CN219148981U

CN219148981U - Combined drug delivery device with nano-microneedle wafer

Info

Publication number: CN219148981U
Application number: CN202223045730.2U
Authority: CN
Inventors: 陈魁; 阮晖; 江高原野; 吴渊; 蒋可若; 丁丽娜; 竺莹莹
Original assignee: East Salamander Life Technology Zhejiang Co ltd
Current assignee: East Salamander Life Technology Zhejiang Co ltd
Priority date: 2022-11-16
Filing date: 2022-11-16
Publication date: 2023-06-09
Anticipated expiration: 2032-11-16

Abstract

The present application provides a combination drug delivery device with a nano-wafer. The combined drug delivery device with the nanometer microneedle wafer comprises an output part, wherein the output part comprises: a head; the clamp is arranged on the head part; the clamp is connected with the chassis, a plurality of liquid flow holes are formed in the chassis, and liquid in the combined type drug delivery device can flow from one side of the chassis to the other side through the liquid flow holes; the plurality of nanometer microneedle wafers are arranged on the chassis; and the sponge is arranged on the chassis and is in contact with the nanometer microneedle wafer. The application is provided with the sponge in microneedle department for microneedle pierces and solution injection go on consecutively, has shortened operating time, and microneedle pierces and substance such as medicine is applyed more consistently.

Description

Combined drug delivery device with nano-microneedle wafer

Technical Field

The present application relates to the field of medical devices, and in particular to a modular drug delivery device having a nanomicroneedle wafer.

Background

Along with the rapid development of biomedicine, a series of biological agents including cytokines, recombinant proteins, polypeptides, antibodies, vaccines and the like have been widely used in the fields of clinical diagnosis and treatment, skin care and beauty. To preserve biological activity, such biological agents are typically processed by ultra-low temperature freeze-drying (lyophilization) techniques. The biological agent is called freeze-dried biological agent after being treated, is porous solid powder, and can be preserved at-20 ℃, 4 ℃ and even normal temperature, so that the storage stability and the transportation flexibility of the biological agent are greatly improved. When in use, proper solvent can be added according to the requirement, the freeze-dried biological preparation can be switched from a storage state (solid phase) to a working state (liquid phase) in a very short time, and then is applied in an oral administration, injection or external application mode.

Freeze-dried biological formulations involve both storage and administration problems.

Currently, the freeze-dried biological preparation is stored in a solid phase and a solid-liquid combination mode.

Solid phase storage is most commonly carried out by packaging lyophilized biological products in penicillin bottles, and immediately prior to use, directly dissolving the biological products in a corresponding solvent, for example, recombinant insulin, antibodies, vaccine medical preparations are administered by syringe; skin care preparations such as polypeptides are applied by topical application.

The solid-liquid combined storage format is represented by the dual-chamber card bottle shown in fig. 1, which the inventors have appreciated. As shown in fig. 1, the solid-phase lyophilized preparation and the corresponding solvent are integrated by the design of arranging the front and rear double cavities. The front chamber 91 stores the lyophilized biological agent and the rear chamber 92 stores the corresponding solvent, the front chamber 91 and the rear chamber 92 being isolated from each other by an intermediate plug 93 during the daily storage period. The end push rod 94 and the piston 95 are operated just before use, pushing the solvent in the rear chamber 92 from the groove channel 96 into the front chamber 91, and the undissolved lyophilized particles gradually decrease until they disappear. The push rod 94 is pulled back again. The solution in front chamber 91 is withdrawn along groove channel 96 back into rear chamber 92 and the process is repeated several times to dissolve the solute thoroughly to form the working solution and applied.

In the former single solid phase storage mode, when a solvent is added before use, the re-dissolution process of the freeze-dried biological preparation is exposed to the air, so that potential risks such as bacterial infection, medicament cross contamination and the like are difficult to avoid. The latter two-cavity design can ensure that solid-liquid mixing is completed in a sealed environment, so that the potential infection risk is effectively reduced, but the solid phase and the liquid phase are integrated, and the solid-liquid phase and the liquid phase are not suitable for some special freeze-dried preparations (such as measles vaccine, exosomes and the like) with optimal preservation conditions below 0 ℃. In addition, in most cases, the double-cavity card bottle needs to repeatedly push and pull the injection push rod to ensure that the preparation is thoroughly dissolved. In this process, the mechanical shear forces created by the friction of the piston with the sidewall will destroy the structural integrity of the specific biological macromolecules (e.g., high molecular weight proteins, long chain nucleotides) and subcellular organelles (e.g., exosomes) in the formulation solution, thereby impairing the biological activity of the formulation. Furthermore, since the solid and liquid phases are fixed together in advance, the free combination and flexible switching of the respective components and dosages of the lyophilized preparation and the solution cannot be achieved.

On the other hand, the administration modes of the biological agent comprise three modes of injection, oral administration and external application and smearing. The injection mode can break through the subcutaneous part to the blood vessel to maximize the efficacy of the preparation, but the pain caused by the injection mode can obviously reduce the use friendliness of the preparation; the first pass effect cannot be avoided due to the gastrointestinal digestion effect of the human body in an oral way, and the actual absorption rate of the medicament is obviously weakened; the application mode of external application is the mildest, but is limited by the huge resistance of the skin structure of the human body. The animal skin is composed of epidermis, dermis and subcutaneous tissue from outside to inside, and the stratum corneum is arranged outside the epidermis, so that the skin can be effectively protected and the in vivo tissue fluid is prevented from being extravasated, but the animal skin is also a main barrier for absorbing and taking in external application medicines and nutrient components, and particularly prevents the passage of biological macromolecules such as proteins, polypeptides, exosomes and the like and deep into the skin to exert efficacy. The retention of the blocked biomacromolecules outside the stratum corneum can also cause "localized overnutrition", which in turn leads to bacterial overgrowth and skin infection.

Recent popular transdermal administration modes include water-light injection, jet injection and microneedle injection.

The basic principle of the hydro-optical needle is to suck skin by using circulating negative pressure, and simultaneously, a plurality of hollow micro-needles penetrate into a specific layer of skin, nutrient substances or medicines are injected, then the negative pressure disappears, and the injector and the skin are automatically separated. The water optical needle system is complex in design, long in practical operation time, needs professional training, also needs to rely on real-time technical support, and can cause skin adverse reactions such as pain, ecchymosis, infection, allergy, pigmentation and the like due to improper operation, so that the admission threshold of equipment is higher. The water optical needle system has larger equipment size, various accessories and poor overall portability. The factors limit the application range of the water ray needle, and the water ray needle can be only arranged in a professional medical and medical institution and is not suitable for daily use in families.

Jet injection (needleless injection) uses instantaneous high pressure generated by power sources such as springs, voice coil motors, high-pressure gas and the like to enable liquid medicine in the injector to form high-speed (for example, more than 100 m/s) and high-pressure jet flow through a micron-sized nozzle, and the instantaneous administration is realized by puncturing the epidermis. The jet injection device has precise internal design, complex instrument structure, high manufacturing cost and a certain distance, and is widely applicable.

The nanometer microneedle injection mainly forms a micro-channel with a nanoscale aperture on the skin surface through the microneedle, so that the medicament can directly penetrate through the stratum corneum, and gradually becomes a brand new mode of transdermal administration.

The current main flow application mode of the micro-needle is an electric micro-needle device, the specific operation flow is divided into two steps, firstly, the micro-needle is aimed at an epidermis target position, the micro-needle is pushed to pierce the outermost stratum corneum by utilizing electric power, and the pierced state is maintained for a period of time, so that a plurality of nanometer-level holes are formed and maintained in the stratum corneum in a short time, and a temporary channel is provided for percutaneous uptake of macromolecular skin care product preparations or medicaments. Then the microneedle is removed, and the preparation is rapidly smeared on the same part before the nano-hole is reclosed, so that the preparation passes through the hole of the stratum corneum, and the transdermal absorption efficacy of the skin care preparation is improved to the greatest extent.

For example, chinese patent CN110193136a discloses a nano-wafer permeation enhancer which utilizes an electrically powered microneedle device. However, the technical improvement and upgrading space of the device is still huge. For example, the percutaneous success rate of substances such as micro-needles are not effectively guaranteed due to the discontinuous connection between the two steps of penetration and drug application. The electric microneedle device has complex internal structure design and high manufacturing cost.

Disclosure of Invention

To address or ameliorate at least one of the problems noted in the background, the present application provides a combination drug delivery device with a nanomicroneedle wafer.

The combined drug delivery device with the nanometer microneedle wafer comprises an output part, wherein the output part comprises:

a head;

the clamp is arranged on the head part;

the clamp is connected with the chassis, a plurality of liquid flow holes are formed in the chassis, and liquid in the combined type drug delivery device can flow from one side of the chassis to the other side through the liquid flow holes;

the plurality of nanometer microneedle wafers are arranged on the chassis; and

the sponge is arranged on the chassis and is in contact with the nanometer microneedle wafer.

In at least one embodiment, the output part further comprises a body part extending along a straight line, the head part is bent relative to the body part, the axis of one end of the head part far away from the body part forms an included angle alpha with the axis of the body part, and the included angle alpha is more than or equal to 90 degrees and less than or equal to 150 degrees.

In at least one embodiment, a filter is disposed in the body, and liquid in the combination dosing device is filtered through the filter and allowed to enter the head.

In at least one embodiment, the body comprises a first body portion and a second body portion having different inner diameters, the interface between the first body portion and the second body portion forming a stepped configuration against which the filter abuts.

In at least one embodiment, the second body is located between the first body and the head, and the second body has an inner diameter that is smaller than the inner diameter of the first body.

In at least one embodiment, the filter comprises a filter cartridge comprising, or consisting of,

the both sides of filter core are provided with first plug and second plug respectively, first plug with the second plug interference set up in the body.

In at least one embodiment, the filter is provided with a polyethersulfone membrane having a mesh diameter of 0.22 microns or 0.45 microns, or

The filter is provided with a hydrophilic polyvinylidene fluoride filter membrane with a mesh diameter of 0.45 micrometers.

In at least one embodiment, the chassis is oval.

In at least one embodiment, the output portion includes a protection portion, the protection portion is sealingly disposed at one end of the body portion, the output portion includes a casing, and the casing is sleeved outside the collar.

In at least one embodiment, the nanomicroneedle wafer comprises a substrate and nanomicroneedles disposed on the substrate, and the nanomicroneedles are made of porous silicon or copper-plated polymethyl methacrylate.

In at least one embodiment, further comprising a storage portion for storing a substance, the storage portion comprising:

a solvent part, wherein one end of the solvent part is provided with a solvent part first piston, and the solvent part is also provided with a push rod and a solvent part second piston which can be pushed by the push rod and moves in the solvent part;

a solute part which is arranged with the solvent part body and can be connected with the solvent part, one end of the solute part is provided with a plugging body, the solute part is also provided with a solute part piston,

in a state that the solvent portion is connected to the solute portion, the push rod can push the solvent portion second piston, the solvent portion first piston and the solute portion piston in order,

the output part and the solute part body are arranged, one end of the stopper body of the solute part can be connected to the output part, and the output part is used for outputting the liquid in the combined type drug delivery device to the outside of the combined type drug delivery device.

The utility model provides a microneedle department is provided with the sponge for microneedle pierces and solution injection is gone on in succession, has shortened operating time, and microneedle pierces and substance such as medicine is applyed more consistently.

Drawings

Fig. 1 shows a schematic structure of a dual-chamber card bottle.

Fig. 2A and 2B are schematic structural views of a combination drug delivery device according to an embodiment of the present application.

Fig. 3A and 3B are schematic diagrams showing the structure of a solvent portion of a combination drug delivery device according to an embodiment of the present application.

Fig. 4A and 4B are schematic diagrams showing the structure of a solute portion of a combination drug delivery device according to an embodiment of the present application.

Fig. 4C shows a perspective assembly view of the solute portion of the combination drug delivery device of fig. 4A, 4B.

Fig. 5A and 5B are schematic views showing the structure of an output part of the combination drug delivery device according to the embodiment of the present application.

Fig. 5C shows a perspective assembly view of the output of the combination drug delivery device of fig. 5A, 5B.

Fig. 6A and 6B are schematic structural views showing an output part of a combination drug delivery device according to another embodiment of the present application.

Fig. 6C shows a perspective assembly view of the output of the combination drug delivery device of fig. 6A, 6B.

Fig. 6D shows a schematic diagram of the mechanism of the nanomicroneedle wafer at the output of the combination drug delivery device of fig. 6A, 6B.

Fig. 6E shows a schematic structural view of the chassis of the output part of the combination drug delivery device in fig. 6A, 6B.

Fig. 7A, 7B, 7C, and 7D illustrate a flow chart of operation of a combination drug delivery device according to an embodiment of the present application.

Description of the reference numerals

1 a solvent part; 11 a solvent section cylinder; 12 solvent portion caps; 13 a solvent portion first piston; 14 a solvent portion second piston; 15 external threads; 16 a portion to be perforated; 17 push rod;

2 solute parts; 21 solute portion cylinder; 211 internal threads; 22 solute portion cap; 221 internal threads; 23, plugging the body; 231 output tube; 232 caps; 233 external threads; 24 solute portion pistons; 25 air guide holes; 26, a honeycomb duct; 261 straight line portion; 262 bending parts; 27 internal threads; 28 breathable filter screen; 29 a protective film;

3 an output unit; 31 head; 311 external threads; 32 body parts; 321 first body portion; 3211 internal threads; 322 a second body portion; 323 ladder structure; 33 a filter; 331 a filter element; 332 needle; 333 first rubber plug; 334 a second rubber plug; 34 a protective film; 35 sponge base; 36 microneedles; 37 hoops; 38 a casing;

4, solvent;

5 solute;

a chassis 61; 611 liquid flow holes; 612 mounting holes; a 62 nanometer microneedle wafer; 621 a substrate; 622 nanometer microneedles; 63 sponge; 64 hoops; 65 sleeves;

91 front cavity; 92 rear cavity; 93 a middle plug; 94 push rod; a 95 piston; 96 groove channels.

Detailed Description

Exemplary embodiments of the present application are described below with reference to the accompanying drawings. It should be understood that these specific descriptions are merely illustrative of how one skilled in the art may practice the present application and are not intended to be exhaustive of all of the possible ways of practicing the present application nor to limit the scope of the present application.

Referring to fig. 2A, 2B, 3A, 4A, 5A, and 6A, the present embodiment provides a combined type administration device (hereinafter, sometimes simply referred to as "administration device") including a storage part and an output part 3 which are separately provided and can be connected together. The storage portion may include a solvent portion 1 and a solute portion 2 that are provided separately and can be connected together. The solvent section 1 may be used for storing the solvent 4 (see fig. 4B). The solute portion 2 may be used to store a solute 5 and serve as a site for redissolving the solute 5. Solutes 5 include, but are not limited to, lyophilized biological agents. The output unit 3 is configured to output a solution formed by reconstitution of the solute 5 to the outside of the drug administration device, for example, to a human body.

Illustratively, the solvent portion 1, solute portion 2, and output portion 3 may be separately stored in a sealed manner prior to use of the drug delivery device; when in use, the solvent part 1, the solute part 2 and the output part 3 can be quickly connected in a threaded connection, a clamping connection, a reverse hook connection and the like, so that the complete drug delivery device is assembled. The combined use form among the components enables solutes and solutions to be respectively stored in a suitable environment, so that the variety of freeze-dried preparations is greatly enriched. In addition, the types and the dosages of the solute 5 and the solvent 4 can be switched according to the requirements, so that the flexibility is improved.

The components are described in turn below.

< solvent part 1>

Referring to fig. 3A, 3B, in one embodiment of the present application, the solvent portion 1 includes a solvent portion cylinder 11 and a solvent portion cap 12.

One end (front end, upper end of fig. 3A) of the solvent section cylinder 11 may be provided with a solvent section first piston 13, a middle section part in the solvent section cylinder 11 may be provided with a solvent section second piston 14, and a sealed space formed between the solvent section first piston 13 and the solvent section second piston 14 may store the solvent 4.

Illustratively, the solvent section cylinder 11 may have an inner diameter of 14 to 15 millimeters and a length of, for example, 8 centimeters. The material of the solvent part cylinder 11 is preferably polypropylene, polystyrene, or medical grade aluminum alloy. Of course, the present application is not limited to the material thereof.

The front end of the solvent portion cylinder 11 may be provided with an external thread 15, and the external thread 15 may be used to be tightly coupled with an internal thread 27 at one end (rear end) of the solute portion 2. Of course, an internal thread may be provided at the front end of the solvent portion cylinder 11, and an external thread may be provided at the rear end of the solute portion 2, so that the threaded connection effect is achieved.

When the solvent portion 1 and the solute portion 2 are not connected, the solvent portion cap 12 can cover the front end of the solvent portion cylinder 11, preventing the solvent portion first piston 13 from being damaged.

The diameter of the front end of the solvent portion cylinder 11 may be slightly smaller than other portions of the solvent portion cylinder 11, and after the solvent portion cap 12 is covered on the front end of the solvent portion cylinder 11, the outer diameter of the solvent portion cap 12 may be equal to the outer diameter of the portion other than the front end of the solvent portion cylinder 11.

Illustratively, the inner diameter of the solvent portion cap 12 may be 0.5 to 1 mm more than the outer diameter of the front end portion of the solvent portion cylinder 11 so that the solvent portion cap 12 may easily cover or remove the front end of the solvent portion cylinder 11. The material of the solvent portion cap 12 is preferably a transparent medical grade plastic such as polycarbonate or polystyrene. Of course, the present application is not limited to the material thereof.

The diameter of the solvent portion first piston 13 may be 14 to 17 mm (the inner diameter of the solvent portion cylinder 11 may be increased by 0 to 3 mm), and the thickness may be 3 to 5 mm. The material of the solvent portion first piston 13 is preferably butyl rubber, and of course, the material is not limited in this application. The material and diameter of the solvent portion second piston 14 may be the same as those of the solvent portion first piston 13, and the thickness of the solvent portion second piston 14 may be 5 to 10 mm.

The center position of the solvent portion first piston 13 may be provided with a portion to be perforated 16 thinner in thickness than the position other than the center. For example, the radius of 3 mm of the center position of the solvent portion first piston 13 is in the range of the portion to be perforated 16, and the portion to be perforated 16 may be subjected to grinding or hot melting treatment, reducing the thickness of this position to 1 mm or less, facilitating penetration of the draft tube 26 of the solute portion 2 (described later).

The push rod 17 may extend into the other end (rear end, lower end in fig. 3A) of the solvent portion cylinder 11, and may push the push rod 17 and the solvent portion second piston 14 to inject the solvent into the solute portion 2 (described later). The length of the push rod 17 may be 11-13 cm (3-5 cm longer than the length of the solvent section cylinder 11). The push rod 17 may be etched with graduations to precisely indicate the solvent injection dose. The material of the push rod 17 is preferably medical grade aluminum alloy material or aluminized polypropylene. Of course, the present application is not limited to the material thereof.

< solute portion 2>

Referring to fig. 4A, 4B, and 4C, in one embodiment of the present application, the solute portion 2 includes a solute portion cylinder 21 and a solute portion cap 22.

The outer diameter of the solute portion cylinder 21 may be the same as the outer diameter of the solvent portion cylinder 11. The inner diameter of the solute portion cylinder 21 may be the same as the inner diameter of the solvent portion cylinder 11.

One end (front end, upper end of fig. 4A) of the solute portion cylinder 21 may be provided with a stopper 23, a middle section of the solute portion cylinder 21 may be provided with a solute portion piston 24, and a sealed space formed by the stopper 23 and the solute portion piston 24 may store the solute 5, for example, a freeze-dried biological agent. Of course, fig. 4A, 4B, and 4C only schematically illustrate the location of the solute 5.

The front end of the solute portion cylinder 21 may be provided with an internal thread 211, the blocking body 23 may be provided with an external thread 233, and the blocking body 231 may be screwed with the front end of the solute portion cylinder 21.

The occluding body 23 may be partially connected to the solute portion cylinder 21 such that the occluding body 23 partially protrudes from the solute portion cylinder 21. The solute portion cap 22 may have internal threads 221 so that the solute portion cap 22 may be threadably connected to the occluding body 23. When the solute portion cap 22 is not provided, a portion of the blocking body 23 protruding from the solute portion cylinder 21 may be connected to the output portion 3.

The blocking body 23 may have a cylindrical structure, and an output pipe 231 and a cap 232 are provided at the center of one end (front end, upper end of fig. 4C) of the blocking body 23. After the occlusion body 23 is connected to the output part 3, substances such as medicines can be sent from the output pipe 231 to the output part 3 (described later). The output tube 231 may be a gradual diameter tube with a diameter smaller and smaller along the direction away from the plugging body 23, and a cap 232 is arranged at the orifice of the gradual diameter tube. The cap 232 may be an aluminum plastic film with a thickness of 1 mm, so as to facilitate penetration of the needle 332 of the output portion 3 (described later). The other end (rear end, lower end in fig. 4C) of the blocking body 23 is opened.

The outer diameter of the solute-portion piston 24 may be 1 to 2 mm larger than the inner diameter of the solute-portion cylinder 21. The material of solute portion piston 24 may be a low temperature resistant medical silicone rubber. Of course, the present application is not limited to the material thereof.

Referring to the cross-sectional views at the solute-side piston 24 shown in fig. 4A, 4C, an air vent 25 inclined (e.g., 45 °) may be provided in the solute-side piston 24. The inclination of the gas vent 25 may reduce the likelihood of leakage of solute 5 through the gas vent 25. The diameter of the air vent 25 may be 1 millimeter.

A flow guide 26 may be provided at the center of solute-piston 24. The shape of the draft tube 26 may be "J" type, and the draft tube 26 may have a straight portion 261 and a bent portion 262. The straight portion 261 may extend toward the rear end of the solute portion cylinder 21. After the solute portion 2 is connected to the solvent portion 1, the straight portion 261 may penetrate the portion to be perforated 16 of the solvent portion first piston 13, so that the solvent 4 can come to the storage position of the solute 5 of the solute portion 2 via the draft tube 26, and the solute 5 is redissolved. The end of the draft tube 26 may be tapered to enhance the piercing effect.

The bent configuration of the bent portion 262 can reduce the possibility of the lyophilized biological agent falling to other locations along the flow conduit 26, avoiding accidental loss of solute 5.

The flow guide 26 may have an inner diameter of 3-4 mm, an outer diameter of 3.5-5 mm, and a wall thickness of 0.5-1 mm. The material of the draft tube 26 is preferably polypropylene or polystyrene, although the material is not limited in this application.

The rear end of the solute portion cylinder 21 is provided with an internal thread 27, and the internal thread 27 is used for connecting with an external thread 15 of the front end of the solvent portion cylinder 11, so that the solute portion cylinder 21 and the solvent portion cylinder 11 can be connected together.

The side wall of the solute part cylinder 21 is provided with an opening, and an air permeable filter screen 28 is arranged at the opening. Further, in the axial direction of the solute portion 2, a gas-permeable screen 28 may be provided between the solute portion piston 24 and the female screw 27 of the solute portion cylinder 21.

When solvent enters between the solute piston 24 and the blocking body 23 from the flow guide pipe 26, the original gas between the solute piston 24 and the blocking body 23 is extruded and discharged through the air guide holes 25, and is thoroughly transferred out of the drug delivery device through the air permeable filter 28.

The material of the air permeable screen 28 may include Polytetrafluoroethylene (PTFE) or hydrophobic polyvinylidene fluoride (PVDF). Both the two filter membranes have the characteristics of smooth surface, ventilation and water impermeability, and can ensure the passage of gas and effectively block the outflow of liquid. Wherein the pore diameter (diameter) of the mesh may be 0.22 microns or 0.45 microns. The 0.22 micron or 0.45 micron is the pore size standard of the main flow filtration sterilization in the biomedical field, and can effectively prevent most of external microorganisms from entering.

The rear end of the solute portion cylinder 21 may be provided with a protective film 29. The protective film 29 may be an aluminum plastic film for covering the rear end opening of the solute portion cylinder 21 and the air-permeable screen 28 when storing the solute portion 2.

Referring to fig. 4C, illustratively, the encapsulation process of solute 5 is shown below.

Step 1: a protective film 29 is sealed at the rear end of the solute portion cylinder 21;

step 2: a solute 5 of a certain mass is added into the solute portion cylinder 21;

step 3: connecting one end of the blocking body 23 to the solute portion cylinder 21 so that the solute 5 is sealed;

step 4: the other end of the blocking body 23 is covered with a solute cap 22.

< output section 3>

Referring to fig. 5A, 5B, 5C, in one embodiment of the present application, the output 3 comprises a microneedle array, which may be used in a medical wound repair, deep transdermal uptake, etc. use scenario. Referring to fig. 6A, 6B, 6C, and 6D, in another embodiment of the present application, the output portion 3 includes a nanomicroneedle wafer, which may be used in situations such as medical beauty and medical epidermis repair where a lyophilized preparation such as an exosome, a polypeptide, or the like is transdermally taken in a shallow layer.

In another embodiment of the present application, the output 3 may be a disposable medical needle (not shown) for cell therapy.

In view of the separate and connectable arrangement between the output portion 3 and the solute portion 2, the output portion 1 can be conveniently selected and mounted, thereby enabling the drug delivery device to cope with more working scenarios.

Referring to fig. 5A to 6E, the output portion 3 is generally "J" shaped, including a bent head portion 31 and a body portion 32 extending in a straight line.

The body 32 includes a first body 321 and a second body 322 having different inner diameters. The inner diameter of the first body 321 may be the same as the inner diameter of the solute portion cylinder 21, and the first body 321 may be provided with an internal thread 3211, and the internal thread 3211 may be connected to an external thread 233 at the distal end of the occlusion body 23, so that the solute portion 2 and the output portion 3 may be assembled.

Referring to fig. 5C, the inner diameters of the first body portion 321 and the second body portion 322 may be different, and a stepped structure 323 is formed at the boundary of the second body portion 322 and the first body portion 321. Illustratively, the second body 322 may have an inner diameter of 10-11 millimeters.

A filter 33 may be disposed within the body 32. The filter 33 is provided with a 0.22 micron or 0.45 micron pore size polyethersulfone membrane or a 0.45 micron pore size hydrophilic polyvinylidene fluoride membrane.

Referring to fig. 5A and 5C, the filter 33 may include a filter cartridge 331 and a needle 332 connected to the filter cartridge 331. The filter element 331 may rest against the stepped structure 323. The filter membrane may be provided in the filter element 331, or the filter membrane may constitute the filter element 331. The needle 332 may comprise a split two-part structure disposed on both sides of the filter element 331 or be one structure disposed on only one side (e.g., the lower side of fig. 5A). The end of the needle 332 facing the second body portion 322 (also referred to as the liquid inlet end) may be beveled to sharpen it, facilitating piercing the cap 232 of the solute portion 2.

Referring to fig. 5C, the two sides of the filter core 331 may be closely fitted with a first rubber stopper 333 and a second rubber stopper 334 to form a rubber stopper-filter assembly. The diameter of the first rubber stopper 333 may be larger than the inner diameter of the first body 321, the diameter of the second rubber stopper 334 may be larger than the inner diameter of the second body 322, and the diameter of the filter core 331 of the filter 33 may be 13 mm, which is larger than the inner diameter of the second body 322. The inner diameter of the first body 321 may be larger than the inner diameter of the second body 322, so that the filter element 331 can be supported by a supporting force towards the liquid inlet end after being abutted against the step structure 323, and the position of the filter 33 is more stable. Of course, through holes may be provided in the first and second rubber plugs 333 and 334 so that the needle 332 can pass through the rubber plugs to directly contact the filter core 331. The liquid can enter the filter element 331 for filtration through the needle 332 at the liquid inlet end, and then enter the second body 322 from the needle structure at the other side of the filter element 331.

The dimensional and positional relationship of the above components allows the filter 33 to be securely fastened to the stepped structure 323, avoiding displacement of the filter 33 during normal transport, and avoiding displacement of the filter 33 under the thrust of the push rod 17 and liquid during operation of the device.

The end of the output part 3 where the first body 321 is located can be sealed and protected by a sealing protection part. The protection part may be a protection film 34, an end cover, a rubber plug, etc. Illustratively, the protective film 34 may be an aluminum plastic film.

The angle α of the axis of the end (front end) of the head 31 remote from the body 32 and the axis of the body 32 may be 90 ° or more and 150 ° or more, or other angles. Preferably 90 deg., increasing the comfort of the gripping operation.

The front end of the head 31 may be provided with external threads 311 for connection to other components (described below).

Referring to fig. 5A, 5B, and 5C, in one embodiment of the present application, the front end of the head 31 is provided with a sponge base 35, microneedles 36, a clip 37 with internal threads, and a sleeve 38.

The sponge base 35 may be oval in shape as a whole, and may have a minor axis of 2-3 cm and a major axis of 4-5 cm, so as to facilitate attachment to skin areas such as the corners of the eyes. Of course, the sponge base 35 may have other shapes such as a circular shape. The sponge base 35 may be a rigid polyvinyl alcohol medical grade microporous sponge and the liquid may pass from one side of the sponge base 35 to the other.

A plurality of microneedles 36 are arranged in an array on the sponge base 35 to be combined into a microneedle array. The clip 37 is fixedly attached to the outside of the sponge base 35. The clip 37 has an internal thread, and the clip 37 can be connected to the external thread 311 of the front end of the head 31 by means of the internal thread thereof, so that the sponge base 35 and the micro needle 36 are fixed to the front end of the head 31.

The housing 38 is used to protect the microneedle and the housing 38 may cover the outside of the collar 37 when the drug delivery device is not in operation (when the output 3 is not outputting solution). The material of the casing 38 may be polycarbonate, although the material is not limited in this application.

Referring to fig. 6A, 6B, and 6C, in another embodiment of the present application, the front end of the head 31 of the output part 3 is provided with a chassis 61, a nanomicroneedle wafer 62, a sponge 63, a collar 64 having internal threads, and a casing 65.

The material of the chassis 61 may be polypropylene. The chassis 61 may be provided with a flow hole 611 for liquid to pass through the chassis 61 to the sponge 63 and a mounting hole 612 for mounting the nanomicroneedle wafer 62. The liquid flow hole 611 may be a hole having a diameter of 1 to 2 mm. The chassis 61 may be elliptical in shape overall, with a minor axis of 2-3 cm and a major axis of 4-5 cm to facilitate attachment to skin areas such as the corners of the eyes. Of course, the cross section of the chassis 61 may be circular or other shapes.

The output 3 may include a plurality of nanomicroneedle wafers 62, the plurality of nanomicroneedle wafers 62 being secured to the chassis 61. Referring to fig. 6D, the nanomicroneedle wafer 62 may include a substrate 621 and nanomicroneedles 622 disposed on the substrate 621. The bottom surface of the base 621 may be square, triangular or other shape, and the side may be 3 mm. The substrate 621 is provided with, for example, 40×40 micro needles 622 to form an array. The effective height of the nanomicroneedles 622 may be 100-200 microns and the bottom side length may be 500-800 nanometers. The size of the tip may vary depending on the size of the solvent 4. For example, the size of the tips (e.g., diameter or side length at the tips) of the nanomicroneedles 622 may be set in the range of 50 nanometers to 160 nanometers.

The nanomicroneedles 622 on the same nanomicroneedle wafer 62 may be the same size. The material of the micro needle 622 is preferably porous silicon or copper plated polymethyl methacrylate.

A sponge 63 may be disposed around the nanomicroneedle wafer 62 on the base plate 61 such that the sponge 63 contacts the nanomicroneedle wafer 62. Sponge 63 may be a rigid polyvinyl alcohol medical grade microporous sponge.

The clamp 64 can fix the chassis 61, the nanomicroneedle wafer 62, and the sponge 63 into a combination. The clip 64 may be attached to the front end of the head 31 by means of internal threads thereof.

The housing 65 is used to protect the nanomicroneedle wafer 62 and the housing 65 may cover the outside of the collar 64 when the drug delivery device is not in operation (when the delivery unit 3 is not delivering solution to the outside). The material of the casing 65 may be polycarbonate, of course, the material of which is not limited in the present application.

The operational flow of the overall apparatus of the present application is described below by way of example.

Referring to fig. 7A, solute portion 2 is removed from, for example, a low-temperature storage environment, left standing at room temperature for a period of time (for example, 15 minutes), and protective film 29 is peeled off; removing the solvent portion cap 12 of the solvent portion 1; the solvent portion 1 and the solute portion 2 are butted.

Referring to fig. 7B, after the solvent portion 1 and the solute portion 2 are connected, the flow guide tube 26 of the solute portion 2 pierces the portion to be pierced 16 of the solvent portion first piston 13 of the solvent portion 1; pushing the push rod 17, the solvent 4 enters the storage position of the solute 5 through the flow guide pipe 26 to redissolve the solute 5. In this process, the solvent portion 1 and the solute portion 2 can be inverted, so that the possibility that the solute 5 falls into the solvent portion 1 is further reduced, and gas discharge is facilitated.

Referring to fig. 7C, push rod 17 is pushed to solvent portion second piston 14 beyond air permeable screen 28; turning over the solvent portion 1 and the solute portion 2, standing for a period of time (for example, 5 minutes) to ensure thorough dissolution of the solute 5; a solute portion cap 22 for removing the solute portion 2; tearing off the protective film 34 of the output part 3; the solute portion 2 is connected to the output portion 3, and the needle 332 of the output portion 3 pierces the cap 232 of the solute portion 2.

Referring to fig. 7D, the casing (e.g., casing 38 or casing 65) is removed and pushing on the push rod 17 continues to deliver solution to the output 3; the solution wets the sponge (e.g., sponge base 35 or sponge 63) at head 31.

Illustratively, the microneedle of the output part 3 may be closely attached to a target site such as the skin of the eye, and left for 3 to 5 minutes, and then moved to an adjacent site to perform the microneedle penetration after the completion of the microneedle penetration. In this process, the solution of lyophilized formulation, for example, impregnated in the sponge surrounding the microneedle or nanomicroneedle wafer, can be passed smoothly through the stratum corneum into the epidermis layer through the temporary holes formed by the previous microneedle penetration, and it will be appreciated that the push rod 17 can be pushed properly during this process. By continuously repeating the steps, the cycle of micro-needle puncture and transdermal ingestion of the freeze-dried preparation solution is formed, so that the freeze-dried preparation can continuously penetrate through the stratum corneum by means of the nano-scale temporary holes manufactured by each nano-micro-needle puncture, and the biological efficacy of the freeze-dried preparation can be exerted to the greatest extent.

The application has the advantages that:

1. the solute part and the solvent part are independently designed aiming at special preservation conditions such as freeze-dried biological preparations, so that the special requirements of freeze-dried preparation freeze preservation are met, and the combination of the types and the dosages of the solute and the solvent is flexibly diversified.

2. Aiming at the defects of complex structure and high manufacturing cost of the traditional microneedle system, the design generally adopts a simple structure and has low manufacturing cost. The novel combination of the microneedles and the sponge allows for consistent penetration and solution injection, shortening the handling time, and more consistent application of substances such as pharmaceuticals. The continuous process of the micro-needle penetration and the ingestion of the freeze-dried preparation is realized, the onset time of the freeze-dried biological preparation solution can be greatly shortened (the degradation risk is reduced), and the real absorption rate and the active efficacy of the freeze-dried biological preparation can be greatly improved.

3. The material of the breathable filter screen at the solute portion is systematically compared and optimized in the application. As shown in table 1 (the rear), the filter membrane of the air-permeable filter was air-permeable and impermeable, and effectively blocked the invasion of external microorganisms. Polytetrafluoroethylene (PTFE) or hydrophobic polyvinylidene fluoride (PVDF) filters are very suitable for gas filtration. A pore size of 0.22 μm or 0.45 μm effectively blocks most of the external microorganisms while corresponding gas flow rates are appropriate. According to the air-permeable filter screen, the air-permeable filter screen made of the materials is arranged, the air-permeable holes are additionally formed, and the problem of pneumatic layout during solvent injection is perfectly solved.

4. The present application also systematically prefers the material of the filter membrane in the output. The selection consideration of the filter membrane is concentrated on parameters such as liquid flow rate, chemical tolerance, mechanical strength, pore diameter, dissolution (secondary pollution), protein adsorption capacity and the like. After systematic comparison of various filter membrane materials in table 1, a 0.22 micron or 0.45 micron pore size Polyethersulfone (PES) filter membrane is preferred, and the filter membrane has strong tolerance to acid, alkali and organic components, and can be compatible with acid, alkali and organic components in any freeze-dried preparation; the mechanical strength is high, the flow speed is high, and the stable and smooth passing of the freeze-dried solution can be ensured; the adsorption force to key active factors such as protein in the solution is extremely low, and the loss of active ingredients of the freeze-dried preparation can be effectively avoided; the pore size of 0.22 microns or 0.45 microns can filter out microorganisms, so that the biosafety of the freeze-dried solution is ensured, and trace undissolved residual solutes can be effectively filtered out, so that the finally applied freeze-dried solution is in a completely dissolved liquid state. Hydrophilic polyvinylidene fluoride (PVDF) material filter membranes with 0.45 micron pore size can be selected, the hydrophilic polyvinylidene fluoride filter membranes have excellent characteristics similar to those of polyether sulfone filter membranes, and the pore size of 0.45 micron can also ensure a higher flow rate.

5. The combined type drug delivery device has simple structure, is easy to carry and hold, can be operated by one hand, and increases the usability.

The combined drug delivery device with the advantages has great application potential in the fields of medical diagnosis and treatment, medical plastic repair, alopecia recovery, cell therapy and the like.

Applicants have experimentally obtained comparative table 1 (table 1) of filter materials and parameters useful in the biochemical and biomedical fields, as follows.

Table 1:

note that: HPLC indicates liquid chromatography and NA indicates unknown.

The dimensional characteristics described above in this application are that all of A to B represent the end point values of the dimensions A, B, and that, for example, the radius r is A to B, and A.ltoreq.r.ltoreq.B. The pore size as previously described herein refers to diameter.

While the foregoing is directed to the preferred embodiments of the present application, it will be appreciated by those skilled in the art that changes and modifications may be made without departing from the principles of the present application, such changes and modifications are to be considered as within the scope of the present application.

Embodiments of the present application disclose the following.

The combination drug delivery device comprises a storage portion for storing a substance, the storage portion comprising:

the push rod can push the solvent portion second piston, the solvent portion first piston, and the solute portion piston in this order in a state where the solvent portion is connected to the solute portion.

In at least one embodiment, a flow guide pipe is provided in the solute portion piston, and in a state where the solvent portion is connected to the solute portion, the flow guide pipe is capable of piercing the solvent portion first piston so that the solute portion and the solvent portion communicate through the flow guide pipe.

In at least one embodiment, the draft tube includes a straight portion and a bend portion, the bend portion being located between the solute portion piston and the occlusion body.

In at least one embodiment, the solute portion piston is provided with an air vent penetrating through the solute portion piston, the side wall of the solute portion is provided with an opening, the opening is provided with an air permeable filter screen, the solute portion piston is positioned between the air permeable filter screen and the plugging body in the axial direction of the solute portion,

The gas between the solute part piston and the plugging body can be discharged out of the combined type drug delivery device through the gas guide holes and the gas permeable filter screen.

In at least one embodiment, the material of the air permeable screen comprises polytetrafluoroethylene or hydrophobic polyvinylidene fluoride, and the mesh openings in the air permeable screen have a diameter of 0.22 microns or 0.45 microns.

In at least one embodiment, the combination drug delivery device further comprises an output,

In at least one embodiment, a filter is arranged in the output part, the substances in the combined type drug delivery device are output to the outside of the combined type drug delivery device after passing through the filter,

the filter is provided with a polyethersulfone filter membrane with a mesh diameter of 0.22 micrometers or 0.45 micrometers, or

In at least one embodiment, the filter comprises a needle, the occluding body comprises a cap,

The needle is capable of piercing the cap in a state where the solute portion is connected to the output portion, and the liquid in the combination drug delivery device is capable of being output to the outside of the combination drug delivery device via the needle and through the filter.

In at least one embodiment, the solute portion comprises a solute portion cylinder, the blocking body is detachably connected to one end of the solute portion cylinder, and the blocking body partially protrudes from the solute portion cylinder,

the output portion may be connected to a portion of the occluding body protruding from the solute portion cylinder.

In at least one embodiment, the output comprises a sponge and a microneedle.

The combination drug delivery device with microneedle array comprises an output portion comprising:

a head;

the clamp is arranged on the head part;

a sponge base to which the clip is connected, the liquid in the combination drug delivery device being able to pass from one side of the sponge base to the other; and

the micro-needle array is arranged on the sponge base to form the micro-needle array.

In at least one embodiment, a filter is disposed in the body, and liquid in the combination dosing device is able to enter the head after passing through the filter.

In at least one embodiment, the sponge base is oval.

In at least one embodiment, the output portion includes a protection portion that is sealingly disposed at one end of the body portion.

In at least one embodiment, the output portion includes a housing that is mounted on the outside of the clamp.

a head;

the clamp is arranged on the head part;

the plurality of nanometer microneedle wafers are arranged on the chassis; and

In at least one embodiment, the chassis is oval.

Claims

1. A combination drug delivery device having a nanomicroneedle wafer, the combination drug delivery device having a nanomicroneedle wafer comprising an output portion comprising:

A head;

the clamp is arranged on the head part;

the plurality of nanometer microneedle wafers are arranged on the chassis; and

2. The combination drug delivery device with nanomicroneedle wafer according to claim 1, wherein the output portion further comprises a body portion extending along a straight line, the head portion is bent with respect to the body portion, an axis of an end of the head portion remote from the body portion forms an angle α with the axis of the body portion, and 90 ° or more α or less than 150 °.

3. The combination drug delivery device with nanomicroneedle wafer according to claim 2, wherein a filter is provided in the body, and liquid in the combination drug delivery device can enter the head after being filtered by the filter.

4. A combined drug delivery device having nanomicroneedle wafers according to claim 3, wherein the body comprises a first body portion and a second body portion having different inner diameters, the junction of the first body portion and the second body portion forming a stepped structure against which the filter abuts.

5. The combination drug delivery device with nanomicroneedle wafer of claim 4, wherein the second body is positioned between the first body and the head and the second body has an inner diameter that is smaller than the inner diameter of the first body.

6. The combination drug delivery device with nanomicroneedle wafer according to claim 3, wherein the filter comprises a filter cartridge comprising a filter membrane or the filter cartridge is constituted by the filter membrane,

7. A combined drug delivery device with nanomicroneedle wafer according to claim 3, wherein a polyethersulfone filter membrane with a mesh diameter of 0.22 or 0.45 microns is provided in the filter, or

8. The combination drug delivery device with nanomicroneedle wafer of claim 1, wherein the chassis is oval.

9. The combination drug delivery device with nanomicroneedle wafer according to claim 2, wherein the output portion comprises a protection portion provided in a sealed manner at one end of the body portion, the output portion comprising a housing provided outside the collar.

10. The combination drug delivery device with nanomicroneedle wafer of claim 1,

the nanometer microneedle wafer comprises a substrate and nanometer microneedles arranged on the substrate, wherein the nanometer microneedles are made of porous silicon or copper-plated polymethyl methacrylate.

11. The combination drug delivery device with nanomicroneedle wafer according to claim 1, further comprising a storage portion for storing a substance, the storage portion comprising: