rapidly dissolved and effectively delivered.

In the oral disintegrating film to which the QR code is applied according to the present invention, the oral disintegrating film recognizes the QR code marked on the oral disintegrating film with a device having a QR code reader function to obtain the patient information or drug information. You can check.

Alternatively, the patient information or drug information may be checked by recognizing a file address (URL) included in the QR code on the Internet where the patient information or drug information is disclosed and accessing the Internet page.

The device having the QR code reader function may include, but is not limited to, a smartphone, a camera, a QR code reader, a QR code scanner, and the like having the above function.

The patient information or drug information may be selected from the group consisting of the patient's age, gender, health condition, type of disease, severity, type of prescription drug, sensitivity to drug, dosage, administration time, administration period, and administration method. , but is not limited thereto.

The present invention comprises preparing a mixture by mixing an antipsychotic drug, a film former, a solubilizer, and an acidity regulator; And the prepared mixture is loaded into a 3D printer extruder and melted and extruded to form an oral disintegrating film, and at the same time, a QR code including patient information, drug information, or a file address (URL) on the Internet containing the information It provides an oral disintegrating film manufacturing method to which a QR code is applied, including the step of generating on the oral disintegrating film.

The drug, film forming agent, solubilizer, and acidity regulator may be selected as an agent that can be printed smoothly during 3D printing.

The step of preparing the mixture is carried out by mixing an antipsychotic drug selected from aripiprazole or paliperidone, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator. can

The poloxamer may be mixed in 10 parts by weight based on 100 parts by weight of the polyethylene oxide, and the citric acid may be mixed in an amount of 1 to 2 parts by weight, preferably 1.1 to 1.3 parts by weight, based on 100 parts by weight of the total mixture. Preferably, it is mixed in 1.2 parts by weight so that the oral disintegrating film may be prepared at pH 5 to 7, preferably pH 5.24 to 6.41.

Preferably, the drug, polyethylene oxide, poloxamer, and citric acid may be mixed in a mixing ratio of 1:10:1: (0.1 to 0.2).

Corresponding features may be substituted in the foregoing.

Forming the oral disintegrating film may be performed by loading the prepared mixture into a 3D printer extruder and performing an appropriate manufacturing process such as melting and extruding.

The oral disintegrating film is 290 to 360 kPa, preferably 300 to 350 kPa air pressure; And 110 to 150 ℃, preferably 120 to 140 ℃, more preferably extrusion temperature of 140 ℃; it can be manufactured with a hot melt pneumatic (hot melt pneumatic, HMP) type 3D printer.

According to one embodiment of the present invention, a method of extruding using powder directly without using a filament was used instead of the FDM method of printing by melting a thermoplastic material in the form of a filament in a nozzle.

The 3D printing speed under the above conditions is 2 to 5 mm/s, the size of the nozzle may be 0.2 to 0.4 mm, and it may be designed using Fusion 360 software.

Simultaneously with the formation of the oral disintegrating film, a step of generating a QR code including patient information, drug information, or a file address (URL) on the Internet including the information on the oral disintegrating film may be performed.

The QR code generated on the oral disintegrating film can easily grasp patient information, drug information, etc. through the QR code reader function of a smartphone, etc., can increase the patient's medication compliance and reliability, and can be used by doctors, pharmacists, Mutual communication between patients may be possible.

The oral dispersible film may be formulated with an appropriate pharmaceutically acceptable carrier and, if necessary, may further contain excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, and the like. .

In addition, the present invention provides an oral disintegrating film to which a QR code is applied manufactured according to the above manufacturing method.

Corresponding features may be substituted in the foregoing.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, but the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

<Experiment materials and methods>

1. Matter

Aripiprazole (ARP) and Paliperidone (PAL) were supplied by Dong Wha Pharm (Suwon, Korea). Paliperidone Palmitate (PP) was supplied by Myungin Pharmaceutical (Suwon, Korea). Poly(ethylene oxide) 100,000, PEO 100,000 Da, POLYOX WSR N10, Singapore, Poloxamer 188 (POX, Pluronic® F-68, USA), and citric acid are used to make the film. has been used All other chemicals used in this experiment were of analytical grade.

2. 3D printer

A 3D model of orodispersible film (ODF) (QRODF) with a QR code was designed with Autodesk's Fusion 360 software. The extruder speed and filling amount were controlled by NewCreatorK (ROKIT INVIVO Corp. Korea). The drawing was designed to be compatible with a hot melt pneumatic (HMP) 3D printer with a direct feed nozzle (ROKIT INVIVO Corp. Korea) and converted to a 3D model. The film was 0.3 x 0.3 x 0.03 cm, and the extrusion conditions were set to a nozzle speed of 5 mm/s, a nozzle size of 0.4 mm, a filling amount of 100%, and a layer height of 0.1 mm.

1 schematically shows a method of manufacturing an oral disintegrating film (QRODF) to which a QR code is applied and a form of use thereof according to an embodiment of the present invention.

<Experimental Example 1> Setting Optimization Conditions for Manufacturing Using a 3D Printer

In order to optimize the manufacturing conditions of the 3D printer, the film formation function of polyethylene oxide (PEO) (200mg base) without adding aripiprazole (ARP) and other components was adjusted according to the air pressure and extrusion temperature according to Table 3 below. A preliminary experiment was conducted.

The experiment started at 100 °C and proceeded by increasing the temperature by 20 °C every 30 minutes. The pneumatic was controlled in 50 kPa step increments (250, 300, and 350 kPa) starting at 250 kPa for each temperature (100, 120, 140, and 160 °C). The final weight of each mixture loaded into the extruder was about 5 g.

One 2 3 4 5 6 7 8 9 10 11 12 Air pressure (kPa) 250 250 250 250 300 300 300 300 350 350 350 350 Extrusion temperature (℃) 100 120 140 160 100 120 140 160 100 120 140 160

In the case of HMP 3D printing technology, wettability, flowability, viscosity, and paste characteristics are the most important conditions. The HMP 3D printer used in this experiment uses a steel tip at the end of a pneumatic dispenser to send polymer-based ink through a small orifice at the end of the nozzle.

PEO was chosen as the film former because of its advantageous melting point (65-67° C.) and hot melt extrudability. In addition, PEO has been considered as a solubilizing agent for enhancing the dissolution of water-insoluble drugs. The properties of the formulation should allow the use of commercially available 3D printers for ODF manufacturing.

In order to check the extrusion, the temperature of the 3D printer was raised at 20 ° C intervals, and the pressure was raised from 250 kPa to 350 kPa to block it. If the temperature is low, extrusion does not occur, and if the temperature is too high, the polymer may burn out, so the optimum temperature and pressure were confirmed to be 140 °C and 350 kP, respectively.

The film was less flexible when applied with PEO alone, so POX was used as a plasticizer to control the flexibility of the film.

<Examples 1 to 10> Preparation of oral disintegrating film using 3D printer

A film having a width of 30 mm, a length of 30 mm, and a thickness of 3 mm formed of a QRODF that can be identified by the composition ratio shown in Table 4 below was printed using aripiprazole, a pharmaceutically active ingredient. After each material was put into a blender and mixed using a composition and/or ratio, the powder mixed in a specific ratio was loaded into an extruder of an HMP 3D printer (ROKIT INVIVO Corp. Korea) to prepare a film.

The unit of the values in Table 4 below is mg. In the following examples, the fact that the active drug is not included is a process for establishing a formulation of the formulation. After evaluating the tensile strength and printing degree among the examples without the active drug below, the saliva acidity of the optimal formulation was adjusted by including the active drug and citric acid.

ingredient Example
One
(ODF-1/F1) Example
2
(ODF-2/F2) Example
3
(ODF-3/F3) Example
4
(ODF-4/F4) Example
5
(ODF-5/F5) Example
6
(QR-ODF-6
/F3-1) Example
7
(QR-ODF-7
/F3-2) Example
8
(QR-ODF-8
/F3-3) Example
9
(QR-ODF-9
/F3-4) Example
10
(QR-ODF-10
/F3-5) Aripiprazole
(aripiprazole, APR)
-
-
-
-
-
20
20
20
20
20 polyethylene
oxide N10
(polyethylene
oxide N10, PEO)
200
200
200
200
200
200
200
200
200
200 Poloxamer 188 (POX)
(poloxamer 188)
-
10
20
30
40
20
20
20
20
20 citric acid
(citric acid) - - - - - - One 2 3 4

The following experiments were conducted on the films prepared according to the above examples. It was determined by looking at the tensile strength and surface condition of the film, which are the most important factors in applying the QR code.

<Experimental Example 2> Morphological analysis of film

The surface morphology of the film prepared according to the above example was measured by a field emission scanning electron microscope (FE-SEM, JEOL, JSM-7900F, Tokyo, Japan) at 5 kV. The film was pre-coated with a thin layer of platinum for 10 minutes.

2 is a scanning electron microscope image of the surface of a film according to an experimental example of the present invention. Referring to this, it was observed that the surface of Example 1 (F1) made of only PEO was rough, and Example 2 (F2), In the formulations of Example 4 (F4) and Example 5 (F5), it was observed that the film was non-uniform even though poloxamer (POX) was included.

On the other hand, the surface of Example 3 (F3) having a PEO/POX ratio of 10:1 showed a smooth surface with clear printing lines, which could not be confirmed in other formulations. Therefore, it can be confirmed that POX plays an important role in controlling the flexibility of PEO-based ODF.

<Experimental Example 3> Analysis of tensile strength of film

Tensile strength was measured to confirm the flexibility of the QRODF using an H5KT texture analyzer (Tinius Olsen Corp) with a 500 N-load cell. Films with high tensile strength are less likely to break during storage.

The film was pre-cut to a size of 5x5 mm, and for each measurement, the strip was balanced at 25° C. and placed vertically in the tension grips of the texture analyzer. The crosshead speed was controlled at 0.04 inch/min. The test was stopped after the film broke and the maximum load at the point was recorded.

Figure 3 and Table 5 below show the results of measuring the tensile strength of films according to one experimental example of the present invention. Referring to these, examples 1 (ODF-1) to 5 (ODF- 5), the films prepared according to Example 1 (ODF-1), Example 2 (ODF-2) and Example 3 (ODF-3) showed the highest tensile strength. The films prepared according to Example 4 (ODF-4) and Example 5 (ODF-5) exhibited tensile strength in the brittle state.

formulation example Tensile strength (MPa±SD) ODF-1 (Example 1) 4.38±0.79 ODF-2 (Example 2) 4.75±1.21 ODF-3 (Example 3) 5.00±0.80 ODF-4 (Example 4) 1.91±1.22 ODF-5 (Example 5) 3.05±0.44 QR-ODF6 (Example 6) 5.26±0.12 QR-ODF7 (Example 7) 5.38±0.48 QR-ODF8 (Example 8) 5.35±0.87 QR-ODF9 (Example 9) 5.12±0.10 QR-ODF10 (Example 10) 5.23±0.24

Specifically, the tensile strength of Example 3 was 5 ± 0.8 MPa, Example 4 showed the lowest tensile strength of 1.91 ± 1.22 MPa. Films to which citric acid was added based on Example 3 (QR-ODF-6 to QR-ODF-10) exhibited strength similar to Example 3.

In addition, the strength was found to change depending on the amount of POX added. POX greater than 10% by weight of PEO resulted in brittle formulations.

According to the above, Example 3 was determined to be a formulation suitable for use in the oral disintegrating film to which the QR code was applied, and an experiment based on the prescription of Example 3 (ODF-3) was conducted from the following information.

<Experimental Example 4> Film thickness analysis

The thickness of the film was measured with a constant pressure thickness measuring device PG-12J (TECLOCK Co., Ltd., Nagoya, Japan) (n = 3).

Generally, film formulations in the range of 150 μm to 250 μm are suitable for patients. As a result of analysis through this experimental example, as shown in Table 6 below, it was confirmed that the printed film according to the above embodiment had a thickness in the range of 158 μm to 366 μm, and finally 219 μm, which was a suitable thickness for the patient.

formulation example Film thickness (mm±SD) Example 6 0.216±0.014 Example 7 0.206±0.011 Example 8 0.201±0.015 Example 9 0.219±0.014 Example 10 0.213±0.019

On the other hand, it was found that the thickness of the film increased as the concentration of POX increased. Since POX can affect the melting point of the pre-printing mixture, the flowability of the heated mixture can be adjusted with different concentrations of POX. The higher flowability of the polymer mixture can deliver higher print mass, and its thickness was affected by varying concentrations of POX.

<Experimental Example 5> pH analysis of film

The pH of the film surface was adjusted to avoid irritation of the oral cavity and improve drug dissolution from the film.

After dissolving the above Examples 6 to 10 in 5 mL of phosphate buffer (pH 6.8), the pH was measured using a pH meter (A211, Thermo Scientific, USA). Before measurement, the pH meter was calibrated with a series of reference standards (pH 4, 7, and 10 standard solutions, Sigma). Measurements of each sample were performed three times.

As a result, as shown in Table 7 below, it was found that the pH of the film decreased in proportion to the addition of citric acid. The pH of the film without citric acid was measured at 8.79 to 8.14, and the pH of the film with citric acid was 5.24 to 6.41. This means that the pH range is within the target pH and suitable for oral use.

formulation example pH value±SD Example 6 8.97±0.13 Example 7 6.41±0.08 Example 8 5.88±0.09 Example 9 5.75±0.15 Example 10 5.24±0.14

<Experimental Example 6> Analysis of disintegration time of film

Disintegration experiments were performed with a DIT-200 disintegration apparatus (Labfine Inc., Korea) at 37±0.5°C. Each vessel contained 900 mL of purified water as disintegration medium. Disintegration time was measured when the film collapsed and passed through the mesh. All measurements were performed in triplicate for each formulation.

Rapid disintegration is an important quality attribute in film formulations, and since there is no standard for ODF disintegration time in pharmacopoeia, standard requirements for ODF disintegration time have been considered. According to CDER guidelines, the disintegration time of an orally disintegrating tablet should not exceed 30 seconds.

As a result of analyzing the disintegration time according to this experimental example, as shown in Table 8 below, the disintegration time for the film prepared according to the above example was found to be in the range of 19.7 seconds to 22.2 seconds. Film formulations are more porous than tablets, so the disintegration time may be shorter. Therefore, the film prepared according to the above embodiment can rapidly disintegrate in the oral cavity.

formulation example Disintegration time (mean sec±SD) Example 6 21.6±2.9 Example 7 22.2±1.1 Example 8 22.0±1.6 Example 9 19.7±1.4 Example 10 20.3±0.9

<Experimental Example 7> Analysis of drug content uniformity of film

To evaluate the uniformity of the content of aripiprazole, a drug-loaded QRODF of 3 × 10 cm was dissolved in 90% ACN, and the drug was extracted from the film by ultrasonic treatment for 10 minutes.

Then, after each sample was filtered using a filter (0.45 μm), drug content, standard deviation, and relative standard deviation were analyzed using high-performance liquid chromatography (HPLC, Waters Corp., Massachusetts, USA). The calibration curve ranged from 0.0625 to 1 mg/mL (R ² >0.999).

As a result, as shown in Table 9 below, the drug content of all drug-containing formulations ranged from 96.42% to 104.89%. In all cases, the uniformity of dosage units was within established limits (L1±15%).

formulation example Drug content (mean%±SD) Example 6 96.42±1.28 Example 7 99.69±2.91 Example 8 102.29±3.20 Example 9 101.04±0.68 Example 10 104.89±0.25

<Experimental Example 8> Differential Scanning Calorimetry (DSC) Analysis of Film

Differential scanning calorimetry (DSC) was performed to determine the physical state of the extruded QRODFs of PEO and POX used in this experiment. DSC allows the determination of the effect of processing methods on the crystallinity of formulations, substances and pure drugs. The thermodynamic properties of ARP, PEO, POX, citric acid and QRODF were analyzed using differential scanning calorimetry (DSC, 200, F3 Maia, NETZSCH, Germany). All measurements were performed between 5 °C and 250 °C at a scanning rate of 10 °C/min.

4 is a differential scanning calorimetry analysis result performed according to an experimental example of the present invention. Referring to this, PEO and POX showed melting peaks at 67.7 ° C and 54.6 ° C, respectively. By adding POX to the PEO-based film, the endothermic peak of Example 9 (F3-4) shifted from 67.7 °C to 65 °C, indicating the effect of POX on the melting point control of the printed mixture.

In addition, the melting point peak of ARP disappeared from the spectrum of F3-4, confirming that the crystallinity of ARP can be completely changed to an amorphous state in QRODF.

<Experimental Example 9> Powder X-ray diffraction (PXRD) analysis

The PXRD patterns of each sample, including QRODF, PEO, POX, citric acid, and pure ARP, were analyzed using a powder X-ray diffractometer (D/max-2500V/PC, Rigaku, Japan) using Cu-K radiation at a voltage of 40 kV and a current of 150 mA. ) was analyzed. The sample was scanned in increments of 0.02° from 5° to 60° at a speed of 1 s/scan.

5 is an X-ray diffraction analysis result performed according to an experimental example of the present invention. Referring to this, the PXRD pattern of pure ARP shows many characteristic peaks of high intensity at 20.28 °, 22.00 °, and 24.78 ° , indicated that ARP was highly crystalline in nature. However, the characteristic peak of ARP disappeared from the pattern of Example 9 (F3-4), indicating the conversion of drug crystals in ODF to an amorphous state. This result supports the results of the DSC analysis.

<Experimental Example 10> Evaluation of the solubility of the active pharmaceutical ingredient of the film

In order to confirm the dissolution rate of aripiprazole, a dissolution tester (D-TWELVE, DCM, Seoul, Korea) was used in accordance with the United States Pharmacopoeia (USP) II (paddle method, speed 50 rpm) in a pH 1.2 solution (37 ° C, 500 mL). A dissolution test was performed for 1 hour and repeated three times. Samples were taken for each time period and pre-treated, and then the dissolution rate was analyzed by high-performance liquid chromatography.

Figure 6 and Table 10 below are the results of evaluating the degree of drug release of the oral dispersible film according to an experimental example of the present invention. It was found to reach 40.13% and reach 92.91% after 60 minutes.

To obtain maximum achievement of drug release from the formulation, citric acid was used to adjust the pH value and control the dissolution rate of aripiprazole. As a result, the incorporation of citric acid in the formulation could significantly increase the dissolution rate of aripiprazole from 71.14% to 85.40% at 5 minutes and from 94.22% to 99.19% at 60 minutes. Therefore, it can be confirmed that the oral dispersible film containing citric acid enables a kinetically rapid dissolution of aripiprazole.

hour
(min) Drug release (Mean% ± SD) QR-ODF6
(Example 6) QR-ODF7
(Example 7) QR-ODF8
(Example 8) QR-ODF9
(Example 9) QR-ODF10
(Example 10) Aripiprazole Reference drug One 3.41±0.55 16.14±2.36 52.55±3.58 43.23±3.28 55.18±2.60 10.94±2.17 5 40.13±2.38 85.40±4.48 76.90±1.66 73.87±7.42 71.14±2.24 27.76±3.63 10 57.19±0.64 90.60±7.65 82.55±3.32 83.06±4.42 78.14±2.18 35.11±4.68 15 87.80±7.40 95.12±2.67 85.76±5.78 89.64±0.52 81.66±1.90 32.87±4.06 30 92.10±5.38 95.48±3.62 90.57±5.82 92.53±0.27 87.30±0.17 36.85±5.38 45 92.99±4.91 95.03±2.95 94.86±2.33 92.82±1.19 93.04±7.06 43.33±8.53 60 92.91±4.67 99.19±1.77 94.87±1.12 93.20±1.83 94.22±3.79 43.06±7.05

<Experimental Example 11> QR code recognition evaluation

7 is a QRODF image manufactured according to an embodiment of the present invention. Referring to this, the film is 30 × 30 mm and designed as a 22.3 × 22.3 mm QR code. The film was successfully obtained from an extruded polymer and a QR code was designed on the film.

The QR code on the oral disintegrating film to which the QR code was applied was recognized by a smartphone to confirm whether it was recognized. The QR code of the film was read using a QR scanning application on a smartphone. In this experimental example, a QR Code reader (v. 2.1, NAKAYUBI Corp) and a camera app (iPhone X, Apple Co.) were used.

As a result, it was confirmed that the QR code on the oral disintegrating film to which the QR code was applied was normally recognized and the information displayed on the smartphone. This means that the QR code was accurately applied to the oral disintegrating film.

<Example 11> Manufacturing and Analysis of Oral Disintegrating Film Containing Paliperidone

The experimental example is a prescription based on Example 3. Oral disintegrating films were prepared by the method according to the above example, using only the active ingredient, paliperidone or paliperidone palmitate instead of aripiprazole (FIGS. 8 and 9). Since the melting point differs depending on the drug component, the extrusion temperature was appropriately controlled.

As a result of preparing the film according to the prescription of Example 10, the drug release patterns were shown in Table 11 below. (3 times each)

time (min) Drug release (Mean% ± SD) QR-ODF-PAL
(Paliperidone) QR-ODF-PP
(Paliperidone Palmitate) One 40.13±9.83 0±0 5 56.77±8.94 20.33±10.08 10 72.79±11.19 38.99±14.56 15 83.21±9.26 58.93±6.33 30 92.63±17.66 65.31±5.11 45 92.69±12.89 73.81±12.30 60 93.10±11.97 82.81±8.71

Having described specific parts of the present invention in detail above, it is clear to those skilled in the art that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (13)

An antipsychotic drug selected from aripiprazole, paliperidone or paliperidone palmitate, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator,
A QR code including patient information, drug information, or a QR code containing the above information or a QR code including a file address (URL) on the Internet including patient information, drug information, or the above information is displayed,
The drug, polyethylene oxide, poloxamer and citric acid are included in a ratio of 1: 10: 1: (0.1 to 0.2),
The patient information or drug information is selected from the group consisting of the patient's age, gender, health condition, type of disease, severity, type of prescription drug, sensitivity to drug, dosage, administration time, administration period, and administration method,
The poloxamer is poloxamer 101, poloxamer 105, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331, It is selected from poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer 403 or poloxamer 407;
A thickness of 200 to 230 μm, characterized in that it disintegrates in the oral cavity within 15 to 25 seconds, QR code applied oral disintegrating film. delete delete According to claim 1,
The oral disintegrating film,
Characterized in that it has a tensile strength of 4 to 6 MPa, QR code applied orally disintegrating film. delete delete According to claim 1,
The oral disintegrating film,
An oral disintegrating film with a QR code, characterized in that the patient information and / or drug information can be checked by recognizing the QR code with a device having a QR code reader function. An antipsychotic drug selected from aripiprazole, paliperidone or paliperidone palmitate, polyethylene oxide as a film former, poloxamer as a solubilizer, and citric acid as an acidity regulator. Preparing; and
The prepared mixture is loaded into a 3D printer extruder, melted and extruded to form an oral disintegrating film, and at the same time, patient information, drug information or a QR code containing the above information or patient information, drug information or the above information is included. Generating a QR code including a file address (URL) on the Internet on the oral disintegrating film; A method for manufacturing an oral disintegrating film to which the QR code according to claim 1 is applied, including. According to claim 8,
The oral disintegrating film,
290 to 360 kPa pneumatic pressure and extrusion temperature of 110 to 150 ℃, characterized in that produced by a hot melt pneumatic (HMP) method 3D printer, QR code applied oral disintegrating film manufacturing method. According to claim 8,
The poloxamer,
An oral disintegrating film manufacturing method with a QR code, characterized in that it is mixed in 10 parts by weight with respect to 100 parts by weight of the polyethylene oxide. According to claim 8,
The citric acid is
Based on the total 100 parts by weight of the mixture, it is mixed in 1 to 2 parts by weight, characterized in that the oral disintegrating film is prepared at pH 5 to 7, QR code applied oral disintegrating film manufacturing method. According to claim 8,
The drug, polyethylene oxide, poloxamer and citric acid,
1: 10: 1: (0.1 ~ 0.2) characterized in that the mixing ratio, QR code applied oral disintegrating film manufacturing method. An oral disintegrating film to which a QR code is applied manufactured according to any one of claims 8 to 12.

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