• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    The present invention relates to a precisely obtainable array of different microneedles, including a film having a first (22) and a second (24) outward facing main surfaces. the first outward facing main surface has a plurality of stratum corneum perforating microneedles extending therefrom, and the plurality of microneedles includes a plurality of first microneedles having a first beneficial agent and a plurality of second microneedles having a second beneficial agent.
    公开号:BR112019012728A2
    申请号:R112019012728
    申请日:2017-12-21
    公开日:2019-11-26
    发明作者:Patel Bharat；Morano Emanuel；Lunde Erik；Liu Jan-Joo；Alary Marc；Hopson Peyton
    申请人:Johnson & Johnson Consumer Inc；
    IPC主号:
    专利说明:

    Descriptive Report of the Invention Patent for MICRO-NEEDLE MATRICES AND METHODS OF PREPARATION AND USE.
    FIELD OF THE INVENTION [0001] The present invention relates to devices for the transdermal delivery of beneficial agents to patients through the skin. More particularly, this invention relates to microneedle arrays that comprise a plurality of beneficial agents, and methods for the production and use of such arrays.
    BACKGROUND OF THE INVENTION [0002] The transdermal application of drugs provides several advantages over other routes for administering a beneficial agent formulation to a patient. For example, oral administration of some beneficial agents may be ineffective because the beneficial agent is either destroyed in the gastrointestinal tract or eliminated by the liver, both of which are prevented by the transdermal release of the drug. Parenteral injection with a conventional hypodermic needle also has disadvantages, as it is often painful and inconvenient.
    [0003] The transdermal application of drugs avoids these problems. However, there are obstacles to its use. In particular, the physical barrier properties of the stratum corneum of human skin represent a significant challenge to the transdermal application of drugs. These barrier properties only allow relatively small molecules to be transported through the intact stratum corneum, and many useful drugs are too large to pass through the stratum corneum without any modification of the stratum corneum or other enhancement of transport. Several transdermal enhancement methods are known, including those based on iontophoresis, ultrasound and chemical penetration enhancers. However, these methods may be inadequate to assist in the release of many drugs through an intact skin layer
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    2/25 and / or may be inconvenient or undesirably complicated to use.
    [0004] To address the challenge of intact skin, a variety of drug delivery devices based on microneedle arrays have been developed. These known microneedle arrays generally fall into one of two design categories: (1) solid microneedle arrays with no active component, and (2) microneedles with a hollow central hole, which are similar to the conventional hypodermic needle.
    [0005] Solid microneedle arrays can precondition the skin by piercing the stratum corneum and the upper layer of the epidermis to improve percutaneous penetration of the drug before topical application of a biological vehicle or a traditional plaster. If the solid microneedle arrays are kept in the skin, then the drug cannot readily flow into and through the holes in the skin due to the fact that the holes remain closed by the microneedles. This method has been shown to significantly increase skin permeability; however, this method provides only the limited ability to control the dosage and quantity of drugs delivered or vaccine.
    [0006] To increase dosage control, some methods use solid microneedles with a drug-coated surface. Although this method provides slightly better dosage control, it greatly limits the amount of drug released. In addition, the deposition process is unreliable, and the thin layer of drug formulation on the microneedle could easily be removed from the microneedle during storage, transport or administration (insertion) of the microneedles. The application of a thicker and stronger layer of drug formulation may be undesirable because it reduces the sharpening of
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    3/25 microneedles and therefore makes insertion more difficult and painful. This gap has limited the widespread application of this approach and prevents, for example, the simultaneous application of optimal amounts of combinations of antigens and / or adjuvants in vaccine applications.
    [0007] Micro needles with a hollow central hole attached to a reservoir of beneficial agents are also known. The needle type characteristics of the syringe of these matrices can significantly increase the speed and accuracy of the application, as well as the quantity of the agent released. However, reservoir-based microneedle arrays are expensive to produce and require complex and expensive micro-machining procedures. In particular, it is difficult to make sharp points on hollow microneedles with machining techniques. Consequently, inserting microneedles into a patient's skin can be difficult and often painful. In addition, the central hole of the microneedle is very small and can be easily blocked by the skin tissue during the insertion process, thus blocking the drug delivery duct. It may be even slower than drug diffusion through the stratum corneum in the absence of the microneedle. Therefore, it would be desirable to provide a set of microneedles for drug application that avoids the disadvantages associated with known hollow microneedle array designs.
    [0008] The known methods also involve the use of solid microneedle arrays that are biodegradable, bioabsorbable or dissolvable. This method combines the physical toughness of solid microneedles with the relatively high capacity of the bioactive material, while retaining the desired attributes of manufacture, storage and simple application. Current manufacturing approaches for microneedles based on dissolvable polymer generally use micro-molding processes. For example, a
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    4/25 primary master mold is commonly produced using a combination of complex lithographic and laser engraving technologies. However, lithographic and laser technologies are limited in terms of the range of geometric features they can create, and the materials to which they can be applied. In addition, these highly complex manufacturing technologies do not allow for the rapid or low-cost manufacture of master molds, which can be particularly useful for systematic testing of the bioeffectiveness of several different microneedle geometries and matrices.
    [0009] Finally, the micro-molding process for the production of microneedle matrices based on dissolvable polymer is limited to the production of matrices with a single composition. If there is a desire for personalized treatment that requires dissolvable matrices using microneedles with different compositions or beneficial agents, the micro molding process cannot produce such matrices.
    [0010] In short, the transdermal release of beneficial agents using microneedle matrix-based devices offers attractive theoretical advantages over the prevailing methods of applying needle-based and oral drugs. However, there are considerable practical limitations in the design, manufacture and testing associated with microneedle arrays built using conventional processes. In addition, there is a need for a simple, effective and economically desirable device for transdermally administering the use of microneedle arrays that simultaneously release more than one beneficial agent.
    SUMMARY OF THE INVENTION [0011] Surprisingly, we have found that an array of different microneedles can be obtained precisely, including a film that has first and second main outward facing surfaces. The PRI
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    The main outward facing surface has a plurality of microneedles perforating the stratum corneum extending therefrom, and the plurality of microneedles includes a plurality of first microneedles having a first beneficial agent and a plurality of second microneedles. that has a second beneficial agent.
    BRIEF DESCRIPTION OF THE DRAWINGS [0012] Figure 1 is a perspective view of an embodiment of a microneedle array;
    [0013] Figure 2 is a cross-sectional view of a section of the microneedle matrix of Figure 1 taken along plane 2-2; [0014] Figure 3 is a top view of a section of the microneedle matrix of Figure 1;
    [0015] Figure 4 is a cross-sectional view of a section of a second modality of the microneedle matrix;
    [0016] Figure 5 is a cross-sectional view of a section of a third modality of the microneedle matrix;
    [0017] Figure 6 is a cross-sectional view of a section of a fourth modality of the microneedle matrix;
    [0018] Figure 7 is a cross-sectional view of a section of the microneedle matrix of Figure 6 after the microneedles have penetrated the patient's skin;
    [0019] Figure 8 is a cross-sectional view of a section of a fifth modality of the microneedle matrix; and [0020] Figure 9 is a cross-sectional view of a section of a sixth modality of the microneedle matrix.
    DETAILED DESCRIPTION OF THE INVENTION [0021] The present invention relates to devices for the transdermal administration of a plurality of beneficial agents to patients through the skin using microneedle matrix systems, and methods for the production and use of such systems . The description
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    6/25 below is presented to allow the person skilled in the art to produce and use the invention. Several changes in relation to the modalities and the principles and generic aspects described in this document will be readily apparent to those skilled in the art. Thus, the present invention is not intended to be limited to the modalities shown, but must be conceivable within the broadest scope consistent with the resources described here.
    [0022] As used here in the specification and in the claims, the term topical and variants of it mean applied to an isolated part of the body. This includes, without limitation, skin, mucosa and enamel, directly or through an intermediary such as a biofilm.
    [0023] As used here, beneficial agent means an ingredient or material that provides a benefit, for example, improves, relieves, reduces, or treats symptoms or conditions of the skin or body, cosmetic or therapeutic. Other terms of use for beneficial agent include biological agent, active component or bioactive material. These terms refer to pharmaceutically active agents, such as analgesic agents, anesthetic agents, antiasthmatic agents, antibiotics, antidepressant agents, antidiabetic agents, antifungal agents, antihypertensive agents, anti-inflammatory agents, antineoplastic agents, anxiolytic agents, enzymatically active agents , nucleic acid constructs, immunostimulating agents, immunosuppressive agents, vaccines and the like. The beneficial agent material may comprise dissolvable materials, insoluble but dispersible materials, natural or formulated macro, micro and nanoparticles, and / or mixtures of two or more dissolvable, insoluble dispersible and / or macro, micro and nano particulate materials and / or formulated.
    [0024] In some embodiments, the microcarrier matrix systems described here are flexible in order to conform to the three-dimensional format corresponding to the application site of the
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    7/25 beneficial agent to the consumer's skin. In other embodiments, the microneedle matrix may be more rigid; constructed as the three-dimensional shape described to correspond to the topical outline. The matrix can have several treatment zones specific to the customized area to allow the treatment to be applied more effectively. With a matrix adapted to the individual user's body part profile as physical guides, the application becomes easier and more effective, and can assist in locating specific target zones for the precise area for applications. [0025] With reference to the drawings, Figure 1 is a perspective view of an embodiment of a microneedle array 10 that can be used in the present invention. The microneedle array 10 includes a film 20 that has a first outward facing main surface 22 and the second outward facing main surface 24. The first outward facing main surface 22 has a plurality of coring layer microneedles perforating 30 extend from it. Each microneedle 30 has a proximal end 32 and a distal end 34, where the proximal end 32 is the end of microneedle 30 disposed on the first outwardly facing main surface 22 of a microneedle array 10.
    [0026] In Figure 1, the microneedle array 10 is shown with a rectangular projection area. The microneedle matrix film 20 may also have a variety of shapes, depending on the location of the skin treatment. The possible formats of the projection area left by film 20 include, but are not limited to, squares, rectangles, triangles, circles, ovals, reniforms, stars, crosses, characters etc. The corners of these shapes, if any, can be angled or curved to reduce the potential of lifting / removing points. The treatment area could be greater than about 1,000 cm 2 , about 1,000 cm 2 , or about 100 cm 2 , or about 10 cm 2 , or about 1 cm 2 , or less than 1 cm 2 .
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    8/25 [0027] The film element 20 of the microneedle array 10 is preferably relatively thin and flexible, so that they preferably adapt readily to the user's skin and are comfortable to use due to the flexibility and conformability, as well as, to its thin thickness. A microneedle array 10 of the present invention may be intended for extended use, preferably also being formed to be aesthetically elegant without peeling, wrinkling, cracking, or greasy or sticky appearance, or otherwise unpleasant or unattractive in nature . The microneedle array 10 is preferably formed with sufficient rigidity and integrity to be able to withstand normal use when on the skin. In some embodiments, the microneedle array 10 of the invention is preferably formed with sufficient strength to remain intact on the skin when exposed to normal external forces that the skin may experience, for example, from rubbing garments. [0028] In some embodiments, the first main surface facing outward 22 of the film 20 has an adhesive layer on it. The adhesive layer can be used to give the microneedle matrix 10 sufficient strength to remain intact on the skin when exposed to normal external forces. Other means of creating sufficient strength for the microneedle matrix 10 so that the matrix remains intact on the skin will be discussed below.
    [0029] Figure 2 is a cross-sectional view of a section of the microneedle array along the plane 2-2 of Figure 1. The Figure shows a plurality of first microneedles in the stratum corneum 30a and a plurality of second microneedles. coring stratum drilling rig 30a. Each microneedle 30a has a proximal end 32a and a distal end 34a, while each microneedle 30b has a proximal end 32b and a distal end 34b. The plurality of first microneedles 30a comprises a
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    9/25 first beneficial agent and the plurality of second microneedles 30b comprises a second beneficial agent.
    [0030] The dimensions of the microneedle needles in the stratum corneum 30a, 30b can vary depending on a variety of factors such as the type of beneficial agent to be released, the dosage of the beneficial agent to be released, and the desired depth of penetration. In general, the microneedle needles in the stratum corneum are built to provide skin piercing and beneficial agent release functions and, therefore, will be designed to be sufficiently robust to support the insertion and removal of the skin. Each microneedle has a length of about 1 micrometer (pm) to about 5,000 micrometers (pm), or about 1 pm to about 500 pm, or about 100 pm to about 500 pm. The penetration length of the microneedles into the biological barrier is about 50 pm to about 200 pm. In addition, each microneedle has a width of about 1 pm to about 500 pm. In addition, each microneedle has a thickness of about 1 pm to about 200 pm. The person skilled in the art will understand that the width and thickness of the microneedle piercing of the stratum corneum may vary along its length. For example, the base portion may be wider (thicker) than the body portion, or the body portion may have a slight taper when approaching the tip portion.
    [0031] Figure 3 is a top view of a section of the microneedle matrix of Figure 1. The Figure shows drilling microneedles of the stratum corneum 30 extending from the first main surface facing outward 22 of the microneedle matrix 10 Each microneedle 30 has a proximal end 32 and a distal end 34. As shown in the figure, microneedles 30 are arranged in a square pattern on the first main surface facing
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    10/25 out of the microneedle array 10. In other embodiments, microneedles 30 are arranged in other patterns, such as triangular, square, pentagonal, hexagonal, octagonal, etc.
    [0032] The microneedles 30 in the microneedle array 10 of the invention can also have a variety of lengths and geometries. Figure 4 is a cross-sectional view of a section of a second embodiment of the microneedle array. In this embodiment, the plurality of first coring layer microneedles 30a comprises a first beneficial agent and a plurality of second coring layer microneedles 30c comprises a second beneficial agent. In addition, a plurality of microneedles 30a extend from the first main surface facing outward 22 of the film 20 to a height of hi, while the second plurality of second microneedles 30b extend from the first surface 22 of the film 20 to an height of h2. In this embodiment, there may be a desire for deeper penetration into the user's skin for the first beneficial agent contained in the plurality of first microneedles 30a than the second beneficial agent contained in the plurality of second microneedles 30b.
    [0033] Although the Figure shows that the first piercing needles of the stratum corneum 30a have uniform height hi, while the second piercing needles of the stratum corneum 30b have uniform height h2, it should be understood that in other modalities, the microneedles may have any number of different heights. In addition, it is important to note that not all microneedles 30a are composed of a first beneficial agent, nor that all microneedles 30b are composed of a second beneficial agent. In some embodiments, some of the microneedles will not comprise any beneficial agent.
    [0034] In general, the microneedles for drilling the stratum corneum 30
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    11/25 can have any suitable elongated shape to provide perforation of the skin and release of the beneficial agent, with minimal pain for the patient. In various embodiments, an individual microneedle is substantially cylindrical, wedge-shaped, cone-shaped or triangular (for example, similar to a blade). The cross-sectional shape (cut along a plane approximately parallel to the flat substrate or approximately perpendicular to the longitudinal axis of the microneedle) of the microneedle, or at least the portion of the microneedle that is penetrable through the skin, can take a variety of shapes, including rectangular, square, oval, circular, diamond, triangular or star-shaped.
    [0035] The tip portions of the microneedle needles in the stratum corneum 30 are designed to pierce a biological barrier, for example, to pierce the stratum corneum of a patient's skin, to release beneficial agents to the patient's tissue. Preferably, the tip portion of each microneedle should be small and sharp enough to allow skin puncture and penetration with minimal pain. In a preferred embodiment, the individual microneedles 30 are tapered from the first main surface facing outward 22 of the microneedle array 10 to a distal point therefrom. In various embodiments, the tapered tip portion may be in the form of an oblique angle at the tip, or a pyramidal or conical or triangular shape.
    [0036] Figure 5 is a cross-sectional view of a section of a third microneedle matrix modality showing a variety of microneedle shapes for drilling the stratum corneum. The microneedle 30a has a conical shape, with a tapering from the proximal end 32a to the distal end 34a. The microneedle 30d has a cylindrical proximal end 32d, which tapers to a point at the distal end 34d. The microneedle 30e has a proximal end 32e and a distal end 34e, and has a wavy shape. The microneedle 30f has a cylindrical shape, without tapering the
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    12/25 proximal end 32f to distal end 34f. Finally, the microneedle 30g is pyramidal in shape, with a tapering from the proximal end 32g to the distal end 34g.
    [0037] Although Figure 5 shows all the microneedles of drilling of the stratum corneum 30 with substantially uniform height, it should be understood that, in other modalities, the microneedles can have any number of different heights. In addition, microneedles 30a, 30d, 30e, 30f and 30g comprise at least one beneficial agent. Some comprise a first beneficial agent, while others comprise a second beneficial agent, so that microneedle arrays 10 comprise microneedles with two distinct beneficial agents. Of course, not all microneedles 30 of any given shape or height are necessary for everyone to understand the first or second beneficial agent.
    [0038] The microneedle arrays 10 of the present invention can also comprise coring stratum microneedles 30 which comprise multiple compositions. Figure 6 is a cross-sectional view of a section of a fourth microneedle array modality 10 with such microneedles. The Figure shows four different microneedles, with the microneedles having varying heights, and comprising at least two distinct beneficial agents. The microneedle 30h has a cylindrical proximal end 32h, which tapers to a point at the distal end 34h. In addition, the proximal end 32h of the microneedle 30h has a different composition from the distal end 34h of the microneedle 30h. The microneedle 30i is cylindrical and has a core section 32i and a sheath section 34i. Here, core section 32i has a different composition than sheath section 34i. The microneedle 30j has a proximal cylindrical end 32j and a distal cylindrical end 34j, and is substantially linear in shape. Here, the proximal end 32j of the microneedle 30j has
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    13/25 a different composition of the distal end 34j of the microneedle 30j. Finally, the microneedle 30k has a conical shape, with a tapering from the proximal end 32k to the distal end 34k. The proximal end 32k of the microneedle 30k has a different composition from the distal end 34k of the microneedle 30k.
    [0039] Special attention is now given to the microneedle 30i. The microneedle 30i comprises a core section 32i and a sheath section 34i. The core section 32i has a different composition from the sheath section 34i. In some embodiments, the core section 32i does not have the mechanical strength or stiffness to penetrate the skin, while the hem section 34i does. In other embodiments, the sheath section 34i does not have the mechanical strength or stiffness to penetrate the skin, whereas the core section 32i does. Therefore, at least one of the sheath sections comprises a rigid composition. Therefore, materials / assets / drugs that are not strong enough to penetrate the skin can still be released.
    [0040] Special attention is now given to the microneedle 30j. The microneedle 30j has a cylindrical distal end 34j, and has a substantially linear starting shape. After insertion into the skin, the distal end 34j is designed to bend to form a hook-like structure or shape. As mentioned earlier, in some embodiments, the first main surface facing outward 22 of the film 20 has an adhesive layer on it to give the microneedle matrix 10 sufficient strength to remain intact on the skin when exposed to normal external forces. In some embodiments, the microneedle array 10 may have a plurality of microneedles that form hook-like structures. The hook-like microneedles 30j, since they penetrate the skin, may have sufficient strength to keep the microneedle matrix 10 intact on the skin during use.
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    14/25 [0041] The Figure also shows that the drilling microneedles of the stratum corneum have different lengths. In this embodiment, microneedles 30h and 30i extend from the first main surface facing outward 22 of the film 20 to a height of hi, the microneedle 30j extends from the first surface 22 of the film 20 to a height of h2, and the microneedle 30k extends from the first surface 22 of the film 20 to a height of hs. In this modality, there may be a desire for deeper penetration into the user's skin for the different beneficial agents.
    [0042] Although Figure 6 shows drilling needles of the stratum corneum 30 of different heights, it should be understood that, in other modalities, the microneedles can all have the same height, or any number of different heights. In addition, it is important to note that all microneedles 30 are neither comprised of a first beneficial agent nor a second beneficial agent. In addition, not all microneedles 30 are composed of multiple beneficial agents. In some embodiments, some of the microneedle needles in the stratum corneum will not comprise any beneficial agent.
    [0043] The different sizes, compositions and geometries of the microneedle needles in the stratum corneum are demonstrated in a prophetic use. Figure 7 is a cross-sectional view of a section of the microneedle matrix of Figure 6 after the microneedles have been positioned and have penetrated the patient's skin. The Figure shows skin tissue 50 with an outer surface 52. Under outer surface 52 is located epidermis 54, dermis 56, and layers 54 or subcutaneous or hypodermis. The first main surface facing outward 22 of the film 20 is in contact with the outer surface 52 of the skin tissue 50.
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    15/25 [0044] All 30h, 30i, 30j, and 30k microneedles penetrate the outer surface 52 and the epidermis 54. The 30h, 30i and 30j microneedles penetrate deeper into the dermis 56 than the 30k microneedle. In addition, since the proximal end 32h of the microneedle 30h has a different composition from the distal end 34h of the microneedle 30h, the composition of the distal end is deposited more deeply in the dermis than the proximal. The same is true for the 30j and 30k microneedles. Therefore, if there is a desire for personalized treatment at different depths of the skin, the microneedle arrays 10 of the present invention allow a degree of flexibility not available for microneedle arrays produced using the micro-molding process.
    [0045] In addition, as discussed earlier, the distal end 34j of the microneedle 30j is designed to bend to form an implanted hook-like shape upon insertion into the skin. The hook-type microneedle 30j may have sufficient strength to keep the microneedle matrix 10 intact on the skin during use. This may allow the first main surface facing outward 22 of the film 20 to be free of adhesive.
    [0046] In the modalities shown so far, the microneedle array 10 is shown flat. In some embodiments, the matrix may be curved. Figure 8 is a cross-sectional view of a section of a fifth microneedle matrix embodiment of the present invention. The microneedle array 100 includes a curved film 120 which has a first outward facing main surface 122 and a second outward facing main surface 124. The first outward facing main surface 122 has a plurality of coring layer 130 microneedles that extend from it. The Figure shows a plurality of first microneedles for drilling the es
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    16/25 horny tract 130a and a plurality of second microneedles of corneous stratum 130a. Each microneedle 130a has a proximal end 132a and a distal end 134a, while each microneedle 130b has a proximal end 132b and a distal end 134b. The plurality of first microneedles 130a comprises a first beneficial agent and the plurality of second microneedles 130b comprises a second beneficial agent. The proximal ends 132a, 132b are the end of the microneedle 130a, 130b disposed on the first outwardly facing main surface 122 of a microneedle array 100.
    [0047] Figure 8 shows the microneedle matrix 100 with a concave shape in relation to microneedle 130. Figure 9 is a cross-sectional view of a section of a sixth microneedle matrix embodiment of the present invention. In this embodiment, the microneedle array 200 has a concave and convex curvature within the array. The microneedle array 200 includes a curved film 220 that has a first outward facing main surface 222 and the second outward facing main surface 224. The first outward facing main surface 222 has a plurality of coring layer microneedles 230 that extend from it. As in all other embodiments, the microneedle array 200 comprises at least one first beneficial agent and a second beneficial agent.
    [0048] Although Figures 8 and 9 show matrices of curvilinear microneedles in one direction, the matrix can have multiple geometric axes of curvature in localized regions or in general. Other modalities may employ multiple geometric axes of curvature to format the microneedle matrix.
    [0049] The curved microneedle arrays conformed to their
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    17/25 body surface provide microneedles oriented in a normal direction to that surface. This provides better penetration of the microneedles and retention of the matrix for treatment.
    [0050] In preferred embodiments, the film 20, 120, 220, the microneedles for drilling the stratum corneum, 30, 130, 230, or both, are formed from, or coated with, a biocompatible material. The microneedles 30, 130, 230 can be formed from the same material used in the film 20,120, 220, or alternatively, the microneedles can include a material other than the film material. Representative examples of suitable building materials include metals and alloys such as stainless steels, palladium, titanium and aluminum; plastics such as polyether imide, polycarbonate, polyether ether ketone, polyimide, polymethylpentene, polyvinylidene fluoride, polyphenyl sulfone, liquid crystalline polymer, polyethylene terephthalate (PET), glycol modified polyethylene terephthalate (PETG) and polyimide; and ceramics like silicon and glass. The material is preferably selected so that the microneedle is strong enough in its projected dimensions for the microneedle to effectively pierce the skin without significant flexing or breaking of the microneedle. The microneedle and substrate materials must also be non-reactive with the drug formulation being applied by the microneedle matrix.
    [0051] In some embodiments, film 20, 120, 220, microneedles 30,130, 230, or both, are formed from biodegradable or bioabsorbable materials. Representative examples of suitable materials include, but are not limited to, formulations based on poly (lactic acid) (PLA), poly (glycolic acid) (PGA), polydioxanone (PDO), poly (epsilon-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), poly (orthoester) (POE), copolymer (ether-ester) (EEC), carboxymethylcellulose (CMC), or combinations of these materials.
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    18/25 [0052] The film 20, 120, 220, the microneedle needles of the stratum corneum 30,130, 230, or both, can optionally also include secondary construction materials embedded in them or applied as a coating on them. For example, microparticles, nanoparticles, fibers, fibrils, or other particulate materials can be included. These secondary materials can accentuate one or more physical or chemical characteristics of the microneedle matrix 10, 100, 200.
    [0053] In some embodiments, the microneedles for drilling the stratum corneum, 30,130, 230 are formed from biodegradable materials, while the film 20,120, 220 is not biodegradable. In these embodiments, the beneficial agent material may comprise dissolvable materials or insoluble, but dispersible materials. Therefore, the mechanism of release of the beneficial agent can be, for example, the simultaneous biodegradation of the microneedles with the dissolution or dispersion of the beneficial agent. The rate of microneedle degradation can be controlled to allow predetermined drug release rates of the beneficial agent. In some embodiments, the rate of release of the first beneficial agent could differ from that of the second beneficial agent. Once all the microneedles in the stratum corneum have degraded, the film 20,120, 220 can be removed from the treatment site.
    [0054] In another embodiment, several 30j hook-type microneedles may have sufficient strength to keep the microneedle matrix 10 intact on the skin during use. This may allow the first main surface facing outward 22 of the film 20 to be free of adhesive. In this embodiment, the proximal end 32j of the microneedle 30j has a different composition from the distal end 34j of the microneedle 30j. If the composition of the distal end 34j is biodegradable, the microneedle matrix 10 can be kept intact on the skin
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    19/25 until the distal end 34j of the hook-type microneedles 30j has degraded. At that point in time, the microneedle array 10 can be easily removed from the patient's skin.
    [0055] In some embodiments, the microneedle matrix 10 can be additionally coated with a beneficial agent, either on the microneedles alone or in combination with the substrate.
    [0056] Alternatively, the microneedles may have a desired surface structure, such as small directional ridges, to hold the microneedles in place. Beneficial agents can include lubricants, slip agents and the like. Alternatively, beneficial agents can provide one or more benefits to the target topical region. Such beneficial agents can be any of a variety of compositions, including, but not limited to, waxes, oils, emollients, moisturizers and the like.
    [0057] Beneficial agents may include hyaluronic acid; hydroxy acids (for example, glycolic acid, lactic acid, malic acid, salicylic acid, citric acid, tartaric acid); anti-acne agents (for example, salicylic acid, retinol, retinoids, or other keratolytic agents, and benzoyl peroxide, or other antimicrobial agents used to treat acne); gloss control agents (eg rice protein, cotton powder, elubiol (dichlorophenyl-imidazoltioxolane); a retinoid or its derivative, such as tretinoin, isotretinoin, motretinide, adapalene, tazarotene, azelaic acid, and retinol; an inhibitor of Amino acid 5-alpha reductase, for example glycine derivatives; hydrolyzed vegetable proteins, including soy protein and wheat protein, etc .; green tea extract (camellia sinesis) and cinnamon bark extract; moisturizers; antimicrobial agents (for example, cationic antimicrobials, such as benzalkonium chloride, benzethonium chloride, trichlorocarbon, polyhexamethylene biguanide, cetylpyridium chloride, methyl chloride and benzotonium; chlorhexidine salts,
    Petition 870190056841, of 19/06/2019, p. 38/51
    20/25 such as iodopropynyl butylcarbamate, diazolidinyl urea, chlorhexidine digluconate, chlorhexidine acetate, chlorhexidine isethionate, and chlorhexidine hydrochloride; halogenated phenolic compounds, such as 2,4,4'-trichloro-2-hydroxydiphenyl ether (Triclosan); parachloromethane xylenol (PCMX); short chain alcohols, such as ethanol, propanol and the like); antibiotics or antiseptics (mupirocin, neomycin sulphate bacitracin, polymyxin B, 1-ofloxacin, tetracyclines (chlorotetracycline hydrochloride, oxytetracycline 10-hydrochloride and tetracycline hydrochloride), clindamycin phosphate, hexamethylmethylamine, chloramethylamine phenol, quaternary ammonium compounds, teafoot oil, and their pharmaceutically acceptable salts and prodrugs), anti-inflammatory agents (for example, steroidal anti-inflammatory agents suitable as corticosteroids such as hydrocortisone, hydroxyltriamcinolone alpha-methyl dexamethasone, dexamethasone -phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, deoxymethasone, deoxorethasone acetate, dexamethasone, dichlorisone, diphlorasone diacetate, diflucortolone valerate, fluadrenolone, acetonide, fluconolone, fluclarolone, fluorochloride, fludrolone flucortina, fl uocortolone, fluprednidene (fluprednilidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, fluceton, fludrocortone, chlorudone, chlorudone, ammonium, fluoronehydrone, difluorone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluorometalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylproprionate, meprednisone, predionone, trietnamone, parametone, trietnamone, parametones, trietnamone , non-steroidal anti-inflammatory agents, feverfew (Tanacetum parthenium), goji berries (Lycium barbarum), milk thistle extract (Silybum marianum),
    Petition 870190056841, of 19/06/2019, p. 39/51
    21/25 amaranth oil (Amaranthus cruentus), thyme (Punica granatum), yerba mate leaf (Ilex paraguariensis leaf extract), white lily flower extract (Lilium candidum), olive leaf extract (Olea europaea) and floretine (apple extract)); antimycotic / antifungal agents (for example, miconazole, econazole, ketoconazole, sertaconazole, itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazene, haloconazole, nontoxine, soperconazole, halo , cyclopyroxolamine, terbinafine, amorolfine, naphthifine, elubiol, griseofulvin, their pharmaceutically acceptable salts and prodrugs; an azole, an allylamine, or a mixture thereof); external analgesics (for example, ibuprofen or diclofenac; capsaicin, fentanyl, and salts thereof, such as fentanyl citrate; paracetamol (as acetaminophen); non-steroidal anti-inflammatory drugs (NSAIDs) as salicylates; opioid drugs such as morphine and oxycodone; gel containing ibuprofen or diclofenac); antioxidants (for example, sulfhydryl compounds and their derivatives (for example, sodium metabisulfite and N-acetyl cysteine), lipoic acid and dihydrolipoic acid, resveratrol, lactoferrin; ascorbic acid, ascorbic acid esters, and ascorbic acid derivatives (eg ascorbyl palmitate and ascorbyl polypeptide); butylhydroxy anisol, butylated hydroxytoluene (butylhydroxytoluene), retinoids (eg retinol and retinyl palmitate), tocopherols (eg tocopherol acetate), tocotrienols , and ubiquinone; cysteine, n-acetylcysteine, sodium bisulfite, sodium metabisulfite, sodium formaldehyde sulfoxylate, acetone sodium bisulfite, tocopherols, and nordi-hydro-ariaric acid; extracts containing flavonoids and isoflavonoids and their derivatives (for example, genistein and diadzein); extracts containing resveratrol and the like; grape seed, green tea, pine cork, and propolis; polyphenol antioxidants derived from pl tapirs such as cloves, cinnamon, oregano, turmeric, cumin, parsley, basil, curry powder, mustard seed, ginger, pepper, chili powder, paprika, garlic, coriander, onion and cardamom;
    Petition 870190056841, of 19/06/2019, p. 40/51
    22/25 typical herbs such as sage, thyme, basil, tarragon, mint, oregano, savory, basil and dill leaf)); depilatory agents (for example, calcium thioglycolate, potassium thioglycolate); vitamins (for example, vitamin A, vitamin B, vitamin C, vitamin E; alpha, beta, gamma or delta tocopherols, niacin or niacinamide) and vitamin salts or derivatives like diglycoside ascorbic acid and vitamin E acetate or palmitate; sunscreen (for example, titanium dioxide) and / or sunscreens (for example, inorganic sunscreens such as titanium dioxide and zinc oxide; organic sunscreens such as octyl-methoxycinnamate, octyl salicylate, homosalate, avobenzone); vasodilators (for example, niacin); humectants (for example, glycerin); anti-aging agents (for example, retinoids; dimethylaminoethanol (DMAE), copper-containing peptides); alpha-hydroxide acids or fruit acids and their precursors, such as glycolic acid, citric acid, lactic acid, malic acid, mandelic acid, ascorbic acid, alpha-hydroxybutyric acid, alpha-hydroxy-isobutyric acid, alpha-hydroxy-isocaproic acid, atrolatic acid, alpha-hydroxy-isovaleric, ethyl pyruvate, galacturonic acid, glycoheptonic acid, glycoheptone 1,4-lactone, glyconic acid, gluconalactone, glycuronic acid, glucuronolactone, isopropyl pyruvate, methyl pyruvate, muscic acid, pyruvic acid , saccharic acid, 1,4-lactone saccharic acid, tartaric acid and tartaric acid; beta-hydroxy acids such as beta-hydroxybutyric acid, beta-phenyl-lactic acid and beta-phenylpyruvic acid; zinc and zinc-containing compounds such as zinc oxides; botanical extracts such as green tea, soybeans, milk, thistle, seaweed, aloe, angelica, bitter orange, coffee, Coptis herb, grapefruit, hoellen, honeysuckle, tears of our lady, seven-bleeding herb, blackberry, peony , pueraria, nice and saffron, and salts and prodrugs thereof); carotenoids, ceramides, fatty acids, enzymes, enzyme inhibitors, minerals, steroids, peptides, amino acids, botanical extracts, colorants, etc. Substances can affect the skin in any of a variety of ways, such as hydration; accentuation of the tone or color of
    Petition 870190056841, of 19/06/2019, p. 41/51
    23/25 skin (as pigments); treatment or at least mitigation of various skin problems (such as dry or severely dry skin, eczema, psoriasis, atopic dermatitis, allergic rashes, acne, blackheads, pustules, comedones, rosacea, shingles, herpes zoster, wrinkles, canker sores, herpes, corns, warts, sunburn, insect bites, nettles, etc.); application of mechanical force (such as shrinkage) to smooth out wrinkles; or, more generally, treatment or mitigation of symptoms and appearance of unwanted skin imperfections (such as dark circles, acne redness, fine lines and wrinkles, post inflammatory hyperpigmentation (PIH), redness, inflammation, cellulite, wrinkles, signs of age, pigment spots, dark spots, liver spots, puffiness under the eyes); removal of unwanted hair from the body or face; aid in healing wounds; etc. For example, lotions, creams, oils, and masks can be applied to the skin to treat or otherwise affect the skin. Such substances of personal care or health care intended for the consumer are absorbed by the skin, in general, following the principles of diffusion, in which the rate of diffusion or transport through the skin is related to the difference in the active concentration in both sides of the skin.
    [0058] As mentioned earlier, the micromachining or micro molding process for the production of microneedle arrays is limited to the production of arrays of a single composition. In the present invention, personalized treatment uses microneedles perforating the stratum corneum with more than one beneficial agent. Therefore, the micro-machining or micro-molding process cannot be used.
    [0059] The microneedle arrays of the present invention can be produced using additive manufacturing technology. Additive manufacturing is a group of techniques used to quickly manufacture a physical part or assembly using three-dimensional design data
    Petition 870190056841, of 19/06/2019, p. 42/51
    24/25 computer aided (CAD) · The construction of the part or assembly is usually done with the use of additive layer manufacturing technologies such as 3D printing. Additive manufacturing is a simple, effective and economical method for manufacturing microneedle arrays that simultaneously release more than one beneficial agent.
    [0060] In general, the computer aided design workflow - computer aided manufacturing CAD-CAM is the traditional additive manufacturing process. The process begins with the creation of geometric data, such as a 3D solid using a CAD workstation, or 2D slices using a digitizing device. For additive manufacturing, these data must represent a valid geometric model; specifically, one whose contour surfaces contain a finite volume, do not contain holes exposing the interior unless they are projected on the structure, and do not fold back on themselves. In other words, the object must have an interior. The model is valid if for each point in 3D space the algorithm can determine exclusively whether that point is inside, on or outside the contour surface of the model. CAD post-processors will approximate the internal geometric shapes of CAD with a simplified mathematical form which, in turn, is expressed in a specified data format, which is a common feature in additive manufacturing. To obtain the motion control trajectories necessary to activate the additive manufacturing mechanism, the prepared geometric model is typically cut in layers, and the slices are digitized in lines (producing a 2D drawing used to generate a trajectory as in the numerical control button computer), resulting in a layered physical construction process.
    [0061] The 3D printing process allows the creation of different sizes and formats of microneedles, as well as the production capacity
    Petition 870190056841, of 19/06/2019, p. 43/51
    25/25 make microneedle arrays with more than one beneficial agent. The location, sharpening, cavitation and material within the individual microneedles can be much more easily controlled with 3D printing than micro-machining or micro-molding. Soft materials, rigid materials and even liquids can be incorporated into individual microneedles. A change in the application profile can be designed in the system to produce an intelligent microneedle matrix. Incompatible compounds can also be embedded in different sections of the microneedle matrix without fear of cross-contamination.
    [0062] The microneedles need to release active ingredient / drug at least 100 microns or deeper, but can be designed to have a variable penetration at or above 20 microns. Different applications and uses would need different levels of penetration, solubility and design characteristics (size, shape, angle, solubility, etc.). In some cases, the beneficial agent can be dissolved in the microneedle material, while in others, it can be stored in a reservoir and released through a microfluidic channel in the microneedle.
    [0063] Although it is believed that what is shown and described are the most practical and preferred modalities, it is evident that certain discrepancies in relation to the specific designs and methods described and shown may present themselves to those skilled in the art and may be used without move away from the spirit and scope of the invention. The present invention is not restricted to the specific constructions described and illustrated, but must be interpreted in a cohesive manner with all modifications that may fall within the scope of the claims.
    权利要求:
    Claims (13)
    [1]
    1. Microneedle array, characterized by the fact that it comprises a film that has a first and a second main surface facing outwards, the first main surface facing outwards having a plurality of microneedles perforating the stratum corneum that extend to from thereon, and the plurality of microneedles includes a plurality of first microneedles having a first beneficial agent and a plurality of second microneedles having a second beneficial agent.
    [2]
    2. Microneedle matrix according to claim 1, characterized in that it additionally comprises an adhesive disposed on the first main surface facing outwards.
    [3]
    3. Microneedle array according to claim 1, characterized in that each of the plurality of microneedles has a height that extends from the first main surface facing outwards from about 1 micrometer to about 5000 micrometers.
    [4]
    4. Microneedle array according to claim 3, characterized in that the plurality of microneedles has a substantially uniform height.
    [5]
    5. Microneedle array, according to claim 3, characterized by the fact that the plurality of microneedles has variable heights.
    [6]
    6. Microneedle array according to claim 1, characterized by the fact that the individual microneedles are tapered from the first main surface facing outward to a point distal from it.
    [7]
    7. Microneedle array according to claim 1, characterized by the fact that the individual microneedles comprise at least one beneficial agent.
    Petition 870190056841, of 19/06/2019, p. 45/51
    2/2
    [8]
    8. Microneedle array according to claim 7, characterized by the fact that the individual microneedles comprise at least two distinct beneficial agents.
    [9]
    9. Microneedle array according to claim 8, characterized by the fact that at least one individual microneedle comprises a core section and a sheath section.
    [10]
    10. Microneedle array according to claim 9, characterized in that the core section of at least one individual microneedle comprises a rigid composition.
    [11]
    11. Microneedle array, according to claim
    1, characterized by the fact that at least one microneedle has a substantially linear initial shape, which extends substantially normal to the first outwardly facing main surface, and a second implanted shape in which a distal end curves into a hook shape.
    [12]
    12. Microneedle matrix, according to claim 1, characterized by the fact that at least one of the first and second beneficial agents is dissolved in the microneedle material.
    [13]
    13. Microneedle matrix, according to claim 1, characterized by the fact that at least one of the first and second beneficial agents is stored in a reservoir and released through a microfluidic channel in at least one microneedle.
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