Directional adjustment assemblies for in vivo deployment of temporary implants and uses thereof

Abstract

The invention provides a directional adjusting assembly used for deploying a temporary implant in vivo and application thereof.The directional adjusting assembly comprises a gravity adjuster used for carrying the implant and a capsule arranged on one side of the gravity adjuster, and a medicine carrying area is arranged on the side, away from the capsule, of the gravity adjuster; an exhaust hole which is communicated with the capsule body and can be plugged or opened is formed in the medicine carrying area, and the capsule body comprises a main capsule body, a first reactant containing cavity used for containing a first reactant and a second reactant containing cavity used for containing a second reactant; the main capsule body is separated from the second reactant containing cavity through a second soluble isolation device, the second reactant containing cavity is separated from the first reactant containing cavity through a first soluble isolation device, and the first reactant and the second reactant can react to generate gas. According to the directional adjusting assembly, accurate and rapid orientation can be achieved, and meanwhile rapid discharging out of the body can be achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a directional adjustment component for deploying a temporary implant in vivo and an application thereof. Background Art

[0002] In recent years, the global biopharmaceutical market has developed rapidly and has shown a trend of rapid growth. More and more biomacromolecule drugs have been developed for the treatment of infectious diseases, diabetes, tumors and other major diseases. However, there are some problems with biomacromolecule drugs. On the one hand, they have large relative molecular mass, complex structure and strong hydrophilicity, making it difficult to penetrate multiple biological barriers in the body; on the other hand, such drugs have poor stability and are easily metabolized and decomposed when they pass through the action of gastric acid, enzymes and enterohepatic circulation. The bioavailability of biomacromolecule drugs is very low in traditional oral and transdermal administration routes, which makes its current clinical administration form relatively single, mainly injection. Although injection can effectively improve the bioavailability of biomacromolecule drugs, it will cause discomfort, pain and fear to patients, and may even cause skin necrosis and infection at the injection site, thereby reducing patients' medication compliance.

[0003] Therefore, a new drug delivery system is urgently needed. Summary of the invention

[0004] The purpose of the present invention includes providing a directional adjustment component for deploying a temporary implant in the body and its application, which can quickly perform self-positioning while reducing the time it stays in the body.

[0005] The embodiments of the present invention can be implemented as follows:

[0006] In a first aspect, the present invention provides a directional adjustment component for deploying a temporary implant in the body, comprising a gravity regulator for carrying the implant and a capsule arranged on one side of the gravity regulator, a drug loading area being arranged on a side of the gravity regulator away from the capsule, a venting hole being arranged on the drug loading area and being connected to the capsule and being blockable or openable, the capsule comprising a main capsule, a first reactant holding chamber for holding a first reactant and a second reactant holding chamber for holding a second reactant, the main capsule and the second reactant holding chamber being separated by a second soluble isolation device, the second reactant holding chamber and the first reactant holding chamber being separated by a first soluble isolation device, the first reactant and the second reactant can react and generate gas.

[0007] In an optional embodiment, the material of the gravity regulator is at least one of polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polyglycolic acid-lactic acid copolymer (PGLA), polylactic acid-glycolic acid copolymer-polyethylene glycol block copolymer (PLGA-PEG).

[0008] And / or, the axial length of the gravity regulator is 2-5 mm, the length in the direction perpendicular to the axis is 5-16 mm, and the mass of the gravity regulator is greater than the mass of the capsule.

[0009] In an optional embodiment, the material of the capsule is at least one of polyurethane (PU), polyvinyl chloride (PVC), polyamide (PA), polyethylene (PE) and polyethylene terephthalate (PET);

[0010] And / or, after the first reactant and the second reactant react to generate gas, the height of the capsule is 10-20 mm.

[0011] In an optional embodiment, the first soluble isolation device is capable of dissolving under a first preset condition; the second soluble isolation device is capable of dissolving under a second preset condition;

[0012] and / or, the first soluble spacer dissolves before the second soluble spacer dissolves;

[0013] And / or, the second soluble isolation device is a device that isolates solids and liquids but is ventilated.

[0014] In an optional embodiment, the gravity regulator includes an upper layer of the gravity regulator and a lower layer of the gravity regulator fixed to each other, the capsule is provided with an opening, the opening is sleeved on the gravity regulator, and the capsule at the edge of the opening is fixed between the upper layer of the gravity regulator and the lower layer of the gravity regulator;

[0015] Or, the capsule is provided with an opening, the opening is sleeved on the gravity regulator, and a dissolvable elastic ring is sleeved on the opening to fix the capsule and the gravity regulator;

[0016] Alternatively, the gravity regulator is provided with an annular groove along the circumferential direction, the capsule body is provided with an opening, the opening is sleeved on the gravity regulator, and a clamping ring for clamping in the annular groove is provided on the capsule body at the opening.

[0017] In a second aspect, the present invention provides a self-orienting microneedle unit, comprising the directional adjustment component described in any one of the aforementioned embodiments and a microneedle base that can be separated from the gravity regulator, the microneedle base is located in the drug loading area and covers the outlet of the exhaust hole, and the microneedle base is provided with microneedles for drug loading.

[0018] In an optional embodiment, the material of the microneedle substrate is at least one of polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and polyacrylamide (PAM);

[0019] And / or, the method for preparing the microneedle substrate includes: solidifying a raw material liquid on the surface of the gravity regulator to form the microneedle substrate.

[0020] And / or, the microneedle includes a microneedle body and a drug loaded in the microneedle.

[0021] In an alternative embodiment, the drug comprises at least one of growth hormone, parathyroid hormone, an antibody, a chemotherapeutic agent, insulin, a glucagon-like peptide, an immunosuppressant, a vaccine, or an antiparasitic agent;

[0022] And / or, the microneedle is made of a degradable material;

[0023] And / or, the microneedle comprises a microneedle bottom and a microneedle tip, and the drug is loaded on the microneedle tip.

[0024] In a third aspect, the present invention provides a swallowable microneedle device, comprising: one or more self-orienting microneedle units according to any one of the aforementioned embodiments and a capsule for encapsulating the self-orienting microneedle unit.

[0025] In an optional embodiment, there are more than two self-orienting microneedle units, and the connected self-orienting microneedle units are separated by a partition;

[0026] And / or, the capsule is capable of dissolving under a third preset condition to release the self-orienting microneedle unit.

[0027] The beneficial effects of the directional adjustment component, self-directional microneedle unit and swallowable microneedle device for deploying a temporary implant in vivo provided by the embodiments of the present invention include:

[0028] In the present application, when the directional regulation component initially enters the body, the exhaust hole is blocked by the drug or drug-carrying substance in the drug-carrying area. After reaching the designated area of ​​the intestine, such as the colon, the first reactant and the second reactant can react and generate gas, so that the capsule and the gravity regulator together form a structure similar to a tumbler, which can quickly form a direction in the colon area. At the same time, the peristaltic contraction wave of the intestine can be used to squeeze the microneedles on the microneedle base against the inner wall of the intestine, and the microneedles penetrate the mucosa so that the carried drugs act on the inner wall of the intestine. Subsequently, the microneedle base and the gravity regulator are separated from the exhaust hole in the drug-carrying area to be exposed, so that the capsule is exhausted and quickly discharged from the body together with the gravity regulator. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0030] Figure 1 Schematic diagram of the structure of the self-orienting microneedle unit in this application (the capsule is not inflated);

[0031] Figure 2 Schematic diagram of the structure of the self-orienting microneedle unit in this application (capsule inflation);

[0032] Figure 3 It is a schematic diagram of the structure of the capsule in this application;

[0033] Figure 4 The mechanism of action of the self-directed microneedle unit in this application;

[0034] Figure 5 This is a schematic diagram of the first connection method between the capsule and the gravity regulator in this application;

[0035] Figure 6 for Figure 5 A partial schematic diagram of

[0036] Figure 7 This is a schematic diagram of a second connection method between the capsule and the gravity regulator in this application;

[0037] Figure 8 This is a schematic diagram of a third connection method between the capsule and the gravity regulator in this application;

[0038] Fig. 9 Schematic diagram of the structure of the microneedle and gravity regulator in this application;

[0039] Fig.10 This is a schematic diagram of the shape of the microneedle in this application;

[0040] Fig.11 This is a schematic diagram of the structure of the swallowable microneedle device in this application;

[0041] Fig.12 A schematic diagram of the working position of the swallowable microneedle device in this application;

[0042] Fig.13 Schematic diagram of the structure of the swallowable microneedle device of comparative example 1.

[0043] Icons: 100-self-oriented microneedle unit; 101-capsule; 102A-first reactant holding chamber; 102-first soluble isolation device; 102B-second reactant holding chamber; 103-second soluble isolation device; 107-exhaust hole; 108-gas; 104-gravity regulator; 104-1-upper layer of gravity regulator; 104-2-lower layer of gravity regulator; 101-1-capsule at the edge of the opening; 102-1-soluble elastic ring; 102-2-annular groove; 105-microneedle base; 106-microneedle; 106B-microneedle bottom; 106A-microneedle tip; 106D-drug; 200-capsule; 300-partition. DETAILED DESCRIPTION

[0044] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Generally, the components of the embodiments of the present invention described and shown in the drawings here can be arranged and designed in various different configurations.

[0045] Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, further definition and explanation thereof is not required in subsequent drawings.

[0047] In the description of the present invention, it should be noted that if the terms "upper", "lower", "inside", "outside", etc. appear to indicate an orientation or position relationship, they are based on the orientation or position relationship shown in the accompanying drawings, or are the orientation or position relationship in which the product of the invention is usually placed when used. They are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0048] In addition, the terms “first”, “second”, etc., if used, are merely used to distinguish between the descriptions and should not be understood as indicating or implying relative importance.

[0049] It should be noted that, in the absence of conflict, the features in the embodiments of the present invention may be combined with each other.

[0050] In order to improve the bioavailability of the biomacromolecule drug 106D, an implantable drug 106D delivery pump can be used, but it needs to be implanted semi-permanently and still has many limitations of intravenous injection. The use of a microneedle 106 device for delivering the drug 106D has the problem of difficult positioning and difficulty in directional insertion of the microneedle 106 into the intestinal wall. The conventional auxiliary directional adjustment device has limited directional ability on the one hand and difficulty in excretion on the other hand, and has a long retention time in the body.

[0051] To solve the above problems, the present invention provides a directional adjustment component for deploying a temporary implant in vivo, such as Figure 1-3 As shown, it includes a gravity regulator 104 for carrying an implant and a capsule 101 arranged on one side of the gravity regulator 104, a drug loading area is arranged on the side of the gravity regulator 104 away from the capsule 101, and an exhaust hole 107 which is connected to the capsule 101 and can be blocked or opened is arranged on the drug loading area, the capsule 101 includes a main capsule 101, a first reactant holding chamber 102A for holding a first reactant and a second reactant holding chamber 102B for holding a second reactant, the main capsule 101 and the second reactant holding chamber 102B are separated by a second soluble isolation device 103, the second reactant holding chamber 102B and the first reactant holding chamber 102A are separated by a first soluble isolation device 102, and the first reactant and the second reactant can react and generate a gas 108.

[0052] The above structure can realize the rapid orientation of the temporary implant, specifically, Figure 4As shown, at the initial stage of the directional adjustment component entering the body, the exhaust hole 107 is blocked by the drug 106D in the drug carrying area or the drug 106D material. After reaching the designated area of ​​the intestine such as the colon, the first soluble isolation device 102 and the second soluble isolation device 103 are dissolved, and the first reactant and the second reactant can react to generate gas 108. The gas 108 enters the capsule 101 to expand the capsule 101, so that the volume of the capsule 101 gradually increases, and together with the gravity regulator 104, a structure similar to a tumbler is formed, which can quickly form an orientation in the colon area, keep the drug carrying area always parallel to the direction of the intestine, and use the peristaltic contraction wave of the intestine to squeeze the drug carrying area against the inner wall of the intestine, so that the drug 106D carried in the drug carrying area acts on the inner wall of the intestine. The drug 106D carried in the drug loading area will separate from the intestine after acting on the inner wall of the intestine. At this time, the exhaust hole 107 located in the drug loading area will be exposed, allowing the gas 108 in the balloon 101 to be discharged through the exhaust hole 107. The volume of the airbag gradually decreases, which is conducive to the directional adjustment component to quickly pass through the intestine and be discharged from the body, and can shorten the retention time of the directional adjustment component in the body.

[0053] It should be noted that the first soluble isolation device 102 and the second soluble isolation device 103 can separate the capsules 101 on both sides by means of wires, rings, clamps, etc., wherein the separation standard of the first soluble isolation device 102 is that liquid cannot pass through, and the separation standard of the second soluble isolation device 103 can be that solids as the second reactant cannot pass through or only a small amount can pass through without affecting the deployment of the capsule 101. In some embodiments, the second reactant can be a solid and the first reactant can be a liquid.

[0054] The first reactant and the second reactant may include an acid and a base, but it should be noted that since they act on the intestines, the first reactant and the second reactant need to be safe and edible, and the generated gas 108 also needs to not affect human health. For example, the acid may be citric acid, and the base may be sodium bicarbonate or potassium bicarbonate, etc.

[0055] In an optional embodiment, the gravity regulator 104 is a degradable polymer, and its material can be at least one of polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), polyglycolic acid-lactic acid copolymer (PGLA), polylactic acid-glycolic acid copolymer-polyethylene glycol block copolymer (PLGA-PEG).

[0056] In an optional embodiment, the axial length of the gravity regulator 104 is 2-5 mm, and the length in the direction perpendicular to the axis is 5-16 mm, preferably 8-13 mm, and the mass of the gravity regulator 104 is greater than the mass of the capsule 101, which is beneficial to ensure that its center of gravity is biased downward, making it easier for it to reach the drug loading area in the intestine and quickly contact the intestinal wall.

[0057] The gravity regulator 104 can be formed by injection molding or casting, and is preferably circular in shape.

[0058] In an optional embodiment, the material of the capsule 101 is at least one of polyurethane (PU), polyvinyl chloride (PVC), polyamide (PA), polyethylene (PE) and polyethylene terephthalate (PET);

[0059] In an optional embodiment, after the first reactant and the second reactant react to generate the gas 108 , the height of the capsule 101 is 10-20 mm, which cooperates with the gravity regulator 104 to facilitate rapid orientation.

[0060] In an optional embodiment, the first soluble isolation device 102 can be dissolved under a first preset condition; the second soluble isolation device 103 can be dissolved under a second preset condition; specifically, the dissolution conditions of the first soluble isolation device 102 and the second soluble isolation device 103 can be the same, or they can be dissolved at different positions by utilizing environmental conditions (such as the pH difference between the proximal and distal ends of the intestine) so that the airbag can function, thereby achieving precise positioning and drug 106D delivery. However, since the first reactant and the second reactant only need to release a sufficient amount of gas 108 to prop up the airbag, the amount used is relatively small. In order to allow the first reactant and the second reactant to react quickly and fully, preferably, the first soluble isolation device 102 dissolves before the second soluble isolation device 103. After the first soluble isolation device 102 dissolves, the first reactant and the second reactant can react. The second soluble isolation device 103 dissolves after the reaction is completed or nearly completed, so that the second reactant holding chamber 102B is connected to the first reactant holding chamber 102A.

[0061] In an optional embodiment, the second soluble isolation device 103 is a structure that isolates solids and liquids but is ventilated, so that while the first reactant and the second reactant are kept in relatively full contact, the generated gas 108 can pass through the second soluble isolation device 103 as quickly as possible and be transferred into the capsule 101, thereby preventing the second reactant holding chamber 102B and the first reactant holding chamber 102A from being ruptured due to excessive gas 108.

[0062] In an optional embodiment, the gravity regulator 104 includes an upper layer 104-1 and a lower layer 104-2 of the gravity regulator fixed to each other, the capsule 101 is provided with an opening, the opening is sleeved on the gravity regulator 104, and the capsule 101-1 at the edge of the opening is fixed between the upper layer 104-1 and the lower layer 104-2 of the gravity regulator, such as Figure 5-6 The capsule 101-1 with the opening edge is fixed to the upper layer 104-1 of the gravity regulator by bonding or other optional methods.

[0063] In an optional embodiment, the capsule 101 is provided with an opening, the opening is sleeved on the gravity regulator 104, and a dissolvable elastic ring 102-1 is sleeved on the opening to fix the capsule 101 and the gravity regulator 104. Figure 7 shown.

[0064] In an optional embodiment, the gravity regulator 104 is provided with an annular groove 102 along the circumferential direction, and the capsule 101 is provided with an opening, the opening is sleeved on the gravity regulator 104, and a clamping ring for clamping in the annular groove is provided on the capsule at the opening, such as Figure 8 shown.

[0065] The present invention also provides a self-orienting microneedle unit 100, such as Figure 1-3 and Fig. 9 As shown, it includes the directional adjustment component described in any one of the aforementioned embodiments and a microneedle substrate 105 that can be separated from the gravity regulator 104, the microneedle substrate 105 is located in the drug loading area and covers the outlet of the exhaust hole 107, and the microneedle substrate 105 is provided with a microneedle 106 for drug loading.

[0066] After the airbag is filled with gas 108, it forms a tumbler-like structure together with the gravity regulator 104, which can quickly form an orientation in the colon area, keep the drug-carrying area and the microneedle base 105 always parallel to the direction of the intestine, and use the peristaltic contraction wave of the intestine to squeeze the microneedles 106 on the microneedle base 105 against the inner wall of the intestine, and the microneedles 106 penetrate the mucosa, so that the drug 106D carried by the microneedle base 105 acts on the inner wall of the intestine. Because the microneedle base 105 absorbs water in the intestine, the adhesion between the microneedle base 105 and the gravity regulator 104 gradually decreases. After the microneedle 106 penetrates the mucosa, while the microneedle is fixed, the intestine continues to peristaltic contraction. Under the action of external force, the microneedle base 105 is separated from the gravity regulator 104. At this time, the exhaust hole 107 located in the drug-carrying area is exposed, so that the capsule 101 is exhausted and quickly discharged from the body together with the gravity regulator 104.

[0067] The microneedle substrate 105 is responsible for supporting the fixation of the microneedle array 106 and providing reliable support for the precise insertion of the microneedle array 106 into the tissue. The shape of the microneedle 106 can be selected as needed, such as Fig.10 shown.

[0068] The microneedle 106 array contains a biological agent for treatment, which contains one or more of growth hormone, parathyroid hormone, antibody, chemotherapeutic agent, insulin, glucagon-like peptide, immunosuppressant, vaccine or antiparasitic agent;

[0069] In an optional embodiment, the material of the microneedle substrate 105 is at least one of PVA (polyvinyl alcohol), PVP (povidone), and polyacrylamide;

[0070] In an optional embodiment, the preparation method of the microneedle substrate 105 includes: solidifying the raw material liquid on the surface of the gravity regulator 104 to form the microneedle substrate 105. The microneedle substrate 105 prepared in this way has a certain adhesion to the gravity regulator 104, so that the microneedle substrate 105 and the gravity regulator 104 will not fall off before the microneedle 106 penetrates the mucosa, and can fall off after the microneedle 106 penetrates the mucosa. In some embodiments, water absorption holes can be set on the surface of the microneedle substrate to increase the water absorption rate of the microneedle substrate.

[0071] In an optional embodiment, the microneedle 106 includes a microneedle 106 body and a drug 106D loaded in the microneedle 106 .

[0072] In an optional embodiment, the drug 106D includes at least one of growth hormone, parathyroid hormone, antibodies, chemotherapeutic agents, insulin, glucagon-like peptide, immunosuppressants, vaccines or antiparasitic agents; the drug 106D is usually a biological preparation, but in some special cases, it can also be other types of drugs 106D.

[0073] In an optional embodiment, the material of the microneedle 106 is a degradable material; the microneedle 106 array is used for drug loading and intestinal tract penetration, and may be composed of one or more of degradable materials such as polyethylene glycol diacrylate, polylactide-co-lactide copolymer, PCL, hyaluronic acid (Hyaluronic acid, HA), PVA, hydroxypropyl cellulose and chitosan (Chitosan, CS), and is prepared by a molding process. The specific structure of the microneedle 106 may include a barb or no barb, and the shape may also be selected as needed.

[0074] In an optional embodiment, the microneedle 106 includes a microneedle base 106B and a microneedle tip 106A, and the drug 106D is loaded on the microneedle tip 106A.

[0075] The present invention also provides a swallowable microneedle 106 device, comprising: one or more self-orienting microneedle units 100 as described in any one of the above embodiments and a capsule 200 for encapsulating the self-orienting microneedle unit 100, such as Fig.11 shown.

[0076] Compressing the capsule 101 in the capsule 200 facilitates oral administration and greatly increases the drug loading capacity while preventing the self-oriented microneedle 106 units from being exposed to gastric juice.

[0077] In an optional embodiment, there are more than two self-orienting microneedle units 100, and the connected self-orienting microneedle units 100 are separated by a partition 300 to avoid adhesion of adjacent microneedles 106, wherein the partition 300 can be glutinous rice paper or the like.

[0078] In an optional embodiment, the capsule 200 can be dissolved under a third preset condition to release the self-oriented microneedle unit 100. At least a portion of the capsule 200 dissolves when exposed to a selected pH in the intestine to release the self-oriented microneedle unit 100, such as Fig.12 shown.

[0079] It should be noted that, in the embodiments of the present application, the first preset condition, the second preset condition, and the third preset condition may be the same or different, and are usually the pH of a specified position in the intestine. If the first preset condition, the second preset condition, and the third preset condition are the same, the dissolution time may also be adjusted by adjusting the material of the corresponding structure. For example, the first soluble isolation device dissolves faster than the second soluble isolation device, thereby achieving the purpose of dissolving the first soluble isolation device first and the second soluble isolation device later. Specifically, in some embodiments, the first soluble isolation device dissolves about 1 minute after the capsule is dissolved, and the second soluble isolation device dissolves about 5 minutes after the capsule is dissolved.

[0080] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0081] Examples 1-6

[0082] Embodiments 1-6 of the present application provide a self-orienting microneedle unit 100, such as Figure 1-6 , 9 and 11, comprising a cylindrical gravity regulator 104 (made of PCL) for carrying an implant, a capsule 101 (made of PU) disposed on one side of the gravity regulator 104, and a microneedle substrate 105 (made of PVA / PVP blend) that can be separated from the gravity regulator 104;

[0083] A drug loading area is provided on one side of the gravity regulator 104 away from the capsule 101, and an exhaust hole 107 which is connected to the capsule 101 and can be blocked or opened is provided on the drug loading area. The capsule 101 includes a main capsule 101, a first reactant holding chamber 102A for holding a first reactant, and a second reactant holding chamber 102B for holding a second reactant. The main capsule 101 and the second reactant holding chamber 102B are separated by a second soluble isolation device 103, and the second reactant holding chamber 102B and the first reactant holding chamber 102A are separated by a first soluble isolation device 102. The first soluble isolation device 102 dissolves earlier than the second soluble isolation device 103, and the first reactant and the second reactant can react and generate gas 108.

[0084] The gravity regulator 104 includes an upper layer 104-1 and a lower layer 104-2 of the gravity regulator fixed to each other, an opening is provided on the capsule 101, the opening is sleeved on the gravity regulator 104, and the capsule 101-1 at the edge of the opening is fixed between the upper layer 104-1 and the lower layer 104-2 of the gravity regulator;

[0085] The microneedle substrate 105 is located in the drug loading area and covers the outlet of the exhaust hole 107 . Microneedles 106 for drug loading are disposed on the microneedle substrate 105 .

[0086] The dimensions of the inflated bladder 101 and the dimensions of the gravity regulator 104 in each embodiment are shown in Table 1.

[0087] Comparative Example 1

[0088] The present comparative example provides a self-orienting microneedle unit 100, including a cylindrical gravity regulator 104 (made of PCL) for carrying an implant, a capsule 101 (made of 3D printing resin OBJ-04057, with a wall thickness of 1 mm) arranged on one side of the gravity regulator 104, and a microneedle substrate 105 (made of PVA / PVP blend) that can be separated from the gravity regulator 104, and no first reactant holding chamber 102A, second reactant holding chamber 102B, exhaust hole 107 and other structures are provided, as shown in the specific example. Fig.13 shown.

[0089] Table 1

[0090]

[0091] The self-orienting microneedle unit 100 in the above-mentioned embodiments and comparative examples was tested. The testing method is as follows. The test results are shown in Table 2.

[0092] Self-positioning time t1: The self-orienting microneedle unit 100 is placed on a stationary horizontal platform. In the initial state, the axis of the self-orienting microneedle unit 100 is along the vertical direction and the gravity regulator 104 is located above the capsule 101. A camera is used to record the process of their release until a stable state is reached, and each frame of the picture is exported to determine the self-orientation time.

[0093] Self-orientation accuracy rate p: 50 self-orienting microneedle units 100 are placed on a horizontal vibrator (70 rpm). The initial state of the self-orienting microneedle unit 100 is that the axis is along the vertical direction and the gravity regulator 104 is located above the capsule 101. The movement status after 10 seconds is recorded by a camera. If the axis is along the vertical direction and the gravity regulator 104 is located below the capsule 101, it is recorded as self-orientation, otherwise it is recorded as self-orientation failure, wherein the self-orientation accuracy rate p = (the number of microneedle 106 robots that successfully self-orient) / 50.

[0094] The depth d of microneedle 106 robot penetration into tissue: Cy5.5-labeled insulin was loaded on the microneedle tip 106A, and after the colon tissue was fixed for 10 minutes, the microneedle 106 punctured the colon tissue in vitro, and the puncture depth of the microneedle 106 was observed by confocal microscopy; the height of the microscope was adjusted to locate the position with the strongest fluorescence as the initial position of the microneedle 106 hole, and then the height was adjusted in the opposite direction to locate another position with the weakest fluorescence as the final position of the microneedle 106 hole.

[0095] Separation time t2: 1% (mass concentration) agarose gel was prepared to simulate the colon wall. The agarose gel was heated to completely dissolve and incubated at 60°C for 5 minutes, then introduced into a cell culture dish (35 mm in diameter) and kept at a height of 10 mm, and cooled to solidify. The self-oriented microneedle unit 100 was inserted into the gel, and PBS phosphate buffer (pH = 7.4) was slowly added to immerse the microneedle substrate 105, and incubated at 37°C shaker (60 rpm) for different times. The separation of the gravity regulator 104 and the microneedle 106 array was recorded using a camera to determine the separation time t2.

[0096] Excretion time t3: Pigs, whose digestive system has a physiological structure similar to that of the human body, were used as research subjects. However, since the peristalsis time of pig stomach is quite different from that of humans, a gastroscope was used to deliver the self-oriented microneedle unit 100 into the duodenum of the pig, and the time t3 when the self-oriented microneedle unit 100 was excreted from the body was recorded.

[0097] Table 2

[0098]

[0099]

[0100] The above description is only a specific implementation mode of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by a technician familiar with the technical field within the technical scope disclosed by the present invention should be covered within the protection scope of the present invention.

Claims

1. A directional adjustment assembly for deploying a temporary implant in vivo, characterized in that It includes a gravity regulator for carrying an implant and a capsule body arranged on one side of the gravity regulator, a drug loading area is arranged on the side of the gravity regulator away from the capsule body, and an exhaust hole connected to the capsule body and can be blocked or opened is arranged on the drug loading area, the capsule body includes a main capsule body, a first reactant holding chamber for holding a first reactant and a second reactant holding chamber for holding a second reactant, the main capsule body and the second reactant holding chamber are separated by a second soluble isolation device, the second reactant holding chamber and the first reactant holding chamber are separated by a first soluble isolation device, and the first reactant and the second reactant can react and generate gas.

2. The directional adjustment assembly for deploying a temporary implant in vivo according to claim 1, characterized in that: The material of the gravity regulator is at least one of PCL, PLA, PGA, PGLA, and PLGA-PEG; And / or, the axial length of the gravity regulator is 2-5 mm, the length in the direction perpendicular to the axis is 5-16 mm, and the mass of the gravity regulator is greater than the mass of the capsule.

3. The directional adjustment assembly for deploying a temporary implant in vivo according to claim 1, characterized in that: The material of the capsule is at least one of PU, PVC, PA, PE and PET; And / or, after the first reactant and the second reactant react to generate gas, the height of the capsule is 10-20 mm.

4. The directional adjustment assembly for deploying a temporary implant in vivo according to claim 1, characterized in that: The first soluble isolation device is capable of dissolving under a first preset condition; the second soluble isolation device is capable of dissolving under a second preset condition; and / or, the first soluble spacer dissolves before the second soluble spacer dissolves; And / or, the second soluble isolation device is a device that isolates solids and liquids but is ventilated.

5. The directional adjustment assembly for deploying a temporary implant in vivo according to claim 1, characterized in that: The gravity regulator comprises an upper layer and a lower layer of the gravity regulator fixed to each other, the capsule is provided with an opening, the opening is sleeved on the gravity regulator, and the capsule at the edge of the opening is fixed between the upper layer and the lower layer of the gravity regulator; Or, the capsule is provided with an opening, the opening is sleeved on the gravity regulator, and a dissolvable elastic ring is sleeved on the opening to fix the capsule and the gravity regulator; Alternatively, the gravity regulator is provided with an annular groove along the circumferential direction, the capsule body is provided with an opening, the opening is sleeved on the gravity regulator, and a clamping ring for clamping in the annular groove is provided on the capsule body at the opening.

6. A self-orienting microneedle unit, characterized in that: It comprises the directional adjustment component described in any one of claims 1 to 5 and a microneedle substrate that can be separated from the gravity regulator, the microneedle substrate is located in the drug loading area and covers the outlet of the exhaust hole, and the microneedle substrate is provided with microneedles for drug loading.

7. The self-orienting microneedle unit according to claim 6, characterized in that: The material of the microneedle substrate is at least one of PVA, PVP and PAM; And / or, the method for preparing the microneedle substrate comprises: solidifying a raw material liquid on the surface of the gravity regulator to form the microneedle substrate; And / or, the microneedle includes a microneedle body and a drug loaded in the microneedle.

8. The self-orienting microneedle unit according to claim 7, characterized in that: The drug comprises at least one of growth hormone, parathyroid hormone, antibody, chemotherapeutic agent, insulin, glucagon-like peptide, immunosuppressant, vaccine or antiparasitic agent; And / or, the microneedle is made of a degradable material; And / or, the microneedle comprises a microneedle bottom and a microneedle tip, and the drug is loaded on the microneedle tip.

9. A swallowable microneedle device, characterized in that: include: A self-orienting microneedle unit as described in any one of claims 6 to 8 and a capsule for encapsulating the self-orienting microneedle unit.

10. The swallowable microneedle device according to claim 9, characterized in that: There are more than two self-orienting microneedle units, and the connected self-orienting microneedle units are separated by partitions; And / or, the capsule is capable of dissolving under a third preset condition to release the self-orienting microneedle unit.

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