WO2014192887A1 - Système de production d'une préparation pharmaceutique sur micro-aiguille et procédé de conditionnement d'air - Google Patents

Système de production d'une préparation pharmaceutique sur micro-aiguille et procédé de conditionnement d'air Download PDF

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Publication number
WO2014192887A1
WO2014192887A1 PCT/JP2014/064317 JP2014064317W WO2014192887A1 WO 2014192887 A1 WO2014192887 A1 WO 2014192887A1 JP 2014064317 W JP2014064317 W JP 2014064317W WO 2014192887 A1 WO2014192887 A1 WO 2014192887A1
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WIPO (PCT)
Prior art keywords
air
humidity
temperature
microneedle
coating chamber
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PCT/JP2014/064317
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English (en)
Japanese (ja)
Inventor
真平 西村
俊之 松戸
誠治 徳本
Original Assignee
久光製薬株式会社
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Priority to JP2015519942A priority Critical patent/JP6110485B2/ja
Publication of WO2014192887A1 publication Critical patent/WO2014192887A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the present invention relates to a system and an air conditioning method for manufacturing a microneed formulation by applying a drug to microneedles.
  • a microneedle formulation is known as a device for improving transdermal absorption of a drug.
  • a method of applying a drug to microneedles of a microneedle preparation there is a method called a dip method (for example, Patent Document 1).
  • This is a method in which a plurality of openings formed in the mask plate are filled with a coating liquid containing a drug, and microneedles are inserted into the openings to apply the coating liquid to the microneedles. According to this method, a certain amount of coating solution can be applied to the microneedles.
  • the present inventors pay attention to the environment in the coating chamber where the drug is applied to the microneedles in order to prevent variation in the amount of the drug applied on the microneedles, and the temperature inside the coating chamber is within a predetermined range. It has been found that the change in physical properties of the coating liquid can be suppressed by setting the humidity and humidity, thereby suppressing variations in the amount of drug applied to the microneedles.
  • the present inventors have conceived a means for maintaining the inside of the coating chamber at a desired temperature and humidity by supplying air that has been adjusted to a predetermined range of temperature and humidity outside the coating chamber into the coating chamber. It came to.
  • the microneedle preparation needs to be manufactured under aseptic conditions.
  • a means of reducing the humidity and suppressing the growth of microorganisms is adopted. Therefore, in a system for manufacturing a microneedle preparation, there has conventionally been a conflict between high humidity and a sterile condition. It has been considered difficult to realize these two states simultaneously.
  • the present inventors have also responded to this conflicting request by sufficiently adopting means for supplying air, which has been adjusted to a predetermined range of temperature and humidity outside the coating chamber, into the coating chamber. Found.
  • FIG. 1 is an example of a system for producing a microneedle formulation devised by the present inventors based on the above point of focus.
  • the microneedle preparation production 100 shown in FIG. 1 has an air compressor 10, a compressed air temperature adjusting device 12 that adjusts the temperature of air supplied from the air compressor 10, and a temperature adjusted by the compressed air temperature adjusting device 12.
  • the air environment in the coating chamber is within a predetermined range of temperature and humidity, the change in the physical properties of the coating liquid in the coating chamber can be suppressed. Is suppressed.
  • the inside of the coating chamber needs to be 30-70% (RH) humidity (medium humidity) in order to suppress changes in the properties of the coating liquid.
  • RH room humidity
  • the humidity is precisely adjusted and maintained at a lower humidity range. It has also proved difficult.
  • the present invention provides a microneedle preparation manufacturing system and an air conditioning method capable of adjusting the air environment in an application chamber in which a drug is applied to microneedles to a medium humidity of 30 to 70% (RH). For the purpose.
  • the present invention is a microneedle preparation manufacturing system that adjusts the air environment in an application chamber for manufacturing a microneedle preparation by applying a coating liquid containing a drug to microneedles.
  • Humidity control is an air compressor and a moisture permeable membrane type for adjusting the humidity of the air supplied from the air compressor, in which air and moisture as a humidity control source are separated by a moisture permeable membrane.
  • a system for producing a microneedle preparation comprising: a device; a pressure adjusting device for adjusting the pressure of air supplied from an air compressor; and an air filter for sterilizing air supplied into the coating chamber.
  • Air that is controlled to an arbitrary humidity within a range of 30 to 70% (RH) and is in a sterile state can be stably supplied into the coating chamber.
  • the moisture permeable membrane may be formed in a hollow fiber shape. Since the moisture permeable membrane is formed in a hollow fiber shape, the humidity can be adjusted more efficiently.
  • the microneedle preparation manufacturing system preferably includes a humidity sensor and first control means for controlling the pressure regulator based on a signal corresponding to the humidity detected by the humidity sensor.
  • the system for manufacturing a microneedle preparation may include a temperature sensor and second control means for controlling the pressure adjusting device based on a signal corresponding to the temperature detected by the temperature sensor.
  • the microneedle preparation manufacturing system may include a compressed air temperature adjusting device that adjusts the temperature of the air supplied from the air compressor. If the temperature of the environment in which the system is located fluctuates and the air supplied into the system by the air compressor is not in the desired range, the air fed into the coating chamber by providing the system with a compressed air temperature control device Can be adjusted to an arbitrary temperature, and the humidity can be controlled more accurately.
  • the microneedle preparation manufacturing system may include a humidity sensor and third control means for controlling the compressed air temperature adjusting device based on a signal corresponding to the humidity detected by the humidity sensor.
  • the system for manufacturing a microneedle preparation may include a temperature sensor and fourth control means for controlling the compressed air temperature adjusting device based on a signal corresponding to the temperature detected by the temperature sensor.
  • the humidity control apparatus includes a moisture supply device that supplies moisture.
  • the humidity adjusting device has such a configuration, it is possible to easily supply moisture for adjusting the humidity in the system.
  • the water supply device is a constant temperature water tank.
  • the thermostatic water tank as a moisture supply device, the moisture in the moisture supply device can be easily maintained at a constant temperature, so that the temperature and humidity can be controlled with higher accuracy.
  • the water supply device can adjust the water temperature, that is, one that can be adjusted to any temperature within a wide temperature range. Since the moisture supply device has such a function, the moisture of the moisture supply device can be maintained at an arbitrary constant temperature in a wide range.
  • the microneedle preparation manufacturing system may include a humidity sensor and fifth control means for controlling the water temperature of the water supply device based on a signal corresponding to the humidity detected by the humidity sensor.
  • the system for manufacturing a microneedle preparation may include a temperature sensor and sixth control means for controlling the water temperature of the water supply device based on a signal corresponding to the temperature detected by the temperature sensor.
  • an air conditioning method for adjusting an air environment in a coating chamber for manufacturing a microneedle formulation by applying a coating liquid containing a drug to microneedles, Adjusting the humidity of the air to be fed by a humidity control device which is a moisture permeable membrane type in which the air and moisture as a humidity control source are separated by a moisture permeable membrane, and adjusting the pressure of the air sent to the coating chamber
  • a humidity control device which is a moisture permeable membrane type in which the air and moisture as a humidity control source are separated by a moisture permeable membrane
  • an air conditioning method including a step of adjusting by an apparatus, a step of sterilizing the air by an air filter, and a step of introducing sterilized air whose humidity is adjusted and sterilized into an application chamber.
  • the temperature is within a desired range in the coating chamber, and is in the range of 30 to 70% (RH). It is possible to stably supply aseptic air controlled to an arbitrary humidity.
  • air having a desired temperature and an arbitrary humidity in the range of 30 to 70% (RH) and being in a sterile state can be stably introduced into the coating chamber.
  • the inside and outside of the coating chamber can be maintained at a temperature and humidity within a desired range without being affected by fluctuations in temperature and humidity inside and outside the coating chamber, thereby suppressing fluctuations in physical properties of the coating liquid in the coating chamber. be able to.
  • a coating liquid containing a drug is applied to the microneedle in an air environment adjusted by the microneedle formulation manufacturing system or the air conditioning method of the present invention, a microneedle formulation coated with a certain amount of drug is stably produced. can do.
  • FIG. 5 is a cross-sectional view of the microneedle formulation of FIG. 4 taken along the line VV.
  • A)-(c) is a schematic diagram which shows an example of the manufacturing method of a microneedle formulation.
  • (A) to (c) are graphs showing changes in humidity in the coating chamber.
  • the system for manufacturing a microneedle preparation according to the present embodiment (hereinafter also simply referred to as “system” in some cases) is suitable for performing an operation of manufacturing a microneedle preparation by applying a coating liquid containing a drug to the microneedle. It creates an air environment.
  • humidity refers to relative humidity.
  • FIG. 2 is a block configuration diagram showing an embodiment of the system for producing a microneedle preparation of the present invention.
  • the microneedle preparation manufacturing system 200 includes an air compressor 10, a compressed air temperature adjustment device 12, a pressure adjustment device 30, a humidity adjustment device 18, an air volume adjustment device 14, and an air filter 16, respectively, in this order via a blower line L. It is configured by being connected. The end of the air blowing line L is connected to a coating chamber 20 in which microneedles are arranged and medicine is applied.
  • the air compressor 10 in the microneedle preparation manufacturing system 200 is not particularly limited as long as it can generate an airflow at a desired wind speed (flow velocity). . Therefore, the air compressor 10 is not limited to the compressor defined in JIS (B 0132: 2005), and a blower having a low compression ratio may be used.
  • the air volume of air supplied into the system 200 by the air compressor 10 is preferably 10 to 250 L / min, and more preferably 20 to 100 L / min. Further, the air volume may be 0.3 to 10 L / min.
  • the air volume of the supplied air can be calculated as the air volume per volume of the coating chamber 20.
  • the amount of air supplied per 1 L of the coating chamber 20 is preferably 28 to 696 L / min, and more preferably 56 to 278 L / min. Further, the air volume supplied per 1 L of volume of the coating chamber 20 may be 1 to 28 L / min.
  • air supplied into the system 200 by the air compressor 10 air existing outside the system can be used, but any gas can be used depending on the composition of the coating liquid applied to the microneedles. You may mix.
  • the compressed air temperature adjusting device 12 in the microneedle preparation manufacturing system 200 can adjust the temperature of the air supplied from the outside into the system 200 by the air compressor 10 to an arbitrary temperature. Is. Therefore, even when the temperature of the outside air of the system 200 varies between days and days, the temperature of the air flowing in the system 200 can be set within a desired range regardless of the external environment by providing the compressed air temperature adjusting device 12. Can be maintained within.
  • the compressed air temperature adjustment device 12 is preferably adaptable to a range of approximately 5 to 40 ° C. as the temperature of the air injected into the compressed air temperature adjustment device 12.
  • the temperature of the air sent from the compressed air temperature control device 12 to the downstream air blowing line L can be arbitrarily set according to the composition of the coating liquid to be used.
  • the compressed air temperature control apparatus 12 which can control the temperature of exhaust air with the precision of +/- 0.5 degreeC or less.
  • the compressed air temperature adjusting device 12 may be any device that can accurately control the temperature of the compressed air, and a device using a temperature control method, a cooling method, or the like can be used.
  • the humidity adjusting device 18 in the microneedle preparation manufacturing system 200 is used in combination with the compressed air temperature adjusting device 12 described above, so that the air flowing in the system 200 can have a desired humidity, particularly 30 to 30%.
  • the humidity can be adjusted and maintained in the range of 70% (RH).
  • the humidity adjusting device 18 is a moisture permeable membrane type, and has a moisture permeable membrane device 24 including a moisture permeable membrane formed in a hollow fiber shape.
  • a moisture permeable membrane type humidity control device 18 may include a moisture supply device 22 for supplying moisture.
  • the moisture permeable membrane for example, an ion exchange resin formed into a hollow fiber shape can be used.
  • the moisture permeable membrane has a property of allowing water vapor to pass therethrough and preventing liquid water from passing therethrough.
  • the thermostatic water tank is preferably adjustable to a wide temperature range and can be adjusted to an arbitrary temperature with high accuracy.
  • the water used for the moisture supply device 22 is preferably pure water in order to ensure aseptic conditions.
  • the moisture supplied from the moisture supply device 22 to the moisture permeable membrane device 24 is vaporized through the moisture permeable membrane and supplied to the present system 200 as water vapor.
  • the moisture permeable membrane device 24 from the viewpoint of efficiency, it is preferable to use a hollow fiber module in which a large number of moisture permeable membranes formed in a hollow fiber shape are fixed in a bundle.
  • the hollow fiber module is connected to the blower line L of the system 200 so that the air flowing through the system 200 passes through the hollow fiber-shaped moisture permeable membrane.
  • the moisture supply device 22 preferably a constant temperature water tank, is in contact with the outside of the hollow fiber-shaped moisture permeable membrane, and is constantly circulated between the hollow fiber-shaped moisture permeable membrane and the moisture supply device 22. It is preferable to be configured to do so.
  • a gas having a predetermined range of humidity is derived from the hollow fiber module. Therefore, air whose temperature is adjusted by the compressed air temperature adjusting device 12 is introduced into the hollow fiber module, and pure water at a constant temperature passes through the hollow fiber module from the constant temperature water tank, so that the air from the hollow fiber module is within a desired range. It will flow downstream with humidity. Further, by controlling the water temperature of the water supply device 22 such as a constant temperature water tank, the humidity can be controlled with high accuracy.
  • the air flowing in the system 200 can be humidified to a humidity corresponding to the temperature, and conversely, by reducing the water temperature to a certain temperature, the air flowing in the system 200 is It can be dehumidified to a humidity corresponding to the temperature.
  • the moisture permeable membrane device 24 having a hollow fiber module since the hollow fiber module has a filter function, microorganisms that may be contained in the water in the moisture supply device 22 are determined by the hollow fiber module. It is possible to prevent the air from being trapped and mixed in the air flowing into the system 200.
  • the pressure adjusting device 30 in the microneedle preparation manufacturing system 200 can adjust the pressure inside the hollow fiber-shaped moisture permeable membrane of the moisture permeable membrane device 24.
  • the pressure adjusting device 30 is provided downstream of the compressed air temperature adjusting device 12 and upstream of the moisture permeable membrane device 24.
  • the moisture permeable membrane of the moisture permeable membrane device 24 is formed in a hollow fiber shape. Therefore, by adjusting the pressure of the air introduced into the moisture permeable membrane device 24 by the pressure adjusting device 30, The humidity of the air derived from the membrane device 24 can be adjusted, and is particularly suitable for adjusting the humidity in the coating chamber to a moderate humidity of about 30-70% (RH).
  • the pressure adjusting device 30 may be any device that can precisely adjust the pressure. For example, a diaphragm type device can be used. As the pressure adjusting device 30, a device capable of adjusting pressure in the range of 0.02 to 1.0 MPa can be used.
  • the air filter 16 in the microneedle preparation manufacturing system 200 can be used without limitation as long as it can capture and sterilize microorganisms such as bacteria and fungi contained in the passing air. Can do. By using such an air filter 16, not only microorganisms but also dust in the air can be removed.
  • the pore diameter of the filter 16 is preferably 0.2 ⁇ m or less from the viewpoint of sterilization efficiency.
  • two or more air filters such as a combination of a filter having a dust removing effect such as a HEPA (High Efficiency) Particulate Air filter and an air filter having a sterilizing effect may be used.
  • the air supplied from the air compressor 10 is constantly flowing toward the opening 21 of the coating chamber 20, by providing the air filter 16 in the system 200, The inside of the coating chamber 20 can be more aseptically ensured.
  • the air filter 16 is installed on the downstream side of the air volume adjusting device 14, but can be provided at an arbitrary position on the air blowing line L on the downstream side of the air compressor 10 in the system 200. Among these, it is preferable to be provided downstream of the humidity adjusting device 18 in view of installation layout and pressure control efficiency.
  • the air blowing line L in the microneedle preparation manufacturing system 200 may be in any form as long as it does not leak air regardless of its material.
  • the air blowing line L preferably has a heat insulating effect.
  • a heat insulating material may be provided so as to cover the periphery of the air blowing line L, and the material of the air blowing line L itself may be a material having a heat insulating effect. .
  • the air that is derived from the humidity control device 18 as temperature and humidity within a predetermined range and is sterilized by the air filter 16 is used for producing a microneedle preparation by applying a coating liquid containing a drug to the microneedle. It is fed into the coating chamber 20.
  • the coating chamber 20 has an opening 21 in a part of its wall surface.
  • the opening 21 not only serves as an exhaust port through which the air supplied from the system 200 is discharged, but also serves as a carry-in port for a microneedle preparation to which a coating solution is applied.
  • the opening 21 may be provided on the upper surface of the coating chamber 20 or may be provided on a side surface or a lower surface.
  • the opening 21 and the connection portion with the present system 200 are sufficiently separated from each other. It is desirable that the air volume blown into the coating chamber 20 is kept sufficiently high. By keeping the air volume sufficiently high, the inside of the coating chamber 20 can be maintained at a positive pressure with respect to the outside of the system 200, and external air can be prevented from flowing into the coating chamber 20 from the opening 21. Therefore, the inside of the coating chamber 20 can be maintained at a desired temperature and humidity, and fungi can be prevented from entering the coating chamber 20 from the opening 21.
  • a temperature / humidity sensor temperature sensor and humidity sensor
  • the pressure adjusting device 30 and the compression corresponding to the temperature and humidity in the coating chamber 20 This is because the air temperature adjusting device 12 and the humidity adjusting device 18 can be sequentially operated to more precisely control the temperature and humidity of the air in the coating chamber 20.
  • a signal corresponding to the temperature and humidity in the coating chamber 20 detected by the temperature / humidity sensor 26 is transmitted to a control device (first control means and / or second control means for controlling the pressure adjusting device 30, compressed air temperature).
  • the third control means and / or the fourth control means for controlling the adjusting device 12 and the fifth control means and / or the sixth control means for controlling the water temperature of the water supply device 22) are sent to the signal.
  • a system for operating the water supply device 22 in the pressure adjusting device 30, the compressed air temperature adjusting device 12 or the humidity adjusting device 18, that is, a feedback system may be provided.
  • the pressure regulator 30 operates to decrease the set pressure.
  • the pressure controller 30 A feedback system may be provided that operates to increase the set pressure.
  • the heating mechanism of the moisture supply unit 22 is activated, and conversely, when an increase in humidity in the coating chamber 20 is detected, the cooling mechanism of the moisture supply unit 22 is activated.
  • a feedback system can be provided.
  • the heating of the heating mechanism of the compressed air temperature adjusting device 12 is promoted, or the cooling of the cooling mechanism is suppressed.
  • a feedback system that suppresses heating of the heating mechanism of the compressed air temperature adjusting device 12 or promotes cooling of the cooling mechanism may be provided. it can. By providing such a feedback system, temperature and humidity control in the coating chamber 20 can be performed more efficiently and reliably.
  • air is first sucked from the outside by the air compressor 10 and supplied into the system 200.
  • the air supplied by the air compressor 10 is injected into the compressed air temperature adjusting device 12 through the blower line L and adjusted to a predetermined temperature.
  • the air adjusted to a predetermined temperature by the compressed air temperature adjusting device 12 is injected into the pressure adjusting device 30 through the blower line L and adjusted to a predetermined pressure.
  • the air whose pressure is adjusted by the pressure adjusting device 30 is injected into the humidity adjusting device 18 through the blower line L and adjusted to a predetermined humidity.
  • the air whose humidity is adjusted by the humidity adjusting device 18 is sterilized by the air filter 16 after the air volume is adjusted as necessary.
  • the aseptic air whose temperature and humidity are adjusted in this way is supplied into the coating chamber 20 through the blower line L.
  • the air that has existed in the coating chamber 20 until then is exhausted from an opening 21 provided in a part of the wall constituting the coating chamber 20, and the inside of the coating chamber 20 is in a sterile state having a desired temperature and humidity. Filled with air.
  • the air supplied into the coating chamber 20 by the present system 200 is discharged as needed.
  • the air flowing through the system 200 flows in one direction toward the opening 21 in a state where the wind force of the air compressor 10 always has a certain wind speed. Therefore, air does not stay inside the system 200, and even if bacteria are present inside the system 200, the propagation is suppressed.
  • a coating liquid containing a drug in a microneedle is prepared in advance.
  • the inside of the coating chamber 20 is always in a predetermined range of temperature and humidity and in a sterile environment, the vaporization reaction of water contained in the coating liquid and the liquefaction reaction of moisture in the air are performed. Is controlled, and the change in physical properties of the coating liquid is suppressed. As a result, variation in the amount of the drug applied to the microneedles can be suppressed, and the microneedle preparation can be stably produced in an aseptic environment.
  • the CV (coefficient of variation) value indicating the degree of variation in the amount of drug applied to the microneedle is preferably 10% or less, and more preferably 5% or less.
  • the CV value is a value expressed as a percentage by dividing the standard deviation by the average value.
  • the air volume (flow rate) of the air from the air compressor 10 can be adjusted by the function of the air compressor 10 itself, but by connecting the air volume adjusting device 14 to the downstream side of the air compressor 10, the present system It is preferable to be able to adjust the air volume of the air flowing through 200 with higher accuracy.
  • the system 200 includes the air volume adjusting device 14, the amount of the medicine applied to the microneedles can be controlled by finely adjusting the air volume of the air flowing through the system 200.
  • the air volume is a certain amount or more, for example, 0.5 L / min or more, the temperature and humidity distribution in the coating chamber can be made more uniform.
  • the air volume adjusting device 14 is preferably provided downstream of the humidity adjusting device 18 in terms of installation layout and pressure control efficiency.
  • the temperature of the environment in which the system 200 is placed is described as fluctuating.
  • the supply is performed from the air compressor 10.
  • the compressed air temperature adjusting device 12 may not be included in the configuration when the air to be used is already maintained at a predetermined temperature range.
  • the humidity control apparatus 18 was demonstrated as what has the moisture-permeable membrane apparatus 24 which has a hollow fiber-like moisture-permeable film, a moisture-permeable film is not restrict
  • the humidity control device 18 shown in FIG. 3 has a moisture permeable film 23 provided in a partition wall shape.
  • the moisture permeable membrane 23 in FIG. 3 separates the air supplied from the air compressor 10 into the system 200 and the moisture as a humidity control source. Moisture is supplied to the air flowing in the flow path of the present system 200 through the moisture permeable membrane 23 as water vapor.
  • the pressure adjusting device 30 may be provided inside the humidity adjusting device 18 so as to adjust the pressure of the air introduced into the humidity adjusting device 18.
  • FIG. 4 is a perspective view showing an example of a microneedle preparation manufactured using the system according to the present embodiment.
  • a microneedle preparation 40 shown in FIG. 4 includes a substrate 42, a plurality of microneedles 44 arranged two-dimensionally on the substrate 42, and an application layer 46 formed on the microneedles 44.
  • the application layer 46 is applied using the system for manufacturing a microneedle preparation according to this embodiment, and it is preferable that at least a part of the volatile component is removed.
  • the substrate 42 is a base for supporting the microneedles 44. Area of the substrate 42 is preferably 0.5 ⁇ 10 cm 2, more preferably 1 ⁇ 5 cm 2, more preferably 1 ⁇ 3 cm 2. You may make it comprise the board
  • the microneedle 44 has a fine structure, and its height (length) is preferably 50 to 600 ⁇ m.
  • its height (length) is preferably 50 to 600 ⁇ m.
  • the drug contained in the coating liquid can be reliably administered.
  • the length of the microneedle 44 600 ⁇ m or less the microneedle can be prevented from coming into contact with the nerve, the possibility of pain can be reliably reduced, and the possibility of bleeding can be surely avoided. Will be able to.
  • the length of the microneedle 44 is 500 ⁇ m or less, an amount of drug that should enter the skin can be efficiently administered, and administration without perforating the basement membrane is also possible.
  • the length of the microneedle 44 is particularly preferably 300 to 500 ⁇ m.
  • the microneedle 44 is a convex structure and means a needle shape in a broad sense or a structure including a needle shape.
  • the microneedle is not limited to a needle shape having a sharp tip, and may have a shape with no sharp tip.
  • the diameter at the base is preferably about 50 to 200 ⁇ m.
  • the microneedle 44 has a conical shape, but may be a polygonal pyramid shape such as a quadrangular pyramid or a microneedle having another shape.
  • the microneedles 44 are typically spaced so that there is a density of about 1-10 per millimeter (mm) for a row of needles. In general, adjacent rows are separated from each other by a substantially equal distance with respect to the space of the needles in the row and have a density of 100-10000 needles per cm 2 . When there is a needle density of 100 or more, the skin can be efficiently perforated. On the other hand, when the needle density exceeds 10,000, it is difficult to maintain the strength of the microneedles 44.
  • the density of the microneedles 44 is preferably 200 to 5000, more preferably 300 to 2000, and particularly preferably 400 to 850.
  • Examples of the material of the substrate 42 or the microneedle 44 include silicon, silicon dioxide, ceramic, metal (stainless steel, titanium, nickel, molybdenum, chromium, cobalt, etc.) and synthetic or natural resin materials.
  • biodegradable polymers such as polylactic acid, polyglycolide, polylactic acid-co-polyglycolide, pullulan, capronolactone, polyurethane, polyanhydride, etc., or nondegradable polycarbonate, polymethacrylate Synthetic or natural resin materials such as acid, ethylene vinyl acetate, polytetrafluoroethylene, and polyoxymethylene are particularly preferable.
  • polysaccharides such as hyaluronic acid, sodium hyaluronate, pullulan, dextran, dextrin or chondroitin sulfate.
  • the substrate 42 or the microneedle 44 As a manufacturing method of the substrate 42 or the microneedle 44, wet etching processing or dry etching processing using a silicon substrate, precision machining using metal or resin (electric discharge processing, laser processing, dicing processing, hot embossing processing, injection molding processing) Etc.), machine cutting and the like. By these processing methods, the substrate 42 and the microneedles 44 are integrally molded. As a method of making the microneedle 44 hollow, a method of performing secondary processing with a laser or the like after the microneedle 44 is manufactured may be mentioned.
  • the microneedle preparation 40 includes a coating layer 46 on the microneedle 44, but the coating layer 46 is preferably formed by applying a coating solution. Examples of the application method include spray coating and dip coating, and dip coating is preferred.
  • the coating layer 46 is formed on all the microneedles 44, but the coating layer 46 may be formed only on a part of the plurality of microneedles 44.
  • the coating layer 46 is formed only on the tip portion of the microneedle 44, but may be formed so as to cover the entire microneedle 44. Further, the coating layer 46 may be formed on the substrate 42.
  • FIG. 5 is a cross-sectional view taken along line VV in FIG.
  • the microneedle preparation 40 includes a substrate 42, a microneedle 44 provided on the substrate 42, and an application layer 46 provided on the microneedle 44.
  • the coating layer 46 attached on the microneedles contains a drug and can be manufactured through the above-described steps, for example.
  • FIG. 6 (a), 6 (b) and 6 (c) are diagrams showing an example of a method for producing the microneedle formulation 40.
  • FIG. 6A This method is called a dip method.
  • the coating solution 50 is swept in the direction of arrow A by a spatula 54 on a mask plate 52. Thereby, the coating liquid 50 is filled in the opening 56.
  • FIG. 6B the microneedle 44 is inserted into the opening 56 of the mask plate 52.
  • FIG. 6C the microneedle 44 is pulled out from the opening 56 of the mask plate 52.
  • the coating liquid 50 is adhered onto the microneedle 44.
  • the coating liquid 50 may be attached on the substrate 42.
  • the microneedle preparation is manufactured by performing the operations shown in FIGS. 6A, 6B, and 6C in the coating chamber, and the system according to the present embodiment is used as a condition at that time.
  • the inside of the coating chamber is made an aseptic air environment in which the temperature and humidity are controlled.
  • each device in the present system is activated, the air supplied from the air compressor is adjusted to a desired environment, and blown into the coating chamber.
  • An air environment having a desired temperature and humidity is stably maintained by feeding back the temperature and humidity measurement results in the coating chamber to a constant temperature water tank or the like.
  • the volatile components of the coating liquid 50 on the microneedle 44 are removed by a known method such as air drying, vacuum drying, or a combination thereof.
  • the coating layer 46 adheres firmly on the microneedles 44 and typically becomes vitreous or solid, and the microneedle preparation 40 is manufactured.
  • the water content of the coating layer 46 is usually 55% by mass or less, preferably 30% by mass or less, and further 10% by mass or less based on the total amount of the coating layer 46.
  • the height H of the coating layer 46 attached on the microneedle 44 is adjusted by a clearance (gap) C shown in FIG.
  • This clearance C is defined by the distance from the base of the microneedle 44 to the surface of the mask plate 52 (the thickness of the substrate 42 is not involved), and is set according to the tension of the mask plate 52 and the length of the microneedle 44.
  • the distance range of the clearance C is preferably 0 to 500 ⁇ m. When the distance of the clearance C is 0, it means that the coating liquid 50 is applied to the entire microneedle 44.
  • the height H of the coating solution 50 adhering to the microneedles 44 varies depending on the height of the microneedles 44, but can be 0 to 500 ⁇ m, usually 10 to 500 ⁇ m, and preferably about 30 to 300 ⁇ m. Particularly preferably, the thickness is about 40 to 250 ⁇ m.
  • the drug is present in a concentrated manner in a part of the microneedle, that is, the tip part of the needle. Therefore, it is preferable to be present up to 200 ⁇ m from the tip.
  • the coating liquid 50 can dissolve, for example, a polymer compound in an aqueous solution and has a high viscosity, so that the coating layer 46 can be formed on a part of the microneedle.
  • the coating solution 50 held on the microneedles 44 in this manner is simultaneously inserted into the skin when the microneedles 44 are punctured into the skin.
  • the thickness after drying of the coating layer 46 adhering onto the microneedle 44 is preferably less than 50 ⁇ m, more preferably less than 40 ⁇ m, and even more preferably 1 to 30 ⁇ m.
  • the thickness of the coating layer 46 deposited on the microneedles is an average thickness measured across the surface of the microneedles 44 after drying.
  • the thickness of the coating layer 46 adhering onto the microneedle 44 is increased by applying a plurality of coatings of the coating solution 50, that is, by repeating the deposition process after the coating solution 50 is deposited. Can be made.
  • Examples of the drug contained in the coating solution 50 include high molecular compounds such as peptides, proteins, DNA, and RNA, but are not particularly limited. If the molecular weight is about 1000, vaccines, low molecular peptides, sugars, and nucleic acids. Etc.
  • physiologically active substance examples include naltrexone, cetrorelix acetate, tartilelin, nafarelin acetate, prostaglandin A1, alprostadil, ⁇ -interferon, ⁇ -interferon for multiple sclerosis, erythropoietin, follitropin ⁇ , Follitropin alpha, G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, salmon calcitonin, glucagon, GNRH antagonist, insulin, human growth hormone, filgrastin, heparin, low molecular weight heparin, Examples include somatropin, incretin, and GLP-1 derivatives.
  • vaccines include Japanese encephalitis vaccine, rotavirus vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, Lyme disease vaccine, rabies vaccine, pneumococcus pneumoniae Vaccines, yellow fever vaccines, cholera vaccines, seed urticaria vaccines, tuberculosis vaccines, rubella vaccines, measles vaccines, mumps vaccines, botulinum vaccines, herpes virus vaccines, other DNA vaccines, hepatitis B vaccines and the like.
  • hypnotic / sedative flurazepam hydrochloride, rilmazaphone hydrochloride, phenobarbital, amobarbital, etc.
  • antipyretic analgesics butorphanol tartrate, perisoxal citrate, acetaminophen, mefenamic acid, diclofenac sodium, aspirin, alclofenac, ketoprofen , Flurbiprofen, naproxen, piroxicam, pentazocine, indomethacin, glycol salicylate, aminopyrine, loxoprofen, etc.), steroidal anti-inflammatory agents (hydrocortisone, prednisolone, dexamethasone, betamethasone, etc.), stimulants / stimulants (methamphetamine hydrochloride, methylphenidate hydrochloride) Etc.), neuropsychiatric agents (imiplan, hydrochloride, diazepam, sertraline
  • these drugs may be used alone or in combination of two or more, and naturally include any form of drug in the form of an inorganic salt or an organic salt as long as it is a pharmaceutically acceptable salt.
  • the drug is basically included in the coating solution, but it can also be supplied from a through-hole formed in the substrate of the microneedle afterwards without including the drug in the coating solution.
  • the content of the drug (A) in the coating solution is 0.1 to 80% by weight, preferably 1 to 70% by weight, particularly preferably 5 to 60% by weight.
  • the coating solution may contain a polymer compound different from the above-mentioned drug.
  • the polymer compound include polyethylene oxide, polyhydroxymethylcellulose, hydroxypropylcellulose, polyhydroxypropylmethylcellulose, polymethylcellulose, dextran, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, carmellose sodium, chondroitin sulfate, and hyaluronic acid. Dextran, gum arabic and the like.
  • propylene carbonate, crotamiton, l-menthol, mint oil, limonene, diisopropyl adipate, etc. as a solubilizing agent or absorption accelerator as necessary, methyl salicylate, glycol salicylate as medicinal aids , L-menthol, thymol, peppermint oil, nonylic acid vanillylamide, pepper extract and the like may be added.
  • the surfactant may be either a nonionic active agent or an ionic active agent (cation, anion, amphoteric), but from the viewpoint of safety, a nonionic active agent usually used for a pharmaceutical base is desirable.
  • sugar alcohol fatty acid esters such as sucrose fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyethylene glycol fatty acid Examples thereof include esters, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.
  • the coating solution needs to have a certain degree of viscosity so as not to be dripped, and specifically needs a viscosity of about 100 to 100,000 cps.
  • a more preferable viscosity of the coating solution is 100 to 60000 cps.
  • the viscosity is within this range, it is possible to apply a desired amount of the coating solution at a time without depending on the material of the microneedle 44. In general, the higher the viscosity is, the more the amount of coating solution to be applied tends to increase. When the viscosity is less than 600 cps, it becomes difficult to apply the minimum coating solution to the microneedles 44.
  • Example 1 A system for producing a microneedle preparation comprising a compressor, a compressed air temperature adjusting device, a pressure adjusting device, a humidity adjusting device, an air volume adjusting device and an air filter in this order was prepared.
  • a humidity control device a hollow fiber module and a thermostatic water bath were used in combination. Specifically, the inside of the hollow fiber membrane of the hollow fiber module is connected so that the gas flowing in the system passes, and the water at a constant temperature supplied from the constant temperature water tank to the outside of the hollow fiber membrane of the hollow fiber module. Were connected to circulate with the constant temperature water bath.
  • a Teflon (registered trademark) tube and a silicon tube were used for the blower line connecting each device, and a bubble nitrile synthetic rubber heat insulating material was installed around the tube as a heat insulating material.
  • the details of each device used are as follows.
  • Compressor Control pressure 0.6-0.8MPa, discharge air volume 85L / min
  • Compressed air temperature control device electronic cooling type, set discharge temperature 23 ° C
  • Air volume control device Set air volume 30L / min
  • Air filter Polytetrafluoroethylene, pore size 0.2 ⁇ m, effective area 50 cm 2
  • Thermostatic water tank Circulating thermostatic water tank
  • Hollow fiber module Cylindrical module containing 230 hollow fibers made of fluorine-based ion exchange resin with an inner diameter of 1 mm, outer diameter of 1.3 mm, and a length of 300 mm
  • Pressure regulator Feedback control precision regulator The system was connected to the application chamber via a polypropylene tube. An acrylic chamber was used as the coating chamber.
  • the coating chamber was further covered with a booth, and the temperature and humidity inside the booth were controlled by a precision temperature and humidity unit.
  • the constant temperature water bath was set to 23 ° C., and each device was started.
  • the set pressure of the pressure adjusting device was 0.1 to 0.3 MPa, and the relative humidity (%) in the coating chamber under each pressure condition was measured.
  • the results are shown in Table 1.
  • the inside of the coating chamber can be adjusted to an arbitrary humidity of 70% (RH) or less, and adjusted to a moderate humidity of about 30% (RH). It was also possible to do.
  • Example 2 Using the same system as in Example 1, a humidity maintenance test was performed. The humidity in the coating chamber was adjusted by starting each device of the system and appropriately changing the set pressure of the pressure adjusting device. The humidity in the coating chamber was measured over time. The results are shown in FIG. At a humidity of about 30% (FIG. 7 (a)), about 50% (FIG. 7 (b)), and about 70% (FIG. 7 (c)), the humidity in the coating chamber is kept constant for a long time. It was possible to do.
  • Example 3 In the coating chamber in which the temperature and humidity were adjusted to 23 ° C. and 60% (RH) by the method of Example 1, a coating test on the microneedle device was performed.
  • the specific method of the application test is as follows.
  • the coating liquid was applied to the microneedles by the method shown in FIGS. 6 (a) to (c).
  • the obtained coating solution was swept with a spatula into a metal mask plate (thickness 75 ⁇ m, opening diameter 250 ⁇ m, pitch 400 ⁇ m) installed in the coating chamber, and filled in the openings of the metal mask plate.
  • the microneedles were inserted into the filled openings and then pulled out to apply the coating solution to the microneedles.
  • the microneedle after application was air-dried and stored at room temperature. It apply
  • the drug on the microneedle after air drying was extracted with 1 ml of water, and the sodium benzoate concentration in the obtained extract was measured using HPLC. From the obtained measured value, the content per microneedle preparation was calculated. The results are shown in FIG. The variation in the content of the model drug on the microneedle after drying was sufficiently small between devices, the average content of sodium benzoate was 1.8 ⁇ g, the standard deviation was 0.1 ⁇ g, and the CV value was 7.0%. .
  • Example 4 An air volume adjustment test was performed using the same system as in Example 1 and the coating chamber shown in FIG.
  • the size of the coating chamber is as follows. Height 35mm, width 50mm, length 205mm, volume about 0.359L
  • Exhaust port (opening) 21 Rectangular, 25 mm x 30 mm
  • Air supply port to which the air line L is connected Circular, diameter 16mm
  • Example 1 A system for producing a microneedle preparation comprising a compressor, a compressed air temperature adjusting device, an air flow adjusting device, an air filter and a humidity adjusting device in this order was produced. The same devices as in Example 1 were used for each device in common with Example 1.
  • the produced microneedle preparation production system was connected to an acrylic coating chamber via a polypropylene tube in the same manner as in Example 1.
  • the coating chamber was further covered with a booth, and the temperature and humidity inside the booth were controlled by a precision temperature and humidity unit. Each apparatus was started, and the inside of the coating chamber was filled with air with adjusted temperature and humidity.
  • the temperature and humidity in the coating chamber were measured over time. The results are shown in FIGS. 10 (a) and 10 (b).
  • the temperature and humidity in the coating chamber could be adjusted to a desired range, but the humidity was less than 70% (RH) even when the temperature of the water circulating in the hollow fiber module was lowered. It was difficult to stabilize in the state lowered to.
  • Example 2 The compressor, the air volume control device, and the humidity control device were connected in this order via the air blowing line. The same compressor and air volume adjusting device as in Example 1 were used, and settings were made in the same manner. Only a circulating water bath was used as the humidity control device. Changes in temperature and relative humidity in the coating chamber were measured. The results are shown in FIGS. 11 (a) and 11 (b). The temperature in the coating chamber varied between days and days. Moreover, the relative humidity in the coating chamber also fluctuated greatly.
  • SYMBOLS 10 Air compressor, 12 ... Compressed air temperature control apparatus, 14 ... Air volume control apparatus, 16 ... Air filter, 18 ... Humidity control apparatus, 20 ... Coating chamber, 21 ... Opening, 22 ... Moisture supply device, 23 ... Moisture permeability Membrane, 24 ... moisture permeable membrane device, 26 ... temperature / humidity sensor (temperature sensor and humidity sensor), 28 ... control device (first to sixth control means), 30 ... pressure adjusting device, 40 ... microneedle formulation, 42 DESCRIPTION OF SYMBOLS ... Substrate, 44 ... Microneedle, 46 ... Coating layer, 50 ... Coating liquid, 52 ... Mask plate, 54 ... Spatula, 56 ... Opening, 100, 200 ... Microneedle preparation manufacturing system, L ... Air blowing line.

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Abstract

La présente invention concerne un système de production d'une préparation pharmaceutique sur micro-aiguille par revêtement d'une micro-aiguille avec un liquide de revêtement contenant un médicament, et ajustement de l'environnement atmosphérique dans la chambre de revêtement pour produire une préparation pharmaceutique sur micro-aiguille, le système de production de la préparation pharmaceutique sur micro-aiguille étant équipé de : un compresseur d'air ; un dispositif d'ajustement de l'humidité de type film perméable à l'humidité pour ajuster l'humidité de l'air fourni par un compresseur d'air et séparer le contenu en air et en eau servant de source d'ajustement de l'humidité avec un film perméable à l'humidité ; un dispositif d'ajustement de la pression pour ajuster la pression de l'air fourni par le compresseur d'air ; et un filtre à air pour éliminer les bactéries de l'air introduit à l'intérieur de la chambre de revêtement.
PCT/JP2014/064317 2013-05-29 2014-05-29 Système de production d'une préparation pharmaceutique sur micro-aiguille et procédé de conditionnement d'air WO2014192887A1 (fr)

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US11130148B2 (en) 2013-05-29 2021-09-28 Hisamitsu Pharmaceutical Co., Inc. System for manufacturing microneedle preparation, and air-conditioning method

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JP2001202977A (ja) * 2000-01-19 2001-07-27 Honda Motor Co Ltd 加湿装置
JP2002298883A (ja) * 2001-03-30 2002-10-11 Honda Motor Co Ltd 加湿モジュール
JP2005249256A (ja) * 2004-03-03 2005-09-15 Matsushita Electric Ind Co Ltd 中空糸膜式加湿器
JP2006130596A (ja) * 2004-11-05 2006-05-25 Fuji Photo Film Co Ltd 規則配列したナノ構造材料
JP2011500259A (ja) * 2007-10-29 2011-01-06 トランスファーマ メディカル リミテッド 垂直的なパッチ乾燥
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Publication number Priority date Publication date Assignee Title
US11130148B2 (en) 2013-05-29 2021-09-28 Hisamitsu Pharmaceutical Co., Inc. System for manufacturing microneedle preparation, and air-conditioning method

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JP6110485B2 (ja) 2017-04-05

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