Sinus Delivery of Sustained Release Therapeutics
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(19) TZZ¥_Z¥ _T (11) EP 3 103 422 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 14.12.2016 Bulletin 2016/50 A61F 13/00 (2006.01) A61K 9/00 (2006.01) A61K 47/34 (2006.01) (21) Application number: 16182023.8 (22) Date of filing: 12.03.2004 (84) Designated Contracting States: • MORAN, Mary L. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Woodside, CA California 94062 (US) HU IE IT LI LU MC NL PL PT RO SE SI SK TR • BRENNEMAN, Rodney San Juan Capistrano, CA California 92675 (US) (30) Priority: 14.03.2003 US 454918 P (74) Representative: Moore, Jacqueline Frances et al (62) Document number(s) of the earlier application(s) in Cooley (UK) LLP accordance with Art. 76 EPC: Dashwood 04720509.1 / 1 605 863 69 Old Broad Street London EC2M 1QS (GB) (71) Applicant: Intersect ENT, Inc. Palo Alto, CA 94303 (US) Remarks: This application was filed on 29-07-2016 as a (72) Inventors: divisional application to the application mentioned • EATON, Donald J. under INID code 62. Woodside, CA California 94062 (US) (54) SINUS DELIVERY OF SUSTAINED RELEASE THERAPEUTICS (57) The invention provides biodegradable implants for treating sinusitis. The biodegradable implants have a size, shape, density, viscosity, and/or mucoadhesiveness that prevents them from being substantially cleared by the muco- ciliary lining of the sinuses during the intended treatment period. The biodegradable implants include a sustained release therapeutic, e.g., an antibiotic, a steroidal anti-inflammatory agent, or both. The biodegradable implants may take various forms, such as rods, pellets, beads, strips, or microparticles, and may be delivered into a sinus in various pharmaceutically acceptable carriers. EP 3 103 422 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 103 422 A1 2 1 EP 3 103 422 A1 2 Description of the maxillary sinus. [0006] Consequently, a biodegradable implant for ad- RELATED APPLICATIONS ministering a sustained release therapeutic agent to the paranasal sinuses for a prolonged time period without [0001] This application claims priority from U.S. Appli- 5 being substantially cleared by the mucociliary lining of cation Serial No. 60/454,918, filed March 14, 2003. the sinuses, and methods for delivering the implant in a minimally invasive fashion may provide significant med- FIELD OF THE INVENTION ical benefit for patients afflicted with sinusitis. [0002] This invention relates to biodegradable im-10 SUMMARY OF THE INVENTION plants and methods for placing one or more of these im- plants into a paranasal sinus. The implants provide local [0007] The present invention is a biodegradable im- sustained release of a therapeutic agent for the prophy- plant for treating sinusitis that includes a sustained re- laxis or treatment of sinusitis. Included in the description lease therapeutic agent dispersed within a biodegrada- are implants delivered in such various forms as pellets, 15 ble matrix, and which has at least one characteristic that rods, strips, and microparticles. substantially prevents clearance of the implant from the sinus by its mucociliary layer during the intended treat- BACKGROUND OF THE INVENTION ment period after delivery of the implant into the sinus. Characteristics such as size, shape, density, viscosity, [0003] The paranasal sinuses are air-filled cavities20 mucoadhesiveness, or a combination thereof may be al- within the facial skeleton. Each paranasal sinus is con- tered to substantially prevent this clearance. tiguous with a nasal cavity and drains into the nose [0008] The biodegradable implant may include various through a sinus ostium. Although other factors may be therapeutic agents, including, but not limited to, anti-in- involved, the development of sinusitis (inflammation of fective agents, anti-inflammatory agents, and combina- the mucosal lining of the sinuses) is most often attributed 25 tions thereof. Examples of anti-infective agents include to blockage of one or more of these sinus ostia, followed antibacterial agents, antifungal agents, antiviral agents, by mucostasis and microbial overgrowth in the sinus cav- and antiseptics. The anti-inflammatory agent may be a ity. Ostial blockage may stem from predisposing anatom- nonsteroidal anti-inflammatory agent or a steroidal anti- ical factors, or inflammation and edema of the mucous inflammatory agent. In a preferred variation, steroidal an- lining in the area of the ostia, arising from such etiologies 30 ti-inflammatory agents are used. as viral or bacterial upper respiratory infection or chronic [0009] The matrix of the implant may be made from allergic processes. any biodegradable and biocompatible polymer, including [0004] Traditionally, sinusitis has been medically man- such polymers as mucoadhesive polymers, poly(ortho aged by theoral administration of antibiotics and steroids. esters), and poly(lactic-co-glycolic)acid (PLGA) copoly- However, penetration of these systemically delivered35 mer. The biodegradable polymer matrix may also be agents into the sinus mucosa is limited due to poor blood formed as a rod, pellet, bead, strip, or microparticle, and flow to the sinuses. Therapeutic agents contained in placed in a pharmaceutically acceptable carrier if de- aqueoussolutions, creams, or gels,for topical application sired. When the biodegradable implant is a microparticle, in the nose have also been formulated, but usually never usually a plurality of microparticles are delivered into the travel far enough into the nose to reach the sinuses, are 40 sinus to treat sinusitis. The microparticles may or may blocked from entering the sinuses due to obstructed os- not be porous, and may have an average diameter of tia, or have such short contact with the sinus mucosa that between about 0.1-500 mm, between about 0.1-100 mm, absorption of the agent is low. For similar reasons, na- between about 0.1-50 mm, or between about 0.1-10 mm. sally inhaled steroid and anti-infective aerosols that have In some instances, the form of the biodegradable implant been developed to treat sinusitis are equally ineffective. 45 may change after delivery into the sinus. For example, a [0005] The delivery of ampicillin from a poly(lactic-co- poly(ortho ester) implant in the form of a strip having a glycolic)acid (PLGA) film to increase residence time of series of predetermined fracture lines or zones may frac- the antibiotic in rabbit sinuses has been investigated for ture into a plurality of smaller segments as it degrades the treatment of sinusitis (Min et al. Mucociliary Activity along the fracture lines in the sinus. and Histopathology of Sinus Mucosa in Experimental 50 [0010] The biodegradable implant may deliver a sus- Maxillary Sinusitis: A Comparison of Systemic Adminis- tained release therapeutic agent over at least about one tration of Antibiotic and Antibiotic Delivery by Polylactic week, over at least about two weeks, over at least about Acid Polymer. Laryngoscope 105:835-342 (1995) and three weeks, over at least about four weeks, over at least Min et al. Application of Polylactic Acid Polymer in the about six weeks, over at least about two months, or over Treatment of Acute Maxillary Sinusitis in Rabbits. Acta 55 at least about three months. In a preferred variation, the Otolaryngol 115:548-552 (1995)). Although clinical signs sustained release therapeutic agent is delivered into the of sinusitis improved, the procedure for placing the film sinus over about three weeks. required that a hole be drilled through the anterior wall [0011] The biodegradable implants may be delivered 3 3 EP 3 103 422 A1 4 into a sinus using devices of various designs, but at least od of delivery, e.g., through the sinus ostium or by punc- which include a pusher and a conduit, e.g., a catheter, ture through a sinus wall, and a density, viscosity, and/or needle, or angiocatheter. For example, the pusher and/or mucoadhesiveness such that the implant is not substan- conduit may be made such that they are variably stiff tially cleared from the sinus over the duration of treat- along their lengths. In addition, the opening in the conduit 5 ment. Once within the sinus, the implant releases a ther- through which the implant is delivered may be positioned apeutic agent over a prolonged time period, for example, in the conduit side wall or at the tip. Furthermore, the over at least one week, over at least two weeks, over at distal portion of the conduit may be angulated to facilitate least three weeks, or over at least four weeks or more, access of the sinus ostium if indicated. In one variation, to treat sinusitis. the distal portion is malleable such that the physician may 10 angulate the conduit themselves just prior to accessing Definitions the sinus ostium. [0012] The biodegradable implants and devices for [0016] For purposes of this description, we use the fol- their deployment may be used in a system for treating lowing terms as defined in this section, unless the context sinusitis. In general, the system works by first placing the 15 of the word indicates a different meaning. conduit having one or more implants within its lumen ei- [0017] By "sinus" it is meant all sinuses, i.e., the max- ther through a sinus ostium or a sinus wall. A pusher illary, ethmoid, frontal, and sphenoidal sinuses. within the lumen of the conduit is then distally advanced [0018] By "subject" it is meant mammalian subjects, to slidably engage the implant(s) and move it through an preferably humans. Mammals include, but are not limited opening in the distal portion of the conduit into the sinus. 20 to, primates, farm animals, sport animals, cats, dogs, rab- The opening may be in the conduit side wall or tip. Usu- bits, mice, and rats. ally, the conduit will be preloaded with one or more im- [0019] As used herein, the term "treat", "treating", or plants.