Drug delivery device

Abstract

A layered drug delivery device comprising a polymeric tissue interface layer and a polymeric backing layer, wherein the polymeric tissue interface layer comprises at least one therapeutic agent.

Description

Technical Field

[0001] The present invention relates to drug delivery devices, and more particularly to layered drug delivery devices that can be placed against body tissue for the sustained and controlled delivery of one or more therapeutic agents, for example, to assist in wound healing and / or reduce pain.

Background Art

[0002] Any reference to known prior art in this specification does not, unless contrary indication is given, constitute an admission that such prior art was generally known to a person skilled in the art to which this invention pertains at the priority date of this application.

[0003] Recovery from surgery is often painful and can take a long time for the wound to heal. Pain and healing time can be exacerbated by postoperative bleeding. For example, in otolaryngology, the most common surgery is tonsillectomy. Pharyngeal pain remains the main cause of the condition in postoperative tonsillectomy patients and is associated with decreased oral intake, dysphagia, dehydration, and weight loss. Furthermore, postoperative bleeding as a result of these surgeries is associated with poor wound healing and mild infection. In extreme cases, these postoperative bleedings are severe and can lead to hypovolemic shock and death.

[0004] Typical methods of pain management include the intraoperative use of local anesthetics, paracetamol, opioid medications, and non-steroidal anti-inflammatory drugs (NSAIDs). However, each of these has limitations. The intraoperative use of local anesthetics is effective postoperatively but the effect only lasts for a short period (up to 8 hours), paracetamol alone is ineffective, systemic opioid medications cause sedation and respiratory depression, especially in pediatric patients, and the use of NSAIDs is associated with more severe bleeding in cases where bleeding occurs.

[0005] In addition, if medication compliance is insufficient, pain management and wound healing become difficult. Insufficient compliance leads to inappropriate pain management, which in turn results in serious medical conditions for the patient and unnecessary additional costs to the healthcare system. In particular, regardless of the analgesic regimen, cases continue to occur where pain and oral intake are not well controlled, and consultations are made with local physicians (general practitioners) and emergency departments. Summary of the Invention Problems to be Solved by the Invention

[0006] According to one aspect, the present invention attempts to address difficulties related to postoperative pain management, wound healing, and medication compliance. Means for Solving the Problems

[0007] In one broad form, the present invention provides a layered drug delivery device comprising a polymeric tissue interface layer containing at least one therapeutic agent and a polymeric backing layer.

[0008] In some forms, the tissue interface layer comprises a biopolymer and a second polymer. In some forms, the biopolymer is mucoadhesive. In some forms, the biopolymer is chitosan. In some forms, the second polymer is polycaprolactone.

[0009] In some forms, the backing layer or its sublayer is configured to prohibit the diffusion of the therapeutic agent therethrough. In some forms, the backing layer comprises any one or a combination of polycaprolactone, polysiloxane, PLLA, PLGA, and / or a copolymer of PLLA and PLGA.

[0010] In some forms, the layered drug delivery device further includes one or more additional release layers sandwiched between the tissue interface layer and the backing layer, each additional release layer including a polymeric spacing sublayer and a polymeric dosing sublayer containing at least one therapeutic agent, with the sublayers of each additional release layer arranged in an order such that each spacing sublayer is closer to the tissue interface layer than its respective dosing sublayer.

[0011] In some forms, the spacing sublayer of each additional release layer includes any one or a combination of PLLA, PLGA, and / or a copolymer of PLLA and PLGA. In some forms, the dosing sublayer of each additional release layer includes a biopolymer and a second polymer. In some forms, in the dosing sublayer, the biopolymer is chitosan. In some forms, in the dosing sublayer, the second polymer is polycaprolactone.

[0012] In some forms, one or more of the additional release layers are perforated. In some forms, the tissue interface layer is perforated.

[0013] In some forms, the layered drug delivery device is convex on the tissue interface layer side and concave on the backing layer side. In some forms, the device is shaped to be disposed against the wall of the tonsillar fossa.

[0014] In some forms, the layered drug delivery device is a patch or the like disposed against tissue in a treatment area.

[0015] In some forms, the layered drug delivery device is biodegradable. In some forms, the backing layer is configured to degrade more slowly than any other layer within the device.

[0016] In some forms, the layered drug delivery device is substantially porous. In some examples, the pore size of the device ranges from 200 nm to 600 nm. In some examples, the pore size of the device ranges from 6 μm to 60 μm. In some examples, the pore size of the device ranges from 60 μm to 120 μm. Typically, the pore size is configured depending on the thickness of each layer (i.e., small enough not to completely penetrate each layer in which the pores are present). In some forms, the backing layer or its sublayer is not substantially porous.

[0017] In some forms, at least one therapeutic agent includes an anesthetic. In some forms, at least one therapeutic agent includes a biomolecule. In some forms, at least one therapeutic agent includes an antibacterial agent. In some forms, at least one therapeutic agent includes an antifungal agent. In some forms, at least one therapeutic agent includes an antiviral agent. In some forms, at least one therapeutic agent includes a chemotherapeutic agent. In some forms, at least one therapeutic agent includes an immunomodulatory agent. In some forms, at least one therapeutic agent includes a cell growth or differentiation promoter. In some forms, at least one therapeutic agent includes a steroidal or non-steroidal anti-inflammatory agent.

[0018] In some forms, the tissue interface layer is substantially hydrophilic. In some forms, the backing layer is substantially hydrophobic. In some forms, the layer is continuous. In some forms, the layer is substantially planar.

[0019] In one further broad form, the present invention provides a layered drug delivery device comprising a polymeric tissue interface layer comprising at least one therapeutic agent, a polymeric backing layer, and one or more additional release layers sandwiched between the tissue interface layer and the backing layer, each additional release layer comprising a polymeric spacing sublayer and a polymeric dosing sublayer comprising at least one therapeutic agent, the sublayers of each additional release layer being arranged in an order such that each spacing sublayer is closer to the tissue interface layer than its respective dosing sublayer.

[0020] In some forms, the device includes at least two additional release layers. In some forms, the tissue interface layer is formed from a polymeric matrix in which a therapeutic agent is incorporated. In some forms, the dosing sublayer is formed from a polymeric matrix in which a therapeutic agent is incorporated. In some forms, the tissue interface layer includes a polymeric matrix formed from a blend of two or more polymers. In some forms, the tissue interface layer is formed from a blend of chitosan and PCL. In some forms, each dosing sublayer includes a polymeric matrix formed from a blend of two or more polymers. In some forms, the dosing sublayer is formed from a blend of chitosan and PCL.

[0021] In some forms, the spacing sublayer is configured to slow or delay the release of the therapeutic agent from the dosing sublayer. In some forms, the spacing sublayer is formed from a copolymer of PLLA and PLGA.

[0022] In some forms, the backing layer is configured to substantially prohibit the diffusion or permeation of the therapeutic agent therethrough. In some forms, the backing layer includes a layer of PCL. In some forms, the backing layer includes a sublayer formed from a copolymer of PLLA and PLGA and a sublayer formed from PCL, and the PCL sublayer is the outermost layer furthest from the tissue interface layer.

[0023] In some forms, the device is a patch configured to be fixed to the oropharynx. In some forms, the device includes an attachment portion that facilitates fixation to the treatment site.

[0024] In some forms, the tissue interface layer includes two or more continuous cast polymeric sublayers that interpenetrate each other. In some forms, the continuous cast sublayers of the tissue interface layer include chitosan. In some forms, adjacent sublayers interpenetrate each other by about 25-35% proportional to their widths.

[0025] In some forms, one or more intermediate layers are sandwiched between the tissue interface layer and the backing layer. In some forms, each intermediate layer comprises a polymer blend of two or more polymers. In some forms, one or more of the intermediate layers comprises at least one therapeutic agent.

[0026] In a further broad form, the present invention provides a method of treating a mid-pharyngeal wound, the method comprising the step of securing a device provided in any of the forms described herein to the wound. In a further broad form, the present invention provides a method of treating a tonsillectomy wound, the method comprising the step of securing a device provided in any of the forms described herein to the wound.

[0027] In a further broad form, the present invention relates to the use of a device provided in any one of the above forms in the treatment of a mid-pharyngeal wound or a tonsillectomy wound.

[0028] In a further broad form, the present invention provides a tissue interface for a drug delivery device, the tissue interface comprising two or more continuous cast polymer layers that interpenetrate each other. In some forms, the polymer layer is a chitosan layer.

[0029] Embodiments of the present invention are described in more detail below with reference to the drawings from which further features, embodiments, and advantages will be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0030]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35

Figure 36

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Embodiments of the present invention provide a layered drug delivery device that provides controlled and sustained delivery of therapeutic agents to surgical sites and other treatment sites. The device can have various uses including, but not limited to, pain management, wound healing, and / or treatment of tumors, inflammation, and infections. Embodiments of the device have specific uses for tonsillectomy patients, providing means for delivering a local anesthetic after tonsillectomy, promoting wound healing after tonsillectomy, and / or preventing post-tonsillectomy infection and / or bleeding.

[0032] Embodiments of the device include a polymeric tissue interface layer that contains at least one therapeutic agent and a backing (or support) layer. The backing (or support) layer is also typically polymeric. The tissue interface layer is the layer that is positioned against the tissue to be treated during use. The tissue interface layer can include one or more polymers and one or more sublayers. In some examples, the tissue interface layer includes two or more polymers. In one example, the tissue interface layer includes a biopolymer and a second polymer. For example, the tissue interface layer can include a polymer matrix formed from a mixture / blend of a biopolymer and a second polymer, with the therapeutic agent embedded / incorporated therein.

[0033] To facilitate the adhesion of the device to the mucosal tissue / site, the tissue interface layer may be mucoadhesive. Typically, the biopolymer of the tissue interface layer is mucoadhesive and may be, for example, chitosan. An example of the tissue interface layer is formed from a blend of chitosan and polycaprolactone (PCL).

[0034] In another example, the tissue interface layer may be formed from multiple successive cast sublayers of a polymer. For example, in one form, the tissue interface layer includes successive cast sublayers of chitosan. In one form, the chitosan sublayers overlap / fuse / interpenetrate with each other. In one example, they interpenetrate (as a percentage of width) by about 25 - 35%. An exemplary method for providing layer fusion / overlap is described by Example 3. In one example, the tissue interface layer includes four successive cast layers of chitosan that penetrate each other (i.e., having three overlapping / fused phases).

[0035] For the delivery of the therapeutic agent from the tissue interface layer to the treatment site, the therapeutic agent is typically diffused and / or released into the treatment area as the polymer matrix of the tissue interface layer degrades. The backing layer or its sublayer is generally configured to substantially prohibit the diffusion or permeation of the therapeutic agent therethrough in order to substantially prevent the leakage / progression of the therapeutic agent to tissues / regions other than the treatment site. The backing layer is typically formed from a polymer that degrades more slowly than that of the tissue interface layer (to avoid loss of the therapeutic agent away from the treatment site). In some examples, the backing layer may include any one or a combination of PCL, polysiloxane, poly-L-lactic acid (PLLA), poly-L-glycolic acid (PLGA), and / or a copolymer of PLLA and PLGA. The backing layer can be manufactured in some examples according to the methods described in Example 1 or 5.

[0036] Generally, a layered drug delivery device further includes one or more additional release layers sandwiched between a tissue interface layer and a backing layer. Each additional release layer includes a polymeric spacing sublayer and a polymeric dosing sublayer that includes at least one therapeutic agent. The sublayers of each additional release layer are arranged in an order such that each spacing sublayer is closer to the tissue interface layer than its respective dosing sublayer. Each spacing sublayer acts to slow or delay the release of the therapeutic agent from its respective dosing sublayer. For example, in use, when a therapeutic agent is released from the tissue interface layer, the spacing sublayer provides a temporary barrier that slows or delays the release from the adjacent dosing sublayer. To proceed to the treatment area, the therapeutic agent from the dosing sublayer typically diffuses through the spacing sublayer over time and / or is released when the spacing layer is sufficiently degraded.

[0037] In some examples, the spacing sublayer of each additional release layer includes any one or a combination of PLLA, PLGA, and / or a copolymer of PLLA and PLGA. The dosing sublayer of each additional release layer can be similar to the tissue interface layer and can include two or more polymers such as, for example, a biopolymer and a second polymer. In one example, in the dosing sublayer, the biopolymer can be chitosan and the second polymer can be PCL. In other examples, the dosing sublayer can include only a single polymer, for example, it can be formed primarily of chitosan. In some examples, the spacing sublayer and the dosing sublayer are each a substantially planar continuous polymer matrix. In some examples, the additional release layers and / or their sublayers can be made according to the method described in Example 1 or 4.

[0038] It is understood that the drug delivery profile and / or degradation profile of the device can be modified / configured by the selection of the polymers forming each layer / sublayer. Thus, the release kinetics of the device can be pre-engineered / configured for a particular indication / application. For example, it will be understood that different combinations / compositions of polymers will have different properties, such as layer degradation rate, drug release profile, diffusion properties. Thus, the device can be configured for application in different environments within the body. For example, the polymer / layer composition can be configured to degrade in the environment of the oropharynx, e.g., by salivary enzymes, at a pH such as that of the oropharynx (pH 4.0 - 6.0) or the oral cavity (pH 6.0 - 8.0).

[0039] It is understood that the polymer layers / sublayers of the device described herein can each be formed from one or more polymers, copolymers and / or polymer composites. It will also be understood that the layer or sublayer can be manufactured by a continuous cast layer.

[0040] In addition to those already mentioned, suitable polymers that can be implemented in the device include, but are not limited to, marine collagen, alginate, xanthan gum, cellulose, polydioxanone, polylactonone, polylactin, poloxamer, polyrthoesters, polyanhydrides, poly(ethylene-co-vinyl acetate), poly(methyl methacrylate), poly(vinyl alcohol), poly(N-vinylpyrrolidone), poly(acrylic acid), poly(2-hydroxyethyl methacrylate), polyacrylamide, poly(methacryl glycol), poly(ethylene glycol) (ethelene glycol).

[0041] When attempting to modify / configure the drug delivery profile, other parameters can be adjusted, including but not limited to the thickness of each layer / sub-layer, the porosity of the layer / sub-layer, the degree of overlap / interpenetration / mutual fusion between the layers and / or their sub-layers, the biodegradability of the layer / sub-layer, and / or the number of additional release layers sandwiched between the tissue interface layer and the backing layer.

[0042] Regarding the degree of overlap / interpenetration / mutual fusion between the layers and / or their sub-layers, this can offer the following advantages: - No damage due to layer-layer delamination; - There is a smoother drug release profile, i.e., fewer repeated administrations in the conventional dosing schedule of the therapeutic agent, etc., and more of a selected fixed dose, etc. This may be desirable in some situations and can lead to a shortening of the treatment time. The smoother release profile limits the short-term (potentially toxic) burst of the therapeutic agent experienced by the tissue and cells (fibroblasts / epithelial cells / etc.) at the device-tissue interface. This can help achieve rapid and high-quality wound repair tissue; and / or - Improvement of the degradation profile. Similarly, a more consistent degradation profile makes the results of the device more predictable and reduces breakage during administration.

[0043] Instead of a strict layer-layer interface, a device with an initial layer structure having different boundary phases (i.e., mutual fusion phases) on the tissue interface side aids in the growth of cells during wound healing. Cells such as fibroblasts can penetrate the device structure more easily. These cells move faster and fill the conventional wound voids more quickly, reducing the number required to cover the wound cavity. By doing so, less tissue is created in the healing process that subsequently requires further remodeling, such as that associated with wound plugs, etc.

[0044] Typically, during casting, the solvent properties can be configured such that during the making of a layer (e.g., of chitosan), it can penetrate an existing layer and create overlapping layers rather than a hard layer-layer interface. The depth of overlap or penetration is controlled by the relative solvent composition in the polymer solution used during solvent casting. In one example, the tissue interface layer is composed of a plurality of consecutive cast sub-layers of chitosan, and adjacent layers overlap up to about 1 / 3 of their width. Figure 28 shows an example of the mutual fusion phase (30) between adjacent chitosan layers.

[0045] In some examples, the tissue interface layer and / or one or more dosing sub-layers each have a thickness in the range of about 50 μm to about 100 μm, and in some examples, the tissue interface layer and / or one or more dosing sub-layers each have a thickness in the range of about 60 μm to about 80 μm. In some examples, the tissue interface layer and / or one or more dosing sub-layers each have a thickness in the range of about 60 μm to about 70 μm. In some examples, the spacing sub-layer has a thickness in the range of about 0.5 μm to about 3 μm, and in some examples, the spacing sub-layer has a thickness in the range of about 0.7 μm to about 2.8 μm. In some examples, the backing layer has a thickness in the range of about 5 μm to about 100 μm, and in some examples, a thickness in the range of about 10 μm to about 50 μm.

[0046] To facilitate adhesion to the treatment site, one or more of the layers / sublayers may be perforated / windowed / porous, such that new / healing tissue grows within or fully penetrates the perforations / windows / pores, thereby enabling the device to be anchored in place. An adhesive (e.g., tissue glue) or suture may be used initially to fix the device in place, or these may be the primary means of fixation. In some examples, the backing / support layer may be formed from a polymeric matrix that is robust enough to allow suturing. In some examples, the device may include an entire attachment portion (or “island”) and / or outer edge formed from a robust material / polymer configured to provide attachment points for suturing or adhering to the patient. For a patient after tonsillectomy, these attachment points may be adhered or sutured, for example, to the tonsillar pillars and / or tonsillar fossa floor, thereby typically enabling a strong enough fixation to resist forces such as swallowing. In one example, the attachment portion is formed from any one of a combination polymer selected from the group consisting of PLLA, PLGA, a copolymer of PLLA and PLGA, and PCL.

[0047] Typically, the backing or its sublayer may not be porous or may have minimal porosity, such that diffusion / leakage of the therapeutic agent from the dosing layer through / across the backing layer to regions other than the target treatment site may be substantially prohibited / restricted.

[0048] In some examples, one or more of the layers / sublayers, or the entire device, has a porosity or matrix void composition in the range of about 60% to about 90%. In some examples, the pore size is selected to facilitate lymphocyte infiltration, fibroblast proliferation, and / or invasion of new vasculature (without which wound healing is not optimal). In some examples, the minimum pore size is in the range of about 3 μm to about 7 μm. In some examples, the maximum pore size is about 500 μm. In some examples, the pore size is in the range of about 90 μm to about 130 μm. In one example, the spacing sublayer has a pore size in the range of about 250 μm to about 500 μm, and in some examples, about 274 μm to about 450 μm. In some examples, the therapeutic agent is disposed within the pores / matrix voids of the dosing sublayer and the tissue interface layer.

[0049] In some examples, it will be understood that the pore size is configured depending on the thickness of each layer (i.e., small enough not to completely penetrate each layer in which pores are present). It will also be understood that different layers can have different pore sizes. In some examples, the pore size of the device is in the range of 200 nm to 600 nm. In some examples, the pore size of the device is in the range of 6 μm to 60 μm. In some examples, the pore size of the device is in the range of 60 μm to 120 μm.

[0050] Layered drug delivery devices can take various forms and can be, for example, patches, inserts, implants, or meshes. It will be understood that the device can take a substantially planar or non-planar shape. The device is typically biocompatible and biodegradable, so it can decompose / dissolve over time and be absorbed by the body without adversely affecting the body. Degradation may be facilitated by naturally occurring enzymes such as those found in saliva, for example. In some examples, it will be understood that the device need not be completely biodegradable and may be removed after a certain period of time after the therapeutic agent has been administered. In such cases, for example, the backing layer does not biodegrade, and thus, the backing layer in such examples can be composed of any suitable material (including non-polymeric materials) if it is non-toxic. It will be understood that the degradability profile of the backing layer can be changed to suit the intended clinical use. For example, after the entire filled drug content has been delivered / released, degradation of the outer layer / backing layer of the device may be desirable, resulting in the elimination of the need to remove the oral device (the device degrades and becomes incorporated into the underlying tissue).

[0051] Generally, the device is placed at or against the treatment site, and in some examples, the device can be shaped / configured to conform to a particular treatment site, cavity, fossa, etc. In some embodiments, the device is convex on the tissue interface layer side and concave on the backing layer side. In some embodiments, the device is shaped to be placed against the wall of the tonsillar fossa.

[0052] The device is typically understood to be malleable so as to be conformable to the treatment site. In some examples, in order to facilitate bending and / or conforming to the treatment site (e.g., tonsillar fossa), the layers of the device may be configured to have different levels of hydrophobicity / hydrophilicity. For example, the tissue interface layer may be configured to be substantially hydrophilic, while the backing layer may be configured to be substantially hydrophobic, and thus, when placed at a treatment site such as the tonsillar fossa, the tissue interface layer absorbs water and expands to provide a curvature that better conforms to the fossa.

[0053] For example, cast polymer layers may have different water contents and different water uptake capabilities. This can be utilized in high humidity regions to not only improve mucoadhesion but also enable the device to self-mold to the surface / shape of the wound or tissue. This improves the surgeon's experience in handling the device and ultimately increases performance by assisting in providing the best possible coverage / contact at / with the wound site.

[0054] For example, a layer of only chitosan typically has high swellability, a blend layer formed from a combination of chitosan and PLLA / PLGA / PCL typically has moderate swellability, while a PLGA / PLLA / PCL layer typically has limited swellability.

[0055] It will also be understood that, depending on the nature of the device and the patient's anatomy, it can be trimmed / cut to the required size before and / or during insertion / surgery to better conform (e.g., pediatric patient vs. adult patient).

[0056] Drug delivery devices can contain a variety of different types of therapeutic agents, including, but not limited to, drugs, biomolecules, pharmaceutical compositions, and more specifically, anesthetics, antibacterial agents, antitumor agents, antifungal agents, antiviral agents, chemotherapeutic agents, immunomodulators, surfactants, silver and gold particles, steroid and non-steroid anti-inflammatory agents, growth factors, stem cells, cell proliferation or differentiation promoters, nucleic acids (e.g., DNA / RNA), peptides, proteins, or antigens for allergy desensitization therapy. Generally, in the treatment of postoperative pain, the therapeutic agent is an anesthetic. Examples of anesthetics include bupivacaine hydrochloride, lidocaine hydrochloride, ropivacaine hydrochloride, prilocaine hydrochloride, tetracaine hydrochloride, and benzocaine hydrochloride.

[0057] In one particular embodiment shown by the schematic diagrams of FIGS. 1-4, the present invention provides a layered drug delivery patch / insert that aids in pain management and wound healing after tonsillectomy. The patch / insert (1) is shaped to conform to the tonsillar fossa (100) and generally has an oval shape. The tissue interface side (2) is convex and the backing side (3) is concave.

[0058] The device is multilayered and includes a tissue interface layer (4), two additional release layers (5, 6), and a backing layer (7). The tissue interface layer (4) is formed from a mixture / blend of chitosan and polycaprolactone (PCL) and has one or more therapeutic agents (8, 9) (typically analgesics) disposed therein / incorporated therein. Each of the additional release layers (5, 6) includes a spacing sublayer (5a, 6a) and a dosing sublayer (5b, 6b). The dosing sublayers are also each filled with a therapeutic agent.

[0059] Similar to the tissue interface layer, the dosing sublayers are formed from a combination of chitosan and PCL. The spacing sublayers are formed from a copolymer of poly-l-lactic acid (PLLA) and poly-l-glycolic acid (PLGA).

[0060] It will be understood that the thickness of the layer / sublayer can be varied. In one example of this particular embodiment, the tissue interface layer and the dosing sublayer have an average thickness of about 65 μm, the spacing sublayer has an average thickness of about 2.6 μm, and the backing layer has a thickness of about 52 μm.

[0061] In typical use after tonsillectomy, the patch / insert (1) is placed in the tonsillar fossa over the treated wound / tissue area. The mucoadhesiveness of the tissue interface layer (2), particularly its chitosan component, aids in the adhesion of the device to the walls of the fossa (100). The greater flexibility and swelling of the chitosan-containing layer at the tissue interface promotes natural adhesion and expansion to conform to the specific surgical site.

[0062] Typically, the device (1) is sutured in place. Alternatively or additionally, in some cases, glue / adhesive can be used for adhesion to the treatment site. The perforations / windows (2a) within the tissue interface layer (2) also promote the growth of new tissue into the device and further contribute to securing the position within the fossa (100).

[0063] In typical use, after performing a tonsillectomy, the surgeon prepares the patch / insert / device (1) and places it in the tonsillar fossa. The patch / insert device can be provided in multiple sizes to accommodate variations in the dimensions of the tonsillar fossa among patients (e.g., pediatric patients vs. adult patients).

[0064] If necessary, the device can be trimmed to fit the tonsillar fossa. The device can be marked, for example, with a surgical marker, which can assist the surgeon in determining the exact size of the required device. Alternatively, an inert transparent plastic fitting guide can be used to mark the exact dimensions of the tonsillar fossa. The device is then cut to the appropriate dimensions accordingly.

[0065] Figures 5 and 6 show possible variants of the fixation method. Figure 5 shows an example of suturing around the outer edge (20a) of the device, which can be formed from a robust material / polymer (e.g., PLGA, PLLA, a copolymer of PLGA and PLLA or PCL). In this example, the device is typically sutured to the anterior and posterior tonsillar pillars and / or the adjacent mucosa. The surgeon can place the desired number of sutures to achieve proper fixation. In some forms, alternatively, a surgical glue / adhesive can be applied to the edge (20a).

[0066] In the method of Figure 6, the attachment portion or "island" (20b) is carefully localized using a suitable surgical glue and then the device is placed in the tonsillar fossa by applying a constant pressure until the glue sets and the adhesion is sufficient. Another variant may be provided where the glue is pre-incorporated into the polymer of the attachment portion / "island" during manufacture and activated by light energy to achieve adhesion to the underlying tissue. It will also be understood that combinations of these fixation methods can be utilized. The attachment portion / island is typically formed of a robust material / polymer (e.g., PLGA, PLLA, a copolymer of PLGA and PLLA or PCL).

[0067] Once fixed, the therapeutic agents (8, 9) from the tissue interface layer diffuse into and / or are released into the treatment area as the tissue interface layer degrades. The adjacent spacing layer (5a) from the adjacent additional release layer (5) provides a barrier that delays or slows the progression of the therapeutic agent from the adjacent dosing layer (5b) into the treatment area / site. The therapeutic agent from the dosing layer (5a) must diffuse through the spacing layer and / or is released when the spacing layer degrades sufficiently. In this regard, it will be understood how the additional release layers (e.g., 5, 6) provide a delayed pulse of the therapeutic agent to the treatment site and provide sustained controlled release of the therapeutic agent. In this example, there are two additional release layers (5, 6), and thus, after the initial burst from the tissue interface layer, two consecutive pulses of the therapeutic agent are provided to the treatment site. In other forms, it is understood that the device may include any number of additional release layers depending on the required dosing / release profile.

[0068] The backing layer (7) is configured to prohibit / limit the diffusion or permeation of the therapeutic agent from the treatment area to other areas of the oral cavity away from the treatment area. The backing layer (7) includes a sublayer formed from a copolymer of PLLA and PLGA and a sublayer of PCL that forms the outermost surface on the side of the device (1) that does not face the tissue.

[0069] By providing sustained and controlled release of the drug / therapeutic agent, the patient can avoid any dangerous / toxic spikes in the concentration of the administered drug / therapeutic agent by the device. Example 2 and FIGS. 9 and 11 show the release profiles achieved with the device according to this particular embodiment, where the therapeutic agents are lignocaine and bupivacaine. Corresponding to the release profiles, FIGS. 12 - 15 show the levels of the released therapeutic agent over time detected in the local lymph nodes and serum.

[0070] As a whole, the device (1) is formed of a polymeric material that is biodegradable and biocompatible, and over time, as it degrades, it is absorbed by the body without adverse effects. It should be understood that the composition / layers of the device are appropriately configured for the oropharynx such that they are preferably degraded by saliva (e.g., by salivary enzymes) and at the pH of the oropharynx (4.0 - 6.0) or the oral cavity (pH 6.0 - 8.0).

[0071] Similarly, it will be understood that the device (1) is configured for the oral / pharyngeal environment, i.e., to withstand interference from foreign objects (food), the tongue, or the larynx during swallowing. Copolymers of chitosan - PCL and PLLA with PLGA can be used as in the above examples to prevent device breakage during treatment due to their more robust strength characteristics. At the same time, chitosan blends can be included at the tissue interface as in the above examples to maintain the level of moisture interaction, flexibility, and softness necessary to prevent physical discomfort. In other forms, it will be understood that other suitable polymers can be used for the tissue interface layer and additional release layers.

[0072] Regarding the backing layer, protection from extreme moisture and an enzyme - dense system are required. Here, as in the above examples, copolymers of PCL and PLLA with PLGA can be used, which have a high degree of cross - linking, high resistance to degrading enzymes, and high hydrophobicity, thereby enabling the device to operate for a longer time without breaking. In other forms, it will be understood that the backing layer may be formed from other suitable polymers.

[0073] Until the active agent / therapeutic agent is released from within the polymer matrix (e.g., by layer degradation and / or diffusion through the layer), the drug / therapeutic agent is preserved and does not degrade from its active form. Figures 7 and 8 show examples of chromatograms of the released agents (lidocaine and bupivacaine) in an example demonstrating that the active form is preserved.

[0074] The device (1) and its layers can, in one example, be manufactured / fabricated according to the method described in Example 1. It will be understood that the devices described herein can be manufactured using a series of fabrication methods including injection molding, solvent casting, spray coating, spin coating, electrospray. In one example, injection molding of one or more layers can first be done using solvent casting, spray coating, or spin coating before subsequent layers are deposited thereon.

[0075] For tonsillectomy patients, embodiments of the device are the following means: - Means for delivering a local anesthetic to the tonsillar fossa to reduce or eliminate the condition of pain after tonsillectomy; - Means for enhancing the healing of the tonsillar fossa, promoting re-epithelialization, and reducing the risk of bleeding; - Means for providing a hemostatic agent to reduce / limit bleeding; - Means for providing a local antibacterial effect to prevent infection of the healing wound; and / or - Means for providing a physical barrier to the healing wound to prevent removal of the scab due to trauma, may be provided.

[0076] Thus, it will be understood that the device described in the present invention can improve the outcome of tonsillectomy patients by reducing the risk of bleeding after tonsillectomy, optimizing wound healing, and reducing postoperative pain. The continuous analgesic effect reduces the patient's aversion to diet after tonsillectomy, and thus reduces the risks of dehydration, weight loss, and nutritional disorders. This leads to a reduction in clinical dependence on opioids for adequate analgesia, as well as a reduction in the associated risks of sedation, respiratory depression, and death.

[0077] The above specific example relates to a device suitable for placement in the tonsillar fossa after tonsillectomy, but it will be understood that the devices described herein may be shaped / configured for other uses. For example, the device can be shaped for placement in other regions of the oral cavity, airway gastrointestinal tract, or paranasal ducts. Also, for example, the device can be used and the drug delivery profile adjusted for any number of surgical procedures including, but not limited to, lingual tonsillectomy, malignant and benign oral surgeries, pharyngeal and laryngeal surgeries, benign and malignant head and neck surgeries, uvulopalatopharyngoplasty, adenoidectomy, channeling of the base of the tongue, oral and salivary gland procedures, laryngeal surgery, cleft lip and palate surgery, thyroid surgery, skin wounds and / or dental procedures.

[0078] One particular further use relates to oral / mid-pharyngeal cancer / robotic surgery. Transoral robotic surgery is used, for example, in cancer ablation surgery of the larynx to perform complex minimally invasive surgical procedures precisely and accurately. These procedures leave the oral / pharyngeal wounds open with pain for secondary healing and are associated with risks of bleeding, aversion to oral intake, dehydration, poor wound healing, and infection, like tonsillectomy. Ablation wounds vary in size and dimensions based on the extent of tumor resection required.

[0079] In such applications, the device is typically multi-layered as described for tonsillectomy applications, but its physical form / shape can be individualized to fit the intended resection area. This can be achieved by mapping and templating with preoperative imaging and a device solvent cast to the specified dimensions. This iteration is customized to fit the contour of the defect rather than being precisely concave to fit the anatomical space of the tonsillar fossa. This iteration is mainly involved in the one-way release of local anesthetics, growth factors, or steroid drugs for pain control, promotes wound healing and re-epithelialization, and facilitates postoperative oral intake. Further, anti-tumor agents such as cisplatin or 5-fluorouracil can be delivered from the device postoperatively to treat microscopic disease or radiosensitize tissue to external beam irradiation, thereby reducing the required dose of radiation therapy or maximizing its effect.

[0080] Figures 35 and 36 show schematic views of extended transpharyngeal resection and transpharyngeal resection defects of tonsillar cancer, where the shape and contour of the device can be customized.

[0081] It will also be understood that the device is not limited to application at internal treatment sites (e.g., the mucosa of body cavities) and may also be configured to be positioned externally, for example, on the skin to treat external injuries such as trauma. It will also be understood that this device may also be suitable for treating other animals as well as humans.

[0082] A further broad embodiment of the present invention relates to a drug delivery device comprising a polymeric tissue interface layer, a backing layer, and optionally one or more intermediate layers sandwiched therebetween, containing at least one therapeutic agent. As described above, the drug release profile can be modified by appropriately configuring the layer arrangement, the number of layers, and the layer composition. The tissue interface layer can be formed, for example, from a plurality of continuously cast sub-layers that interpenetrate each other. In one example, they interpenetrate (as a percentage of width) from about 25% to 35%. In one example, the tissue interface layer is formed from a plurality of continuously cast layers of chitosan that interpenetrate each other. In one example, the tissue interface layer comprises four continuously cast layers of chitosan that penetrate each other (i.e., having three intermingled / overlapping phases). In one example, this form and other forms of the tissue interface layer can be fabricated according to Example 3. One or more of the intermediate layers can be formed from a blend of two or more polymers, such as any combination of two or more of chitosan, PCL, PLLA, PLGA, etc. Some or a plurality of the intermediate layers may contain at least one therapeutic agent. In one example, this form and other forms of the blend layer can be manufactured according to Example 4. The backing layer may or may not be a polymer, but is typically a polymer. In one example, the backing layer can be formed from any combination of two or more of chitosan, PCL, PLLA, PLGA. In one example, the backing layer of this embodiment and other embodiments can be manufactured according to Example 5. It will be understood that the therapeutic agent can be incorporated into the tissue interface layer and / or the intermediate layer by various techniques. According to Examples 3 - 5, the therapeutic agent may be added to the polymer solution prior to casting, or alternatively, as in Example 6, included as part of a polymer packet or encapsulated within the polymer packet (e.g., for stabilization to preserve the active form).

[0083] It is evident that the above-described layered drug delivery device offers several advantages over conventional methods for pain management and wound care. In particular, since the device adheres to the treatment site, there is no need to repeatedly administer the medicine orally. Instead, the therapeutic agent is automatically delivered stepwise or continuously according to a pre-engineered drug delivery profile. Thus, there are no issues regarding patient compliance. Furthermore, the patch-like nature of the device aids in wound healing, and the ability to deliver different types of therapeutic agents enables the delivery of antibacterial agents (and anesthetic agents), thereby reducing the risk of postoperative infection and related bleeding.

[0084] According to a further aspect, it will also be understood that the present invention provides a unique tissue interface for a drug delivery device. The interface typically comprises a plurality of interpenetrating polymer layers formed of chitosan.

[0085] According to a further aspect, it will also be understood that the present invention provides a unique method for treating oropharyngeal or tonsillectomy wounds by utilizing the device described herein.

[0086] Whenever used, the word "comprising" should be understood in its "open" sense, i.e., the sense of "including", and thus not in its "closed" sense, i.e., the sense of "consisting only of". The corresponding meaning shall be derived from the corresponding words "comprise", "comprised", and "comprises".

[0087] Although specific embodiments of the present invention have been described, it will be apparent to those skilled in the art that the present invention can be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments and examples of the present invention should be considered illustrative in all respects and not restrictive, and thus all modifications apparent to those skilled in the art are intended to be included therein.

Example

[0088] Device Fabrication Synthesis of Polycaprolactone / Chitosan Drug / Biomolecule Delivery Matrix (for Tissue Interface Layer and Dosage Layer) Pellets of polycaprolactone (Polycaprolactione) were immersed in a 10% v / v acetic acid and 50% w / v citric acid solution at a concentration of 5% w / v, heated to 100 - 120 °C, and mixed for 6 hours until dissolved. Then, the solution was diluted with deionized water to a concentration of 14 - 15% v / v, and chitosan (medium molecular weight) was added at a concentration of 1.25% w / v. After mixing at 100 - 120 °C for 2 hours, it was cooled and mixed for 48 hours. The resulting PCL - chitosan ratio was 1:2.

[0089] Synthesis of PLLA / PLGA Copolymer Mixture (for Backing Layer and Spacing Sub - layer) Poly(L - lactide) pellets were immersed in a 1 dichloromethane:12 chloroform solution at a concentration of 0.055% w / v and mixed at room temperature for 48 hours.

[0090] Synthesis of Polycaprolactone Barrier (for Outer Backing Layer) Pellets of polycaprolactone (Polycaprolactione) were immersed in acetic acid at a concentration of 10% w / v, heated to 100 - 120 °C, and mixed for 6 hours until dissolved.

[0091] Drug Incorporation An anesthetic agent such as butivacaine hydrochloride, lignocaine hydrochloride, ropivacaine hydrochloride, prilocaine hydrochloride, tetracaine hydrochloride, benzocaine hydrochloride, etc., but not limited to these, is mixed with a polycaprolactone-chitosan polymer blend at a concentration of 0.005% to 0.24% v / v at room temperature and left mixed for 24 hours.

[0092] Solvent casting method Starting from the backing layer, the PLLA / PLGA copolymer mixture is poured into a glass cast appropriately shaped at a volume ratio per surface area of 0.23 ml / cm at room temperature in an evaporation hood, and the solvent is evaporated for 24 hours. 2 and the solvent was evaporated for 24 hours.

[0093] The drug / biomolecule-loaded PCL-chitosan hydrogel is carefully poured onto the PLLA / PLGA backing layer at a volume ratio per surface area of 0.35 ml / cm at room temperature, covering the lower backing layer. Then, this hydrogel is placed at 37 °C in a temperature-controlled hood, and the solvent is evaporated for 48 hours. 2 covering the lower backing layer. Then, this hydrogel was placed at 37 °C in a temperature-controlled hood, and the solvent was evaporated for 48 hours.

[0094] This process is repeated two more times, and the subsequent PLGA / PLLA sublayer (spacer layer) is poured at a volume ratio per surface area of 0.06 ml / cm, and the PCL-chitosan layer is poured at a volume ratio per surface area of 0.35 ml / cm. 2 and the PCL-chitosan layer was poured at a volume ratio per surface area of 0.35 ml / cm. 2

[0095] To increase the rigidity of the backing layer, 0.1 - 0.2 ml of 10% v / v polycaprolactone in acetic acid can be placed on the concave surface of the device and dried at room temperature to increase the hardness and facilitate suturing (outer sublayer of the backing).

[0096] The window can be achieved by casting on a pre-shaped mold, whereby the polymer adheres around the mold and a windowed device is created.

[0097] ​As a result, a multilayer drug delivery device is obtained that includes a three-layer drug delivery PCL-chitosan matrix (tissue interface layer + two dosing sublayers) with a PLLA / PLGA copolymer intermediate layer (two spacer sublayers) to assist in controlling unidirectional drug delivery to the treatment site.

Example

[0098] Device analysis (Tonsillar application) The device manufactured according to the method of Example 1 was implanted into tonsillectomized pigs.

[0099] At 48, 120, 240, and 336 hours, samples were collected from sacrificed tonsillectomized pigs. At autopsy, the tonsil tissue at the bottom of the device was carefully excised, snap-frozen, and stored at -80 °C. Next, the tissue was cryogenically pulverized and a small amount (20 - 100 mg) was stored in individual Eppendorf tubes. Next, the samples were immersed in methanol for 24 hours to extract the drug in the tissue into the solvent, and the samples were centrifuged to separate the solid and liquid components. Next, the extracted fluid was analyzed using the following LCMS method.

[0100] HPLC analysis Each sample was analyzed using a highly sensitive and highly selective bioassay for bupivacaine and lignocaine by liquid chromatography-ion trap mass spectrometry (LC-MS-MS) to detect the drug concentration in the sample. The specific LCMS method used for the detection of bupivacaine and lidocaine has been validated in the study by Hoizey et al. (2005) (Hoizey G et al. Sensitive bioassay of bupivacaine in human plasma by liquid-chromatography-ion trap mass spectrometry. Journal of pharmaceutical and biomedical analysis. 2005;39:587 - 92).

[0101] Internal standard solution The method outlined by Hoizey et al. (2005) was used for the analysis of our samples. In line with this method, we repeated the validation in our institution to calibrate our machinery.

[0102] Bupivacaine and lignocaine (internal standard) hydrochloride were purchased from Sigma Aldrich Inc (Merck, Darmstadt, DE). All organic solvents and reagents were of analytical grade. Acetonitrile, diethyl ether, methanol, and formic acid were provided by Sigma Aldrich Inc. Purified water was prepared with a “Milli-Q” water purification device and confirmed to be free of signal interference from other ionic compounds or minerals.

[0103] Biological samples and internal validation Simulated saliva made from phosphate buffered saline (pH 7.0) containing human alpha amylase was used as a standard solution. These standard solutions were evaporated to dryness at 40 °C under a nitrogen stream, dissolved in 200 μL of 0.1% formic acid:acetonitrile (50:50 v / v), and 10 μL was injected into the LC column.

[0104] Calibration curve method Stock standard solutions of bupivacaine, lignocaine, and their respective internal standards (IS) were prepared at a concentration of 1 mg / mL in methanol and stored at +4 °C. These were further diluted in methanol to obtain appropriate dilution standard solutions for the preparation of calibration solutions. Standard curves were created with blank simulated saliva (100 μL) such that final concentrations of 3.90, 7.81, 15.63, 31.25, 62.5, 125, 250, and 500 μg / L were obtained. Once this method could be reliably repeated, the tests were advanced to the experimental samples.

[0105] Qualitative sample analysis (Figures 7 and 8) Qualitative sample analysis (or Q1 test) was performed on the selected samples, and it was confirmed that a single spike was detected at a frequency consistent with the calibration curve and no secondary spike was detected (indicating LCMS detection of a single molecule without decomposition products).

[0106] Quantitative sample analysis (Figures 9 - 15) Each sample was analyzed using a highly sensitive and highly selective bioassay for bupivacaine by liquid chromatography - ion trap mass spectrometry (LC - MS - MS) to detect the drug concentration in the sample. The specific LCMS method used for the detection of bupivacaine and lidocaine has been validated in the study by Hoizey et al. (2005).

[0107] Figures 9 and 10 represent the bupivacaine and lignocaine levels detected by the described LCMS method in porcine tonsil tissue collected at necropsy at 0, 48, 120, 240, and 336 hours. Bupivacaine levels are expressed in micrograms and lignocaine levels are expressed in nanograms. These release kinetic curves demonstrate the controlled sustained release from the device described in Example 1 to the tonsil tissue interface.

[0108] Figure 11 represents the cumulative percentage release of bupivacaine and lignocaine detected by the described LCMS method in porcine tonsil tissue collected at necropsy at 0, 48, 120, 240, and 336 hours. These release kinetic curves demonstrate the controlled sustained release from the device described in Example 1 to the tonsil tissue interface.

[0109] Figures 12 and 13 represent the bupivacaine and lignocaine levels detected by the described LCMS method in porcine lymphoid tissue collected from the anterior jugular chain at necropsy at 0, 48, 120, 240, and 336 hours. The bupivacaine levels and lignocaine levels are expressed in nanograms per milligram of lymphoid tissue. These release kinetic curves demonstrate that the safety levels of the drugs detected in the local tissue area are well below the toxicity levels of 4 micrograms per milliliter (bupivacaine) and 5.6 micrograms per milliliter (lignocaine).

[0110] Figures 14 and 15 represent the levels of bupivacaine and lignocaine detected by the described LCMS method in porcine serum collected from the internal jugular vein at 0, 1, 2, 4, 24, 48, 72, 120, 240, 336 hours. The bupivacaine levels and lignocaine levels are expressed in nanograms per milliliter of serum. These release kinetic curves demonstrate that the safe systemic uptake of the drugs detected is well below the toxicity levels of 4 micrograms per milliliter (bupivacaine) and 5.6 micrograms per milliliter (lignocaine).

[0111] Scanning electron microscope Figures 16 and 17 show scanning electron microscope (SEM) images of the device of Example 1 at magnifications of 100 times and 250 times, respectively. The images show the profile of the device, where A represents the interfacial layer between the drug-loaded polycaprolactone-chitosan.

[0112] In Figure 16, B represents the backing or "lumen" surface of the device made of PLLA:PLGA with a polycaprolactone outer layer to inhibit drug release into the oral / mid-pharynx. In Figure 16, C represents the intermediate layer made of PLLA:PLGA, which is designed to slow down drug release from the backing layer to the interfacial layer.

[0113] In FIG. 17, B represents an intermediate drug delivery layer of PCL / chitosan designed to deliver secondary and tertiary pulses of drug delivery unidirectionally towards the interface layer. In FIG. 17, C represents an intermediate layer made of PLLA:PLGA, which is designed to slow down the drug release pulse from the intermediate layer to the interface layer, thereby achieving controlled sustained release of the therapeutic agent.

[0114] Surgical analysis FIG. 18 shows an intraoral view of the device described in Example 1 positioned at the porcine tonsillectomy wound during implantation. The animal is in the supine position, and a tonsillectomy retractor is positioned for access to the mid-pharynx. A is the device with a backing layer visible on the side within the lumen. B is a component of the wound created by the tonsillectomy. C is the hard palate.

[0115] FIG. 19 shows an intraoral view of the device described in Example 1 sutured to the porcine tonsillectomy wound 5 days after implantation. The animal is in the supine position, and a tonsillectomy retractor is positioned for access to the mid-pharynx. The device remains adhered to the wound on day 5. A is the device with a backing layer visible on the side within the lumen. B is the adjacent tonsil tissue. C is the tongue retracted by the tongue depressor.

[0116] Tissue image FIGS. 20 - 27 show the tissue response at the device-tissue interface. These slides were prepared from tissues collected from porcine tonsillectomy samples at autopsy at time points of 48, 120, 240, and 336 hours. The entire tonsillectomy wound including the underlying muscle was excised together with the implant and fixed in 10% formalin. The samples were sliced perpendicular to the plane of device positioning to obtain cross-sectional images of the device including the underlying tissue. Each slide was prepared using the H+E staining technique.

[0117] FIG. 20 is a tissue image slide of the tissue-device interface at 48 hours. Initial granulation tissue (B) at the interface. Mucosa (A) adjacent to the tissue / polymer interface.

[0118] Figures 21 and 22 are slide images of the tissue structure of the interface on the 5th day (all H+E stained). In Figure 21, polymer (A) is seen together with normal granulation tissue (B) (lymphocytes and fibroblasts with early wound contraction). Figure 22 shows a high-magnification view of granulation tissue (A) at the polymer / wound interface (B) with ingrowth of granulation tissue into the polymer substance.

[0119] Figures 23 to 26 are slide images of the tissue structure of the interface on the 10th day. In Figure 23, the junction between adjacent lymphoid tissue (A) and the contracting wound (B) is shown. Figure 24 shows a high-magnification field showing adjacent lymphoid tissue and a contracting wound with squamous epithelium (A), lymphocyte infiltration (B), and newly formed fibrous tissue (C). Figure 25 shows the junction between granulation tissue (A) and muscle with contracting fibrous tissue (B). Figure 26 shows a high-magnification field of the junction between granulation tissue (A) and muscle with contracting fibrous tissue (B).

[0120] Figure 27 is the tissue structure of the interface on the 14th day, showing complete healing of the tonsillar fossa by new lymphoid tissue (A), squamous epithelium (B), and newly formed fibrous capsule (C).

Example

[0121] Preparation of a tissue interface containing an interpenetrating chitosan sublayer. Examples of devices include a tissue-polymer interface or a tissue interface layer. This interface can be in the form of one or more chitosan layers with physical properties optimized for tissue interaction. For example, the properties of the layer include the following: 1. Thickness - (typically 20 μm, or in the range of 10 - 30 μm) 2. Water content - (typically 9.5%, or in the range of 5 - 15%) 3. Water uptake - (typically 88%, or in the range of 70 - 95%) 4. Porosity - (typically 12%, or in the range of 5 - 25%) 5. Flatness - (typically 100%, or in the range of 90 - 100%) 6. Elasticity - (typically 12%, or in the range of 5 - 35%) 7. Crystallinity - (typically 8.5%, or in the range of 5 - 20%) 8. Tensile strength - (typically 50 MPa, or in the range of 35 - 75 MPa) 9. Surface pH - (typically 7.2, or in the range of 6.8 - 7.8) 10. Water contact angle - (typically 102°, or in the range of 85 - 110°) 11. Surface roughness - (typically 0.07 μm, or in the range of 0.05 - 0.20 μm) 12. Conductivity - (typically zero, or in the range of zero) One or more of the above may be included.

[0122] Further surface modifications such as surface pH modification, chemical surface ionization, chemical or plasma resurfacing may also be included.

[0123] Exemplary methods for fabricating a tissue interface comprising a mutually fused or mutually penetrated chitosan layer are as follows: The chitosan - tissue interface layer was fabricated according to the modified solvent casting method and purified by including sintered glass filtration and a solution pH corrected to approximately 5.0 prior to casting.

[0124] Under clean conditions, medium - molecular - weight chitosan (190 - 300 kDa and >85% DDA) was dissolved in a 2% (w / v) stock aqueous solvent solution. The stock solvent solution contained 97.75% MilliQ water, 2% (v / v) glacial acetic acid, and 0.25% (v / v) citric acid. However, the solution may include an additional 0.05% (v / v) lactic acid.

[0125] The gelatinous solution was sealed from the atmosphere and continuously stirred at room temperature (25 °C) for 48 hours, and then refrigerated at 4 °C for 24 hours. The chitosan solution was centrifuged (15 minutes, 15,000 g) to separate undissolved fine particles. Using a glass medium with a pore size of 35 μm, undissolved smaller fine particles were removed by vacuum filtration through a sintered funnel. While continuously stirring, the solution was adjusted to pH 5.0 using a pH probe, and 2M NaOH was added dropwise. At this stage, therapeutic agents such as lignocaine hydrochloride (1% or 2% solution) and bupivacaine (0.25% or 0.5% solution) were added.

[0126] Next, the polymer solution was cast onto a sterile plastic medium at a density of 0.095 - 0.110 ml / cm2. The polymer layer was formed by evaporating the solvent in a sterile laminar flow at room temperature (25 °C) for about 14 days.

[0127] The solvent casting method was repeated as necessary to obtain the desired number of fused phases during polymer addition. The degree to which the polymer layer produced a transition or fused phase was controlled by surface ionization. Each sample was washed twice with 0.01M NaCl and dried before each polymer addition. This resulted in a suitable transition phase depth of approximately 25 - 35% of the previous polymer addition.

[0128] Thus, the first addition was approximately 2 / 3 body, 1 / 3 upper transition. The second addition was 1 / 3 lower transition, 1 / 3 body, and 1 / 3 upper transition. All additions resulted in three phases, which were repeated until the final addition, which was the opposite bottom addition, i.e., 1 / 3 lower transition, and 2 / 3 body.

Example

[0129] Preparation of Blend Layer / Intermediate Layer Examples of the devices described herein may include one or more layers containing two or more blend polymers. These may include, for example, combinations of chitosan, PCL, PLLA, or PLGA. These blend layers can also carry the loading amounts of one or more therapeutic agents, either together or interchangeably. In one example, these layers can be implemented in combination with those produced in Examples 3 and 5.

[0130] An exemplary method for forming a blend layer of chitosan with PCL, PLLA, or PLGA is as follows: Under clean conditions, medium molecular weight chitosan (190 - 300KDa and >85% DDA) was dissolved in a stock aqueous solvent solution at 2% (w / v). The stock solvent solution contained 97.75% MilliQ water, 2% (v / v) glacial acetic acid, and 0.25% (v / v) citric acid. However, the solution may contain an additional 0.05% (v / v) lactic acid. Polycaprolactone, polylactic acid, or poly(lactic - co - glycolic acid) was also added to separate solutions in addition to 10% (w / v) glacial acetic acid and 50% (w / v) citric acid. The solution may contain an additional 0.05% (v / v) lactic acid. These solutions were then mixed.

[0131] The gelatinous solution was sealed from the atmosphere 、1 Stirred continuously at 0 - 120°C for 48 hours and then refrigerated at 4°C for 24 hours. The chitosan polymer blend solution was centrifuged (15 minutes, 15,000g) to separate undissolved fine particles. Undissolved smaller fine particles were removed by vacuum filtration through a sintered funnel using a glass medium with a pore size of 35μm. While stirring continuously, the solution was adjusted to pH 5.0 using a pH probe and 2M NaOH was added dropwise. At this stage, a therapeutic agent such as lignocaine hydrochloride (1% or 2%) or bupivacaine hydrochloride (0.25% or 0.5%) was added as an aqueous solution.

[0132] Next, the polymer solution was cast onto the existing sample at a density of 0.095 - 0.110 ml / cm2. The polymer layer was formed by evaporating the solvent in a sterile chemical fume hood at room temperature (25°C) for approximately 14 days.

[0133] The solvent casting method was repeated as necessary to obtain the desired number of polymer layers. Each sample was washed twice with 0.01 M NaCl in 70% ethanol and dried before each solvent casting.

Example

[0134] Backing layer / oral interface Examples of the device may include an oral-polymer interface layer or a backing layer. This interface may be in the form of one or more chitosan layers with physical properties optimized to interact with the oral environment and withstand the troublesome problems associated with the oral environment.

[0135] Such problems include, but are not limited to: - High shear stress, friction, torque, and elasticity - Damage by foreign objects - High bioburden, abundant degrading enzymes - Very high water content Regarding the problems of the desired environment / position of the device, the interface layer can include, but is not limited to, one or more of the following inherent properties.

[0136] Examples include one, two, or more polymer layers containing one or more polymers, or one or more layers of blend polymer layers. Suitable polymers may include, for example, chitosan, PCL, PLLA, or PLGA. These layers can be implemented in combination with those provided in Examples 3 and 4 in one embodiment.

[0137] The properties of the layer include the following: 1. Thickness - (Typically 15 μm, or in the range of 10 - 30 μm) 2. Water content - (typically 10%, or in the range of 5 - 15%) 3. Water uptake - (typically 15%, or in the range of 10 - 25%) 4. Flatness - (typically 100%, or in the range of 90 - 100%) 5. Elasticity - (typically 12%, or in the range of 5 - 35%) 6. Tensile strength - (typically 80 MPa, or in the range of 55 - 95 MPa) 7. Surface pH - (typically 7.2, or in the range of 6.8 - 7.8) 8. Water contact angle - (typically 90°, or in the range of 65 - 95°) One or more of the above may be included.

[0138] Subsequently, including the addition of poly(dimethylsiloxane - co - alkylmethylsiloxane), the surface roughness can be reduced, and both friction and hydrophilicity can be significantly reduced.

[0139] Examples of the production method are as follows: The method follows the method of Example 4. Lactic acid is added to the solvent mixture at a maximum of 0.2% v / v.

[0140] In the repetition incorporating poly(dimethylsiloxane - co - alkylmethylsiloxane), both dichloromethane and poly(dimethylsiloxane - co - alkylmethylsiloxane) are added at 0.5% w / v to the polymer solution (PCL, PLLA or PLGA outlined in Example 4 before the initial mixing), or applied to the back side of the cast polymer.

Examples

[0141] Polymer "packet" In an example of the device, i.e., as outlined in Examples 3 - 5, it may not be necessary to directly add the therapeutic agent to the polymer solution before solvent casting.

[0142] For example, “packets” of stabilized therapeutic agents can be produced and added to any of the polymer solutions, such as those outlined in Examples 3-5, or added to the surface modification steps, such as those outlined in Examples 3-5.

[0143] This allows the therapeutic agent to be included in the device, as described herein, regardless of its original stability. The location of the therapeutic package can be within the polymer layer, within the polymer interphase, or between the polymer layers themselves.

[0144] Examples of methods for incorporating a stabilized therapeutic agent into a polymer packet are as follows: Except for chitosan, the polymer solution prepared for Example 5 was spray dried to produce polymer microparticles.

[0145] Spray drying method - A polymer solution of any of PCL, PLLA, PLGA supplemented with Span40 and DMSO to reduce viscosity and surface tension. Using pump setting 25, aspirator setting 80, spray flow rate 350 L / hour, and pressure 30 mmHg, the solution was fed to a Buchi Mini Spray Dryer Model B-290 (Buchi Laboratoriums) at an inlet temperature of 50°C. The particles were collected in a collection chamber with an outlet temperature of 35°C.

[0146] The polymer microparticles were then mixed with a chitosan solution containing the therapeutic agent until homogeneous, as described in Preferred Method 1. Chitosan and the therapeutic agent covered the polymer particles of any of PCL, PLLA, or PLGA, and then were remixed to the volume of the respective starting solution of PCL, PLLA, or PLGA. This solution was then spray dried again with the respective settings outlined above.

[0147] These doughnut-like particles contain a stabilized chitosan / therapeutic agent within a protective polymer jacket.

[0148] Next, for example, as described in Examples 3-5, can these stabilized particles be used to substitute for the direct addition of the therapeutic agent, or can these stabilized particles, in addition to the surface preparation cleaning outlined in Examples 3-5, enable the deposition of additional therapeutic agent between the structural polymer layers thereby?

Claims

1. A layered drug delivery patch, comprising: a perforated polymer tissue interface layer containing at least one therapeutic agent; a polymer backing layer; one or more additional release layers sandwiched between the tissue interface layer and the backing layer, each additional release layer comprising: a polymer spacing sublayer; a polymer dosing sublayer containing at least one therapeutic agent; a patch, wherein the sublayers of each additional release layer are arranged in an order such that each spacing sublayer is closer to the tissue interface layer than its respective dosing sublayer.

2. The patch according to claim 1, comprising at least two additional release layers.

3. The patch according to claim 1 or 2, wherein the tissue interface layer is formed from a polymer matrix in which a therapeutic agent is incorporated.

4. The patch according to any one of claims 1 to 3, wherein the dosing sublayer is formed from a polymer matrix in which a therapeutic agent is incorporated.

5. The patch according to any one of claims 1 to 4, wherein the tissue interface layer comprises a polymer matrix formed from a blend of two or more polymers.

6. The patch according to claim 5, wherein the tissue interface layer is formed from a blend of chitosan and polycaprolactone (PCL).

7. The patch according to any one of claims 1 to 6, wherein each dosing sublayer comprises a polymer matrix formed from a blend of two or more polymers.

8. The patch according to claim 7, wherein the dosing sublayer is formed from a blend of chitosan and polycaprolactone (PCL).

9. The patch according to any one of claims 1 to 8, wherein the spacing sublayer is configured to slow down or delay the release of the therapeutic agent from the dosing sublayer.

10. The patch according to any one of claims 1 to 9, wherein the spacing sublayer is formed from a copolymer of poly-L-lactic acid (PLLA) and poly-L-glycolic acid (PLGA).

11. The patch according to any one of claims 1 to 10, wherein the backing layer is configured to prohibit the diffusion or permeation of the therapeutic agent therethrough.

12. The patch according to any one of claims 1 to 11, wherein the backing layer comprises poly-L-lactic acid (PLLA) and / or poly-L-glycolic acid (PLGA).

13. The backing layer includes a sublayer formed of a copolymer of poly-L-lactic acid (PLLA) and poly-L-glycolic acid (PLGA), and a sublayer formed of polycaprolactone (PCL), and the polycaprolactone (PCL) sublayer is the outermost layer farthest from the tissue interface layer. The patch according to any one of claims 1 to 12.

14. The patch according to any one of claims 1 to 13, comprising an attachment portion that facilitates fixation to the treatment site.

15. The patch according to any one of claims 1 to 14, wherein the tissue interface layer includes two or more continuous cast polymer sublayers that mutually penetrate each other.

16. The patch according to claim 15, wherein the continuous cast sublayer of the tissue interface layer contains chitosan.

17. The patch according to claim 16, wherein adjacent sublayers mutually penetrate each other by 25 to 35% in proportion to their widths.

18. The patch according to any one of claims 1 to 17, wherein one or more of the additional release layers are perforated.

19. The patch according to any one of claims 1 to 18, wherein the tissue interface layer, the sublayers of the one or more additional release layers, and the backing layer are continuous.

20. The patch according to any one of claims 1 to 19, wherein the at least one therapeutic agent includes an anesthetic.

Images