Submucosal bioresorbable drug eluting platform

Abstract

To provide a submucosal bioresorbable drug eluting platform.SOLUTION: Described here are systems and methods for delivering an active agent to target tissues of the ear, nose or throat using a drug delivery platform having a therapeutic drug embedded as part of the drug delivery platform. The drug delivery platform is implanted in a target tissue, and the active agent elutes out of the body of the drug delivery platform for a target period of time, delivering a therapeutic dose of the drug for that period of time. The duration of therapy for an implant in a sinus tissue can be from 3 to 12 months, or longer, thereby providing relief for the full duration of an allergy season. Moreover, the duration of therapy can provide relief to individuals with chronic paranasal sinus symptoms for a period of time longer than presently available therapeutic drugs, thus allowing only semi-annual or annual applications of the therapeutic drugs.SELECTED DRAWING: None

Description

Technical Field

[0001] Related Applications This application claims the benefit of priority to U.S. Patent Application No. 17 / 004,753, filed Aug. 27, 2020, which claims priority to U.S. Provisional Patent Application No. 62 / 894,113, filed Aug. 30, 2019, the entire disclosures of each of which are incorporated herein by reference.

[0002] This application generally relates to systems, devices, and methods for the injection or implantation of a drug delivery platform capable of delivering one or more active therapeutic agents to target tissue of the ear, nose, and throat (ENT). The systems, devices, and methods employ a bioabsorbable platform having size and shape factors suitable for implantation into target tissue, which platform is embedded, coated, and / or injected with a therapeutic agent such as, for example, a drug or biologic, or a combination thereof. When the platform is inserted into the target tissue, a clinically significant dose of the therapeutic agent is locally released to the target tissue over an extended period of time.

Background Art

[0003] Rhinosinusitis is a prevalent paranasal sinus condition that is generally understood to encompass sinusitis and / or rhinitis. Typically, rhinosinusitis is characterized by symptoms such as nasal discharge, nasal congestion, facial congestion, facial pain, facial pressure, loss of smell, fever, and headache. Many individuals have chronic rhinosinusitis (CRS), which is generally defined as swelling and inflammation of the paranasal sinuses that interfere with the normal drainage pathway of mucus and persist for more than three months even with treatment. Chronic sinusitis can be caused by infection, growth in the sinuses (e.g., nasal polyps), swelling of the inner lining of the sinuses, or a combination of these. Allergic rhinitis (AR) is another prevalent paranasal sinus condition that is associated with a group of nasal symptoms that occur when an individual with the condition breathes in allergens such as dust, mold, or animal dander. Allergens trigger the release of histamine, which typically causes sneezing, itching and watering eyes, runny nose, swelling and inflammation of the nasal cavity, increased mucus production, and in some individuals, hives or other rashes.

[0004] Treatment of CRS often involves mechanical modification of the nasal anatomical structure, including surgical means that involve trauma to the patient and a tissue recovery period, such as functional endoscopic sinus surgery (FESS). Additional surgical procedures (revision surgery) may be required to address procedures that do not provide complete treatment or to address postoperative scarring and / or the development of nasal polyps. Furthermore, there are patients for whom FESS may not be an appropriate option due to other medical concerns, and there are patients who do not benefit from rapid surgical procedures but may exhibit symptomatic severity of CRS that is likely to result in a later need for surgery. In other words, pre-FESS strategies for CRS symptoms may include delaying surgical procedures until the need becomes urgent.

[0005] The treatment of allergic rhinitis includes oral medications, sprays, and topical applications of active agents such as antihistamines and decongestants, which have limited effectiveness and duration. Allergic rhinitis can also be treated with immunotherapy regimens that take several weeks or months to complete, but generally do not provide symptom relief, at least during the initial period of the regimen, and are not guaranteed to be fully effective.

[0006] The treatment of both CRS (FESS and pre-FESS) and AR patients often involves the use of steroids, which can be oral steroids or steroids injected as a liquid. The use of these treatments is a systemic therapy that dilutes the effect of the steroid on the local target tissue and may also cause undesirable side effects from the systemic effects of the steroid. Additionally, it can be difficult to ensure compliance in patients prescribed such steroid regimens.

[0007] Therefore, there is a need to address CRS and non-allergic rhinosinusitis and / or other forms of rhinitis using a sustained medical treatment approach before performing the conventional first-choice mechanical treatment of the anatomical structure of the paranasal sinuses. Similarly, there is a need to address allergic rhinitis using a sustained medical treatment approach instead of temporary relief by spray-based drug delivery and / or during the very long period of an immunotherapy regimen in which the patient continues to exhibit symptoms. Furthermore, when steroid treatment is appropriate, there is an advantage in not using steroids that have systemic effects. Also, considering the variability in patients who consistently apply pharmaceuticals with limited duration (e.g., nasal sprays), there is a need to provide pharmaceuticals for which patient compliance is not a significant factor that could compromise treatment. Such treatment methods would be particularly beneficial for inflammation management to achieve long-term symptom relief in individuals who do not comply with the application of other pharmaceuticals.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure is directed to an implantable drug delivery platform that provides local and sustained delivery of a therapeutic agent. The drug delivery platform has a relatively small form factor compared to the anatomical structure into which the drug delivery platform can be implanted, such that the platform is minimally irritating and / or invasive to the subject receiving the implant. The size and form factor of the drug delivery platform (also referred to as a "pellet", "depot", "reservoir", "implant", "rod", etc.) enables delivery of a uniform drug dose over a longer period of time and at higher doses than is possible with other conventional drug delivery methods (e.g., nasal sprays, drug-coated implants, intraluminal packing materials, topical coatings, etc.). In some clinical applications, the drug delivery platform can be injected or implanted subcutaneously and / or submucosally into ear, nose, and / or throat tissues. The platform can be injected or implanted subcutaneously and / or submucosally using a needle-based delivery system, thereby providing superior efficacy, safety, and patient comfort compared to other existing therapies. In further clinical applications, the drug delivery platform can be injected or implanted into nasolacrimal tissue, or other ear, nose, tracheal, or esophageal tissue.

[0009] In some modification examples, a system for locally delivering a therapeutically effective amount of an active agent to a target tissue is sized for implantation or placement into the tissue of a patient's ear, nose, or throat, and can include a drug delivery platform shaped therefor, the drug delivery platform having a rod-like structure of a small size (small compared to the target anatomical structure) with an outer diameter of less than half a millimeter (<0.5 mm) and a length of less than 5 centimeters (<5 cm). The drug delivery platform can have other cross-sectional shapes (e.g., square, rectangular, tubular, triangular, etc.) and / or additional surface structures (e.g., ribs, angled edges, angled ends, rough surfaces, etc.) that can be utilized to enhance tissue retention. The drug delivery platform further includes one or more channels and / or protrusions that impart structural strength to the platform, while also having a structure that provides a space that can be filled or packed with a certain amount of the active therapeutic component.

[0010] In some variations, a system for locally delivering a therapeutically effective amount of an active agent to a target tissue can be loaded with a therapeutic agent incorporated into a drug delivery platform. A method of forming such a drug delivery platform may include, for example, the following processing steps: grinding and / or reducing an excipient polymer to a target particle size; grinding and / or reducing a drug (in solid form) to a target particle size; dry mixing the drug and the excipient; combining the drug (optionally with the excipient) and a bioabsorbable polymer by hot melt extrusion (HME) to completely encapsulate the drug within a rod-shaped or pellet-like bioabsorbable polymer. Subsequently, the rod can be cut to a target size, loaded into a delivery cartridge, and packaged into a minimally invasive delivery system. The entire system can be sterilized by electron beam sterilization or other suitable methods. Additionally, or alternatively, a system for locally delivering a therapeutically effective amount of an active agent to a target tissue can dissolve all components including the drug, polymer, and excipient in a suitable solvent, and then spray dry the appropriate surface area of the system to obtain a mixture of uniform particle size among the drug, polymer, and excipient, followed by performing hot melt extrusion combination to load the therapeutic agent.

[0011] In some variations, a platform for locally delivering a therapeutically effective amount of an active agent to a target tissue can be configured to efficiently elute the total amount of the active agent over 14 days, 30 days, 60 days, 90 days, 180 days, 360 days, or 2 years. In further variations, the platform can elute the total amount of the active agent in less than 14 days, for example, within 7 days. In a specific exemplary embodiment, the platform can elute 25% of the active agent by 7 days (post-implantation), 50% of the active agent by 30 days, and 70% of the active agent by 90 days.

[0012] The methods described herein may include locally delivering a therapeutically effective amount of an active agent to a target tissue by placing and / or positioning a delivery system of small outer dimensions near and / or parallel to the target tissue, delivering or pushing an implant into the lumen of the target tissue, leaving the implant in the tissue lumen, and then removing or reversing the barrel of the delivery device.

[0013] Any active therapeutic agent used to treat a condition of the ear, nose, or throat may be included in the drug delivery platform, and for example, a corticosteroid may be employed. Mometasone furoate (MF) may be a corticosteroid useful for the treatment of rhinosinusitis. The drug delivery platform may further include excipients such as, for example, PLGA (poly(lactide-co-glycolide)), poly(vinylpyrrolidone), polysorbate, poly(ethylene glycol), propylene glycol, glycerol, glyceryl caproate, or combinations or mixtures thereof.

[0014] The drug delivery platform may be used to treat inflammation of mucosal tissues, such as mucociliary tissues, which are present particularly in the nasal cavity and paranasal sinuses among other structures of the respiratory system. In some variations, the condition being treated may be a nasal condition selected from the group including postoperative inflammation, nasal and paranasal sinus cancers, rhinosinusitis, chronic rhinosinusitis with or without nasal polyps, and rhinitis including both allergic rhinitis and non-allergic rhinitis. In such variations, the target tissue site may be the paranasal sinuses, paranasal sinus ostia, inferior turbinate, middle turbinate, superior turbinate, nasal cavity, nasal vestibule, nasal septum, nasal polypoid tissue, natural ostium route of the middle meatus, nasopharynx, adenoid tissue, or one or more of such tissues. Suitable active agents for treating the above-described paranasal sinus and / or nasal conditions, including but not limited to the active agents listed herein, may be incorporated as part of the drug delivery platform.

[0015] In other modification examples, the target tissue may be ear tissue, and the condition to be treated may be an ear condition selected from the group including postoperative inflammation, otitis media, Meniere's disease, eustachian tube dysfunction, hearing loss, and tinnitus. In such modification examples, the target tissue site may be the eustachian tube, external auditory canal, middle ear, inner ear, or one or more of such tissues. Treatment of the eustachian tube may also be beneficial for the treatment of hearing loss, earache, and dizziness. Suitable active agents for treating the above ear conditions, including but not limited to the active agents listed in this specification, may be incorporated as part of the drug delivery platform.

[0016] In other modification examples, the target tissue may be laryngeal tissue (e.g., tissue of the pharynx, esophagus, or trachea), and the condition to be treated may be a laryngeal condition selected from the group including postoperative pain, esophageal cancer (and other oral or pharyngeal cancers), airway stenosis (e.g., proximal tracheal stenosis or subglottic stenosis), esophageal constriction or stenosis, chronic laryngitis, tonsillitis, vocal cord polyps, and pharyngitis. Suitable active agents for treating the above laryngeal-related conditions, including but not limited to the active agents listed in this specification, may be incorporated as part of the drug delivery platform.

[0017] In a further modification example, the target tissue may be skin tissue, and the condition to be treated may be a skin condition and / or wound requiring healing selected from the group including alopecia areata, discoid lupus erythematosus, keloid scarring (e.g., scarring of wounds and injuries), hypertrophic scarring, surgical scarring (e.g., plastic surgery scarring), granulomatous disorders (e.g., granuloma annulare), hypertrophic lichen planus, chronic simple lichen, psoriasis vulgaris, necrobiosis lipoidica, cystic acne, infantile hemangioma, and bullous pemphigoid. In such applications, the drug delivery platform may be implanted subdermally, or may be placed at a position spanning the dermis and subcutaneous tissue / subcutaneous layer. Suitable active agents for treating the above skin disease conditions, including but not limited to the active agents listed in this specification, may be incorporated as part of the drug delivery platform.

[0018] It should be understood that the treatment of the conditions enumerated above and other medical conditions using the drug delivery platform can be reactive, prophylactic, or both. As an example of forward-looking use, the drug delivery platform may be implanted into the target tissue simultaneously with the completion of surgery to prevent or reduce the severity of harmful physiological reactions or physiological conditions that may occur due to surgery. As an example of reactive use, the drug delivery platform may be implanted into the target nasal sinus tissue following the symptoms of AR in the patient. Further, it should be understood that the drug delivery platforms of the present disclosure can be configured and formulated to deliver therapeutic agents to other tissues and anatomical structures such as, for example, tissues of the eye or lacrimal gland, and soft tissues within and around joints.

[0019] During manufacture, the drug delivery platform may be infused or saturated with the drug by methods including, but not limited to, spray coating, dip coating, melt extrusion thermoforming, compounding, thermoforming, solvent casting, water-in-oil emulsion, injection molding, spray drying, or combinations thereof.

[0020] To improve the adhesion of the drug layer, the platform may be washed with a solvent and dried prior to coating. Further, plasma treatment with an inert gas (e.g., argon) or oxygen after washing can increase the cleanliness and wettability of the platform surface, resulting in increased adhesion of the drug layer and increased release of the layer upon insertion into the target tissue. In some variations, the manufacturing method can include treating the platform surface with plasma and then drying the coated platform at room temperature or elevated temperature. In other variations, the manufacturing method can include treating the platform surface with plasma and then exposing the coated platform to solvent vapor (solvent vapor annealing).

[0021] Exemplary aspects of the present disclosure are described in detail below with reference to the following drawings. The embodiments and figures disclosed herein are intended to be illustrative rather than limiting.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0040] Described herein are systems and methods for the delivery of an active agent to a target tissue of the ear, nose, or throat using an embedded or saturated embedded drug delivery platform in which an active agent is embedded in a therapeutic agent. In some embodiments, the drug delivery platform may be coated with a therapeutic agent. The drug delivery platform can be injected or implanted into the target tissue and then act as an in situ drug depot, enabling the maintenance of a therapeutic concentration of the active agent over a desired period following the procedure. The drug delivery platform may be delivered submucosally and / or subcutaneously within the target tissue. The systems and methods can be useful when drug delivery to mucosal tissue, such as the sinuses, is desired. Also described herein is a method for manufacturing the drug delivery platform.

[0041] The drug delivery platform of the present disclosure is directed to an implantable drug delivery depot having a relatively small form factor that provides local and sustained therapeutic agents within and to a target tissue. This size and feature of the implant results in minimal irritation and minimal invasiveness to the patient. The implantable drug delivery platform is further designed for use as a submucosal implant, particularly for otolaryngological applications (however, the implant is not limited to use in such anatomical structures). Where useful or appropriate, the drug delivery platform may be designed for use as a subcutaneous implant. The platform allows for relatively high and uniform drug loading into a very small form factor and enables larger doses and longer release periods than are observed with drug coating methods (e.g., spray coating of the implant surface with a drug). Some exemplary uses for this implantable drug delivery platform are described below.

[0042] In one use, the implantable drug delivery platform can be used for the treatment of allergic rhinitis via submucosal implantation and delivery in the inferior turbinate. Considering the local inflammation localized in the inferior turbinate and its high level of angiogenesis, the drug delivery platform has distinct advantages over local allergic rhinitis therapies by at least locally high total drug content, improved drug dosing, and improved drug distribution. Considering that potential systemic exposure is reduced and the required dose is decreased, the implantable drug delivery platform method is less risky than systemic therapies. In contrast to liquid injection therapies, the implantable drug delivery platform is safer considering there is no risk of embolization to the ophthalmic artery. In another use for the inferior turbinate, the implantable drug delivery platform can be used to reduce the size of an abnormally enlarged inferior turbinate. The implantable drug delivery platform method is much less traumatic than mechanical or surgical methods for reducing the size of the turbinate. In further uses, the implantable drug delivery platform can be used similarly for the middle and superior turbinates.

[0043] In another use, the drug delivery platform can be used for delivering anti-inflammatory agents such as corticosteroids to reduce inflammation after surgery (e.g., after functional endoscopic sinus surgery) or after a mechanical procedure (e.g., dilation of the sinuses or sinus ostia). The drug delivery platform can be particularly used when no additional mechanical support or permanent implant is required after sinus surgery or other nasal procedures.

[0044] In a further use, the drug delivery platform can be used for drug delivery to the eustachian tube before and after a procedure (e.g., balloon dilation) to treat conditions such as eustachian tube dysfunction or other ear diseases. In such cases, the small form factor of the drug delivery platform enables treatment modalities where larger devices (such as stents) are not appropriate or are invasive. In other ear-related uses, the drug delivery platform can be used to access and deliver drugs to the middle ear or inner ear to treat conditions such as otitis media, Meniere's disease, tinnitus, hearing loss, or other such diseases. The drug delivery platform can also be used for subcutaneous drug delivery to the external ear canal for chronic otitis media or otitis externa. In some embodiments, the drug delivery platform can be implanted near, within, or into the tympanic membrane.

[0045] In another use, the drug delivery platform can be used for drug delivery to the larynx for conditions such as postoperative pain, tonsillectomy pain, tumors, airway stenosis, chronic laryngitis, laryngotracheitis, other inflammatory diseases, or other diseases of the larynx. Drug release from the drug delivery platform as a submucosal implant is a safer alternative than topical implants that may need to penetrate the inner lining of the larynx and may even be swallowed.

[0046] The therapeutic agent is generally a drug contained on and / or within the structure of the platform, and the platform is sufficiently porous so that the drug contained within the platform elutes from the platform into the surrounding tissue over time. Drugs directly exposed to the outer surface of the platform are released into the surrounding tissue more rapidly than drugs present within the interior of the platform. Thus, the drug delivery platform provides a local source of therapeutic agent at the implantation site.

[0047] The drug delivery platform can have several uses. For example, it may be adapted in size, composition, and material for different uses in different tissues such as the ear, nose, or throat. The drug delivery platform can be useful for treating conditions associated with mucosal inflammation. In some variations, the systems and methods can be used for the treatment of one or more sinus or nasal conditions, including but not limited to chronic rhinosinusitis, rhinitis, allergic rhinitis, acute sinusitis, and chronic sinusitis with or without polyps. In other variations, the device and method can be performed during dilation procedures. For example, one or more drugs (e.g., corticosteroids) can be delivered via the implanted platform to reduce inflammation after balloon formation, dilation, or other surgeries of the sinuses and / or sinus ostia. In other variations, one or more drugs are delivered to the sinuses and / or sinus ostia and allergic symptoms can be alleviated. In yet another example, the drug delivery platform can be used for the delivery of anti-inflammatory agents (e.g., corticosteroids) to reduce inflammation after functional ethmoid surgery, including cases where mechanical support and permanent implants are not required.

[0048] In other modification examples, the system and method may be used to treat one or more conditions of the ear. For example, the drug delivery platform may deliver a drug to the eustachian tube to treat eustachian tube dysfunction. As another example, the drug delivery platform may be used for drug delivery to the external ear canal for acute otitis media, chronic otitis media, or otitis externa. The drug delivery platform may also be used for drug delivery to the middle ear and / or inner ear to treat Meniere's disease, tinnitus, hearing loss, or other applicable conditions.

[0049] In other modification examples, the drug delivery platform may also have applications in the larynx, in which case the drug delivery may be for, e.g., postoperative pain such as pain after tonsillectomy, or for esophageal cancer, airway stenosis (e.g., tracheal stenosis or subglottic stenosis), chronic laryngitis, epiglottitis, other inflammatory diseases, and / or other conditions of the larynx.

[0050] As used herein, the term "bioabsorption" generally refers to the absorption of substances by the body, such as substances that are broken down in body tissues or body cavities and are later assimilated or removed by the body. In various aspects, bioabsorption of a substance may or may not be complete over a target period or a reference period, in which case the substance may be only partially digested and remain in local body tissues or body cavities for longer than the target period or reference period. As used herein, the terms "biodegradation" and "bioerosion" refer to the breakdown of substances in the body by mechanical work and / or chemical processes under the physiological conditions of a biological environment. Both biodegradable and bioerodible substances can be bioabsorbable. As used herein, the term "bioresorbable" comprehensively refers to substances that are bioabsorbable, biodegradable, bioerodible, or a combination thereof.

[0051] As used herein, the term "drug delivery platform" refers to a combination of biodegradable materials that act as primary structural components (referred to as "skeletons", "scaffolds" or "carriers") for the platform and as therapeutic components (e.g., drugs or other active agents), where the drug is loaded, injected, formed or otherwise incorporated into the biodegradable material. Optionally, the drug delivery platform may further comprise excipients, or release rate modifying excipients, or a polymeric top coat layer. The drug delivery platform may also be referred to as an "implant" or an "implantable drug delivery platform". In contrast, the term "delivery device" refers to a device used by an operator or physician to implant a drug delivery platform. The term "drug delivery system" is used to refer to a combination of a drug delivery platform and a delivery device, such as when one or more implants are loaded onto the delivery device.

[0052] As used herein, the term "about", when used to modify a numerical value, indicates a range of plus or minus 10% from the value, unless otherwise explicitly stated.

[0053] Device Implantable drug delivery platform The implantable platforms described herein are generally biodegradable, although alternative embodiments of the implantable platforms can be fully biodegradable, fully non-biodegradable, or partially biodegradable and partially non-biodegradable. Generally, biodegradable polymers are preferred materials such that the drug delivery platform is not retrieved or extruded from the patient as a foreign body. Natural biodegradable polymers that can be used in the structure of the drug delivery platform include chitosan, collagen, elastin, silk, silk-elastin, alginate, cellulose, dextran, polyalkenoate, hyaluronic acid, gelatin, and gellan. When made to be biodegradable using synthetic materials, the platform backbone can be formed from, but is not limited to, materials such as polylactide, poly(lactide-co-glycolide) (PLGA), poly(D,L-lactide-co-glycolide), poly(L-lactide) (PLLA), poly(lactide co-caprolactone) (PLA-PCL), polyglycolide (PGA), poly(D,L-lactide) (PDLLA), poly(L-lactide-co-caprolactone) (PLLA-PCL), polyhydroxybutyrate, polyhydroxyvalerate, poly(ethylene glycol) (PEG), polydioxanone (PDX), polyalactin, poly(ε-caprolactone), polyglyconate, poly(glycolide-co-trimethylene carbonate), poly(sebacic acid), poly(ester urethane), poly(ester urethane) urea, or combinations thereof. For some of these materials, the ratio of the components can be varied to achieve specific material properties such as, for example, a targeted biodegradation time profile. For example, when poly(D,L-lactide-co-glycolide) is used in the scaffold of the drug delivery platform, the ratio of lactide to glycolide (L:G) can be 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 33:67, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 67:33, 70:30, 75:25, 80:20, 85:15, 90:10, 95:5, or another such ratio.When made to be at least partially bioabsorbable, the device, or a coating on the device, may be bioabsorbable and may include, for example, polyethylene glycol, propylene glycol, polysorbate, etc., a release rate modifier and / or a plasticizer. The implantable platform may have any suitable shape, length, height, diameter, or width, and in such cases, such structural characteristics of the implantable platform may further be configured to affect or control the bioabsorption time profile.

[0054] When treating paranasal sinus tissue, the implantable platform may beneficially have a rod-like shape and be about 2 to about 40 times (2x - 40x) longer than its width and height. Further, it may be useful for the implantable platform to have a cross-sectional outer shape that is cylindrical, oval, rhomboid, elliptical, triangular, square, rectangular, pentagonal, hexagonal, octagonal, or ribbed. Generally, the implantable platform configured for paranasal sinus tissue may have a length of about 0.5 cm to about 5 cm or more, and a width or diameter of about 0.21 mm to about 1.19 mm (i.e., a width that can fit within the inner diameter of a 27G - 16G subcutaneous needle).

[0055] When treating laryngeal tissue, it may further be beneficial for the implantable platform to have a cross-sectional outer shape that is cylindrical, oval, rhomboid, elliptical, triangular, square, rectangular, pentagonal, hexagonal, octagonal, or ribbed, or to have a distal end that is at least partially tapered. For laryngeal tissue, it may also be beneficial for the implantable platform to have a biodegradation duration of approximately up to about 6 months. Generally, the implantable platform configured for laryngeal tissue may have a length of about 0.5 cm to about 2 cm or more, and a width or diameter of about 0.21 mm to about 1.19 mm.

[0056] When treating the eustachian tube or the external auditory canal, it may be further beneficial for the implantable platform to have a cylindrical, conical, or tapered shape. Additionally, it may be useful for the implantable platform to have a cross-sectional outer profile that is cylindrical, oval, rhomboidal, elliptical, triangular, square, rectangular, pentagonal, hexagonal, octagonal, or ribbed. For the eustachian tube or the external auditory canal, it may also be beneficial for the implantable platform to have a biodegradation duration of approximately up to about 6 months. Generally, the implantable platform configured for the eustachian tube can have a length of about 0.5 cm to about 2 cm or more, and a width or diameter of about 0.21 mm to about 1.19 mm.

[0057] In some embodiments, the implantable platform can be configured to have a longitudinal channel that extends along the length of the platform.

[0058] Figure 1A shows a diagram of an exemplary implantable drug delivery platform 100 generally having a cylindrical shape. Figure 1B shows a diagram of an exemplary implantable drug delivery platform 102 having a repeating rhomboidal shape. Figure 1C shows a diagram of an exemplary implantable drug delivery platform 104 having a shape with a wavy width or a varying diameter. Figure 1D shows a diagram of an exemplary implantable drug delivery platform 106 having a structure with a linear central region and bifurcated Y-shaped ends on both sides of the platform. Each of the drug delivery platforms shown herein can generally have a smooth surface, or at least a partially rough or ridged surface. Although a particular embodiment of Figure 1A is detailed below, it should be understood that the features and compositions of this example are equally applicable to all embodiments of the drug delivery platform.

[0059] In some embodiments, the drug delivery platform may be formed to have a certain degree of curvature, or may be formed to have a spring force such that when implanted, the platform restores to a shape having a certain degree of curvature. The spring force of such a drug delivery platform can provide tension and contact with the surrounding tissue, which helps prevent the platform from falling off after implantation.

[0060] The amount of drug in the platform is relatively large, thereby achieving a relatively highly effective dosage over the relatively small total surface area of the implant. In some embodiments, when filled with a therapeutic agent, the drug occupies from about 40% to 60% of the total mass of the drug delivery platform. In certain embodiments, the drug occupies about 50% of the total mass of the drug delivery platform.

[0061] The exemplary drug delivery platform 100 shown has a composition of 50% mometasone furoate as the drug and 50% poly(D,L-lactide-co-glycolide) (75:25) as the backbone. In alternative embodiments, the composition may be 40% mometasone furoate and 60% poly(D,L-lactide-co-glycolide) (50:50) as the backbone. In further embodiments, the composition may be 45% mometasone furoate and 55% poly(D,L-lactide-co-glycolide) (65:35) as the backbone. In another embodiment, the composition may be 35% mometasone furoate and 65% poly(D,L-lactide-co-glycolide) (75:25) as the backbone. It should be understood that further variations of the drug delivery platform may have a ratio of drug to backbone ranging from 5% drug and 95% backbone to 95% drug and 5% backbone, including incremental ratios therein. It should also be understood that variations of the drug delivery platform using PLGA may have a composition ratio for the design of the (L:G) backbone ranging from (5:95) to (95:5).

[0062] A plasticizer or excipient may be added to the implant to reduce vulnerability, increase toughness, or both. Such plasticizers and excipients include, but are not limited to, poly(ethylene glycol), glycerol, polysorbate, propylene glycol, or combinations thereof.

[0063] The drug delivery platform 100 is a carrier for a therapeutic agent, which may be embedded within the drug delivery platform 100 and elutes the therapeutic agent into the surrounding tissue when the drug delivery platform 100 is implanted into the target tissue. For example, if the implant is about 50% mometasone furoate, an implant with a diameter of 0.3 mm X 10 mm in length can elute 450 μg of mometasone furoate into the locally implanted tissue over a period of 6 months. In another example, if the implant is about 50% mometasone furoate, an implant with a diameter of 0.36 mm X 6 mm in length can elute 500 μg of mometasone furoate into the locally implanted tissue over a period of 6 months.

[0064] When implanted at the target tissue site, the drug delivery platform 100 can provide consistent and controlled local drug delivery to the surrounding tissue. Furthermore, the local delivery of drugs via this drug delivery platform 100 is beneficial in that the drugs delivered by the platform do not diffuse throughout the patient's body. In other words, by involving controlled pharmacokinetics, the drugs act on specific target tissues of the subject and the drugs remain in a relatively local area around the target tissue. The drugs do not cause potential side effects or dose reduction that may occur when diffusing systemically around the body.

[0065] The drug delivery platform can have a composition such that the therapeutic agent is released from the platform over a period of weeks to months or years. In some embodiments, the in vivo release of the drug from the implanted platform can be from about 3 months to about 12 months (3 - 12 months). The release time and release profile can be adjusted according to the profile of drug loading and the degradation time of the targeted biodegradable polymer. With regard to the composition of the drug delivery platform, exemplary substances that can be used include PLGA and PDLLA, and the molar ratio of the component structures of each substance changes the release and absorption profiles. For example, PLGA formed with an L:G molar ratio of 70:30 or 60:40 can be selected as a substance for a drug release duration in the range of 3 - 12 months. In another example, PLGA formed with an L:G molar ratio of 50:50 can be selected as a substance for a drug release duration in the range of 1 - 3 months. In another example, PLGA formed with an L:G molar ratio of 40:60 or 30:70 can be selected as a substance for a drug release duration in the range of 3 - 9 months. In further embodiments, different substances can be mixed to form the drug delivery platform. For example, a mixture of PLGA and PDLLA, or two forms of PLGA with different L:G molar ratios can be mixed together to achieve the desired release and absorption profiles.

[0066] The size, length, and shape of the drug delivery platform may be designed for specific anatomical structures and uses. The length of the drug delivery platform may vary based on the various tissues into which the platform can be implanted. For example, a longer platform may be used for insertion into the inferior turbinate compared to a relatively short platform used for insertion into the middle turbinate or superior turbinate. A shorter length may be utilized for pediatric patients. The shape of the drug delivery platform (e.g., as illustrated in FIGS. 3A - 3J and FIGS. 4A - 4C below) can be selected for penetration or conformity to a specific anatomical structure. Also, the shape of the drug delivery platform can be selected with respect to the orientation of the platform surface to provide some control over the direction in which the released therapeutic agent elutes.

[0067] In some variations, the implantation device for the drug delivery platform can be delivered by a physician using one hand. Drug composition

[0068] The formulation of the therapeutic agent in the drug delivery platform of the present disclosure can be any one of corticosteroids (e.g., mometasone furoate, fluticasone propionate, etc.), antihistamines (azelastine, diphenhydramine azelastine, diphenhydramine), cytostatic agents (e.g., sirolimus, everolimus, zotarolimus, etc.), cytotoxic agents (e.g., paclitaxel), or combinations thereof. In certain embodiments, the therapeutic agent is mometasone furoate, or a pharmaceutically acceptable variant thereof.

[0069] The drug may be loaded or embedded in the implant by methods such as hot melt extrusion or melt compounding, solvent casting, emulsion-based spray drying, spray coating, injection molding, thermoforming, etc. In the case of hot melt extrusion using PLGA as the skeletal material, PLGA may first be crushed (e.g., physically crushed, cryogenic milling, etc.) to a micro-particle size similar to that of the drug particles. Then the drug and PLGA are dry mixed, melt compounded together, extruded, and cut to form helical, rod-shaped, pellet-shaped, or other extrusion shapes.

[0070] The implant may contain approximately about 40 - 60% by mass of the drug, with the remainder being a polymeric excipient. For example, the implant may contain 60 - 40% by mass of PLGA. The drug content may be uniform throughout the implant. Alternatively, the implant can be fabricated such that the drug is distributed with a gradient where the drug concentration is higher near the surface relative to the center, resulting in a higher initial drug release after implantation.

[0071] The drug coating top coat or polymer top coat may be further compounded or spray coated to add additional drug release control to the implant. The drug coating top coat will provide a high initial drug release. The polymer top coat will lower the initial release and potentially extend the drug release over a longer period of time.

[0072] The drug release profile from the drug delivery platform may follow a first release profile with an initial high-dose release over a relatively short period followed by a sustained low-dose release over a long period. The resulting tissue pharmacokinetics will show a long-term therapeutic drug exposure of 3 - 12 months (3 - 12 months). If the drug delivery platform includes a polymer top coat or is formed from a scaffold with a longer absorption duration (e.g., due to having an adjusted PLGA ratio), the implant may show a longer sustained release and generally exhibit a zero-order profile drug release kinetics.

[0073] In some examples, an antihistamine such as azelastine may be combined with a corticosteroid such as mometasone furoate as a dual-drug release implant system to provide immediate relief of nasal congestion. In some examples, a cytotoxic agent such as paclitaxel may be utilized to stop benign tissue growth in the ear, nose, or throat.

[0074] Directional control of drug delivery may be controlled by end-capping the implant to achieve mainly radial drug release. Also, the end may be made to be relatively highly porous and directed towards a fast drug release profile depending on the rate of water absorption. A gradient of drug amount may also be achieved by multiple supply compounds.

[0075] In some modification examples, excipients having a molecular weight of 1000 g / mol or less may be beneficial for enhancing drug uptake through mucosal tissues. Exemplary mucosal adhesive excipients include, but are not limited to, carbomers, glyceryl monooleate, hypromellose, oleic acid, polycarbophil, polyethylene oxide, poly(ethylene glycol), and sodium alginate. Other mucosal adhesives can obtain their adhesive properties by means of soluble coatings or wetting of polymers, charge adhesion (e.g., charge adhesion of anionic polymers such as polyacrylic acid, cellulose, chitosan, gellan, carbopol, etc.), and covalent adhesion with protein-reactive gels such as, for example, PEG-NHS (poly(ethylene glycol)-N-hydroxysuccinimide). In one modification example, the mucosal adhesive is poly(ethylene glycol). Exemplary penetration enhancers include, but are not limited to, dimethyl sulfoxide, glyceryl monooleate, glycolfurole, isopropyl myristate, isopropyl palmitate, lanolin, mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitic acid, polyoxyethylene alkyl ether, polyoxyglyceride, pyrrolidone, sodium lauryl sulfate, thymol, tricaprylin, triolein, and combinations and mixtures thereof.

[0076] Additionally or alternatively, the therapeutic agent may be a lipophilic agent. In these modification examples, since the drug delivery platform is implanted in proximity to and in contact with the tissue at the treatment site, the lipophilic nature of the drug contained in the drug delivery platform promotes elution from the platform and further promotes movement into and absorption by the tissue. Moisture in the tissue can facilitate this movement. Other factors that can affect drug movement from the platform include the amount of contact pressure exerted by the tissue on the implanted platform and the surface area of the drug delivery platform.

[0077] The drug or active agent of the drug delivery platform can include any suitable drug or agent, depending on its desired use. The drug or active agent may include, for example, at least one of a diagnostic agent or a therapeutic agent. Suitable types of drugs include, for example, local anesthetics, analgesics (especially non-opioid analgesics), vasoconstrictors, antiseptics, antioxidants, anti-inflammatory agents, anti-allergens, anti-cholinergic agents, antihistamines, anti-infective agents, antiplatelet agents, anticoagulants, antithrombotic agents, scarring inhibitors, anti-proliferative agents, chemotherapeutic agents, anti-neoplastic agents, decongestants, wound healing promoters, and vitamins (e.g., retinoic acid, vitamin A, depaxapanthenol, vitamin B and their derivatives), hyperosmotic agents, immunomodulatory substances, immunosuppressants, mucolytics, as well as combinations and mixtures thereof.

[0078] In some embodiments, when the site to be treated includes mucosal tissue or mucociliary tissue, the drug layer may include, for example, a penetration enhancer, a mucoadhesive, and / or a mucolytic to enhance drug delivery through the mucus layer or, in cases where it is useful, to remove the mucus layer. Such excipients can ensure the target dose of drug delivery when the implant is not placed precisely by the physician as instructed to achieve a perfect implantation. Examples of mucolytics that can be used for these applications include carbocisteine, erdosteine, acetylcysteine, bromhexine, expigen syrup (sorbimacrogol laurate 300 and ammonium chloride), guaifenesin, glyceryl guaiacolate, iodinated glycerol, or combinations or mixtures thereof.

[0079] Examples of antioxidant substances include tocopherol (vitamin E), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid monohydrate, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, monothioglycerol, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium thiosulfate, sulfur dioxide, citric acid monohydrate, tartaric acid, and thymol.

[0080] Examples of local anesthetics include ropivicaine, mepivicaine, cocaine, procaine, lidocaine, hydrocodone, oxycodone, fentanyl, and morphine. Examples of vasoconstrictors include epinephrine, levonordefrin, Afrin, and adrenaline. Examples of non-opioid analgesics include ibuprofen, acetaminophen, bupivacaine, aspirin, and naproxen.

[0081] Anti-infective agents generally include antibacterial agents, antifungal agents, anti-parasitic agents, anti-viral agents, preservatives, iodine (e.g., povidone iodine), potassium sorbate, sorbic acid, thimerosal, thymol, butylene glycol, coconut oil, and vanillin. Anti-inflammatory agents generally include steroid and non-steroid anti-inflammatory agents.

[0082] Examples of anti-allergic agents that may be suitable for use in the described methods and devices include, but are not limited to, pemirolast potassium (ALAMAST®, Santen, Inc.), and any of its prodrugs, metabolites, analogs, homologs, containers, derivatives, salts, and combinations. Examples of anti-proliferative agents include, but are not limited to, sirolimus, everolimus, temsirolimus, actinomycin D, actinomycin IV, actinomycin I1, actinomycin X1, actinomycin C1, and dactinomycin (COSMEGEN®, Merck & Co., Inc.). Examples of antiplatelet agents, anticoagulants, antifibrin agents, and antithrombin agents include, but are not limited to, heparin sodium, low molecular weight heparin, heparinoids, hirudin, argatroban, forskolin, beraprost, prostacyclin and prostacyclin analogs, dextran, D-phe-pro-arg-chloromethyl ketone (synthetic antithrombin), dipyridamole, glycoprotein IIb / IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitor (ANGIOMAX®, Biogen, Inc.), and any of their prodrugs, metabolites, analogs, homologs, containers, derivatives, salts, and combinations. Examples of wound healing promoters include, but are not limited to, vitamin A.

[0083] Examples of cytostatic or antiproliferative agents that may be suitable for use in the methods and devices described include, but are not limited to, angiopeptin, angiotensin-converting enzyme inhibitors such as captopril (CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril or lisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channel blockers such as nifedipine; colchicine; fibroblast growth factor (FGF) antagonists, fish oil (omega 3 fatty acids); histamine antagonists; lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodies including, but not limited to, antibodies specific for platelet-derived growth factor (PDGF) receptors; nitroprusside; phosphodiesterase inhibitors; prostaglandin inhibitors; suramin; serotonin blockers; steroids; thioprotease inhibitors; PDGF antagonists including, but not limited to, triazolopyrimidines; and nitric oxide, as well as their prodrugs, metabolites, analogs, homologs, conjugates, derivatives, salts and combinations thereof.

[0084] Examples of antibacterial agents (antibiotics) that may be suitable for use in the methods and devices described include, but are not limited to, aminoglycosides, amphenicols, ansamycins, beta-lactams, such as beta-lactams like penicillin, lincosamides, macrolides, nitrofurans, quinolones, sulfonamides, sulfones, tetracyclines, vancomycin, and any of their derivatives, or combinations thereof. Examples of penicillins that may be suitable for use in the methods and devices described include, but are not limited to, amdinocillin, amdinocillin pivoxyl, amoxicillin, ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin, bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium, carbenicillin, carindacillin, cromadillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin, lenampicillin, methampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, penamesillin, penetamert hydroiodide, penicillin G benethamine, penicillin G benzathine, penicillin G benzhydrylamine, penicillin G calcium, penicillin G hydrabamine, penicillin G potassium, penicillin G procaine, penicillin N, penicillin O, penicillin V, penicillin V benzathine, penicillin V hydrabamine, penimepicycline, phenethicillin potassium, piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin, and ticarcillin. In one variation, the antibacterial agent includes ciprofloxacin. In another variation, the antibacterial agent includes amoxicillin.

[0085] Examples of antifungal agents suitable for use in the methods and devices described include, but are not limited to, any of allylamines, imidazoles, polyenes, thiocarbamates, triazoles, and their derivatives. Examples of antiparasitic agents that may be employed include, but are not limited to, atovaquone, clindamycin, dapsone, iodoquinol, metronidazole, pentamidine, primaquine, pyrimethamine, sulfadiazine, trimethoprim / sulfamethoxazole, trimethoprim, and combinations thereof.

[0086] Examples of antiviral agents suitable for use in the methods and devices described include, but are not limited to, acyclovir, famciclovir, valacyclovir, edoxudine, ganciclovir, foscamet, cidovir (vistide), vitrasert, fomivirsen, HPMPA (9-(3-hydroxy-2-phosphonomethoxypropyl)adenine), PMEA (9-(2-phosphonomethoxyethyl)adenine), HPMPG (9-(3-hydroxy-2-(phosphonomethoxy)propyl)guanine), PMEG (9-[2-(phosphonomethoxy)ethyl]guanine), HPMPC (1-(2-phosphonomethoxy-3-hydroxypropyl)-cytosine), ribavirin, EICAR (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide), pyrazofurin (3-[beta-D-ribofuranosyl]-4-hydroxypyrazole-5-carboxamide), 3-deazaguanine, GR-92938X (1-beta-D-ribofuranosylpyrazole-3,4-dicarboxamide), LY253963 (1,3,4-thiadiazol-2-yl-cyanamide), RD3-0028 (1,4-dihydro-2,3-benzodithiin), CL387626 (4,4'-bis[4,6-d][3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonylimino]-1,3,5-triazin-2-ylamino-biphenyl-2-,2'-disulfonic acid disodium salt), BABIM (bis[5-amidino-2-benzimidazolyl]-methane), NIH351, and combinations thereof.

[0087] Examples of preservatives suitable for use in the methods and devices described include, but are not limited to, alcohol, chlorhexidrine, iodine, triclosan, hexachlorophene, and silver-based agents such as silver chloride, silver oxide, and silver nanoparticles.

[0088] As anti-inflammatory agents, steroid and non-steroid anti-inflammatory agents may be included. Examples of suitable steroid anti-inflammatory agents include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoxymethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, flucortolone, fluorometholone, flupelolone acetate, fluprednylidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, halopredone acetate, hydrocortamate, hydrocortisone, loteprednol etabonate, madipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylamino-acetate, prednisolone sodium phosphate, prednisone, prednibar, prednylidene, remexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, any of their derivatives, and combinations thereof. In some variations, corticosteroids are used in the sinuses and other body structures described herein to prevent or reduce postoperative inflammation. Corticosteroids generally have high potency and high binding to glucocorticoid receptors and low bioavailability. For example, in some variations, the corticosteroid includes mometasone furoate, or a pharmaceutically acceptable salt, solvate, hydrate, ester, free base, enantiomer, racemate, polymorph, amorphous form or crystalline form thereof.In another modification, the corticosteroid includes dexamethasone, or a pharmaceutically acceptable salt, solvate, hydrate, ester, free base, enantiomer, racemate, polymorph, amorphous form or crystalline form thereof.

[0089] Examples of suitable non-steroidal anti-inflammatory agents include, but are not limited to, COX inhibitors. These COX inhibitors include COX-1 or COX non-specific inhibitors such as salicylic acid and derivatives, aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, sulfasalazine and olsalazine; para-aminophenol derivatives such as acetaminophen; indole and indene acetic acids such as indomethacin and sulindac; heteroaryl acetic acids such as tolmetin, dicofenac and ketorolac; arylpropionic acids such as ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, and oxaprozin; anthranilic acids (fenamate salts) such as mefenamic acid and meloxicam; enolic acids such as oxicams (piroxicam, meloxicam), and alkanones such as nabumetone. Also included as COX inhibitors are selective COX-2 inhibitors such as diaryl-substituted furanones such as rofecoxib; diaryl-substituted pyrazoles such as celecoxib; indole acetic acids such as etodolac and sulfonanilides such as nimesulide.

[0090] Examples of chemotherapeutic / antineoplastic agents that can be used in the devices described herein include, but are not limited to, anti-tumor agents (e.g., cancer chemotherapeutic agents, biological response modifiers, angiogenesis inhibitors, hormone receptor blockers, cryotherapeutic agents, or other agents that destroy or inhibit neovascularization or tumor formation), such as alkylating agents or other agents that directly kill cancer cells by attacking their DNA (e.g., cyclophosphamide, ifosfamide), nitrosoureas or other agents that kill cancer cells by inhibiting the changes necessary for cellular DNA repair (e.g., carmustine (BCNU) and lomustine (CCNU)), antimetabolites or other agents that interfere with specific cellular functions, usually DNA synthesis, to impede the growth of cancer cells (e.g., 6-mercaptopurine and 5-fluorouracil (5FU)), antitumor antibiotics and other compounds that act by binding to or intercalating with DNA to interfere with RNA synthesis (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin C and bleomycin), plant (vinca) alkaloids and other antitumor agents derived from plants (e.g., vincristine and vinblastine), steroid hormones, hormone inhibitors, hormone receptor antagonists, and other agents that affect the growth of hormone-responsive cancers (e.g., tamoxifen, herceptin, aromatase inhibitors, such as aminoglutethimide and formestane, triazole inhibitors, such as letrozole and anastrozole, steroidal inhibitors, such as exemestane), anti-angiogenic proteins, small molecules, gene therapy, and / or other agents that inhibit angiogenesis or vasculogenesis of tumors (e.g., meth-1, meth-2, thalidomide), bevacizumab (Avastin), squalamine, endostatin, angiostatin, angiozyme, AE-941 (Neovastat), CC-5013 (Revimid), medi-522 (Vitaxin), 2-methoxyestradiol (2ME2, Panzem), carboxyamidotriazole (CAI), combretastatin A4 prodrug (CA4P), SU6668, SU11248, BMS-275291, COL-3, EMD121974, IMC-1C11, IM862, TNP-470, Celebrex, Vioxx, interferon alpha, interleukin-12 (IL-12), or any of the compounds identified in "Science" Vol. 289, Pages 1197-1201 (Aug. 17, 2000), which is hereby expressly incorporated by reference, biological response modifiers (e.g., interferon, Bacillus Calmette-Guerin (BCG), monoclonal antibodies, interleukin 2, granulocyte colony-stimulating factor (GCSF), etc.), PGDF receptor antagonists, Herceptin, asparaginase, busulfan, carboplatin, cisplatin, carmustine, chlorambucil, cytarabine, dacarbazine, etoposide, fotemustine, fluorouracil, gemcitabine, hydroxyurea, ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, thioguanine, thiotepa, tomudex, topotecan, treosulfan, vinblastine, vincristine, mitoazitrone, oxaliplatin, procarbazine, streptocin, taxol, paclitaxel, docetaxel, docetaxel analog / conjugate, derivatives of such compounds, and combinations thereof.

[0091] Examples of decongestants that can be used in the devices and methods described herein include, but are not limited to, epinephrine, pseudoephedrine, oxymetazoline, phenylephrine, tetrahydrozoline, and xylometazoline. Examples of mucolytics that can be used in the devices and methods described herein include, but are not limited to, acetylcysteine, dornase alpha, and guaifenesin. Antihistamines such as azelastine, diphenhydramine, and loratadine can also be used in the systems and methods described herein.

[0092] Suitable hyperosmotic agents that can be used in the devices described herein include, but are not limited to, furosemide, sodium chloride gel, and other salt preparations that draw water out of tissues, or substances that directly or indirectly change the osmotic pressure of the mucosal layer.

[0093] Other bioactive agents useful in the present invention include, but are not limited to, free radical scavengers, nitric oxide donors, rapamycin, methylrapamycin, everolimus, tacrolimus, zotarolimus, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, tetrazole-containing rapamycin analogs such as those described in U.S. Patent No. 6,329,386, estradiol, clobetasol, idoxifene, tazarotene, alpha-interferon, host cells including, but not limited to, prokaryotes and eukaryotes such as epithelial cells and genetically engineered epithelial cells, dexamethasone, botulinum toxin and other neurotoxins, and any prodrugs, metabolites, analogs, homologs, conjugates, derivatives, salts and combinations thereof.

[0094] Examples of free radical scavengers include, but are not limited to, 2,2’,6,6’-tetramethyl-1-piperinyloxy, free radical (TEMPO); 4-amino-2,2’,6,6’-tetramethyl-1-piperinyloxy, free radical (4-amino-TEMPO); 4-hydroxy-2,2’,6,6’-tetramethyl-piperidine-1-oxy, free radical (TEMPOL), 2,2’,3,4,5,5’-hexamethyl-3-imidazolinium-1-yl oxy methyl sulfate, free radical; 16-doxyl-stearic acid, free radical; superoxide dismutase mimetic (SODm), and any analogs, homologs, congeners, derivatives, salts and combinations thereof. Examples of nitric oxide donors include, but are not limited to, S-nitrosothiol, nitrite, N-oxo-N-nitrosamine, substrates of nitric oxide synthase, such as diazeniumdiolate, for example spermine diazeniumdiolate, and any analogs, homologs, congeners, derivatives, salts and combinations thereof.

[0095] The choice of drug type, drug form (e.g., crystalline or amorphous), timing of delivery, and drug dosage may be determined by the intended treatment plan and may be further fine-tuned to meet the specific needs of the individual patient. The components of the drug delivery platform and the loading of the therapeutic agent onto the drug delivery platform can be varied to adjust the rate of drug release and / or the rate of movement of the drug into the tissue.

[0096] The desired type of movement can be achieved by changing the structure of the drug delivery platform, altering the components of the formulation and / or their amounts therein, and / or changing various steps of the manufacturing process of the drug delivery platform. For example, if linear or zero-order drug movement is desired, the drug may be provided with a non-drug polymer top coat. In an alternative embodiment, a primer coating that does not contain the drug can be incorporated between each drug layer. In other examples, first-order release is desired, and drugs that are combined with the polymer backbone and / or drugs that are combined in the top coating may be utilized.

[0097] The dosage of the drug (e.g., mometasone furoate) when the drug is delivered can range from about 10 micrograms to about 10 milligrams (10 μg - 10 mg), depending on the size of the implant and the amount of drug. For example, a drug implant that is 50% loaded, 0.3 mm in diameter, and 10 millimeters (10 mm) in length can contain 450 micrograms (450 μg) or 0.64 mg / mm 3 of drug dosage, and the drug is eluted in a sustained manner in vivo over 6 months. In another example, a drug implant that is 0.2 mm in diameter and 10 mm in length can contain 400 micrograms (400 μg) of drug dosage, and the drug elutes in vivo over 4 months. Of course, the treatment procedure may use multiple implants to increase the overall dosage of the drug delivered to the target tissue or the set of local tissues of the patient.

[0098] The therapeutic agent carried by the drug delivery platform can include any suitable number or combination of drugs and excipients, depending on the condition being treated, the desired drug release rate, coating migration, and the like. The drug delivery platform can include one, two, three, four, or five drugs, or six or more drugs. When two drugs are included in the drug delivery platform formulation, the drugs may be mometasone furoate and an antihistamine, or mometasone furoate and an antibacterial agent. Similarly, the drug delivery platform can include one, two, three, four, or five excipients, or six or more excipients. When the tissue to be treated includes mucociliary tissue, it may be beneficial for the drug layer to include one or more penetration-enhancing excipients, mucoadhesive excipients, or mucolytic excipients. For example, the drug delivery platform can include mometasone furoate as a drug, polysorbate as a penetration enhancer, polyacrylic acid as a mucoadhesive, and acetylcysteine as a mucolytic. The drug delivery platform can include a drug-to-excipient ratio in the range of about 3:1 to about 1:3.

[0099] By implanting a drug delivery platform that has a set pharmacokinetic profile and is local to the target tissue, controlled release of the drug limited to the target area is made possible. This further reduces patient compliance dependence on the intake of nasal steroid sprays or oral steroids. Additionally, concentrated local delivery is more beneficial than nasal sprays where the drug may be washed out before it can penetrate the mucosal tissue. Again, the drug delivery platform improves safety and avoids the systemic effects of steroids on the patient.

[0100] In one modification, the drug delivery platform formulation comprises a corticosteroid and a mucoadhesive excipient. In another modification, the drug delivery platform formulation comprises a corticosteroid and a muco-lytic excipient. In yet another modification, the drug delivery platform formulation comprises a corticosteroid and a permeation enhancer as an excipient. Also, the drug delivery platform formulation may comprise a corticosteroid, a mucoadhesive excipient, and a muco-lytic excipient, or may comprise a corticosteroid, a mucoadhesive excipient, a muco-lytic excipient, and a permeation enhancer. The corticosteroid in the aforementioned drug delivery platform may be mometasone furoate. Other drug delivery platform formulations may comprise an antibacterial agent in combination with one or more of a mucoadhesive excipient, a muco-lytic excipient, and a permeation enhancer. In some examples, the muco-lytic agent may be an active drug rather than an excipient in the drug delivery platform.

[0101] In some modifications, a drug delivery platform for treating nasal conditions comprises, as an active agent, an antibacterial agent such as amoxicillin, for example, and polysorbate as an excipient. In other modifications, a coating for treating nasal conditions comprises, as an active agent, an antibacterial agent such as amoxicillin, for example, and poly(vinylpyrrolidone) as an excipient. In yet another modification, a coating for treating nasal conditions comprises, as an active agent, an antibacterial agent such as amoxicillin, for example, and poly(ethylene glycol) as an excipient. Alternatively, a coating for treating nasal conditions may comprise, as an active agent, an antibacterial agent such as amoxicillin, for example, and a combination of polysorbate, poly(vinylpyrrolidone), and poly(ethylene glycol) as excipients.

[0102] When the nasal condition involves treatment of the inferior turbinate, a short delivery platform (e.g., less than 5 cm in length) may be useful for treating the anterior edge of the turbinate, while a medium-length delivery platform (e.g., 7 - 8 cm) may be useful for treating the posterior part of the inferior turbinate. For treating the turbinate, a slightly angled approach may be constructed within the distal end of the delivery system, and in this case the angle may be about 5 degrees to 45 degrees (5° - 45°), whereby delivery of the implant into or against the bone tissue within the anatomical structure can be avoided. For example, a delivery needle having a distal end bent at an angle of 10 degrees (10°) can facilitate accurate implantation of the drug delivery platform into the target turbinate tissue. When the nasal condition involves treatment of the middle turbinate, a relatively long delivery platform having a length greater than 8 cm (>8 cm) may be useful. When the nasal condition involves treatment of the nasal septum or other suitable tissue sites, a tissue pinching delivery device may be utilized for optimal implant penetration depth. Other nasal tissue sites may include the olfactory organ, the paranasal ostium, and / or the paranasal sinuses.

[0103] When the nasal condition is damage or hypofunction to the external nasal nerve, the drug delivery platform may contain a growth factor as a therapeutic agent. In such applications, the drug delivery platform can be implanted in proximity to the external nasal nerve, and in this case the growth factor carried on the delivery platform elutes locally to stimulate the growth of the external nasal nerve and / or stimulate healing to restore some degree of olfactory function. Growth factors considered for the treatment of sensorineural hearing loss include, but are not limited to, insulin-like growth factor, hepatocyte growth factor, fibroblast growth factor, and the like.

[0104] When the nasal condition is epistaxis, the drug delivery platform can be implanted in proximity to the target tissue site within the patient's nose where the bleeding source appears most. In such applications, the drug delivery platform may contain a vasoconstrictor and / or a hemostatic agent as a therapeutic agent.

[0105] When the ear condition is being treated, the drug delivery platform formulation may include an excipient or combination of excipients in addition to an antibacterial agent, an anti-inflammatory agent such as a corticosteroid like dexamethasone, or a combination thereof. For example, the antibacterial agent may include ciprofloxacin or amoxicillin, and the excipient may include polysorbate, poly(vinylpyrrolidone), or poly(ethylene glycol). In one variation, the drug delivery platform formulation includes ciprofloxacin as the antibacterial agent and polysorbate as the excipient. In another variation, the drug delivery platform formulation includes ciprofloxacin as the antibacterial agent and poly(vinylpyrrolidone) as the excipient. In yet a further variation, the drug layer formulation includes ciprofloxacin as the antibacterial agent and poly(ethylene glycol) as the excipient. In some examples, it may be useful for the drug layer formulation to include ciprofloxacin, as well as polysorbate, poly(vinylpyrrolidone), and poly(ethylene glycol) as excipients.

[0106] When the ear condition is sensorineural hearing loss, the drug delivery platform may include a growth factor as a therapeutic agent. In such an application, the drug delivery platform can be implanted in proximity to the cochlea, in which case the growth factor carried by the delivery platform elutes locally to stimulate cochlear growth and / or healing to restore some degree of hearing. Growth factors considered for the treatment of sensorineural hearing loss include, but are not limited to, insulin-like growth factor, hepatocyte growth factor, fibroblast growth factor, and the like.

[0107] When the ear condition is Meniere's disease, the drug delivery platform can include therapeutic agents including, but not limited to, ciprofloxacin, meclizine, diazepam, dexamethasone, mometasone furoate, fluticasone propionate, glycopyrrolate, lorazepam, and the like. In such an application, the drug delivery platform can be implanted in proximity to the inner ear, in which case the therapeutic agent carried by the platform can elute locally.

[0108] When the condition of the larynx is treated, the drug delivery platform formulation may include, as an active agent, an analgesic, an anesthetic, an anti-inflammatory agent (e.g., corticosteroid), an antibiotic, or a combination thereof. More specifically, when the condition of the larynx is tonsillitis, the drug delivery platform may include, but is not limited to, a non-steroidal anti-inflammatory agent, an analgesic, a therapeutic agent such as penicillin, etc. When the condition of the larynx is vocal cord polyp, the drug delivery platform may include, but is not limited to, a therapeutic agent such as prednisone, betamethasone, prednisolone, triamcinolone, methylprednisolone, mometasone furoate, fluticasone propionate, etc.

[0109] Transplant / delivery device The drug delivery platforms described herein may be delivered using any suitable injection device or transplant device (also referred to as an "applicator"). The transplant device can be configured to deliver the drug delivery platform as a minimally invasive means. The drug delivery platform is loaded into the transplant device, deployed from the transplant device at the target tissue treatment site of the subject, and then left in the target tissue, while the transplant device is removed from the subject.

[0110] Figure 2A shows an image of an exemplary implantation device 200 for injection or implantation of a drug delivery platform. The implantation device 200 has a distal end from which the drug delivery platform is injected into the target tissue site. It also has a proximal end from which a user can hold and manipulate the implantation device 200. The distal end of the implantation device 200 mainly includes a hypodermic needle 202 that can load the drug delivery platform. The hypodermic needle 202 can have a gauge and shape that can accommodate the size and shape of the corresponding drug delivery platform. In some embodiments, the hypodermic needle 202 may have a length of about 5 millimeters to about 100 millimeters (5 mm to 100 mm) or an increment of length within that range. For example, in certain embodiments, the hypodermic needle 202 may have a length of about 10 millimeters (10 mm), about 15 millimeters (15 mm), or about 20 millimeters (20 mm). In some embodiments, the hypodermic needle 202 may have a gauge (G) and inner diameter, or a gradient of the gauge and inner diameter, that is large enough to accommodate the width and diameter of the drug delivery platform, in which case the hypodermic needle 202 may be, for example (but not limited to), a 20G needle, 21G needle, 22G needle, 22sG needle, 23G needle, 24G needle, 25G needle, 26G needle, 26sG needle, 27G needle, 28G needle, 29G needle, or 30G needle.

[0111] The implant device 200 has a connector 204 that couples a subcutaneous needle 202 to a shaft 206 that constitutes the body of the implant device 200. In some embodiments, one or more drug delivery platforms can be disposed within the shaft 206 of the implant device 200 and configured to move into and through the subcutaneous needle 202. The one or more drug delivery platforms can be stored directly within the shaft 206 or within a cartridge loaded within the shaft 206. Two curved anchors 208 are disposed on opposing sides of the shaft 206 to provide a location for the user to place a finger. A plunger 210 having a curved base is provided at the proximal end of the implant device 200, where the plunger 210 is sized to fit within the shaft 206. When the plunger is pushed (distally) into the shaft 206, the drug delivery platform loaded within the subcutaneous needle 202 is pushed outward from the implant device 200. The distal end of the plunger (not shown) may be shaped to conform to or accommodate the shape of the drug delivery platform, thereby ensuring engagement and a smooth stroke as the drug delivery platform is pushed out of the implant device 200 while the plunger 210 is depressed. The implant device 200, and the various components of the implant device 200, can be formed from suitable materials including, but not limited to, plastics, metals, ceramics, combinations thereof.

[0112] Figure 2B shows an image of an alternative implantation device example 220 for injection or implantation of a drug delivery platform. The implantation device 220 has a distal end from which the drug delivery platform is injected into the target tissue site. It also has a proximal end from which a user can hold and manipulate the implantation device 220. The distal end of the implantation device 220 mainly includes: a hypodermic needle 222 that can be loaded with the drug delivery platform, and a rotary connector 224 that connects the hypodermic needle 222 to a shaft 226 that constitutes the body of the implantation device 220. In some embodiments, one or more drug delivery platforms can be arranged to be stored within the shaft 226 of the implantation device 220 and move into and through the hypodermic needle 222. The rotary connector 224 can have an indicator that aligns with an implant counter 228 engraved on the surface of the shaft 226. The rotary connector 224 can be adjusted manually or automatically along each injection of the drug delivery platform to track the implant counter 228 and continuously track the number of drug delivery platforms discharged (or not yet discharged) from the implantation device 220 by a visible signal or count. A driver 230 (also referred to as a slider) is disposed on the surface of the implantation device 220 and arranged to move along a long longitudinal slot of the shaft 226, thereby moving the driver from the proximal end to the distal end of the implantation device 220 and discharging the drug delivery platform. In some embodiments, individual drug delivery platforms can be discharged by the forward movement of the driver 230, while in other embodiments, the discharge of individual drug delivery platforms occurs after a cycle of moving the driver in the distal direction and then back to the proximal starting point of the subsequent drug delivery platform.

[0113] In some embodiments, one or more drug delivery platforms can be stored directly within the shaft of the delivery device, or within a cartridge loaded within or on the delivery device, or within a delivery system package. In other embodiments, the mechanical actuation system for expelling the drug delivery platform can be a button-based system, a spring injection system, or other spring-loaded system. Such systems allow the user to pre-load and inject the platform implant without directly pushing on the implant through a conventional finger-operated depressor or plunger. In some variations, the individual drug delivery platforms can be sequentially released and expelled from the device into the target tissue conduit.

[0114] For embodiments of the drug delivery platform formed with a degree of curvature, the subcutaneous needle of the implantation device can have a corresponding curvature at its distal end. In some embodiments, the distal end of the subcutaneous needle can have a curvature of about 10° relative to a length that is approximately equal to the length of the corresponding drug delivery platform. This curvature allows the platform to be implanted within tissue near the relaxed position of the platform.

[0115] Figure 2C shows a schematic view of the multi-implant rotation device loading structure 230 for the implant device described herein. The rotation device loading structure 230 may be incorporated into the implant device structure and may be a fixed module or a detachable / replaceable module of the implant device. The rotation device loading structure 230 includes a cylinder 232 having an opening 234 and a shaft 236, and each drug delivery platform (shown herein as the plurality of exemplary implanted drug delivery platforms 100 of FIG. 1A) can pass through the opening. The shaft 236 and the drug delivery platform 100 are within the housing 238, and the drug delivery platform 100 is attached inside the housing 238. The drug delivery platform 100 may be attached to the shaft 236, the cylinder 232, or both, and each of the plurality of drug delivery platforms 100 may be attached alongside each respective opening 234 of the cylinder 232. The drug delivery platform 100 may be attached using a structure such as a belt conveyor or a carousel, in which case the drug delivery platform 100 is firmly enough to move or reciprocate with rotation but loose enough to be easily removable when engaged at the proximal end by the drive member 240 and is connected to the conveyor or carousel. In the illustrated embodiment, the plurality of drug delivery platforms attached within the rotation device loading structure 230 may be five (5), and in an alternative embodiment, the plurality of drug delivery platforms attached within the rotation device loading structure 230 may range from two (2) to twelve (12). The cylinder 232 and the shaft 236 can be rotated (e.g., in the direction of the exemplary arrow shown), whereby one of the plurality of drug delivery platforms 100 is aligned with the drive member 240 (or also referred to as a "plunger").Similarly, the drive member 240 may also be aligned with the subcutaneous needle (disposed distal to the rotational device loading structure 230), such that, when the drive member 240 is actuated (e.g., when translating distally in a direction parallel to the longitudinal axis of the implantation device), the drive member 240 extrudes one of the plurality of drug delivery platforms 100 through each of the respective openings 234 of the cylinder 232 to the subcutaneous needle. The drive member 240 is mechanically coupled to different modules of the implantation device that are operated by a user, whereby the drive member 240 is enabled to be actuated.

[0116] Figure 2D shows a schematic view of the multiple implant magazine loading structure 242 for the implant device described herein. The magazine loading structure 242 may be incorporated into the implant device structure and may be a fixed module or a detachable / replaceable module of the implant device. The magazine loading structure 242 includes a casing 244 in which a plurality of drug delivery platforms (shown herein as the plurality of exemplary implantable drug delivery platforms 100 of FIG. 1A) are loaded, and also includes a rack 246 on which a plurality of drug delivery platforms 100 are mounted, and further includes a ring 248 which is arranged to align with one drug delivery platform 100 as the rack 246 moves through the proximal side of the ring 248. In the illustrated embodiment, the plurality of drug delivery platforms mounted within the magazine loading structure 242 may be six (6), and in alternative embodiments, the plurality of drug delivery platforms mounted within the magazine loading structure 242 may range from two (2) to twelve (12). As shown, a spring 250 is optionally disposed within the casing 244 and may be arranged to apply a force to drive the rack 246 in a direction such that the plurality of drug delivery platforms 100 move sequentially and align with the ring 248. The spring 250 applies a force to the rack 246 and does not directly apply a force to any of the individual drug delivery platforms 100. Thereby, accidental damage to the implant is avoided while it is loaded within the magazine loading structure 242. Alternatively, the movement of the rack 246 and any drug delivery platform 100 mounted thereon can be performed by manual translation using mechanical means by the user of the implant device. The rack 246 can be translated in a direction such that one of the plurality of drug delivery platforms 100 is aligned with the drive member 240. Similarly, the drive member 240 may also be aligned with the hypodermic needle (disposed distal to the magazine loading structure 242), whereby when the drive member 240 is actuated (e.g., when translating distally along the longitudinal axis of the implant device), the drive member 240 extrudes one of the plurality of drug delivery platforms 100 through the opening of the ring 248 into the hypodermic needle.The drive member 240 is mechanically coupled to different modules of the implant device that are operated by a user, whereby the drive member 240 is enabled to operate.

[0117] In another embodiment, by using a drug delivery platform having sufficient internal structural strength, the drug delivery platforms can be stacked directly on top of each other without a rack structure, and the spring can directly push in an array of stacked drug delivery platforms to advance or reciprocate the platforms to the insertion position. In such a tight loading configuration, the individual drug delivery platforms may be adhered together using a medium-strength adhesive that holds the platforms together when mounted within the magazine loading structure but does not prevent the drive member from separating the individual platforms during implantation.

[0118] For at least both the rotary device loading structure 230 and the magazine loading structure 242, the extraction length of the drive member 240 can be shortened to facilitate the implantation procedure. One way to shorten the extraction length of the drive member 240 is to use a mechanical connection between the drive member and the part of the implant device where the user applies force to increase the firing length of the drive member 240 by a ratio of 2:1 or more. Another way to increase the efficiency of the loaded implants is to use a helical loader within the handle of the implant device, thereby activating the drive member function to implant the platform and, simultaneously or sequentially, loading the next platform into the position required for the next implantation. Further, a tactile indicator (e.g., a notch or protrusion along the internal path of the drive member 240) and / or a visual indicator (e.g., a counter on each structure or on the implant device) can be used for confirmation of implantation to indicate to the user that the implant has been ejected from the rotary device loading structure 230 or the magazine loading structure 242.

[0119] By comparing the loading structures of FIGS. 2C and 2D, different advantages can be derived from the contrasting structures. For example, the opening 234 of the rotary device loading structure 230 can be constructed independent of the length of the implant, thereby allowing for a wider range of implant diameters to be used. In contrast, for the magazine loading structure 242, the tolerances and internal structure of the magazine loading structure 242 are dictated by the size and diameter of the implant, although such a tight loading structure can allow for a relatively compact form factor for the magazine loading structure 242. Both the loading structures of FIGS. 2C and 2D offer the advantage of being removable and interchangeable from the underlying delivery device, thereby providing greater efficiency and ease in manufacturing, sterilization, and clinical use. For example, in the case of sinus applications, a single delivery device having two multiple implant rotary device loading structures 230 (or two magazine loading structures 242 for a corresponding delivery device) can be provided to the physician. Each of the two loading structures can be a complete complement to the drug delivery platform implanted on one side of the sinus, and by efficiently fabricating the left and right implant cartridges, the physician can simply control the dosage on each side of the sinus based on the number of implants available within the cartridge.

[0120] Figure 2E shows a schematic view of two multiple implant loading needle structures 252 for the implant device described herein. In this case, a plurality of drug delivery platforms (shown herein as the plurality of exemplary embedded drug delivery platforms 100 of FIG. 1A) can be loaded in line with the subcutaneous needle 254 of the implant device, thereby facilitating point delivery from the delivery device. Thus, the drive member 240 disposed proximal to the subcutaneous needle 254 can be actuated (e.g., translated distally in a direction parallel to the long axis of the implant device) to directly extrude a plurality of drug delivery platforms 100 through the subcutaneous needle 254. The inner diameter (ID) of the subcutaneous needle 254 and the outer diameter (OD) of the drug delivery platform 100 can be matched such that while advancing by the drive member 240, the ID surface of the subcutaneous needle 254 provides sufficient support to the drug delivery platform 100 to avoid damage to the implant within the subcutaneous needle 254 even when loaded continuously in series. As shown, the right - hand embodiment of the needle structure 252 further includes a buffer element 256 disposed between each of the plurality of drug delivery platforms 100 within the subcutaneous needle 254. The loaded needle structure 252 may be connected to the distal end of the implant device or may be a fixed module or a detachable / replaceable module of the implant device. Further, a tactile indicator (e.g., a notch or protrusion along the internal path of the drive member 240) and / or a visual indicator (e.g., a colored mark indicating the position of the drive member 240 on the exterior of the implant device) can be used for confirmation of implantation to indicate to the user that the implant has been discharged from the loaded needle structure 252.

[0121] The buffer element 256 can reduce the risk of damage to the drug delivery platform 100 when it is present within and extruded through the subcutaneous needle 254. The buffer element 256 can be made of a gel, an aerogel, a water-soluble gel, a biodegradable substance, or other substances generally biologically neutral and non-toxic. Alternatively, the buffer element 256 can be made of a substance that is not configured to be implanted and is more powerful than a gel that is not necessarily biodegradable. Rather, with such a powerful buffer element, the implantation procedure can include a traction step, such as a proximal half-crank, for example, after the implantation of the drug delivery platform, such that while the platform is inserted within the tissue, the buffer substance is drawn out of the tissue by the traction. Thus, the buffer element can be expelled from and removed from the tissue region, after which subsequent implantation of the platform is performed.

[0122] In an alternative embodiment, a combination design can be used that combines the pre-loaded needle tip shown in FIG. 2E with either the multiple implant loading structure shown in FIG. 2C or FIG. 2D. In such a configuration, either a rotary device or a magazine's multiple implant loading structure is positioned in a proximal location within the delivery device, and the loaded needle structure is positioned in a distal location. When the implant is extruded from the proximal loading structure, it moves into the distal subcutaneous needle, and the structures are arranged such that the implant is extruded at the distal end of the needle. In this case, the implant can be a pre-loaded implant or an implant that has been previously moved into the needle from the reciprocation of a previous implant from the proximal loading structure.

[0123] Figure 2F shows a schematic (external and cross-sectional) view of the multi-lumen loading needle structure 258 for the multi-site implantation device described herein. Here, the lumen loading needle structure 258 includes an outer needle shaft 260 along with three lumens 262 disposed along the length of the lumen loading needle structure 258. Each of the three lumens 262 may have a series of drug delivery platforms 100 loaded therein in series. The drive member 240 is disposed proximal to the outer needle shaft 260 and is actuated (e.g., translated distally in a direction parallel to the long axis of the implantation device) to push directly into one of the lumens 262, thereby extruding one or more of the plurality of drug delivery platforms 100 through the lumen loading needle structure 258. After a drug delivery platform 100 is ejected from one lumen 262, a section of the lumen loading needle structure 258 can be rotated to realign the drive member 240 with a subsequent lumen 262. In one embodiment (labeled as any rotation A), the drive member 240 can be rotated by a mechanical operation to be sequentially aligned with one of the lumens. In another embodiment (labeled as any rotation B), the outer needle shaft 260 can be rotated by a mechanical operation to be sequentially aligned with the drive member 240. In a further alternative embodiment, the multi-site implantation device can have three drive members 240 aligned with each of the lumens 262, thereby enabling the simultaneous implantation of three drug delivery platforms 100. In another alternative embodiment, there may be two lumens 262 housed within the outer needle shaft 260, and the drive member 240 can be oriented accordingly. When using two or three lumens 262, the outer needle shaft 260 may have a diameter of less than 5 millimeters (<5 mm), which diameter may be advantageous for the operation of the device by a physician. In other embodiments, by using a wider gauge subcutaneous needle, four or more lumens loaded with drug delivery platforms can be disposed within the subcutaneous needle.

[0124] When the drive member 240 contacts the drug delivery platform, the distal end of the drive member 240 can be tapered to control movement and reduce the risk of clogging or damage to the drug delivery platform while being extruded through the subcutaneous needle. Similarly, the tip of the subcutaneous needle can be tapered to assist in advancing the implant into the tissue without damage or clogging of the drug delivery platform as it passes from the implantation device into the tissue.

[0125] Figures 3A - 3J show cross - sectional views of exemplary embodiments of an implantable drug delivery platform. Each of the illustrated embodiments has a body 300 of the platform into which a therapeutic agent is injected. Various embodiments of the drug delivery platform are illustrated as follows: Figure 3A shows a drug delivery platform having a circular cross - section. Figure 3B shows a drug delivery platform having a rectangular cross - section, specifically shown as having a square cross - section. Figure 3C shows a drug delivery platform having a triangular cross - section, shown as an equilateral triangle, but including non - equilateral triangles as well. Figure 3D shows a drug delivery platform having an oval cross - section. Figure 3E shows a drug delivery platform having a pentagonal cross - section. Figure 3F shows a drug delivery platform having a hexagonal cross - section. Figure 3G shows a drug delivery platform having a rhombic cross - section, where the interior angles of the rhombus can be adjusted to achieve the height and width of the target. Figure 3H shows a drug delivery platform having an octagonal cross - section. Figure 3I shows a drug delivery platform having a cross - shaped cross - section. Figure 3J shows a drug delivery platform having a four - pointed star cross - section.

[0126] Figures 3K - 3M show cross - sectional and perspective views of further exemplary embodiments of the implantable drug delivery platform. Again, each of the illustrated embodiments has a body 300 of the platform into which a therapeutic agent is injected. Various embodiments of these versions of the drug delivery platform further include a longitudinal channel along the major axis of the implant. Conversely, these structures may also be considered to be longitudinal protrusions along the major axis of the implant body 300. Figure 3K shows a pair of images (cross - sectional and perspective views) of a drug delivery platform having a generally circular cross - section with 10 channels. Figure 3L shows a pair of images (cross - sectional and perspective views) of a drug delivery platform having a generally circular cross - section with 4 channels. Figure 3M shows a pair of images (cross - sectional and perspective views) of a drug delivery platform having a generally oval cross - section with 4 channels. Figure 3N shows a drug delivery platform having a generally circular cross - section with 16 channels and further having the channels filled with a drug. It should be understood that the versions of the drug delivery platform shown in Figures 3K - 3M can also be filled with a drug in each of their channels, similar to the embodiment of Figure 3N.

[0127] The main non - drug components of the body 300 are generally formed from PLGA, and the L:G molar ratio of the PLGA can range from 100% lactide to 100% glycolide, or more specifically, from 10:90 to 90:10, or can be the remainder of the L:G ratios within that range. For example, in certain embodiments, the L:G molar ratio of the PLGA can be 5:95, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, or 95:5. Examples of variations in the composition of the body include PLGA formed with molar ratios other than those listed above, for example, intrinsic viscosity ( "IV" or η inh) can be achieved through additional control of material properties. For example, two or more forms of PLGA with different L:G molar ratios and / or intrinsic viscosities can be mixed together during the manufacturing process of the body 300. The intrinsic viscosity of the polymeric material used herein may vary from 0.2 dL / g to 1.0 dL / g, and in this case the material may be provided with an increment or gradient of IV within this range. In some variations, the IV of the polymeric material used herein may be greater than 1.0 dL / g. Another way to form a variation of the composition of the body may be through the use of ester-cap polymer end chains or acid-cap polymer end chains, or combinations thereof, which may act to control the biodegradation rate (i.e., slow down or speed up the rate). Various embodiments of the drug delivery platform may include any combination of one or more of the properties shown herein.

[0128] In some embodiments, as shown in FIGS. 3A and 3D, the body 300 may further include an optional core region 302. In some aspects, the core region 302 may be formed from a material different from the body 300. In other aspects, the core region 302 may be the same material as the body 300 but formed with a different design. For example, in one embodiment, both the body 300 and the core region 302 may be formed from PLGA, in which case the L:G molar ratio of the PLGA may include the remainder of the L:G ratios within that range and may be from 10:90 to 90:10, and different from the L:G molar ratio of the body 300.

[0129] In other embodiments, as shown in FIGS. 3B and 3E, the body 300 may be coated with an additional coating layer 304, in which case the coating layer may include the same or different therapeutic agents as the body 300. The coating layer 304 may additionally or alternatively include a release rate modifier (e.g., an excipient) that increases or decreases the rate at which the therapeutic agent is released from the drug delivery platform to the surrounding tissue.

[0130] In a further embodiment, as shown in FIGS. 3B and 3H, the body 300 can be kept empty (hollow) and filled with a therapeutic agent that is the same as the therapeutic agent embedded within the body 300, but in a different form (e.g., a crystalline, liquid, or gelled form of the agent), or can be filled with a therapeutic agent different from the therapeutic agent embedded within the body 300 (e.g., the channel region may contain a biological therapeutic agent), and may include a core region 306 (also referred to as the "inner channel"). In embodiments where the core region 306 is hollow, the implantable drug delivery platform may provide a flushing or drainage pathway through tissue or through an occluded space (e.g., a pathway partially blocked by inflamed tissue). In one exemplary embodiment, an implantable drug delivery platform having such a core region 306 may be implanted in the region of the middle ear or proximal tissue and provide treatment for otitis media that allows for the drainage and release of symptomatic fluid. Similarly, the core region 306 may provide a pathway through which pharmaceuticals can be delivered further into the ear canal (through inflamed or obstructed tissue or obstructions), more directly treat infection vectors, and / or deliver analgesics.

[0131] In some embodiments, as shown in FIGS. 3K - 3N, the body 300 may include one or more channels 308 (also referred to as "outer channels", "long pockets", "grooves" or "surface channels") that extend along the main axis (long axis) of the implant. The channels 308 may be formed within the body 300 of the implant by using a mold that provides a target cross-sectional shape during extrusion of the implant. Alternatively, the channels 308 may be (physically or chemically) engraved or etched within the body 300 of the implant, which is generally extruded with a smooth surface. In various embodiments, the number of channels 308 that may be formed within the body 300 of the implant may be one (1) to sixteen (16), as shown herein. The channels 308 may be arranged symmetrically or asymmetrically with respect to the outer perimeter of the implant. The channels 308 may be biased over a particular region of the implant; for example, all of the channels 308 may be formed on one side of the implant exterior, and the other surface of the exterior may remain smooth or uniform. The number of channels 308 formed within the implant may be odd or even. In a further variation, one or more channels 308 may be formed to proceed helically (twisted) around the surface of the body 300.

[0132] Channel 308 may be arranged in various patterns or arrays on the surface of the implant as a means for fine adjustment of flexibility, as a means for increasing the surface area for drug delivery, as a means for preventing movement of the implant within the tissue, and / or as a means for assisting in fixing the implant within the tissue. Compared to an implant without surface etching, channel 308 reduces the amount of material over the length of body 300. Nevertheless, the implant provides bending performance similar to the annular cross-section version of the implant, but due to at least a reduced amount of the bent body 300 structure, it has high flexibility from one end of body 300 to the other when bent and less physical distortion, and the presence of channel 308 can increase the structural elasticity of body 300. Further, when two or more implants are arranged adjacent to each other within the same tissue or are adjacent to each other in a row (for example, when three implants are successively placed within the inferior turbinate by a single delivery device), it is particularly important to prevent movement of the implants within the tissue, thereby preventing physical overlap and maintaining the desired therapeutic effect.

[0133] In other embodiments, as shown in FIG. 3N, one or more of the channels 308 may be additionally loaded or filled with an active therapeutic agent, referred to as a "fill agent" 310. Here, in addition to the body 300 formed of both a polymer backbone (e.g., PLGA) incorporating an active therapeutic agent (e.g., mometasone furoate), the channels 308 are further filled with the fill agent 310. Thus, by using additional agents that are mainly on the implant surface, even more doses of the agent can be delivered to the target tissue site. In contrast to later performing a drug-containing coating on the surface of the implant, the fill agent 310 is retained within the channels 308, reducing the risk of loss of the agent due to shear or friction during loading, transport, and implantation of the body 300. Further, since the fill agent 310 is on the surface of the implant and not incorporated as part of the body 300 of the implant, the implant can provide a two-stage drug delivery profile, where the fill agent 310 is first released from the channels 308 and then the agent is released from the body 300 structure. In practice, the number of channels that can be formed in the exterior of the implant, as well as the channel depth of such channels, is limited based on the overall width or diameter of the nasal, ear, and / or throat tissue implant.

[0134] In FIG. 3N, the channel depth (CD) is shown in more detail compared to the platform diameter (PD). In some aspects, each channel 308 may have the same channel depth within the body of the body 300 of the implant. In other aspects, one or more of the channels 308 may have different channel depths within the body of the body 300 of the implant. In various aspects, the channel depth of one or more of the channels 308 of the implant shown in FIG. 3N may be from about 5% to about 15% of the platform diameter.

[0135] In some embodiments, the channels may have a tapered depth and provide different implant rigidities from the proximal end to the distal end. In another embodiment, different dosages of the active therapeutic agent, or different amounts of the active therapeutic agent, may be packed in opposing sides or sections of the implant. The amount of the filling agent on the exterior of the implant may also provide a selective rigidity profile or bending profile. In other embodiments, materials with different hardnesses may be packed in the channels of the implant, in which case the material may not necessarily contain the active therapeutic agent, and the material may also provide a selective rigidity profile or bending profile. In further embodiments, free-floating or embedded materials may be packed in the exterior channels of the implant, in which case the material may not necessarily contain the active therapeutic agent.

[0136] Generally, the channels for any given drug delivery platform contemplated herein may have a channel depth of about 5%, about 10%, about 15%, about 20%, or about 25% of the platform diameter, or may have a depth between those percentage ranges. In a specific example, when using a circular implant with a platform diameter of 0.76 mm, the channel depth of all channels within the body is 0.06 mm, whereby the individual channel depth corresponds to about 8% of the platform diameter. Any one or more of the channels of the implant body may have different depths. Further, the number of channels within the implant body may affect the depth of those channels to ensure that the implant has sufficient structural strength and / or flexibility.

[0137] In a further modification example, the drug delivery platform may include one or more channels (extending within the platform diameter of the implant body) and one or more protrusions (extending beyond the platform diameter of the implant body). In such a modification example, the channels and protrusions may be arranged alternately, may be arranged opposite to each other, or may be biased to one section of the periphery or outer circumference of the implant.

[0138] Figures 4A - 4C show cross-sectional views of sections of an exemplary embodiment of an implantable drug delivery platform. The embodiments of Figures 4A - 4C further show versions of a drug delivery platform having a textured or rough surface, having a structure including protrusions, depressions, returns, anchors, etc. disposed around the surface perimeter of the drug delivery platform. Such a structure extends out from or into the body of the drug delivery platform, providing undulations and edges in the surface that can be captured, retained and / or fixed on the tissue into which the drug delivery platform 400 is implanted, thereby increasing the retention of the drug delivery platform 400 in the tissue.

[0139] Various undulating structures that modify the surface area by extending into or away from the core of the drug delivery platform 400 may be angularly offset from the long axis direction of the drug delivery platform 400, in which case the undulating structure may have an angle of about 45°. In other aspects, the undulating structure may have an angle in the range of an offset of about 15° to about 75° from the long axis of the drug delivery platform, or an incremental angle within the range. The undulating structures may be patterned around the surface area of the drug delivery platform 400 and may be linearly offset from each other on the drug delivery platform 400. Further, the undulating structures may be spaced from each other along the length of the surface area of the drug delivery platform 400 at a distance of about 1 millimeter (1 mm) or about 2 millimeters (2 mm). In some aspects, the undulating structures may be unidirectional when disposed on the drug delivery platform 400.

[0140] In FIG. 4A, the drug delivery platform 400 includes a recess 402, and the recess provides undulations and edges on the surface of the drug delivery platform 400. Although the recess 402 in FIG. 4A is shown as triangular, it is understood that the geometric shape of the recess may have another shape or may include a combination of different shapes. In FIG. 4B, the drug delivery platform 400 includes grooves 404 and protrusions 406, and they provide undulations and edges on the surface of the drug delivery platform 400. Although the grooves 404 and protrusions 406 in FIG. 4B are shown as having a chevron-like shape, it is understood that the geometric shapes of such grooves and protrusions may have another shape or may include a combination of different shapes. In FIG. 4C, the drug delivery platform 400 includes a protrusion 408, and the protrusion provides undulations and edges on the surface of the drug delivery platform 400. Although the protrusion 408 in FIG. 4C is shown as triangular, it is understood that the geometric shape of the protrusion may have another shape or may include a combination of different shapes.

[0141] FIG. 4A further shows a modified example of the drug delivery platform 400 having an arrowhead 410 at the distal end adapted for penetration into tissue. FIG. 4A further shows a modified example of the drug delivery platform 400 having a tail 412 at the proximal end, having a Y-shaped or arrow-shaped configuration and adapted for retention within tissue.

[0142] After the drug delivery platform is implanted into the target tissue, the implantation device is removed from the target tissue site.

[0143] Method The drug delivery platforms described herein may be delivered to target tissues of the nose, ear, or throat and may be used to treat conditions affecting those tissues. As described above, in some variations, the drug delivery platform may be delivered to the paranasal sinuses, paranasal ostia, nasal cavity, ethmoid sinuses, inferior turbinates, middle turbinates, natural ostium of the middle meatus, nasal septum, nasal vestibule, and / or nasal cavity. The method may be, for example, a method for treating nasal conditions such as postoperative inflammation, rhinosinusitis, and / or allergic rhinitis. In other variations, the drug delivery platform may be delivered to the eustachian tube, external auditory canal, and / or inner ear. The method may be a method for treating ear conditions such as postoperative inflammation, otitis media, Meniere's disease, and / or tinnitus. In yet other variations, the drug delivery platform may be delivered to the larynx for the treatment of postoperative pain such as pain due to tonsillectomy, or for the treatment of cancer (e.g., esophageal cancer), airway stenosis, chronic laryngitis, or epiglottitis. In further variations, the drug delivery platform may be delivered to a region or section of the skin to treat a wound or skin condition. The drug delivery platform may contain a dosage of drug designed to locally deliver an active agent to the target tissue and provide a sustained or prolonged release of the active agent at a therapeutic level for a desired period of time.

[0144] The methods described herein may include locally delivering a therapeutically effective amount of an active agent to a target tissue by insertion of a delivery device, deployment of a drug eluting implant, and retrieval of the delivery device.

[0145] FIG. 5A is a diagram of a paranasal sinus structure 500 showing the positions of the paranasal sinuses and implants with respect to a method of delivering a therapeutic agent using a drug delivery platform. In FIG. 5A, the left side of the image shows the structure of a healthy paranasal sinus, and the right side shows the structure of an affected and / or inflamed paranasal sinus. Specific portions of the paranasal sinus structure are labeled on the left side as follows: frontal sinus (FS), maxillary sinus (MS), ethmoid sinus (ES), nasal septum (NS), superior turbinate (ST), middle turbinate (MT), and inferior turbinate (IT). Candidate positions are shown on the right side of the image (using dashed lines). Considering the bilateral structure of the paranasal sinus structure, it is understood that the analogous structures on the right side have the same names and that the number of platforms that can be implanted within the structures on both sides of the paranasal sinus structure is the same. Position 502 is within the inferior turbinate, which can generally be accessed via the nasal passage, and one (1) to four (4) platforms can be implanted therein. Position 504 is within the middle turbinate, which can generally be reached via surgical access, and one (1) to three (3) platforms can be implanted therein. Position 506 is within the superior turbinate, which can generally be reached via surgical access, and one (1) to two (2) platforms can be implanted therein. Position 508 is within the nasal septum, which can generally be accessed via the nasal passage, and one (1) to four (4) platforms can be implanted therein. Position 510 is within the ethmoid sinus, which can generally be reached via surgical access, and one (1) to four (4) platforms can be implanted therein. In some examples, it may be desirable to also implant platforms in tissues of the frontal sinus, maxillary sinus, sphenoid sinus (not shown), ethmoid cells, middle meatus, natural ostium route of the middle meatus, nasal dike, or combinations thereof, and these paranasal sinuses can generally be reached via surgical access, and one or more platforms can be implanted therein.

[0146] Figure 5B shows a schematic diagram of an exemplary implantation configuration for a drug delivery platform 512 within an exemplary paranasal turbinate. As shown, the first turbinate 520, the second turbinate 530, and the third turbinate 530 have the drug delivery platform 512 implanted both in and across both the rostral (R) half (the region anterior from the frontal face of the turbinate) and the caudal (C) half (the region posterior from the frontal face of the turbinate) of each turbinate. Each turbinate shown may represent an implantation strategy for either the patient's superior turbinate, middle turbinate, or inferior turbinate. In the first turbinate 520, two platforms 512 are implanted in a stacked configuration that is substantially parallel to the long axis of the turbinate and in the relatively anterior rostral half of the center of the first turbinate 512 (above / below relative to each other). Such a relatively shallow implantation strategy, for example, may assist in the control of potential bleeding. The distance between the stacked drug delivery platforms can range from about 1 centimeter (1 cm) to about 5 centimeters (5 cm). In the first turbinate 520, the two platforms 512 are also implanted in the caudal half at an angle that is inclined with respect to the long axis of the turbinate. An implantation at an angle from a lower position to the turbinate, such as to access a certain anatomical structure or a particular anatomical structure that requires more urgent drug delivery treatment, may be preferred. Insertion at such an angle can of course also be done in the rostral half of the turbinate. In the second turbinate 520, three platforms 512 are implanted in a row with each other, spanning from the rostral half to the caudal half of the turbinate. Such an aligned insertion strategy, for example, can be performed in a series without removing the delivery device from the tissue and thus may assist in a speed - focused procedure that reduces the time required to implant all of the platforms 512. In the third turbinate 540, generally two platforms 512 are implanted along the same row, generally biased towards the rostral half of the turbinate but crossing the frontal face (i.e., the middle) of the turbinate. Further, both platforms are inclined with respect to the long axis of the turbinate at different angles with respect to each other. This implantation strategy may be performed by operating the delivery device during a single insertion into the tissue or by individual insertions into the tissue from an upper or lower position relative to the tissue.It is understood that the platform 512 can also be implanted with a certain offset or angle from the sagittal plane of each turbinate.

[0147] The agent may be formulated into an implant skeletal material such as PLGA by, for example, a melt fusion method or other suitable means. Thus, an exemplary drug delivery platform may be an implant in which 40 to 60% by mass is PLGA and the remainder is an active drug (e.g., mometasone furoate) (i.e., the other is 60 to 40% by mass). The PLGA used as the implant skeleton may have an L:G ratio of 10:90 to 90:10, or any incremental ratio within this range. In some examples, a certain percentage of the implant mass may be a different polymeric excipient.

[0148] The drug delivery platform may be placed within the tissue for any suitable period. It may be desirable to place the drug delivery platform in a given location for a sufficient period to move the drug contents and deliver one or more drugs to the tissue.

[0149] The implant may be removable, for example, by surgical means such as the creation and removal of tissue pockets. A retrieval aid may be designed at the proximal end of the device to grasp and remove the implant. In other examples, the implant may be non-biodegradable and removable. In some embodiments, the implant may have a certain degree of radiopacity, thereby allowing the implant to be located and removed.

[0150] In one exemplary use, the drug delivery platform can be implanted within the turbinate. For turbinate injection, pain from the procedure can be minimized by treating the subject with lidocaine or other topical drug or anesthetic. The subject may also be treated with a vasoconstrictor and / or hemostatic agent to minimize bleeding during the procedure. Also, pain and bleeding can be minimized by using an appropriately small implant and an injection needle profile of a delivery system such as a needle of 25G or less.

[0151] Multiple drug delivery platforms can be implanted into tissue up to clinically tested safety limits, in which case the multiple platforms are pre-loaded into the delivery device either directly or via a cartridge. Thus, the number of implants used can control the dosage of the active agent delivered to the target tissue. For example, at a dosage of 400 μg per platform, four (4) platforms can be pre-loaded into the device for use in implantation, achieving a total target dosage of 1600 μg per given tissue area.

[0152] After the drug delivery platform is implanted into the target tissue, the active agent is gradually eluted over time. In some variations, depending on the particular therapeutic application, therapeutic-level drug delivery may be provided for a treatment time of about 1 month to about 12 months. In other variations, the treatment time may range from about 2 months to about 3 months, about 3 months to about 6 months, about 6 months to about 9 months, etc. For example, if the method is for the treatment of allergic rhinitis, it may be desirable to maintain a therapeutic level of drug during the allergy season (e.g., about 2 months to about 3 months). In another example, if the method is for the treatment of perineal allergic rhinitis, it may be desirable to maintain a therapeutic level of drug for as long as possible (e.g., about 6 months to 12 months) to minimize the total number of clinic visits required to obtain symptom relief. In other examples, the implant can be non-biodegradable and designed to elute for up to 2 years.

[0153] In some examples, the treatment method may include multiple rounds of treatment. For example, patients suffering from chronic conditions such as otitis media, or patients experiencing multiple allergy seasons per year (e.g., due to different allergens), may receive treatment once or twice a year. This can provide an effective continuous treatment regimen in addressing the condition and / or providing ongoing relief from symptoms associated with the condition.

[0154] For applications where long-term mechanical support is desired, the methods described herein may be combined with separate implantable devices. For example, the methods described herein may be combined with the placement of a scaffold or stent disposed in the nasal cavity or nasal cavity oropharynx that can maintain the physical configuration of the nasal cavity structure. In some variations, the scaffold or stent may be drug-eluting. If such a scaffold or stent is biodegradable, the drug delivery platform and the scaffold or stent may have the same pharmacokinetic profile, but this is not essential. In some variations, the scaffold or stent may be expandable (e.g., balloon-expandable or self-expanding). In some variations, the scaffold or stent may be biodegradable (e.g., including a biodegradable synthetic biopolymer), but this is not essential. If such a scaffold or stent is biodegradable, the drug delivery platform and the scaffold or stent may have the same biodegradation time profile, but this is not essential.

[0155] FIG. 6 is a flowchart 600 showing the steps of a method for delivering a therapeutic agent using a drug delivery platform to a patient's nasal cavity. At block 602, a treatment strategy can be prepared (e.g., by an ENT physician). One element of the treatment strategy may include the correlation between the number of drug delivery platforms to the implant and the dosage of the drug used in the treatment. For various strategies, the treatment may include implanting one to ten (1-10) drug delivery platforms on at least one bilateral side of the patient's nasal region. In one example, the treatment strategy may be symmetric and may involve implanting four (4) drug delivery platforms on both the left and right sides of the patient's nasal region. In this case, each platform has a dosage of 500 μg of API for a total of 8 implants, and the cumulative dosage is 4000 μg of API. In another example, the treatment strategy may be asymmetric and may involve implanting three (3) drug delivery platforms on the right side of the patient's nasal region and six (6) drug delivery platforms on the left side of the patient's nasal region. In this case, each platform has a dosage of 400 μg of API for a total of 9 implants, and the cumulative dosage is 5400 μg of API. In a further example, the treatment strategy may be asymmetric and may involve implanting zero (0) drug delivery platforms on the right side of the patient's nasal region and five (5) drug delivery platforms on the left side of the patient's nasal region. In this case, each platform has a dosage of 300 μg of API, and the cumulative dosage is 1500 μg of API. It should be understood that the treatment strategy can vary with different API dosages, different symmetric or asymmetric implant site biases, and include more or fewer drug delivery platforms compared to the above-described examples.

[0156] Another element of a treatment strategy may include determining the number of drug delivery platforms to implant in a particular tissue. In other words, multiple drug delivery platforms may be implanted at the location of a single tissue. When using an applicator having multiple platforms loaded into the delivery device, multiple platforms may be implanted while inserting the applicator into the target tissue once. Further, the medical condition being treated may lead to the number of drug delivery platforms to implant in a particular tissue. For example, with respect to the treatment of allergic rhinitis (AR), the strategy may be biased to have relatively more implants in the lower region of the nasal anatomical structure (e.g., inferior turbinate). In contrast, with respect to the treatment of chronic rhinosinusitis (CRS), the strategy may be biased to have relatively more implants in the upper region of the nasal anatomical structure (e.g., middle turbinate and superior turbinate). With respect to the treatment of anosmia attempting to restore a patient's "persistent loss of smell", the strategy may focus on the delivery of implants to olfactory receptors, the superior turbinate, or adjacent tissues.

[0157] At block 604, a determination may be made to take a treatment delivery method that focuses on the rate of treatment, or hemostatic control of the patient. The choice of a rate approach, or a hemostatic control approach, often depends on the assessment of the surgeon and the individual receiving the implant. A physician who is familiar with a given patient's medical history may prefer to select a hemostatic control approach to the implantation procedure if the physician believes the patient is more likely to experience relatively severe nasal bleeding. Conversely, if the physician considers the duration of the procedure and potential pain management to be greater concerns, the physician may select a rate approach to the procedure. Additionally or alternatively, guidance may be provided to the operator delivering the implant to the patient, explaining one or more rate-focused approaches and hemostatic control-focused approaches for delivering the therapeutic agent, and further explaining the patient characteristics that may assist the physician in making a determination between a rate-focused approach and a hemostatic control-focused approach.

[0158] When proceeding along the velocity approach of flowchart 600, at block 606, using the first applicator, the drug delivery platform is implanted into all the selected structures on both first sides of the patient's paranasal sinuses. In other words, either the left or right paranasal sinus of the patient is selected as the first side of the procedure, and then a determined number of drug delivery platforms are implanted into the selected tissue. The related tissue structures may include the inferior turbinate, middle turbinate, superior turbinate, nasal septum, tissue defining the ethmoid sinus, or other structures in the nasal cavity. One or more drug delivery platforms can be implanted into any one or more of the selected tissues. In one example, the treatment strategy may be to implant two platforms into the inferior turbinate, one platform into the middle turbinate, and one platform into the superior turbinate. In another example, the treatment strategy may be to implant one platform into the inferior turbinate, one platform into the middle turbinate, one platform into the superior turbinate, and one platform into the upper region of the nasal septum.

[0159] At block 608, using the same or a subsequent applicator, the drug delivery platform is implanted into all the selected structures on the second sides of the patient's paranasal sinuses, and the second side is opposite to the first sides of block 606. In some embodiments of the method, the treatment strategy for the second sides of the paranasal sinuses may be the same as the strategy for the first sides of the paranasal sinuses. In other embodiments, the treatment strategy for the second sides of the paranasal sinuses may be different from the first sides of the paranasal sinuses, and may involve using more or fewer drug delivery platforms and / or implanting more or fewer platforms into mirror structures (e.g., implanting 3 platforms into the left middle turbinate and 4 platforms into the right middle turbinate). After implanting the drug delivery platforms into the second sides of the patient's paranasal sinuses, at block 620, the applicator is removed and the procedure is completed.

[0160] When proceeding along the hemostasis control approach of flowchart 600, at block 610, using the first applicator, the drug delivery platform is implanted into the first selected structure on the first bilateral sides of the patient's paranasal sinuses, and then into the first supplementary selected structure on the second bilateral sides of the patient's paranasal sinuses. One approach to bleeding control may be to implant a plurality of platforms in a row within a sufficiently large structure, such as the inferior turbinate for example, whereby the total number of insertions and removals into the required tissue can be reduced. For example, in this step, two (2) platforms may be implanted into the right inferior turbinate, and then two (2) or more platforms may be implanted into the left inferior turbinate. Regarding the hemostasis control approach, by switching sides during the procedure, the amount of short-term trauma to the local paranasal sinuses or nasal region can be reduced, thereby generally avoiding excessive bleeding from local capillaries.

[0161] At block 612, using the first applicator, or a subsequent applicator, or a combination thereof, the drug delivery platform is implanted into the second selected structure on the first bilateral sides of the patient's paranasal sinuses, and then into the second supplementary selected structure on the second bilateral sides of the patient's paranasal sinuses. For example, in this step, two (2) platforms may be implanted into the right middle turbinate, and then one (1) or more platforms may be implanted into the left superior turbinate. When continuing along the hemostasis control approach, at block 614, using the first applicator, or a subsequent applicator, or a combination thereof, the drug delivery platform is implanted into the third selected structure on the first bilateral sides of the patient's paranasal sinuses, and then into the third supplementary selected structure on the second bilateral sides of the patient's paranasal sinuses. For example, in this step, two platforms may be implanted into the left middle turbinate, and then if accessed from the right side of the patient's nasal region, another one (1) platform may be implanted into the nasal septum.

[0162] For some treatment strategies, it is understood that on a given side of the nasal region of a patient who requires implantation of a drug delivery platform, there may be only one or two target tissues. Thus, in some embodiments, blocks 612 and 614 are optional or may require only partial (one-sided) completion. Conversely, as reflected in block 614, for a given treatment strategy, additional sequential implantations (e.g., fourth or fifth cycles) may be required. After implanting the drug delivery platform into the last of the selected target tissues, at block 620, the applicator is removed and the procedure is complete.

[0163] When the methods described herein are combined with another implantable device, the drug delivery platforms described herein may be delivered to the target tissue prior to implantation of the other implant, or inserted into the tissue to be used after implantation of the other implant. In a variation where an expandable member is used first, the expandable member device can help to pre-expand the small holes and improve the ease of delivery and implantation of the implant into the target tissue. In a variation where the expandable member is used second, the device can help to expand the implant later to improve alignment. In addition to assisting in the delivery of an effective local dose of the drug, when combined with a scaffold or stent, the methods described herein can, for example, help to maintain the patency of the sinuses and prevent blockages caused by adhesions between the healed mucosal surface or the inflamed mucosal surface.

[0164] Manufacture The devices described herein can be made in any suitable manner. Generally, a mold may be used to form a drug delivery platform designed for a particular anatomical structure, and the material selected for the drug delivery platform may be based on the desired compliance for a particular application.

[0165] The drug can be loaded, impregnated, dispersed, saturated, incorporated, packed, or embedded onto or within the implant by methods such as heat-melt extrusion molding, melt compounding, solvent casting, emulsion-based spray drying, spray coating, injection molding, thermoforming, etc. In the case of heat-melt extrusion molding, PLGA may first be pulverized (e.g., by crushing, cryogenic grinding, etc.) to a smaller micro-particle size close to the size of the drug particles. Then the drug and PLGA are dry mixed, melt compounded together, extruded, and cut to form into a helical shape, rod shape, pellet shape, etc.

[0166] FIG. 7 is a flowchart 700 showing the steps related to a method for fabricating a drug delivery platform via partially thermal melt extrusion. The overall details regarding the thermal melt extrusion process can be found in "AAPS PharmSciTech", Vol. 17, No. 1, pp. 20 - 42 (February 2016), which is hereby expressly incorporated by reference. First, two routes for preparing the feedstock to be run through the extrusion process are shown. In the first route, at block 702, a source of the drug (or also referred to as "active pharmaceutical ingredient" or "API") to be used in the drug delivery platform is provided, where the API is generally provided in particulate form. It should be understood that one or more APIs can be supplied in this step, for example, to provide a desired therapeutic effect. At block 704, a source of the polymeric material to be used to form the drug delivery platform together with the API is provided. Similarly, it should be understood that one or more polymeric materials can be provided in this step to provide the targeted biodegradability and drug release profile. Optionally, at block 706, one or more excipients are provided simultaneously to form a drug delivery platform containing the API material and the polymeric material provided separately. At block 708, the polymeric material is milled such that the polymeric material becomes a size similar to that of the API material. For the components of this process, particularly for the API, cryogenic milling can be a beneficial technique used to control (i.e., dissipate) the heat generated from the mechanical impact and friction milling process, such that the API does not undergo an unintended chemical reaction or degradation due to the heat absorbed by the polymer during the milling process. At block 710, the API, the milled polymer, and the optional excipients are received from this first route, generally in the hopper of the thermal melt extrusion system.

[0167] Along a second path, at block 703, a source of the mixed API substance and the polymeric substance is provided. Again, it should be understood that one or more API substances and one or more polymeric substances may be provided to achieve the targeted therapeutic effect and drug release profile. Optionally, at block 705, one or more excipients are provided such that a drug delivery platform including the mixed or fused API and polymeric substances is simultaneously formed. At block 707, the source of the fused API and polymeric substances is milled such that the API and polymeric substances have similar particle sizes. Again, cryogenic milling, which is used to control heat so that the API does not undergo an unintended chemical reaction or decomposition caused by heat during the milling process, may be a beneficial technique. At block 710, the milled API, polymer, and optional excipient are received from this second path, generally in the hopper of a heat melt extrusion system.

[0168] Regarding the cryogenic milling of the polymers described in this specification, the cryogenic milling process may include the following steps and parameters to achieve a functional and targeted milling result. In some embodiments, the source polymer material used may be pre-cooled for 3 to 10 minutes, or for a longer time as needed, before being milled. After pre-cooling, the milling of the polymer may proceed for 2 to 6 minutes. In some embodiments, multiple pre-cooling - milling cycles (e.g., 2 cycles, 3 cycles, 4 cycles, etc.) may be used to achieve the targeted polymer particle size. The duration of mixing may help provide a uniform distribution of the polymer and the API, and in this case, the overall or total duration of mixing may range from 10 minutes to 60 minutes or more. The amount of the milled source polymer may be in the range of about 5 milliliters to about 50 milliliters (5 - 50 mL), and the volume of this polymer can be maintained at a temperature as low as -196 °C by the use of liquid nitrogen or liquid oxygen. The size of the cryogenically milled polymer may be about 100 micrometers (100 μm), and in some aspects, may further be in the range of about 10 micrometers to about 400 micrometers (10 - 400 μm). At a particle size of about 10 - 400 μm, the polymer may have a relatively high intrinsic viscosity sufficient to retain its structure after extrusion, molding, or other implant-forming processes when combined with the API. Further, at a particle size of about 10 - 400 μm, the polymer is relatively small enough to cover the drug when melted and mixed together when combined with the API (e.g., mometasone furoate). Additionally, making the milled polymer and the API approximately the same size may help provide a uniform distribution of the polymer and the API.

[0169] In block 712, the hot melt extrusion system heats and / or melts the material received in block 710. The hot melt extruder moves the API and the polymeric material (and any excipients) along a screw device at a temperature above the melting point of the input material. In some embodiments, the temperature of the HME is controlled such that the polymer is melted to substantially surround the API. The screw device of the hot melt extruder may be a single screw extruder (SSE), a twin screw extruder (TSE), or a multi-screw extruder (MSE). By using a polymer and an API with a relatively uniform distribution as the feed material to the hot melt extruder, the resulting product compound has a similarly uniform distribution of the polymer and the API. The operating parameters of the screw device can be appropriately configured according to the size, properties, and amount of the input material to form a product containing components with a uniform distribution. In some embodiments, the hot melt extruder may have a rotating orifice of a desired shape that generates a helical channel when the implant is extruded.

[0170] In block 714, the product of the hot melt extrusion system is produced and cut to a target length suitable for implantation as a drug delivery platform.

[0171] In current examples of drug delivery platforms, the implant's skeleton is formed from PLGA, and the active therapeutic agent is mometasone furoate. It should be understood that, upon reading the present disclosure as a whole, other specified biodegradable polymers and substances can be used as the implant's skeleton, and other specified drugs can be used as the implant's active therapeutic agent. PLGA and mometasone furoate can be combined by hot melt extrusion to form a drug delivery platform that, while achieving a high drug load, maintains the drug in a crystalline structure and has consistent manufacturability to meet targeted specifications. In the hot melt extrusion process, both the drug and the skeletal material (e.g., PLGA) can be provided as particles, both having a particle size of about 10 to about 500 micrometers (10 - 500 μm), and dry mixed prior to extrusion. Optionally, the drug and PLGA can be pelletized by crushing, milling, cryogenic milling, or other mechanical techniques to reach the targeted particle size. Optionally, the mixture of drug and PLGA can be combined in a first melt and then pelletized into particles of the targeted size.

[0172] The combined drug and PLGA pellets, or a mixed population of drug pellets and PLGA pellets, are continuously extruded in a hot melt process and can then be hot drawn or cold drawn to the planned size and shape of the drug delivery platform. The extruded drug delivery platform can then be cut to length.

[0173] Further improvements to the manufacturing process include scaling up the batch sizes of PLGA cryogenic milling and PLGA hot melt extrusion. Automated feeding, laser micrometer measurement of the extrudate size, as well as automated sorting and cutting are further manufacturing improvements. Further improvements can include an additional process where the pellets from the first hot melt extrusion process are fed through a second hot melt extrusion process to further improve the uniformity of the drug content.

[0174] In further embodiments, different polymers and / or different APIs may be used to similarly vary the milling and / or HME process to achieve implants having target structure, drug elution, and bioabsorption characteristics. For example, by using other APIs having different sizes, the corresponding polymers can be milled to similar sizes or to smaller sizes. In other embodiments, different excipients may be used to vary the dissolution rate and / or biodegradation rate of the platform. In other embodiments, the drug delivery platform may be a dual drug delivery platform, where two APIs are combined together or individually incorporated into the polymer backbone. Such dual drugs may be, for example, a corticosteroid and an antihistamine, or a corticosteroid and an antibiotic. By extension, the drug delivery platform may also be formed of three APIs that are tripled or individually incorporated with the polymer.

[0175] In alternative embodiments, the drug delivery platform may have one or more coating layers coated, packed, or layered on the surface of the platform. The one or more coating layers may be applied onto the platform by dip coating, spray coating, or other such processes. The one or more coating layers may be configured to slow down the release of the API from the drug delivery platform and / or slow down the bioabsorption rate, such that the time the platform remains intact within the tissue is extended. The one or more coating layers may be designed to have the same API as the core body of the drug delivery platform at the same dose or different doses, may be designed to have a different API from the core body of the drug delivery platform, or may be designed to have no API.

[0176] In some embodiments, the drug delivery platform may be formed to have a uniform distribution of API along the length of the platform, such that the drug eluting from the platform results in a similarly uniform area. In contrast, the drug delivery platform may be formed to have a gradient of API distribution along the length of the platform (e.g., when delivered by an applicator, the distal end of the platform has a relatively higher drug population than the proximal end), such that a similarly biased drug elution pattern results from the platform. In other embodiments, the drug delivery platform may be formed to have a uniform API distribution radially outwards from the center of the platform, such that generally constant or decelerating drug elution is provided over the biodegradation period of the implant. In contrast, the drug delivery platform may be formed to have a biased API distribution radially outwards from the center of the platform (e.g., the center of the platform has a relatively higher drug concentration than the surface area of the platform), such that generally constant, decelerating, or accelerating drug elution is provided over the biodegradation period of the implant. In other words, by using a configured gradient, the drug delivery platform may be formed to (i) have a high speed followed by a low speed release rate, such that a relatively high dose is achieved at the beginning of treatment and a relatively low dose is achieved at the end of the treatment period, (ii) have a low speed followed by a high speed release rate, such that a relatively low dose is achieved at the beginning of treatment and a relatively high dose is achieved at the end of the treatment period, or (iii) have a relatively constant release rate over the treatment period, such that a constant dose is achieved.

[0177] Target specifications for an exemplary embodiment of the implant include dimensions compatible with a 25G needle, at least 50% of the drug amount (at least 50% of the implant is the active therapeutic agent), mechanical integrity for loading into the delivery device, mechanical integrity for implantation into the target tissue, and drug release and bioabsorption for 6 - 9 months.

[0178] In addition to the specific components of the agent, the manufacturing methods described herein can help minimize drug loss during delivery to the treatment site and maximize drug delivery at the time of implantation and upon contact with tissue.

Examples

[0179] The following examples are illustrative only and are not to be construed as limiting the present disclosure in any way.

[0180] Example 1: Drug Release and Pharmacokinetics Figures 8A and 8B are graphs showing the experimental results of the first test regarding this drug delivery platform, showing the cumulative drug release over time in the sheep nasal turbinate model. Specifically, implants loaded with mometasone furoate were tested for the cumulative release over time (average %) in the target animals. Figure 8A shows the relative cumulative drug release over time, and Figure 8B shows the relative concentration of the drug in the tissue over time.

[0181] Regarding implants, the folic acid mometasone-loaded drug delivery platform was manufactured with 50% folic acid mometasone by a microcompounder in either poly(D,L-lactide-co-glycolide) 50:50 or poly(D,L-lactide-co-glycolide) 75:25. The formed substance was cut into 10 mm lengths. Each drug delivery platform (one example is specifically shown as Figure 1A) contained an average of 450 μg of folic acid mometasone (MF). Samples were sterilized by electron beam irradiation and then implanted into the sheep nasal turbinates using a 23-gauge injection needle device (specifically, the implantation device shown in Figure 2A). The drug delivery platforms were then recovered at various time points as shown in the data of Figures 8A and 8B. The recovered platforms were measured for folic acid mometasone concentration by high performance liquid chromatography (HPLC). Turbinate tissue and plasma from the subject sheep were measured for folic acid mometasone concentration by liquid chromatography-mass spectrometry (LC-MS). As detailed in Tables 8A and 8B below, and as shown in Table 1 and considered, drug release from the implant was demonstrated to be approximately 25% at 7 days post-implantation, 50% at day 30, and 70% at day 90. The respective concentrations of folic acid mometasone in the local tissue (micrograms of MF per gram of tissue) were measured to be 0.2 μg / g at 7 days, 122.0 μg / g at 30 days, and 417.2 μg / g at 90 days. Folic acid mometasone has shown therapeutic efficacy at a concentration level of 0.1 μg / g, and thus, at all measured time points, therapeutic levels of MF concentration were shown. Blood samples taken from the subject sheep were also measured for folic acid mometasone (representing systemic concentrations), but at all measured time points, all blood samples were registered as below the lower limit of quantification (LLOQ). The lower limit of quantification of the subject protocol is 20 pg / mL.

[0182] When the implant is refocused, Figure 9 shows a pair of images of the recovery site of the drug delivery platform from the ovine turbinate (i.e., the target tissue after implant removal) at day 60 (left image) and day 90 (right image). Each turbinate shown has two positions (indicated by dashed circles), and at each position, one (1) drug delivery platform was implanted. Generally, the ovine inferior turbinates were used in the study, and the average length was 8.5 cm.

[0183] Figure 10 is a graph showing the experimental results of implant drug delivery platforms implanted within various parts of the ovine nasal structure. Specifically, the average in vivo tissue concentration (μg / g) over time from the implant drug delivery platforms in different ovine nasal tissues is shown. Table 1 is a summary of the data shown in the graph of Figure 10.

Table 1

[0184] In Table 1 (and Tables 3 and 5 below), some of the data points have standard deviation values. This reflects the fact that at a given time point, more than one drug delivery platform was recovered from the designated site. At other data points, there is only one measurement. This reflects the fact that at a given time point, only one drug delivery platform was recovered from the designated site.

[0185] As most notably seen from the data of the maxillary sinus and turbinate tissues, the amount of drug is sustained and even increasing at 30 and 90 days after implantation. By extrapolation, it can be predicted from this data that the implanted drug delivery platform has a drug delivery profile with release for up to 6 months or more.

[0186] Example 2: Feasibility of Implant Delivery and Recovery; Formulation Analysis; Drug Release and Pharmacokinetics The second test of this drug delivery platform was conducted in three cohorts (A, B1, and B2), evaluating the efficacy of drug release and pharmacokinetics in tissue recovered from sheep, along with the feasibility of implant delivery and recovery (using sheep tissue). Additionally, in this example, two alternative formulations of the API, mometasone furoate, were tested against each other. All implants were fabricated in the same manner as the implants described in Example 1 above, specifically, reloaded with 450 μg of MF again. The second test was extended to have three cohorts as more samples, time points, and formulations were added to the analysis.

[0187] An exemplary drug delivery platform had a first formulation of the drug, which was implanted into various nasal sinus structures of sheep subjects and then recovered at various time points. And the relevant tissues were assayed for mometasone furoate concentration. As shown in Table 2, at the time point of Day 0, in the frontal sinus, maxillary sinus, and nasal cavity tissues, each tissue contained a single 450 μg MF implant, and the amount of MF that had migrated into the tissue was relatively low but still exceeded the therapeutic level of 0.1 μg MF / tissue g. At the time point of Day 30, on both the left and right sides of the maxillary sinus and turbinate tissues, three 450 μg MF implants were included, and therapeutic amounts of MF were present in all of the assayed tissues. Further, at the time point of Day 90, again on both the left and right sides of the maxillary sinus and turbinate tissues, three 450 μg MF implants were included (1350 μg of MF in total dose), and therapeutic amounts of MF were present in three of the four assayed tissues.

Table 2

[0188] Subsequently, the exemplary drug delivery platform had a second formulation of the drug, which was implanted into various paranasal structures of the sheep subjects and then recovered at various time points. The relevant tissues were then assayed for mometasone furoate concentration. As shown in Table 3, at the 7-day time point, in the maxillary sinus and nasal tissues, each tissue contained a single 450 μg MF implant, and the amount of MF that had migrated into the tissue was relatively low, but still exceeded the therapeutic level of 0.1 μg MF / tissue g. At the 30-day time point, on both the left and right sides of the maxillary sinus and turbinate tissues, three 450 μg MF implants were included, and therapeutic amounts of MF were present in four of the six tissues assayed. At the 60-day time point, on the left and right sides of the turbinate tissues, three 450 μg MF implants were included, and therapeutic amounts of MF were present in both of the tissues assayed. At the 90-day time point, again on both the left and right sides of the maxillary sinus and turbinate tissues, three 450 μg MF implants were included (1350 μg MF total dose), and therapeutic amounts of MF were present in all six of the tissues assayed. At the 120-day time point, on the left and right sides of the turbinate tissues, three 450 μg MF implants were included, and therapeutic amounts of MF were present in both of the tissues assayed.

Table 3

[0189] Figure 11 is a graph showing the experimental results of Table 3 for the drug delivery platform using formulation 2. In the graph of Figure 11, it can be seen that the peak of the MF distribution in the tissue is at the 60-day time point, and the curve of the MF concentration present in the tissue extends beyond the 30, 60, 90, and 120-day time points.

[0190] Figure 12 shows four images of the recovery sites of the drug delivery platform from the ovine turbinate at day 60 (upper left image), day 90 (upper right image), and day 120 (lower two images). These implants were the drug delivery platforms of formulation 2. Each turbinate shown has multiple positions (indicated by the dashed circles), and at each position, one (1) drug delivery platform was implanted.

[0191] From the data shown in Tables 2 and 3 and in Figure 11, and the data shown in Figure 12, the ability of the drug delivery platforms described herein to deliver a therapeutic amount of drug to the target tissue for at least 120 days after implantation is supported.

[0192] As shown in Table 4, blood samples taken from the target sheep in the second trial were also measured for mometasone furoate as a representative of the systemic concentration. At all measurement time points, almost all blood samples were registered as below the lower limit of quantification of 20 pg / mL. This suggests that there is no significant systemic effect regarding MF delivery from the implanted platform.

Table 4

[0193] The implants recovered after removal were verified for the amount of drug remaining on the platform. As shown in Table 5, for both formulation 1 and formulation 2, a therapeutically effective amount of drug remained on the platform at all time points of day 0, day 30, and day 90. This suggests that sufficient drug remains on the platform and elution into the tissue continues, thereby delivering the therapeutic agent to each tissue.

Table 5

[0194] In summary, as presented in Table 6, the drug delivery platform used in the second test delivered mometasone furoate to the tissue, where it was implanted at therapeutic levels for at least 90 days for formulation 2 and at least 120 days.

Table 6

[0195] Therefore, this data indicates that the implanted drug delivery platform had a drug delivery profile with a release period of at least 4 months and, by extension, an even longer drug release period of more than 6 months.

[0196] Example 3: Drug Dosage and Distribution Analysis In a third test on this drug delivery platform, the number of drug delivery platforms implanted into the nasal turbinate was varied to verify drug administration. All implants were fabricated in the same manner as the implants described in Example 1 above, specifically loaded again with 450 μg of MF. The MF compound and the implant used the formulation specified as formulation 2 in Example 2 above. In Table 7, all tissues were examined on day 30 post-implantation to verify administration using the "minimum dose" of two (2) implants in the nasal turbinate, the "low dose" of three (3) implants in the nasal turbinate, and the "nominal dose" of six (6) implants in the nasal turbinate. The implants were placed in the nasal turbinate either at a relatively rostral or caudal position, and the opposite end of the nasal turbinate was left without implants in the adjacent area of the tissue. Each nasal turbinate tissue from the sample was tested in two parts. The nasal turbinate part without implants was isolated from the nasal turbinate part with implants to evaluate the amount of drug movement from the implant to the implant-free area.

Table 7

[0197] Figure 13 is a table plotting the data shown in Table 7 together with the control reference obtained from Formulation 2 of Example 2 above. As can be seen, the tissue sample without implant contained MF at therapeutic levels on day 30. This indicates that MF from the implant migrated through the turbinate tissue and was present at therapeutic levels for at least 30 days thereafter.

[0198] Figure 14 shows four images of the recovery sites of the drug delivery platform from the right turbinates of three different sheep on day 30 (the three left - hand images), and the recovery site of the drug delivery platform from the left turbinate of a sheep on day 180 (the right - hand image). Each of the turbinates shown has multiple positions (indicated by dashed circles), and at each position, one (1) drug delivery platform was implanted. For the day 30 samples, all implants could be removed from the mucosa of the turbinate tissue. For the day 180 samples, the implants were visible but were softer compared to day 30, and accordingly, recovery was more difficult.

[0199] As shown in Table 8, blood samples taken from the sheep subjects of the third test were also measured for mometasone furoate as a representative value of the systemic concentration. Similar to the initial test, almost all blood samples were registered as below the lower limit of quantification of 20 pg / mL at all measurement time points. This suggests that there is no significant systemic effect regarding MF delivery from the implanted platform.

Table 8

[0200] Figure 15 is a graph further showing the experimental results of the third test, verifying the distance that mometasone furoate moved starting from the implanted drug delivery platform and passing through the ovine turbinate tissue. In this case, a total of 18 drug delivery platforms were implanted in the left and right turbinates of the sheep, with 9 turbinates on each side in a mirror arrangement. The tissue was harvested on the 180th day and examined for the MF concentration. By measuring from each implanted platform, it was found that MF was at a therapeutic level in the range of 0.1 μg / g to 40 μg / g at a distance ranging from 1.2 cm to 5.5 cm away from each platform. This further supports that the drug from the implanted platform moves through the local tissue over 180 days.

[0201] Again, the implants recovered after removal were verified for the amount of drug remaining on the platform. As shown in Table 9, the implants were recovered from 4 animals on the 30th day. The implants were recovered from either the left or right turbinate and from either the rostral or caudal region of each turbinate. As can be seen from the data, on the 30th day, sufficient drug remained on the platform and elution into the tissue continued, thereby delivering the therapeutic agent to each tissue.

Table 9

[0202] In summary, as presented in Table 10, the drug delivery platform used in the third test delivered mometasone furoate to the tissue and was implanted at a therapeutic level there for at least 180 days.

Table 10

[0203] Therefore, this data shows that the implanted drug delivery platform has a drug delivery profile with a release of more than 6 months.

[0204] Unless the context clearly indicates otherwise, or the context is not clearly inconsistent, in the context of describing the present invention (especially in the context of the following claims), the use of the terms "a", "an", "the" and similar terms of reference is considered to include both the singular and the plural. Unless otherwise stated, the terms "comprising", "having", "including" and "containing" are to be construed as open-ended terms (i.e., meaning "including but not limited to"). The term "connected" is to be construed as meaning that, even if there is something intervening, part or all of it is included therein, added thereto, or joined together. Unless otherwise indicated herein, the recitation of a range of values herein is intended to serve as a concise way of referring individually to each separate value within that range or gradient thereof, and each separate value is incorporated herein as if it were individually recited herein. Unless otherwise indicated herein, or the context is not clearly inconsistent, all methods described herein can be performed in any suitable order. The use of any and all examples presented herein, or exemplary language (e.g.), is intended to more particularly illustrate embodiments of the present invention and, unless otherwise claimed, does not limit the scope of the present invention. There is no language in this specification that should be construed as suggesting that any unclaimed element is essential to the practice of the present invention.

[0205] For the purpose of carrying out the present invention, preferred embodiments of the present invention, including the best mode known to the inventor, are described herein. The present invention is capable of accepting various modifications and alternative structures, and specific exemplary embodiments thereof are shown in the drawings and described in detail above. Within the scope of the gist of the present invention, modifications of those preferred embodiments may become apparent to those skilled in the art upon reading the foregoing description. The inventor expects those skilled in the art to appropriately adopt such modifications, and the inventors intend that the present invention be implemented in ways other than those specifically described herein. Accordingly, while there is no intention to limit the present invention to the specific forms disclosed, on the contrary, it is to be understood that the present invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto, when permitted by applicable law. Further, unless otherwise indicated herein or clearly contradicted by context, in all possible variations, any combination of the above elements is included in the present invention. In certain embodiments, for example, the following are provided: (Item 1) A system for locally delivering a therapeutically effective amount of an active agent to a target tissue, comprising a bioabsorbable drug delivery platform, and an implantation device for the bioabsorbable drug delivery platform. (Item 2) The bioabsorbable drug delivery platform is a polymeric material scaffold, wherein the polymeric material is poly(D,L-lactide-co-glycolide), and the molar ratio of the poly(D,L-lactide-co-glycolide) can range from 0% to 100% lactide and 0% to 100% glycolide, and an active drug incorporated into the polymeric material scaffold. The system according to Item 1. (Item 3) The implantation device is a subcutaneous needle, A shaft mechanically coupled to the subcutaneous needle and configured to load and hold one or more drug delivery platforms, and A plunger engaged with the drug delivery platform loaded in the shaft and configured to move the drug delivery platform out through the subcutaneous needle, the system according to item 1. (Item 4) The implant device is A subcutaneous needle, A shaft mechanically coupled to the subcutaneous needle and configured to attach a cartridge, the cartridge being configured to hold one or more drug delivery platforms, the shaft, and A mechanical actuation system incorporating the shaft, the mechanical actuation system being configured to sequentially engage with the one or more drug delivery platforms loaded in the cartridge and individually move the one or more drug delivery platforms out through the subcutaneous needle, the system according to item 1. (Item 5) A bioabsorbable drug delivery platform, A polymer substance scaffold, and An active drug incorporated into the polymer substance scaffold, the bioabsorbable drug delivery platform. (Item 6) The platform according to item 5, wherein the platform comprises a core region and a body, and further wherein the core region comprises a design of a polymer substance and an active drug different from the design of the body. (Item 7) The platform according to item 5, wherein the platform further comprises a hollow channel, the hollow channel being configured to hold a volume of a therapeutic agent. (Item 8) The biodegradable drug delivery platform according to item 5, wherein the platform has a surface on the outer surface of the platform with depressions, grooves and protrusions that provide undulations, edges and shapes, or combinations thereof. (Item 9) The biodegradable drug delivery platform according to item 5, wherein the platform has a cross-sectional shape that is circular, rectangular, square, triangular, elliptical, cross-sectional, pentagonal, hexagonal, rhomboidal, octagonal, cruciform, or star-shaped. (Item 10) The biodegradable drug delivery platform according to item 5, wherein the therapeutic agent includes, but is not limited to, steroid or non-steroid anti-inflammatory agents such as mometasone furoate, fluticasone propionate, dexamethasone, and COX inhibitors. (Item 11) The biodegradable drug delivery platform according to item 5, wherein the therapeutic agent includes, but is not limited to, antibiotics such as ciprofloxacin and amoxicillin. (Item 12) The biodegradable drug delivery platform according to item 5, wherein the therapeutic agent includes, but is not limited to, analgesics such as ibuprofen, acetaminophen, bupivacaine, aspirin, and naproxen. (Item 13) The biodegradable drug delivery platform according to item 5, wherein the therapeutic agent includes, but is not limited to, growth factors such as insulin-like growth factor, hepatocyte growth factor, and fibroblast growth factor. (Item 14) The biodegradable drug delivery platform according to item 5, wherein the therapeutic agent includes, but is not limited to, anti-tumor agents such as paclitaxel, cancer chemotherapeutic agents, biological response modifiers, angiogenesis inhibitors, hormone receptor blockers, cryotherapeutic agents, or other agents that destroy or inhibit new tissue formation or tumor formation. (Item 15) The biodegradable drug delivery platform according to item 5, wherein the polymeric material scaffold has an intrinsic viscosity of 0.2 dL / g to 1.0 dL / g. (Item 16) The biocompatible drug delivery platform according to item 5, wherein the polymer of the polymer substance scaffold is an ester end cap, an acid end cap, or a combination thereof. (Item 17) A method for treating symptoms of a chronic, acute, or persistent condition, delivering a biocompatible drug delivery platform to a target tissue, eluting a therapeutic agent from the biocompatible drug delivery platform, and biodegrading the biocompatible drug delivery platform within the target tissue, the method comprising. (Item 18) The method according to item 17, wherein the condition includes, but is not limited to, postoperative inflammation, nasal cancer and paranasal sinus cancer, rhinosinusitis, chronic rhinosinusitis with or without nasal polyps, and paranasal sinus-related conditions including rhinitis such as allergic rhinitis and non-allergic rhinitis. (Item 19) The method according to item 17, wherein the condition includes, but is not limited to, ear-related conditions such as postoperative inflammation, otitis media, Meniere's disease, eustachian tube dysfunction, hearing loss, and tinnitus. (Item 20) The method according to item 17, wherein the condition includes, but is not limited to, larynx-related conditions such as postoperative pain, esophageal cancer, oral cancer, pharyngeal cancer, airway stenosis, tracheal stenosis, subglottic stenosis, chronic laryngitis, tonsillitis, vocal cord polyps, and epiglottitis.

Claims

【Claim 1】 The invention described in the specification.

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