Manufacturing method for film preparation and manufacturing system for film preparation

Abstract

To provide a technique that enables on-site preparation of medicines tailored to each patient, in response to personalized medicine.SOLUTION: The present invention provides a method for producing a film formulation, comprising (1) ejecting a solution containing one or more active pharmaceutical ingredients from a print head and printing it onto a soluble substrate film, the active pharmaceutical ingredients being printed onto the soluble substrate film so as to contain a dose that exerts a desired effect when administered to a subject. The soluble substrate film printed here can be formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches. The present invention also provides a production system for a film formulation for carrying out the method.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a method for manufacturing a film preparation and a manufacturing system for a film preparation.

Background Art

[0002] In order to treat a patient's disease, it is necessary to be appropriately prescribed according to the patient's condition, such as not only the symptoms but also the patient's medical history, weight, gender, age, etc. For example, in the case of a patient suffering from multiple diseases, the prescribed medicine must be surely ingested at a predetermined timing and amount. Conventional medicine has been provided on the premise that the same medicine is provided to patients diagnosed with the same disease. However, even when the same treatment is performed, the treatment effects and side effects differ depending on various factors such as the patient's constitution, medical history, weight, gender, and age.

[0003] According to research, as the understanding of diseases progresses, it is becoming clear that differences in treatment effects and side effects are related to differences in genes related to the disease and differences in the patient's own genes. Personalized medicine that pre-checks the patient's genes and genes related to the disease and performs treatment suitable for each patient according to the gene type has attracted attention and is being developed for realization.

[0004] In order to realize personalized medicine, research on individualized formulation for providing medicines suitable for each patient has been promoted, and film preparations that are flexible and can freely control their size are being recognized as one of the promising dosage forms. Conventionally, inkjet technology for attaching dyes to paper or objects has also been applied in the medical field. For example, a technology for inkjet printing a low-molecular-weight drug substance onto a film oral preparation has been developed.

[0005] So far, technologies for formulating low-molecular-weight drug substances into films for oral administration have been developed (Non-Patent Documents 1 to 8).

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0007] As described above, technologies for formulating low-molecular-weight active pharmaceutical ingredients into films for oral administration have been developed so far. However, these are technologies developed on the premise of oral administration, and diversification of modalities other than oral administration has not been achieved. In the future, as personalized medicine progresses, technologies that enable the preparation of pharmaceuticals tailored to each patient on-site will be required, and the present invention aims to provide means for solving such problems.

Means for Solving the Problems

[0008] In response to the above problems, the inventors of the present invention have conducted intensive studies and developed the present invention. That is, the present invention includes the following.

[0009] [1] A method for manufacturing a film preparation, comprising: (1) A step of discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing it on a soluble substrate film, wherein the pharmaceutical active ingredient is printed on the soluble substrate film so as to include a dose that exhibits a desired effect when administered to a subject; and the soluble substrate film printed here is capable of being formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches. A method for manufacturing a film preparation. [2] (2) A step of evaluating whether a predetermined amount of the one or more pharmaceutical active ingredients is contained in the printed soluble substrate film obtained in the step (1); The method for manufacturing a film preparation according to item 1, further comprising: [3] (2) A step of evaluating whether a predetermined amount of the one or more pharmaceutical active ingredients is contained in the printed soluble substrate film obtained in the step (1); and (3) A step of packaging the soluble substrate film evaluated to contain a predetermined amount of the pharmaceutical active ingredient in the step (2). The method for manufacturing a film preparation according to item 1, further comprising: [4] The method for manufacturing the film preparation according to item 2 or 3, wherein the step (2) is carried out by visible light, Raman spectroscopy, near-infrared spectroscopy or X-ray spectroscopy. [5] The method for manufacturing the film preparation according to item 1 or 2, wherein the pharmaceutical active ingredient is selected from the group consisting of low molecular weight compounds, peptides, proteins and nucleic acids. [6] The method for manufacturing the film preparation according to item 3, wherein the steps (1) to (3) are carried out continuously. [7] Immediately before the step (1) (0) A step of forming a soluble substrate film The method for manufacturing the film preparation according to item 1 or 2, further comprising. [8] The method for manufacturing the film preparation according to item 7, wherein the soluble substrate film is formed by an electrospinning method, a heat melting method, or a solvent casting method.

[0010] [9] A film preparation manufacturing system, A printing device for discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing on a soluble substrate film, wherein the pharmaceutical active ingredient is configured to be printed on the soluble substrate film so as to contain a dose that exhibits a desired effect when administered to a subject. Comprising The soluble substrate film is capable of being formulated into a drug delivery system selected from the group consisting of injections, suppositories and patches. Film preparation manufacturing system.

[10] An evaluation device for evaluating whether a predetermined amount of the pharmaceutical active ingredient is contained in the printed soluble substrate film. The film preparation manufacturing system according to item 9, further comprising.

[11] An evaluation device for evaluating whether a predetermined amount of the pharmaceutical active ingredient is contained in the printed soluble substrate film and A packaging device for packaging the soluble substrate film and The film preparation manufacturing system according to item 9, further comprising.

[12] Further, a film forming apparatus for forming a soluble substrate film, The film preparation manufacturing system according to item 9 or 10, comprising

[13] The film forming apparatus is an apparatus for forming a soluble substrate film by an electrospinning method, a heat melting method, or a solvent casting method. The film preparation manufacturing system according to item 12.

[14] The evaluation apparatus is implemented by a visible light imaging apparatus, a Raman spectroscopy apparatus, a near-infrared spectroscopy apparatus, or an X-ray spectroscopy apparatus. The film preparation manufacturing system according to item 10 or 11.

[15] The pharmaceutical active ingredient is selected from the group consisting of low molecular weight compounds, peptides, proteins, and nucleic acids. The film preparation manufacturing system according to item 9 or 10.

Effect of the Invention

[0011] According to the present invention, it is possible to provide a preparation of a soluble substrate film applicable to a drug delivery system selected from the group consisting of injections, suppositories, and patches, which has not been provided so far for realizing personalized medicine.

Brief Description of the Drawings

[0012]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0013] The present invention will be described below with reference to the drawings as necessary. However, the following embodiments do not limit the invention according to the claims, and not all combinations of the features described in the embodiments are essential for the solution of the invention.

[0014] In one embodiment, the invention of the present application is a method for manufacturing a film formulation, comprising: (1) A step of discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing it on a soluble substrate film, wherein the pharmaceutical active ingredient is printed on the soluble substrate film so as to include a dose that exhibits a desired effect when administered to a subject. including wherein the soluble substrate film printed here can be formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches. A method for manufacturing a film formulation is provided (see, for example, FIGS. 1 and 2).

[0015] In the present specification, the "film formulation" is one of the dosage forms and refers to a film-shaped formulation containing a pharmaceutical active ingredient (API). The film formulation provided by the present invention can be manufactured by discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing it on a soluble substrate film.

[0016] The "soluble substrate film" used in the present invention may be any that can be formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches.

[0017] For example, when a film formulation, i.e., a printed soluble substrate film, is used for the purpose of being formulated into an injection, the soluble substrate film can be dissolved by a solvent, such as a sterile aqueous solution (e.g., purified water, physiological saline, etc.) or a non-aqueous solution (e.g., ethanol, etc.), and it may be composed of biocompatible components. The film formulation provided by the present invention can be easily prepared into an injection containing a pharmaceutical active ingredient (API) in a dose that can exert a desired effect when administered to a subject by dissolving it in a predetermined amount of a diluent (solvent). The film formulation of the present invention may be used for the purpose of preparing an injection for application to one subject, or may also be used for the purpose of preparing an injection for application to a plurality of subjects. In the latter case, the amount of the pharmaceutical active ingredient (API) printed on the soluble substrate film may be adjusted according to the number of subjects to be applied.

[0018] For example, when the film formulation, i.e., the printed soluble substrate film, is a suppository or a patch (e.g., a poultice, a plaster, or a patch for mucous membranes), it may be applicable to mucous membranes, for example. The film formulation provided by the present invention as a suppository or a patch contains a pharmaceutical active ingredient (API) in a dose that can exert a desired effect when administered to a subject. Therefore, when the film formulation of the present invention is applied to a desired location (suppository: e.g., anus or vagina; patch: e.g., skin, mucous membrane, etc.), a desired effect can be exerted by the printed pharmaceutical active ingredient.

[0019] As materials for the soluble substrate film, for example, a polymer compound having a glucose ring as a structural unit, a polymer compound formed by addition polymerization of a monomer having a vinyl group, or a polymer compound having a glucose ring as a structural unit or a polymer compound formed by addition polymerization of a monomer having a vinyl group that has been chemically modified is preferably used. Particularly preferably, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl methylcellulose, methylcellulose, povidone, copovidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethylcellulose, and polyvinyl pyrrolidone, and those formed from combinations thereof may also be used.

[0020] The soluble substrate film that can be used in the present invention may contain various additives described below as necessary, as long as the effects of the present invention are not impaired. Examples of the various additives may include plasticizers, excipients, disintegrants, flavoring agents, coloring agents, and the like.

[0021] As the plasticizer, glycerol, triacetin, triethyl citrate, castor oil, etc. can be used. In addition, povidone, copovidone, etc., which are polymer compounds, may be blended as plasticizers.

[0022] Examples of the excipient include saccharides (glucose, fructose, lactose (including lactose hydrate), sucrose, trehalose, maltose, oligosaccharides, etc.), crystalline celluloses (crystalline cellulose, etc.), starches (corn starch, potato starch, rice starch, wheat starch, etc.), sugar alcohols (mannitol, erythritol, xylitol, sorbitol, maltitol, etc.), sodium phosphates, calcium phosphates (calcium hydrogen phosphate, etc.), gelatin, etc., but are not limited thereto. The excipient may be used alone or in combination of two or more.

[0023] Examples of the binder include, but are not limited to, hydroxypropyl starch, carrageenan, dextrin, alpha - starch, partial alpha - starch, pullulan, pectin, gum arabic, etc. The binder may be used alone or in combination of two or more kinds.

[0024] Examples of the disintegrant include, but are not limited to, calcium carmellose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, cellulose and its derivatives (e.g., low - substituted hydroxypropyl cellulose, etc.), alpha - starch, partial alpha - starch, sodium starch glycolate, etc. The disintegrant may be used alone or in combination of two or more kinds.

[0025] In the present invention, the soluble substrate film may be one in which step (1) is carried out using a pre - formed soluble substrate film, or may be one having a step of "(0) forming a soluble substrate film" immediately before the step (1) (see, for example, FIG. 1).

[0026] The step of manufacturing the soluble substrate film is not limited, but may be obtained, for example, by a solvent casting method. That is, a chemical solution containing a polymer compound for forming the soluble substrate film is pumped out, uniformly coated on a liner using a coating knife so that the thickness after drying becomes a desired thickness, for example, 0.01 - 2 mm, preferably 0.015 - 0.2 mm, and dried by a heater or the like (see, for example, FIG. 2).

[0027] Also, the step of manufacturing the soluble substrate film may be formed by an electrospinning method. The electrospinning method is a method of spinning fibers by applying a high voltage to a chemical solution containing a polymer compound for forming the soluble substrate film or a polymer compound in a molten state. Further, the step of manufacturing the soluble substrate film may be formed by a heat - melting method. The step of manufacturing the soluble substrate film can be actually carried out by using a known film - forming apparatus for carrying out the above - mentioned method.

[0028] The print head that can be used in the present invention may adopt a print head used in known inkjet printing technology. For example, a piezo-type or thermal (bubble) type print head may be adopted. The piezo-type print head is a print head that discharges ink particles using a piezoelectric element (piezo element) whose volume changes when a voltage is applied. The piezo element is attached to a unit filled with ink, and pressure is applied using the volume change to discharge the ink particles from the nozzle. The thermal (bubble) type print head is a print head that generates bubbles in the ink by heater heating and discharges the ink particles. The heater is attached to a unit filled with ink, and by heating, boiling bubbles are generated in the ink to discharge the ink from the nozzle.

[0029] In step (1), the solution containing one or more pharmaceutical active ingredients (APIs) is printed on the soluble substrate film so as to include a dosage that exhibits a desired effect when administered to the subject. The pharmaceutical active ingredient applicable to the present invention may be appropriately selected from known pharmaceutical active ingredients according to the disease of the subject, and is, for example, selected from the group consisting of low molecular weight compounds, peptides, proteins, and nucleic acids. In this specification, the "dosage that exhibits a desired effect" is a dosage administered to exert an effect capable of treating or preventing the disease of the subject. For example, the amount determined by a doctor's prescription is printed on the soluble substrate film of a predetermined area. The amount of the pharmaceutical active ingredient to be printed may be an amount input by a computer by a doctor or a person who has received instructions from a doctor, or may be an amount calculated by an artificial intelligence that has learned the treatment results of known diseases based on information about the subject, such as test data, medical history, weight, gender, age, height, etc.

[0030] In step (1), a solution containing one or more pharmaceutical active ingredients (APIs) is printed on a soluble substrate film. The solution containing the pharmaceutical active ingredient (API) may be printed at a predetermined interval, for example, at a constant interval in the vertical and horizontal directions, or may print letters, symbols, or figures. For example, the patient's name, ID, or common name, or the administration date and time (e.g., morning, noon, night, or specific date and time (e.g., January 1, 2022, 7:00, 12:00, 18:00, etc.)) may be printed, or a barcode, two-dimensional barcode (e.g., QR code (registered trademark)), or any symbol or figure may be printed. This prevents misidentification of the film formulation and enables recognition of the administration date and time.

[0031] In one embodiment, the invention of the present application is (2) In the printed soluble substrate film obtained in step (1), a step of evaluating whether a predetermined amount of the one or more pharmaceutical active ingredients is contained, may further be included (see, for example, FIG. 1). By performing step (2), it becomes possible to confirm online whether a predetermined amount of the one or more pharmaceutical active ingredients is surely contained in the soluble substrate film. Thereby, it becomes possible to confirm the quality of the film formulation provided by the present invention immediately after production.

[0032] In one embodiment, step (2) may be performed by Raman spectroscopy, near-infrared spectroscopy, or X-ray spectroscopy. Raman spectroscopy or near-infrared spectroscopy using Raman spectroscopy or near-infrared spectroscopy is a method that enables non-contact qualitative analysis because a spectrum based on molecular vibration is obtained when irradiating a desired sample. Also, X-ray photoelectron spectroscopy using X-ray spectroscopy irradiates a substance with soft X-rays such as MgKα or AlKα, and supplements the photoelectron e - emitted due to the ionization of the substance and performs energy analysis. Any of these methods is a known method, and an evaluation apparatus capable of performing the method, for example, a Raman spectrometer, a near-infrared spectrometer, or an X-ray spectrometer, can be applied in the present invention.

[0033] Also, in one embodiment, step (2) may be carried out by using visible light. For example, a known visible light imaging device (e.g., a CCD camera, etc.) capable of photographing an object under visible light may be applied to the present invention.

[0034] In one embodiment, the present invention (3) a step of packaging the soluble substrate film evaluated to contain a predetermined amount of the pharmaceutical active ingredient in the step (2), may further be included (see, for example, FIGS. 1 and 2). Packaging can be carried out using a known packaging device according to the end use, such as a vial, an ampoule, a plastic bottle, a packaging film, a plastic bag, a blister pack, a tube, etc.

[0035] In one embodiment, the above steps (1) to (3) may be carried out continuously (see FIG. 1). By carrying out steps (1) to (3) continuously, it becomes possible to provide a film preparation formulated in a facility for implementing personalized medicine.

[0036] The present invention is a system for carrying out the above method, a printing device for discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing on a soluble substrate film, wherein the pharmaceutical active ingredient is configured to be printed on the soluble substrate film so as to include a dose that exhibits a desired effect when administered to a subject. comprising the soluble substrate film is provided with a system that can be formulated into a drug delivery system selected from the group consisting of an injection, a suppository, and a patch (see FIGS. 1 and 2).

[0037] The description of the components applied to the method for manufacturing the above film preparation is also applicable to the description of the manufacturing system of the film preparation.

[0038] The method and system of the present invention are preferably implemented under conditions that meet the requirements for manufacturing pharmaceuticals in the country where the method and system are implemented, i.e., GMP (Good Manufacturing Practice).

Example

[0039] The present invention will be described in more detail below based on examples, which do not limit the present invention in any way.

[0040] The evaluation of this example was performed using a piezometric inkjet evaluation unit (SIJ Technology Inc., Tsukuba, Japan). A syringe was filled with a mixture of 0.5 mL of 5 w% enalapril maleate, 0.25 mL of water, and 0.25 mL of a 0.04 w% bromothymol blue solution (for coloring), and set in an evaluation unit having a print head with a discharge port having a diameter of 25 μm. The mixture in the syringe was heated to 50 degrees and discharged from the print head under the conditions of a voltage of 12.5 V, a frequency of 1000 Hz, an application time of 250 msec, and a pitch of 250 μm, and printed on a film formed of a composition containing hydroxypropylmethylcellulose and glycerol (hydroxypropylmethylcellulose:glycerol = 83.3:16.7 (w / w)).

[0041] The film printed with the solution containing enalapril maleate was imaged and observed.

[0042] The solution containing enalapril maleate was printable on the film.

Explanation of Signs

[0043] 1 Manufacturing system for film preparations 10 Print head 11 Solution containing pharmaceutical active ingredient (API ink) 12 Chemical solution containing polymer compound for forming soluble substrate film 13 Pump 14 Coating Knife 15 Soluble Substrate Film 16 Heater 17 Printed API Ink

Claims

1. A method for manufacturing a film formulation, comprising: (1) A step of discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing it on a soluble substrate film, wherein the pharmaceutical active ingredient is printed on the soluble substrate film so as to include a dose that exhibits a desired effect when administered to a subject; and wherein the printed soluble substrate film can be formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches. A method for manufacturing a film formulation.

2. (2) A step of evaluating whether a predetermined amount of the one or more pharmaceutical active ingredients is contained in the printed soluble substrate film obtained in the step (1); The method for manufacturing a film formulation according to claim 1, further comprising:

3. (2) A step of evaluating whether a predetermined amount of the one or more pharmaceutical active ingredients is contained in the printed soluble substrate film obtained in the step (1); and (3) A step of packaging the soluble substrate film evaluated as containing a predetermined amount of the pharmaceutical active ingredient in the step (2). The method for manufacturing a film formulation according to claim 1, further comprising:

4. The step (2) is carried out by visible light, Raman spectroscopy, near-infrared spectroscopy or X-ray spectroscopy. The method for manufacturing a film formulation according to claim 2 or 3.

5. The pharmaceutical active ingredient is selected from the group consisting of low molecular weight compounds, peptides, proteins, and nucleic acids. The method for manufacturing a film formulation according to claim 1 or 2.

6. The steps (1) to (3) are carried out continuously. The method for manufacturing a film formulation according to claim 3.

7. Immediately before the step (1), (0) A step of forming a soluble substrate film The method for manufacturing a film formulation according to claim 1 or 2, further comprising:

8. The soluble substrate film is formed by an electrospinning method, a heat melting method, or a solvent casting method. The method for manufacturing a film formulation according to claim 7.

9. A film formulation manufacturing system, comprising: A printing device for discharging a solution containing one or more pharmaceutical active ingredients from a print head and printing it on a soluble substrate film, wherein the pharmaceutical active ingredient is configured to be printed on the soluble substrate film so as to include a dose that exhibits a desired effect when administered to a subject. and The soluble substrate film can be formulated into a drug delivery system selected from the group consisting of injections, suppositories, and patches. A manufacturing system for film formulations.

10. An evaluation device for evaluating whether a predetermined amount of the pharmaceutical active ingredient is contained in the printed soluble substrate film. The manufacturing system for film formulations according to claim 9, further comprising the evaluation device.

11. An evaluation device for evaluating whether a predetermined amount of the pharmaceutical active ingredient is contained in the printed soluble substrate film, and A packaging device for packaging the soluble substrate film. The manufacturing system for film formulations according to claim 9, further comprising the evaluation device and the packaging device.

12. Furthermore, a film forming device for forming a soluble substrate film. The manufacturing system for film formulations according to claim 9 or 10, comprising the film forming device.

13. The film forming device is a device for forming a soluble substrate film by an electrospinning method, a heat melting method, or a solvent casting method. The manufacturing system for film formulations according to claim 12.

14. The evaluation device is implemented by a visible light imaging device, a Raman spectrometer, a near-infrared spectrometer, or an X-ray spectrometer. The manufacturing system for film formulations according to claim 10 or 11.

15. The pharmaceutical active ingredient is selected from the group consisting of low molecular weight compounds, peptides, proteins, and nucleic acids. The manufacturing system for film formulations according to claim 9 or 10.

Images