EP2501433A1 - Vorrichtung zur implantation von zusammensetzungen sowie verfahren und kits dafür - Google Patents

Vorrichtung zur implantation von zusammensetzungen sowie verfahren und kits dafür

Info

Publication number
EP2501433A1
EP2501433A1 EP10832332A EP10832332A EP2501433A1 EP 2501433 A1 EP2501433 A1 EP 2501433A1 EP 10832332 A EP10832332 A EP 10832332A EP 10832332 A EP10832332 A EP 10832332A EP 2501433 A1 EP2501433 A1 EP 2501433A1
Authority
EP
European Patent Office
Prior art keywords
conduit
housing
implantation device
stylet
actuation mechanism
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10832332A
Other languages
English (en)
French (fr)
Inventor
William R. George
Christopher Loew
Jonathan O'keefe
Corinne Bright
David Henkel-Wallace
Jeffrey C. Cerier
Dawn M. Davila
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Talima Therapeutics Inc
Original Assignee
Talima Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Talima Therapeutics Inc filed Critical Talima Therapeutics Inc
Publication of EP2501433A1 publication Critical patent/EP2501433A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0069—Devices for implanting pellets, e.g. markers or solid medicaments

Definitions

  • the devices may be ergonomically designed so that they can be easily manipulated with the fingers of one hand.
  • the compositions may provide local sustained release of an antifungal agent for the treatment of a variety of fungal conditions, including onychomycosis. Implantation methods and kits including the devices are also described.
  • the nail may be afflicted by inflammatory conditions such as psoriasis and lichen planus; nail tumors such as glomus tumor or digital myxoid cyst; and infections such as paronychia and onychomycosis.
  • inflammatory conditions such as psoriasis and lichen planus
  • nail tumors such as glomus tumor or digital myxoid cyst
  • infections such as paronychia and onychomycosis.
  • the pathophysiology of each condition is closely tied to nail structure and function.
  • an understanding of nail anatomy and function is beneficial in developing therapy for nail conditions.
  • the human nail is a modified cutaneous structure often described as a unit comprising several parts: the nail matrix, the nail bed, the nail plate, the nail folds, and the cuticle.
  • the nail matrix is located beneath the proximal nail fold, and is the germinative portion of the nail unit that produces the nail plate.
  • the nail bed is a layer of epithelium lying between the lunula (the portion of the nail matrix usually visible as a gray-white half moon projecting just distal to the proximal nail-fold cuticle) and the hyponychium (the distal epithelium at the free edge of the nail).
  • the nail plate (fingernail or toenail) is produced by the matrix and progresses toward the tip of the fingers or toes as new plate is formed.
  • the primary function of the nail plate is to protect the underlying digit, but fingernails and toenails are often also cosmetically important for many patients.
  • Nail infections are common conditions of the nail. Onychomycosis, a fungal infection of the nail bed, matrix, and/or nail plate, is the most common nail infection.
  • onychomycosis The primary clinical features of onychomycosis are distal onycholysis (separation of the nail plate from the nail bed), subungual hyperkeratosis, and a dystrophic, discolored nail. Patients afflicted with onychomycosis are usually embarrassed by their nail disfigurement, but the infection is more than a cosmetic problem. It can sometimes limit mobility and indirectly decrease peripheral circulation, thereby worsening conditions such as venous stasis and diabetic ulcers.
  • Fungal infections of the nail can also spread to other areas of the body and potentially to other persons. The fungal infection can be caused by dermatophytes (e.g., Trichophyton rubrum and T. mentagrophytes), but may also be due to infection by Candida species or nondermatophyte molds such as Aspergillus species, Scopulariosis brevicaulis, Fusarium species, and Scytalidium species.
  • ketoconazole, Sporonox® capsules itraconazole
  • ketoconazole, Sporonox® capsules itraconazole
  • Lamisil® tablets terbinafine hydrochloride
  • Novartis Pharmaceuticals, East Hanover, NJ Diflucan® tablets (fluconazole)
  • fluconazole Pfizer, New York, NY
  • oral griseofulvin are commonly prescribed antifungal agents.
  • these oral antifungal products are associated with many systemic side effects such as headaches, stomach upset, skin rashes, and
  • Fluconazole is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of fungal nail infections.
  • FDA U.S. Food and Drug Administration
  • associated cure rates are not high and relapse is common. This is primarily due to the prolonged duration of treatment, e.g., one dose daily for at least three months, or once weekly for nine to twelve months, which often leads to poor patient compliance.
  • Topical therapy with antifungal agents such as fluconazole, ketoconazole, miconazole, terbinafine, tolnaftate, and undecylenic alkanolamide has been developed as alternative in treating onychomycosis.
  • antifungal agents such as fluconazole, ketoconazole, miconazole, terbinafine, tolnaftate, and undecylenic alkanolamide
  • Penlac® nail laquer (ciclopirox solution, 8%) (Dermik Laboratories, Berwyn, PA)
  • Topical mode of administration is seldom effective to treat more than mild nail unit infections because the active agent is unable to effectively penetrate the nail.
  • Topical therapy accompanied by chemical or physical abrasion of the nails has also been largely unsuccessful.
  • Topical antifungal therapy usually also involves daily application to the nails for several months, and thus, also poses a compliance problem.
  • compositions e.g., antifungal compositions
  • digit refers to a finger or a toe of a subject.
  • the antifungal compositions may be used to treat any suitable fungal condition, including onychomycosis.
  • composition composition, depot, and “implant” are used interchangeably throughout.
  • implantation devices may be configured so that they are capable of manipulation using the digits of one hand. In some instances, no more than two digits of one hand of a user are needed to manipulate the device.
  • the device may be designed such that it can be used either hand.
  • the implantation devices may also be configured to be disposable (and for single use) or for multiple use and re-sterilizable, if intended for reuse.
  • the device may be sterilized or re- sterilized by any suitable means including steam sterilization, electron beam sterilization, gamma irradiation sterilization, ethylene oxide sterilization, and dry heat sterilization.
  • the devices may also include beneficial safety features.
  • the devices may include a spring loaded actuation mechanism that fully retracts a skin- penetrating conduit and stylet into the housing after the antifungal composition is implanted.
  • Such an actuation mechanism may automatically initiate retraction of the stylet by retraction of the conduit.
  • the retraction of the conduit and stylet may be simultaneous or sequential. In some variations, retraction of the conduit may be staged.
  • Another beneficial feature of the implantation devices described here may be a stylet that remains stationary within the conduit (holding an antifungal implant within its lumen) while the conduit is advanced through the skin, and while the conduit is retracted to expose the implant.
  • a stylet is not actively deployed, i.e., advanced or pushed, to move the implant out of the conduit to the target location.
  • the stylet may serve, in part, to hold the implant in position within the conduit so that upon conduit retraction, the implant is left in place at the target location.
  • the stylet may be configured to be slidably disposed within the conduit lumen, it may also be capable of retracting into the housing after implanting the composition.
  • the implantation devices described here generally include a housing, a conduit having a lumen extending therethrough, where the conduit is slidably attached to the housing, a stylet slidably disposed within the conduit lumen, and a trigger for activating an actuation mechanism contained within the housing.
  • the devices may include one or more preloaded implants within the conduit.
  • the devices include a removable cap. In some embodiments the cap may also cover the actuator in order to prevent premature actuation of the device.
  • the devices include an acoustic silencer for dampening the sound of the actuation mechanism when it is activated.
  • the housing may be of any suitable size and shape.
  • the housing is sized and shaped for manipulation with the digits of one hand.
  • the housing may be rectangular, square, cylindrical, circular, or ovoid in shape, or define an orientation for use of the device.
  • the housing may also be configured to include features such as distinct areas for gripping, anti-slip elements, and markers for indicating depth of implantation.
  • the housing may also be provided with certain features that aid verification or confirmation that the antifungal composition has been left at the target location.
  • the housing may be made from a transparent material so that the distal end of the conduit and/or stylet can be easily visualized after being retracted. In other variations, a viewing window may be provided on the housing to visualize the distal end of the conduit and/or stylet.
  • the implantation devices will generally comprise an actuation mechanism that is configured to initiate retraction of the stylet upon retraction of the conduit.
  • the actuation mechanisms employed will generally hold the conduit and stylet in a first, extended position where the implant is contained within the conduit lumen, and upon activation by a trigger, move the conduit and stylet to a second, retracted position within the housing.
  • the devices include a spring loaded actuation mechanism.
  • the actuation mechanism comprises a rack and pinion assembly.
  • the actuation mechanism is configured to provide automatic retraction of the stylet upon retraction of the conduit.
  • a locking mechanism may also be included on the device to prevent premature activation of the actuation mechanism, or if the device is intended for single use, to prevent reuse.
  • the method includes gripping an implantation device comprising a conduit having a lumen, a stylet concentrically disposed within the lumen, and an actuation mechanism; positioning the device at a target location; and implanting the antifungal composition within the tissue of the target location by activating the actuation mechanism.
  • the device may be positioned, in part, by advancing the conduit through the skin to the target location.
  • the steps of gripping, positioning, and implanting may be completed with the digits of one hand, and implantation may generally occur by activating an actuation mechanism that initiates retraction of the stylet by retraction of the conduit.
  • the steps of gripping, positioning, and implanting are completed with no more than two digits of one hand. With respect to retraction, the conduit and stylet may be retracted simultaneously or sequentially.
  • compositions may be implanted within any suitable tissue or combination of tissues of a digit.
  • the compositions may be implanted within the nail fold, nail bed, and/or nail matrix. Any suitable number of compositions may be implanted.
  • Factors that may affect the number of compositions used may be the severity of the medical condition, the location of the disease in the nail unit, the active agent employed, or the particular digit being treated.
  • compositions that are implanted within the tissue of a digit may be used to treat any suitable medical condition of the digit and/or nail unit.
  • tissue into which the compositions may be implanted into include epidermal, dermal or subcutaneous or combinations thereof.
  • Suitable medical conditions that may be treated include infections, inflammation, and tumors affecting a digit and/or nail unit.
  • nail infections include, but are not limited to, distal and lateral subungual onychomycosis, endonyx onychomycosis, white superficial onychomycosis, proximal subungual onychomycosis, total dystrophic onychomycosis, Candida onychomycosis, and paronychia.
  • nail inflammation examples include, but are not limited to, those conditions associated with inflammatory diseases such as psoriasis and lichen planus.
  • nail tumors include, but are not limited to, glomus tumor, digital myxoid (mucus) cyst, subungual exostosis, and periungual angiofibromas.
  • the compositions may also be used to treat cosmetic nail unit conditions such as pitting, brittleness, or discoloration.
  • compositions described here generally include an active agent and a biocompatible carrier or a matrix forming material that may be a biodegradable, bioerodible, or bioabsorbable polymer.
  • the compositions may have any suitable form, and any suitable type of release, e.g., they may be configured for sustained release or immediate release. They may also be provided as solids, semi- solids, solids including particles, etc. When provided as a solid, the composition may be, e.g., a cylindrical implant. The particles may be formed as granules, pellets, beads, microcapsules, and microspheres, and the like.
  • the compositions may or may not also take the form of a semi-solid that solidifies after implantation.
  • Solidification may occur due to temperature changes after implantation or to diffusion of a solvent out of the composition into the surrounding tissue.
  • Exemplary compositions that may be used are described in assignee's co-pending U.S. Application Serial Nos. 11/302,014 and 11/441,747, which are hereby incorporated by reference in their entirety.
  • compositions described here may be delivered in any size, shape, and/or volume compatible with the site of implantation, as long as they have the desired drug loading and release kinetics, and deliver an amount of active agent that is therapeutic for the intended nail condition.
  • solid compositions may be formed as particles, sheets, discs, filaments, rods, and the like.
  • the compositions may be formed to have volumes between 0 mm 3 to about 20 mm 3 , between 0 mm 3 to about 10 mm 3 , or between about 1 mm 3 to about 20 mm In some instances, the compositions may be formed to have a volume between 0 mm 3 to about 1 mm 3. However, in some variations, the volume may be greater than 20 mm .
  • the implants may have a total weight from greater than 0 mg to about 25 mg, from about 0.1 mg to 10 mg, from about 10 mg to about 20 mg, from about 0.25 mg to about 5 mg, or from about 0.125 mg to about 1 mg. However, in some variations, the weight of the implant may be greater than 20 mg.
  • the composition is formulated as a solid implant and includes an active agent generally dispersed in a biocompatible carrier or matrix material.
  • the carrier or matrix material may be any biocompatible polymeric or non-polymeric material.
  • the biocompatible materials may also be biodegradable, bioerodible, or bioabsorbable.
  • the compositions may include at least about 30% by weight of an active agent, or in some instances, at least about 75% by weight of an active agent.
  • compositions described herein generally include any suitable active agent.
  • an antifungal agent may be used.
  • antifungal agents include without limitation, amorolfine, ciclopirox, flucytosine, griseofulvin, haloprogrin, potassium iodide sodium pyrithione, undecylenic acid, imidazole derivatives, triazole derivatives, allylamines, polyene antifungal antibiotics, antifungal organic acids, and combinations thereof. Allylamines such as terbinafine may be especially beneficial.
  • kits including the implantation devices are also described here.
  • the kits may comprise one or more implantation devices and one or more compositions, e.g., one or more antifungal compositions.
  • the compositions may be separately packaged or preloaded within the devices.
  • the kits include a plurality of compositions, the compositions may comprise the same or different active agent
  • FIG. 1 shows a perspective view of an exemplary implantation device.
  • Fig. 2 shows the implantation device of Fig. 1 broken apart to provide a more detailed view of the device components.
  • FIG. 3 provides a perspective view of the housing interior and actuation mechanism.
  • FIGs. 4-6 illustrate how the actuation mechanism of the implantation device in Fig. 1 works in an exemplary fashion to implant the antifungal composition.
  • Fig. 4 shows an exemplary way to release the distal end of the latch from the conduit hub to retract the conduit
  • Figs. 5 and 6 show an exemplary way to release the proximal end of the latch from the stylet hub to retract the stylet.
  • the implantation devices may be configured with one or more ergonomic features for ease of use, and/or one or more safety features.
  • the implantation devices may be configured in a manner that allows the user to grip it using one hand, and in some instances, with no more than two fingers, and implant a composition with minimal movement of the same hand used to grip the device. The minimal movement employed may impart greater accuracy to implantation of the composition.
  • the implantation devices described here may include a double retraction system that fully retracts both the conduit and the stylet disposed within the conduit into the housing of the device after implantation of the composition.
  • Implantation devices for implanting antifungal compositions within one or more digits are described.
  • the implantation devices may be configured so that they are capable of manipulation using no more than two digits of one hand of the user.
  • the devices may also include improved safety features.
  • the devices may include an actuation mechanism that fully retracts the skin-penetrating conduit and stylet into the housing after the composition is implanted. Such an actuation mechanism may automatically initiate retraction of the stylet by retraction of the conduit.
  • Implantation methods and kits comprising the devices are also described.
  • the implantation devices described here generally include a housing, a conduit having a lumen extending therethrough, a stylet slidably disposed within the conduit lumen, and a trigger for activating an actuation mechanism contained within the housing.
  • the devices may include one or more preloaded implants within the conduit.
  • the devices include a removable cap.
  • the cap may also cover the actuator in order to prevent premature actuation of the device.
  • the devices include an acoustic silencer for dampening the sound of the actuation mechanism when it is activated.
  • the housing is that portion of the implantation device that the user grips (holds) to implant the composition.
  • a conduit and stylet concentrically disposed therein may extend from the housing.
  • the conduit and stylet may be used in conjunction with an actuation mechanism contained within the housing to implant a composition.
  • a trigger for activating the actuation mechanism may also be included on the housing.
  • the housing may be of any suitable shape.
  • the shape employed will generally be one that allows manipulation of the device with one hand.
  • the housing is configured to be grasped with the palm of a user's hand.
  • the housing is shaped so that the user is capable of manipulating the device with no more than two fingers.
  • the housing may circular, ovoid, rectangular, or square in shape.
  • the device is shaped to define an orientation of use.
  • a substantially circular device may include a portion defining a flat surface for approximation to (placement against) the skin of a digit.
  • the housing is configured to include a grip portion.
  • the grip portion will typically be the area of the housing that the user holds when manipulating the implantation device.
  • the grip portion may be configured as a depressed or raised portion of the housing that the user can easily determine is to be used for finger placement.
  • the grip portion includes a compressible material that may enhance gripping ability or for comfort, etc. Exemplary compressible materials include compressible polymers, rubber, foam, and combinations thereof.
  • the grip portion may also include an anti-slip element to improve the grip and manipulation ability of the user.
  • the grip portion of the housing may be configured to include treading, grooves, ridges, or textured areas that aid grip.
  • the housing may be of any suitable size, but will generally be sized so that the implantation device can be manipulated with the digits of one hand. In some instances, the housing will be sized so that the devices can be manipulated with no more than two fingers of the same hand.
  • the housing will typically be configured to have a length, width, and thickness.
  • the housing may have a length ranging from about 5 cm to about 8 cm, or about 5cm to about 7 cm, or about 5 cm to about 6 cm.
  • the width of the housing may be between about 2 cm to about 4 cm, or about 2 cm to about 3 cm. Thickness of the housing may be between about 0.5 cm to about 1 cm.
  • the diameter of the housing may range from about 0.25 cm to about 3 cm, about 0.5 cm to about 1.5 cm, or about 0.5 cm to about 1.0 cm.
  • the housing may be made from any suitable material.
  • Exemplary materials for making the housing include, without limitation, fluoropolymers; thermoplastics such as polyetheretherketone, polyethylene, polyethylene terephthalate, polyurethane, nylon, and the like; and silicone.
  • the housing may be made from a transparent material to aid confirmation of implantation once the conduit and stylet have been retracted.
  • Materials with suitable transparency are typically polymers such as acrylic copolymers, acrylonitrile butadiene styrene (ABS), polycarbonate, polystyrene, polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG), and styrene acrylonitrile (SAN).
  • Acrylic copolymers that may be useful include, but are not limited to, polymethyl methacrylate (PMMA) copolymer and styrene methyl methacrylate (SMMA) copolymer (e.g., Zylar 631® acrylic copolymer).
  • the housing may include a viewing window configured to allow visualization of the distal end of the conduit and/or stylet in their retracted position so that implantation can be verified.
  • the housing is formed from an upper portion and a lower portion that are configured to be releasably or permanently secured to one another.
  • the upper and lower portions may include tabs, notches, grooves, channels, other openings, etc., that allow them to be screwed or snap fit together.
  • the upper and lower portions are secured using any suitable medical grade adhesive, such as cyanoacrylate or epoxy adhesive, and other adhesives, which are well known.
  • the upper and lower portions are secured using ultrasonic welding.
  • the housing may also be configured to include other features for improving the accuracy and safety of implantation.
  • the housing may include any suitable depth marker that may function as a ruler to indicate how far the conduit has been advanced into the tissue.
  • An exemplary depth marker would be markings on the housing adjacent a slide button coupled to the housing for advancing the conduit.
  • the conduit may untreated or treated with a coating.
  • Coating materials may be selected to create a hydrophilic surface, e.g. hydrophilic polymer coatings or a lubricous surface, e.g. siliconization. Coatings may be used inside the conduit that provides a barrier between the composition and the needle surface.
  • a locking mechanism may also provided on or within the housing that prevents premature activation of the actuation mechanism or if the device is intended for single use, prevents a reuse of the device.
  • the actuation mechanism may include a groove or channel so that upon receipt of a pin or other protrusion, the actuation mechanism may be locked in placed.
  • Other tongue- and- groove type locks and mechanisms including depressible tabs are also contemplated.
  • a conduit having a proximal end, a distal end, and a lumen extending therethrough will generally extend from the housing.
  • proximal end it is meant the end closest to the user's hand, and opposite the end near the implant, when the implantation devices are positioned against the skin.
  • One or more implants may be contained within the lumen of the conduit. These implants may be preloaded within the conduit or placed therein shortly before the implantation procedure.
  • the proximal end may include a conduit hub for releasable connection to the actuation mechanism.
  • the distal end will generally be configured to be sharp, beveled, or otherwise capable of skin penetration.
  • the conduit employed may be of any suitable gauge, for example, about 18 gauge, about 19 gauge, about 20 gauge, about 21 gauge, about 22 gauge, about 23 gauge, about 24 gauge. 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29 gauge, or about 30 gauge.
  • the wall of the conduit may also have any suitable wall thickness.
  • the wall thickness of the conduit may be designated as thin wall (TW), extra/ultra thin wall (XTW/UTW), or extra-extra thin wall (XXTW). These designations are well known to those of skill in the relevant art.
  • the conduit includes a retention element that helps retain the implant within its lumen until implantation.
  • retention elements include, without limitation, crimps, dimples, spurs, barbs, adhesives, perforable membranes, and combinations thereof.
  • materials may be placed in the lumen of the conduit distal to the implant in order to retain the implant within the lumen until implantation.
  • retention materials include without limitation, bone wax or any number of medical grade adhesives, gels, or greases, including silicones, cyanoacrylates, polyurethanes, polyethylene glycol and or other biocompatible polymers that may be used in the implant and epoxies.
  • the conduit may also be permanently or removably attached to the housing.
  • the conduit may be configured to be attached to the housing shortly before use of the device.
  • the conduit may be attached using one or more attachment mechanisms such as luer locks, tabs, or the like.
  • the connection between the attachment mechanism and the conduit should be able to withstand a push or pull force of between 0.5 pounds and 10 pounds.
  • the conduit includes a depth marker for implanting the composition a predetermined distance within the tissue.
  • the predetermined distance may be selected based on the location (e.g., depth) of the target location within the tissue, the desired plane into which the implant is placed, the desired angle of the conduit with the skin surface during conduit advancement, type of medical condition being treated, and/or user preference.
  • the predetermined distance may be between about 0.5 mm to about 10 mm.
  • the predetermined distance may be about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, or about 10 mm.
  • a stylet having a proximal end and a distal end may be concentrically and slidably disposed within the conduit lumen.
  • the stylet includes a stylet hub at the proximal end for releasable connection to the actuation mechanism.
  • the stylet may also help to hold the implant in place within the conduit lumen.
  • one or more implants are held within the conduit lumen between the stylet and a retention element.
  • the implantation devices will generally comprise an actuation mechanism that is configured to initiate retraction of the stylet upon retraction of the conduit. Retraction of the stylet may immediately follow retraction of the conduit or be delayed for a certain period of time.
  • the actuation mechanisms employed will generally hold the conduit and stylet in a first, extended position where the implant is contained within the conduit lumen, and upon activation by a trigger, move the conduit and stylet to a retracted position. Retraction of the stylet will generally occur after the conduit is retracted far enough so that the implant can be left within the tissue and its position undisturbed by movement of the stylet.
  • the retracting conduit may apply a frictional force to the implant in the retraction direction.
  • the stylet which would be stationary during this retraction, would oppose the retraction force and prevent implant movement.
  • the stylet should be designed to oppose a retraction force of between 0.5 ounces to 50 ounces.
  • the actuation mechanisms are configured to retract the stylet after retraction of the conduit has substantially exposed the implant.
  • the actuation mechanisms may be configured to retract the stylet after the conduit has retracted between about 1 mm to about 11 mm, between about 5 mm to about 10.5 mm, or between about 8 mm to about 10.5 mm.
  • the actuation mechanisms may be configured to retract the stylet after the conduit has retracted about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, or about 11 mm.
  • the actuation mechanism is configured to retract the stylet after the conduit has retracted between about 8.2 mm to about 10.5 mm.
  • the actuation mechanism may also be configured to partially retract the conduit and/or stylet (so that a portion still extends from the housing) or fully retract the conduit and/or stylet within the housing. Retraction may also be staged to proceed from partial retraction to full retraction.
  • the device includes a spring loaded actuation mechanism.
  • the amount of force provided by one or more springs in such systems upon activating the trigger may be about 0.25 lbf (pound-force) to about 2.5 lbf. In one variation, the amount of force provided is about 1 lbf.
  • the spring loaded actuation mechanism is a double retraction system.
  • the actuation mechanism is configured to provide automatic retraction of the stylet upon retraction of the conduit.
  • any suitable trigger may be provided on the housing to activate the actuation mechanism.
  • press buttons slidable buttons (slides), rotatable wheels, etc.
  • the trigger When the trigger includes a rotatable wheel, it may be part of a rack and pinion assembly (pair of gears) which is well known to those of skill in the mechanical arts.
  • the teeth on the wheel (pinion) will engage teeth on a linear bar (rack) so that rotational motion applied to the pinion will cause the rack to move linearly (and in turn, retract the conduit).
  • the slide may be coupled to the conduit so that retraction of the slide correspondingly retracts the conduit, which in turn, would facilitate retraction of the stylet. Further details on the retraction (actuation) mechanism are provided below.
  • the implantation devices described here may additionally include an acoustic silencer (not shown) to reduce the amount of noise made by the device during retraction of the conduit and stylet.
  • the device may include one or more coatings and/or liners with acoustic dampening properties.
  • the spring (140) may be selected based on one or more characteristics that may affect noise such as the amount of time for expansion. To illustrate, a spring configured to expand over a longer period of time may generate less sound than a spring configured to expand over a shorter period of time.
  • internal components such as the conduit hub (126) and/or the stylet hub (134) may be fabricated using a noise-dampening material.
  • the implantation devices lack one or more of the features used to dampen noise, and instead, may be configured with an audible indicator that lets the user know the implant has been deployed.
  • the device (100) comprises a housing (102) and a conduit (104) extending therefrom.
  • a depth marker (120) is provided on the conduit to indicate the depth to which the conduit should be inserted into the tissue.
  • the housing (102) includes a grip portion (106) with a depressed region (108) for placement of all or a part of the user's finger, e.g., a thumb. Adjacent the depressed region (108) is a ramped portion (110) where a part of the user's finger may also rest, e.g., for comfort or to aid pressing the trigger, which here is a push button (112).
  • the trigger may be a separate part, or it may be configured to be integral with the housing. When it is integral to the housing, it may be configured as a flexure, e.g., a "living hinge," which allows movement when the trigger is pressed. Other suitable triggers may also be used.
  • a compressible material (not shown), e.g., a compressible polymer, rubber, or foam may cover all or a portion of the depressed region (108) and/or ramped portion (110).
  • Treading (114) is provided on the housing (102) to enhance the grip and maneuverability of the device. Although the treading (114) is shown on a side of the device in Fig. 1, it may be placed on any suitable portion of the housing.
  • housing (102) may include an upper portion (116) and a lower portion (118). As previously stated, these portions may be configured to snap fit together or be attached using screws or well known medical grade adhesives. Also shown in Fig. 2 is the conduit (104) having a proximal end (122) and a distal end (124). The conduit (104) will usually have a lumen (not shown) extending therethrough. In this variation, a conduit hub (126) having a slot (127) is included at the proximal end (122). The conduit hub (126) may be attached to the conduit (104) by any suitable method. For example, medical grade adhesives, insert molding, etc., may be used. The distal end (124) is sharp and beveled to easily penetrate the skin.
  • the stylet (128) which is generally disposed concentrically within the conduit lumen, also includes a proximal end (130) and a distal end (132).
  • a stylet hub (134) is provided at the proximal end (130).
  • the stylet hub (134) may also be attached to the stylet (128) using medical grade adhesives, insert molding, etc.
  • the implant (136) will generally abut the distal end (132) of the stylet (128) within the conduit lumen.
  • Fig. 2 further shows, in part, an exemplary actuation mechanism of an implantation device.
  • the actuation mechanism comprises a latch (138) and a helical spring (140).
  • a helical spring is shown, it is understood that other types of springs are contemplated for example, a solenoid or linear induction motor, a bistable magenetic actuator, a bistable mechanism or a multi-stable structure (as in a carpenter's tape), a gas pressurized in a container coupled to a valve and a plunger.
  • the pressurized container may be provided, pressurized by a manual pump, or gas generating compound and a plunger.
  • part of the needle proximal to the housing can be cut helically, for example with a laser and the helix stretched, becoming the spring.
  • the latch (138) includes a proximal end (142) and a distal end (144).
  • the proximal end (142) may include an opening (146) for releasable connection to the stylet hub (134), and the distal end (144) may be configured to releasably connect to the conduit hub (126).
  • FIG. 3 the upper portion (116) of the housing (102) has been removed to illustrate the relationship of the implantation device components (as described for Figs. 1 and 2) when set in the device.
  • the conduit (104) is shown extending from the housing (102) in a first, extended position.
  • a helical spring (140) is concentrically disposed around the conduit (104).
  • the internal portion of the housing (102) will generally be configured so that prior to implantation, the spring (140) can be held in its compressed state. For example, narrowed regions, walls, etc., may be formed within the housing, as known in the art, to maintain spring compression.
  • the spring (140) is also held in its compressed state against conduit hub (126).
  • conduit hub (126) is held stationary by the latch distal end (144).
  • the stylet (128) (not shown) extends through the conduit lumen.
  • the stylet hub (134) provided at the proximal end of the stylet projects through the opening (146) to maintain the extended position of the stylet within the conduit lumen.
  • tabs (148) that fit within corresponding slots (150) within the housing maintain the axial position of the latch (138) within the housing at all times.
  • the user may then brace the device or the fingers being used to hold the device against the subject adjacent or near the injection site such that relative motion between the device and the subject during actuation is minimized.
  • the device is then fired when a user presses the trigger (112). Upon pressing the trigger, portions of the trigger force the distal end (144) of the latch (138) to lift and become released (disengaged) from the slot (127) in the conduit hub (126). This in turn allows the spring (140) to change from a compressed state to an uncompressed state, and retract the conduit proximally (partially or fully) to thereby expose the implant (136) to the surrounding tissue.
  • the conduit hub (126) continues to travel proximally to contact an angled portion (152) of the latch (138).
  • the angled portion (152) may form an angle with the horizontal plane of the latch of between about 30° to about 90°.
  • the angled portion (152) may form an angle with a horizontal plane of the latch of about 30°, about 35°, about 40°, about 45°, about 50°, about 55°, about 60°, about 65°, about 70°, about 75°, about 80°, about 85°, or about 90°.
  • the implantation devices may be adapted for implanting multiple implants
  • compositions within the tissue of one or more digits of the same subject may be modified to stop the retraction of the conduit at specific distances.
  • more than one latch may be provided and/or other types of springs may be used.
  • the device may implant a distalmost composition by retracting the conduit a distance sufficient for its deployment.
  • the user may reposition the device and again actuate the actuation mechanism to deploy the remaining implant, or current distalmost implant into the tissue. This sequence may be repeated any number of times, depending on the number of compositions to be implanted.
  • the devices may be reloaded with additional implants. In other variations, the devices are preloaded with the number of compositions to be implanted.
  • the devices When the devices are reused, they may be configured so that the latch and the spring may be repositioned (reset) in their original latched and compressed states without opening the housing.
  • the devices may include a second coiled spring proximal to the stylet hub that is compressed when the stylet and/or the conduit is retracted into the housing.
  • a second actuation mechanism may then release the second coiled spring to extend the conduit and/or the stylet out of the housing.
  • the actuation mechanism may also be reset manually, e.g., by use of a second slide or resetting tool that could reposition the mechanism through a hole in the housing.
  • the device would be sterilized between uses.
  • the implantation devices described here may implant one or more compositions within the tissue of a digit.
  • the implants may be of any suitable form, e.g., a solid, semi-solid, particles, suspension, emulsions, gel, liquid, crystals, or combinations thereof.
  • the implants may also be configured to have any suitable type of release profile.
  • the implants may be configured to release the active agent in a sustained release, controlled release, immediate release, burst release, etc., type profile.
  • the implants may include any suitable active agent.
  • analgesics narcotic and non-narcotic analgesics
  • anesthetics narcotic and non-narcotic analgesics
  • anti-infective agents anti-inflammatory agents
  • chemotherapeutic agents other small molecules, and combinations thereof
  • anti-infective agents include antibacterial agents, antifungal agents, antiviral agents, and antiseptics.
  • anti-inflammatory agents include nonsteroidal anti- inflammatory agents and steroidal anti-inflammatory agents.
  • compositions may contain any suitable antifungal agent.
  • antifungal agents include, but are not limited to, ciclopirox; flucytosine; griseofulvin; haloprogrin; potassium iodide sodium pyrithione; pentamidine; dapsone;
  • Atovaquone atovaquone; ; imidazole and triazole derivatives, including without limitation, albaconazole, bifonazole, butoconazole, clomidazole, clotrimazole, croconazole, econazole, fenticonazole, fluconazole, fosfluconazole, ketoconazole, isoconazole, Miconazole, miconazole,
  • triamcinolone acetonide, dexamethasone, and betamethasone may also be co-administered in the composition with the antifungal agent.
  • the implants used with the devices described here may also be made from any suitable biocompatible materials that are typically polymeric.
  • Exemplary materials that may be used include without limitation, polymers such as poly(lactide)s; poly(glycolide)s;
  • poly(lactide-co-glycolide)s poly(lactic acid)s; poly(glycolic acid)s; poly(lactic acid-co- glycolic acid)s; poly(caprolactone)s; poly(orthoester)s; poly(phosphazene)s;
  • Exemplary materials are also provided in copending U.S. Application Nos. 11/302,014 and 11/441,747, referred to above.
  • biocompatible implant polymeric materials that may be used alone or in combination with the biocompatible polymers mentioned above, include, but are not limited to, polyethylene glycol (PEG), polyvinylpyrrolidone, carboxymethylcellulose, ,natural polysaccharides such as chitosan, alginate, gelatin, and the like, , extracellular matrix components such as collagen, laminin, hylauronic acid, and the like, and blends and mixtures thereof may be used.
  • PEG polyethylene glycol
  • Other implant materials that may be used include, but are not limited to, vitamin E and its derivatives, dimethyl sulfone (MSM), and carbamide.
  • compositions that are implanted may also be of any suitable size, shape, and/or volume compatible with the site of implantation.
  • the solid implants may be formed as particles, sheets, discs, filaments, rods, and the like.
  • the solid implants may be formed to have volumes from between about 0.1 mm 3 to about 20 mm 3 , between about 0.1 mm 3 to about 15 mm 3 , between about 0.1 mm 3 to about 10 mm 3 , between about 0.1 mm 3 to about 5 mm 3 , or about 0.1 mm 3 to about 1 mm 3.
  • the solid implants may be formed to have volumes between about 1 mm 3 to about 10 mm 3 or between about 0.25 mm 3 to about 2 mm .
  • the implants When the implants are solid rods, they may be formed to have lengths between about 0.5 mm to about 8.0 mm.
  • the solid rods may have a length of about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, or about 8 mm.
  • the implants may have a total weight from greater than 0 mg to about 25 mg, from about 0.1 mg to 10 mg, from about 10 mg to about 25 mg, from about 0.25 mg to about 5 mg, or from about 0.125 mg to about 1 mg. However, in some variations, the weight of the implant may be greater than 25 mg.
  • the method includes gripping an implantation device comprising a conduit having a lumen, a stylet concentrically disposed within the lumen, and an actuation mechanism; positioning the device at a target location; and implanting a composition within the tissue of the target location by activating the actuation mechanism.
  • the device may be positioned, in part, by advancing the conduit through the skin to the target location. For example, the user may hold the device and advance the conduit through the skin until the depth marker is reached. The user may then brace the device or the fingers being used to hold the device against the subject adjacent or near the injection site such that relative motion between the device and the subject during actuation is minimized.
  • the steps of gripping, positioning, and implanting may be completed with the digits of one hand, and implantation may generally occur by activating an actuation mechanism that initiates retraction of the stylet by retraction of the conduit.
  • the steps of gripping, positioning, and implanting are completed with no more than two digits of one hand.
  • the device is gripped and held within the palm of the user.
  • the conduit is advanced within the tissue to the target location, and the actuation mechanism activated by a trigger using a finger of the gripping hand. With respect to retraction, the conduit and stylet may be retracted simultaneously or sequentially.
  • the positioning of the device against the skin of the subject may generally involve positioning of the conduit against the skin overlying the target area so that advancement of the conduit through the skin will be directed to the target area.
  • the shape of the housing may define an orientation of use of the device.
  • a substantially circular or disc-shaped housing may include a flat/linear side or edge that could be easily be approximated against the skin surface (either before or after implantation).
  • Implantation of the compositions by the actuation mechanisms described herein may occur, e.g., by the process illustrated in Figs. 4-6.
  • one or multiple compositions may be implanted.
  • the compositions may also be implanted within any tissue of the digit, e.g., the dermis, epidermis, subcutaneous tissue, hypodermis, the hyponychium, the nail bed, the nail matrix, the nail fold (including proximal, lateral, and distal nail folds), and combinations thereof.
  • the digit of implantation may be a finger or a toe.
  • the implants may be used to treat any suitable medical condition of the digit.
  • exemplary medical conditions include, but are not limited to, infections, inflammation, and tumors.
  • nail infections include without limitation, onychomycosis; including distal and lateral subungual onychomycosis, endonyx
  • nail inflammation examples include, but are not limited to those conditions associated with inflammatory diseases such as psoriasis and lichen planus.
  • nail tumors include, but are not limited to, glomus tumor, digital myxoid (mucus) cyst, subungual exostosis, and periungual angiofibromas.
  • the implants may also be used to treat cosmetic nail unit conditions such as pitting, brittleness, or discoloration.
  • kits may include any number of the devices and implants described herein. In general, the kits will also include instructions on how to use the device, e.g., how to assemble the devices if assembly is required, load the implants, position the device against the skin, etc.
  • One or more implants may be provided in the kit. When a plurality of implants is provided, they may of the same or different form, comprise the same or different active agents, and/or include the same or different doses of the active agent.
  • Each device and implant may be packaged in a separate sterile package or container. Instructions may be in written or pictograph form, or may be on recorded media including audio tape, audio CD, video tape, DVD, CD-ROM, or the like.
  • the kits may also include other supplies that may be used in conjunction with the implantation procedure such as gloves, drapes, betadine, alcohol wipes, gauze, bandages, anesthetic, etc.
  • kits may be tailored to treat specific medical conditions.
  • a kit may be designed for onychomycosis treatment.
  • Such a kit may include, for example, one or more implantation devices and one or more implants comprising terbinafine.
  • the kits may also be tailored to treat onychomycosis of the finger or toe.
  • a system for treating a fungal infection of the nail unit comprising: an implantation device; and a composition
  • the implantation device comprises: a housing; an actuation mechanism contained within the housing; a trigger coupled to the housing and configured to activate the actuation mechanism; a conduit slidably attached to the housing, the conduit having a proximal end, a distal end, and a lumen extending therethrough, and further having one or more depth markers and a gauge between 18 and 30; and a stylet concentrically disposed within the conduit lumen and having a proximal end and a distal end, and wherein the composition is preloaded within the lumen of the conduit, the composition comprising a biocompatible polymer and an active agent for treating the fungal infection.
  • conduit further comprises a conduit hub at the conduit proximal end.
  • stylet further comprises a stylet hub at the stylet proximal end.
  • the actuation mechanism comprises: a latch having a proximal end and a distal end, the distal end being releasably connected to the conduit hub and releasably coupled to the trigger; an opening at the proximal end of the latch releasably connected to the stylet hub; and a spring concentrically mounted about the stylet.
  • conduit comprises a retention element with the conduit lumen.
  • water-soluble matrix forming material is selected from the group consisting of polyethylene glycol, polylactic acid, a poly(lactic acid-co-glycolic acid) copolymer, a polyvinylpyrrolidone, or combinations thereof.
  • composition is a solid, a liquid, a semisolid, a suspension, or an emulsion.
  • An implantation device comprising: a housing sized and shaped for manipulation with the digits of one hand; an actuation mechanism contained within the housing; a trigger coupled to the housing and configured to activate the actuation
  • actuation mechanism configured to initiate retraction of the stylet upon retraction of the conduit.
  • conduit further comprises a conduit hub at the conduit proximal end.
  • stylet further comprises a stylet hub at the stylet proximal end.
  • actuation mechanism is a manual actuation mechanism.
  • actuation mechanism comprises: a latch having a proximal end and a distal end, the distal end being releasably connected to the conduit hub and releasably coupled to the trigger; an opening at the proximal end of the latch releasably connected to the stylet hub; and a spring
  • polymer wherein the polymer is selected from the group consisting of acrylic copolymers, acrylonitrile butadiene styrene (ABS), polycarbonate, polystyrene, polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG), and styrene acrylonitrile (SAN).
  • ABS acrylonitrile butadiene styrene
  • PVC polyvinyl chloride
  • PETG polyethylene terephthalate glycol
  • SAN styrene acrylonitrile
  • a method for implanting a composition comprising: gripping an implantation device comprising a conduit having a lumen, a stylet concentrically disposed within the lumen, and an actuation mechanism; positioning the device on a digit; and implanting the composition within the tissue of digit at a target location by activating the actuation mechanism, wherein the steps of gripping, positioning, and implanting are completed with the digits of one hand, and wherein the activation mechanism initiates retraction of the stylet by retraction of the conduit.
  • composition comprises an antifungal agent.
  • kits comprising the implantation device of embodiment 35 and one or more implants comprising an antifungal agent.
  • kit of embodiment 100 wherein the kit comprises a plurality of implants.
  • kits of embodiment 102, wherein the plurality of implants comprise the same or different antifungal agents.
  • the plurality of implants comprise the same or different doses of the antifungal agent.

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AU2021366739A1 (en) 2020-10-22 2023-06-08 Dan CARLISLE Systems and methods for tissue expansion

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