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(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- 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 . 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 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. In some instances, a tool for visualizing the sinus "treatment" refers to the resolution, reduction, or preven- ostium or sinus wall is desired. Examples of such tools tion of sinusitis or the sequelae of sinusitis. include endoscopes and computed tomography (CT)25 [0020] As used herein, the term "therapeutic agent", scanners. "active agent", and "drug" are used interchangeably and [0013] The biodegradable implants may also be used refer to any substance used to treat sinusitis. for reducing inflammation from a sinus procedure. These [0021] By "therapeutic amount" it is meant a concen- implants would also include a sustained release thera- tration of therapeutic agent that has been locally deliv- peutic agent dispersed within a biodegradable matrix and 30 ered to a sinus that is appropriate to safely treat sinusitis. have at least one characteristic that substantially pre- vents clearance of the implants from a sinus during a Biodegradable Implants treatment period after delivery of the implant into the si- nus. The treatment period may be of any duration which [0022] The implants of this invention generally include the physician deems is suitable to reduce the inflamma- 35 a therapeuticagent dispersed within a biodegradable pol- tion. ymer. The therapeutic agent may be homogeneously or inhomogeneously dispersed throughout the implant. Im- BRIEF DESCRIPTION OF THE DRAWINGS plant compositions may vary, depending, for example, on the particular therapeutic agent employed, duration [0014] 40 of desired drug release, type of sinusitis being treated, and medical history of the patient. However, in all instanc- Figures 1A-1B are cross-sectional views of the distal es, the biodegradable implant is formulated for sustained portion of an implant delivery device. In Figure 1A, release of the therapeutic agent. the biodegradable implant is delivered through a side opening in the conduit. In Figure 1B, the biodegrad- 45 Therapeutic agents able implant is delivered through the tip of the con- duit. [0023] The therapeutic agents that may be used in the Figure 2A is a cross-sectional view of a distal portion biodegradable implants include, but are not limited to, of a multiple implant delivery device. anti-infective agents, anti-inflammatory agents, or a com- Figure 2B is a cross-sectional view of a handle that 50 bination thereof. Anti-infective agents generally include may be coupled to the distal portion of the multiple antibacterial agents, antifungal agents, antiviral agents, implant delivery device shown in Figure 2A. and antiseptics. Anti-inflammatory agents generally in- clude steroidal and nonsteroidal anti-inflammatory DETAILED DESCRIPTION OF THE INVENTION agents. 55 [0024] Examples of antibacterial agents that may be [0015] The biodegradable implants of this invention incorporated in the biodegradable implants include may take various forms, but are generally designed to aminoglycosides, amphenicols, ansamycins, β-lactams, have a size and shape appropriate for the intended meth- lincosamides, macrolides, nitrofurans, quinolones, sul-

4 5 EP 3 103 422 A1 6 fonamides, sulfones, tetracyclines, and any of their de- benetonide, triamcinolone hexacetonide, rivatives. In one variation, β-lactams are the preferred and any of their derivatives. In one variation, antibacterial agents. is included in the implant as the steroidal anti-inflamma- [0025] β-lactams that may be included in the implants tory agent. In another variation, the steroidal anti-inflam- include carbacephems, carbapenems, cephalosporins, 5 matory agent may be furoate. In yet another cephamycins, monobactams, oxacephems, penicillins, variation, the steroidal anti-inflammatory agent may be and any of their derivatives. In one variation, penicillins beclomethasone. (and their corresponding salts) are the preferredβ- [0029] The therapeutic agent may constitute from lactams. about 5% to about 90%, about 15% to about 75%, or [0026] The penicillins that may be used in the biode- 10 about 30% to about 60% by weight of the implant. The gradable implants include amdinocillin, amdinocillin amount of therapeutic agent used will usually depend on pivoxil, amoxicillin, ampicillin, apalcillin, aspoxicillin, azi- factors such as the particular agent incorporated, the sus- docillin, azlocillin, bacampicillin, benzylpenicillinic acid, pected etiology of the sinusitis, and the severity of clinical benzylpenicillin sodium, carbenicillin, carindacillin, clom- symptoms, but in all instances will usually be an amount etocillin, cloxacillin, cyclacillin, dicloxacillin, epicillin, fen- 15 that is therapeutic upon delivery into a sinus. Ancillary benicillin, floxacillin, hetacillin, lenampici llin, metampicil- agents such as topical decongestants may also be in- lin, methicillin sodium, mezlocillin, nafcillin sodium, oxa- cluded. cillin, penamecillin, penethamate hydriodide, penicillin G benethamine, penicillin G benzathine, penicillin G ben- Polymer Matrix zhydrylamine, penicillin G calcium, penicillin G hydrab- 20 amine, penicillin G potassium, penicillin G procaine, pen- [0030] Selection of the biodegradable polymer matrix icillin N, penicillin O, penicillin V, penicillin V benzathine, to be employed will vary depending on the residence time penicillin V hydrabamine, penimepicycline, phenethicillin and release kinetics desired, method of implant delivery, potassium, piperacillin, pivampicillin, propicillin, quinacil- particular therapeutic agent used, and the like. An exem- lin, sulbenicillin, sultamicillin, talampicillin, temocillin, and 25 plary list of biodegradable polymers that may be used ticarcillin. In one variation, amoxicillin may be included are described in Heller, Biodegradable Polymers in Con- in the biodegradable implant. In another variation, the trolled Drug Delivery, In: "CRC Critical Reviews in Ther- biodegradable implant includes ampicllin. Penicillins apeutic Drug Carrier Systems", Vol. 1. CRC Press, Boca combined with clavulanic acid such as Augmentin® Raton, FL (1987). In all instances, the polymer matrix (amoxicillin and clavulanic acid) may also be used. 30 when degraded results in physiologically acceptable [0027] Examples of antifungal agents that may be used degradation products.The biodegradable polymer matrix in the biodegradable implants include allylamines, imi- may constitute at least about 10%, at least about 20%, dazoles, polyenes, thiocarbamates, triazoles, and any of at least about 30%, at least about 40%, at least about their derivatives. In one variation, imidazoles are the pre- 50%, at least about 60%, at least about 70%, at least ferred antifungal agents. 35 about 80%, at least about 90%, or at least about 95% by [0028] Typically, if inclusion of an anti-inflammatory weight of the implant. agent is desired, a steroidal anti-inflammatory agent, [0031] In one variation, adhesiveness of the polymer e.g., a , is employed. Examples of steroidal matrix to the sinus mucosa is particularly desired. Mu- anti-inflammatory agents that may be used in the im- coadhesive polymers are typically hydrophilic, and upon plants include 21-acetoxypregnenolone, , 40 moistening, swell and become adhesive. Examples of algestone, , beclomethasone, betametha- mucoadhesive polymers that may be employed in the sone, budesonide, , , biodegradable implants include homopolymers of acrylic , , , , acid monomers such as polyacrylic acid and any of its , , , , desoximeta- pharmaceutically acceptable salts; copolymers of acrylic sone, , , , diflu- 45 acid and methacrylic acid, styrene, or vinyl ethers; vinyl prednate, , , flucloronide, flumetha- polymers such as polyhydroxyethyl acrylate, polyhydrox- sone, , acetonide, , yethyl methacrylate, polyvinyl alcohol, and polyvinyl pyr- butyl, , , fluper- rolidone; cellulosic derivatives such as methyl cellulose, olone acetate, acetate, , ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl flurandrenolide, propionate, , hal- 50 cellulose, hydroxypropylmethyl cellulose, and car- cinonide, halobetasol propionate, , halo- boxymethyl cellulose; polysaccharides such as alginic predone acetate, , , lotep- acid, sodium alginate, and tragacanth gum; collagen; gel- rednol etabonate, , , mepred- atin; and any combination thereof. nisone, , mometasone furoate, [0032] In another variation, the biodegradable matrix , , , pred-55 is made from an orthoester, alone or in combination with nisolone 25-diethylamino-acetate, prednisolone sodium other monomers. In a preferred variation, a poly(ortho phosphate, , prednival, , rimex- ester) is used to constitute the polymer matrix. olone, , triamcinolone, , [0033] In yet a further variation, polymers of hydroxy-

5 7 EP 3 103 422 A1 8 aliphatic carboxylic acids, either homo- or copolymers, zones may fracture into a plurality of smaller segments are used to form the matrix. For example, polyesters in- as it degrades along the fracture lines. cluding homo- or copolymers of D-lactic acid, L-lactic ac- id, racemic lactic acid, glycolic acid, caprolactone, and Additional Agents combinations thereof may be used. Copolymers of gly- 5 colic and lactic acid are of particular interest, where the [0038] The implants of this invention may further in- rate of biodegradation is controlled by the ratio of glycolic clude components such as preservatives, buffers, bind- to lactic acid. The percent of each monomer in poly(lactic- ers, disintegrants, lubricants, and any other excipients co-glycolic)acid (PLGA) copolymer may be 0-100%, necessary to maintain the structure and/or function of the about 20-80%, about 30-70%, or about 40-60%. In a pre- 10 implants. Furthermore, the implants may be placed in a ferred variation, a 50/50 PLGA copolymer is used. pharmaceutically acceptable carrier, e.g., when the im- [0034] In one variation, PLGA may be combined with plants are microparticles, to form a suspension such as budesonide to form the biodegradable sinus implant. In a semi-solid gel. Common gel bases include, but are not another variation, PLGA may be combined with mometa- limited to, carbomer, liquid paraffin, water, glycerol, pro- sone furoate. If inclusion of an antibacterial agent is de- 15 pylene glycol, hyaluronic acid or sodium hyaluronate, or sired in the PLGA matrix, alone or in combination with a a combination thereof. The types of gels that may be steroidal anti-inflammatory agent, Augmentin® may be formed include, e.g., inorganic and organic gels, hydro- used. If first-line antimicrobial therapy fails, or for peni- gels, or organogels. cillin allergy, a cephalosporin such as ciprofloxacin or [0039] In addition to microparticle density, the viscosity macrolide such as erythromycin may be used in the20 of the gel may be adjusted to a level that allows delivery PLGA matrix. into the sinus and prevents substantial clearance of the [0035] The biodegradable implants may be solid or microparticles (implants) from the sinus. The gel may al- semisolid and take a variety of suitable forms, such as so be prepared in adhesive form (using adhesive poly- rods or approximately spherical or rectangular pellets, merssuch as polyacrylic acid, sodium carboxymethyl cel- beads, strips, or microparticles, so long as their size and 25 lulose, or polyvinylpyrrolidone) to increase the contact shape is compatible with the selected sinus of implanta- time of the therapeutic agent with the sinus mucosa. tion, and so long as the implants exhibit the desired re- lease kinetics and deliver an amount of drug therapeutic Release Kinetics for the intended type of sinusitis. In one variation, the implant is a rod having a length of about 1 mm to about 30 [0040] In general, the implants of this invention are for- 10 mm and a diameter of about 0.05 mm to about 5 mm. mulated with particles of a therapeutic agent dispersed In another variation, the implant is a rod having a length within a biodegradable polymer matrix, and formulated of about 4 mm and a diameter of about 2 nun. In yet a to provide sustained-release of the therapeutic agent. If further variation, the implant is a microparticle. When made from a non-swellable polymer, e.g., PLGA or po- treating sinusitis, a plurality of these microparticles with 35 ly(ortho ester), release of the active agent from the matrix or without a carrier are delivered into the sinus. The mi- is probably achieved by erosion of the biodegradable pol- croparticles may or may not be porous, and may have ymer matrix and by diffusion of the particulate therapeutic an average diameter of between about 0.1-500 mm, be- agent into the mucous layer of the sinus. Factors that tween about 0.1-100 mm, between about 0.1-50 mm, be- may influence the release kinetics include such charac- tween about 0.1-10 mm, between about 0.1-1 mm, or be- 40 teristics as the size of the drug particles, the solubility of tween about 0.1-0.5 mm. the drug, the ratio of drug to polymer(s), the method of [0036] Also important is that the implant remain in the implant manufacture, the implant surface area exposed, sinus during the intended period of drug delivery. The and the erosion rate of the matrix polymer(s). In the case sinuses are lined with a ciliated epithelium and a layer of of polymer swelling, as seen with hydrogels, a therapeu- mucus. The cilia beat continuously, causing the mucous 45 tic agent is released as liquid diffuses through exposed layer to slowly flow out of the sinus toward the pharynx. pathways in the implant. Accordingly, in order to effectively treat sinusitis with an [0041] The therapeutic agent may be released from implant, the implant must typically remain in the sinus the implant over a prolonged time period including, but long enough to deliver a drug in a therapeutic amount. not limited to, at least about one week, at least about two The biodegradable implants of this invention have a mu- 50 weeks, at least about three weeks, at least about four coadhesiveness, size, shape, viscosity, and/or density weeks, at least about 6 weeks, at least about two months, that allows a substantial amount of the implant to remain or at least about three months. In one variation, the ther- in the sinus during the intended period of drug delivery. apeutic agent is released over about two weeks to about [0037] Furthermore, the implant may be of a design four weeks. that allows it to take a form that is different after it is55 delivered into the sinus from that before delivery. For Delivery Device instance, an implant delivered into the sinus as a rod or strip having a series of predetermined fracture lines or [0042] The biodegradable implants may be placed into

6 9 EP 3 103 422 A1 10 the sinus using various implant delivery devices. The de- livery device having a conduit 28 with a side wall 30, a vice generally includes a conduit, e.g., a catheter, having lumen 32, a distal portion 34, an opening 36 in the distal an elongate pusher within its lumen. The conduit and portion 34, a tip 38, a pusher 40, and a ramp 42. Pusher pusher may be flexible or rigid, or may be designed to 40 is distally advanced a preset distance to slidably en- have varying degrees of stiffness along its length, e.g., 5 gage the most proximal implant 44 within lumen 32. The the distal portion of the conduit may be stiffer than the pusher 40 is then further distally advanced a preset dis- proximal portion. In addition, the distal portion of the con- tance, e.g., a distance approximately equal to the length duit may be variously angulated to facilitate positioning of one implant, to move the most distal implant 46 through and advancement of the conduit through the sinus os- opening 36 into the sinus. tium. For example, the distal portion may be angulated 10 [0048] A handle 48, as shown in Figure 2B, may be from about 0° to about 175°, from about 0° to about 135°, coupled to conduit 28 such that the handle lumen forms or from about 0° to about 90°. a continuous lumen with the lumen 32 of the conduit 28. [0043] The conduit may be made from any biocompat- The pusher 40 can then slide through this continuous ible material including, but not limited to, stainless steel lumen. The handle 48 further includes an injector 42, and any of its alloys; titanium alloys, e.g., nickel-titanium 15 adjacent to and longitudinally aligned with the pusher 40, alloys; polymers, e.g., polyethylene and copolymers and a stepped slot 44 with various positions "O", "A", "B", thereof, polyethylene terephthalate or copolymers there- and "C". Initially, when the injector 42 is pressed, the of, nylon, silicone, polyurethanes, fluoropolymers, poly pusher 40 is distally advanced, and a key 46 coupled to (vinylchloride), and combinations thereof, depending on the injector 42 moves the pusher 40 between positions the amount of flexibility or stiffness desired. The pusher 20 "O" and "A". The distance between positions "O" and "A" may be made from similar materials. is approximately equal to the length of the dispensed [0044] Usually, the device will be preloaded with a sin- implant. Pusher 40 may then be rotated to move the key gle implant within the lumen of the conduit, but more than 46 from position "A" to position "B" in the stepped slot one implant may be preloaded if desired. Once access 44. Pressing the injector 42 again then moves the key through a sinus ostium has been obtained with the con- 25 along step "B" to position "C", and the pusher 40 a cor- duit, the pusher slidably engages the implant and is ad- responding length to dispense another implant. Multiple vanced until the implant exits the catheter into the sinus. implantsmay be delivered in this fashion, with thenumber An endoscope may also be used while positioning the of implants delivered depending on the number of steps conduit to aid with visualization of the ostium. in the stepped slot. [0045] In certain cases, e.g., when ostia are closed or 30 [0049] Although the various implant delivery devices difficult to access, implant placement into one or more describedabove deploy solid implants, thisinvention also sinuses may be completed through the sinus wall using contemplates the use of the devices to deliver various a sharp-tipped conduit, e.g., a needle, trocar, or angi- semi-solid implants and gels into the sinus. A force ap- ocatheter, with or without visualization using computer plied to a predetermined amount of a semi-solid implant image-guided technology or endoscopy. Once the ap- 35 or gel composition in the conduit, e.g., by contact with a propriate access point for the sinus has been determined, pusher or pressurized gas, could be used to deliver the force is applied to the sharp-tipped conduit so that it punc- implant or gel into the sinus. tures the sinus wall. Advancement of a pusher through the conduit lumen then deposits an implant into the sinus. Applications [0046] Figures 1A-1B show examples of single implant 40 delivery devices. The devices include an implant 10, a [0050] The implants may be used to treat sinusitis af- conduit 12 having a side wall 14, a lumen 16, a distal fecting one or more of the maxillary sinus, the frontal portion 18, an opening 20 in the distal portion 18, a tip sinus, the ethmoidal sinus, and the sphenoidal sinus. 22, and a pusher 24. In Figure 1A, the conduit 12 includes [0051] Furthermore, the biodegradable implants may a ramp 26 and an opening 20 positioned in the side wall 45 be used to treat acute or chronic sinusitis arising from 14. If delivering a solid implant, the opening will usually predisposing anatomical conditions, chronic allergic be approximately twice the diameter of the implant. The processes, or conditions related to infection by various pusher 24 is advanced distally within the lumen 16 to pathogens (e.g., bacteria, fungi, and viruses). slidably engage the implant 10 and move it up the ramp [0052] Examples of bacteria that may cause sinusitis 26 through the side wall 14 into the sinus. In Figure 1B, 50 include Alpha-hemolytic streptococci, Beta-hemolytic the opening 20 is positioned at the tip 22 of the conduit streptococci, Branhamella catarrhalis, Diptheroids, Hae- 12, and pusher 24 is advanced distally within the lumen mophilis influenzae, Moraxella species, Pseudomonas 16 to slidably engage the implant 10 and move it through aeroginosa, Pseudomonas maltophilia, Serratia marces- the tip 22. Although the conduit tips are shown to be blunt cens, Staphylococcus aureus, and Streptococcus pneu- in the Figures, they may also be sharp and/or beveled, 55 moniae. usually depending on the implant delivery method. [0053] Examples of fungi that may cause sinusitis in- [0047] Figure 2A shows a device that delivers multiple clude Aspergillosis, Candida, Cryptococcus, Coccidio- implants. The device is similar to the single implant de- ides, Histoplasma, and Mucor species.

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[0054] The biodegradable implants may also be used PREFERRED EMBODIMENTS to reduce inflammation resulting from a sinus procedure, typically, a sinus drainage procedure. Examples of sinus [0059] drainage procedures include, but are not limited to, wid- ening/enlargement of a narrowed ostium, antral puncture 5 1. A biodegradable implant for treating sinusitis com- and washout, and intranasal antrostomy. The implants prising a sustained release therapeutic agent dis- may be delivered into a sinus using one of the methods persed within a biodegradable matrix, wherein the previously described, usually after the procedure is com- biodegradableimplant has at leastone characteristic pleted, but they can also be delivered into a sinus before that substantially prevents clearance of the implant the procedure or during the procedure. 10 from a sinus during a treatment period after delivery [0055] If enlarging an ostium, the affected sinus will of the implant into the sinus. generally be accessed through that enlarged ostium. The biodegradable implant(s) may then be deployed into the 2. The biodegradable implant of clause 1 wherein sinus via the enlarged ostium. With respect to antral the at least one characteristic is size of the implant. puncture and drainage or intranasal antrostomy, the af- 15 fected sinus usually will be accessed at the antral punc- 3. The biodegradable implant of clause 1 wherein ture site or through the antrostomy. The biodegradable the at least one characteristic is shape of the implant. implant(s) will also usually be deployed into the sinus through the antral puncture site or antrostomy. However, 4. The biodegradable implant of clause 1 wherein if desired, the biodegradable implant(s) may be delivered 20 the at least one characteristic is density of the im- through a natural ostium despite antral puncture or an- plant. trostomy being perfomed. 5. The biodegradable implant of clause 1 wherein Method of Making the Implants the at least one characteristic is viscosity of the im- 25 plant. [0056] The method of preparing the implants of this invention will generally depend on the particular thera- 6. The biodegradable implant of clause 1 wherein peutic agent or matrix polymer used, form of the implant, the at least one characteristic is mucoadhesiveness and the release kinetics desired, but may be made by of the implant. any one of the numerous methods known in the art. For 30 example, the implants may be made by such processes 7. The biodegradable implant of clause 1 wherein as compression, extrusion, molding, solvent evapora- the sustained release therapeutic agent is selected tion, or solvent extraction. from the group consisting of anti-infective agents, [0057] All publications, patents, and patent applica- anti-inflammatory agents, and combinations thereof. tions cited herein are hereby incorporated by reference 35 in their entirety for all purposes to the same extent as if 8. The biodegradable implant of clause 1 wherein each individual publication, patent, or patent application the sustained released therapeutic agent comprises were specifically and individually indicated to be so in- an anti-infective agent. corporated by reference. Although the foregoing inven- tion has been described in some detail by way of illus- 40 9. The biodegradable implant of clause 8 wherein tration and example for purposes of clarity of understand- the anti-infective agent is selected from the group ing, it will be readily apparent to those of ordinary skill in consisting of antibacterial agents, antifungal agents, the art in light of the teachings of this invention that certain antiviral agents, and antiseptics. changes and modifications may be made thereto without departing from the spirit and scope of the appended45 10. The biodegradable implant of clause 8 wherein claims. the anti-infective agent comprises an antibacterial [0058] The claims of the parent application are repro- agent. duced below on pages 17-23. These clauses define pre- ferred embodiments. The applicant reserves the right to 11. The biodegradable implant of clause 10 wherein pursue protection for the combinations of features set 50 the antibacterial agent is selected from the group out in these clauses, and/or for any other subject-matter consisting of aminoglycosides, amphenicols, contained in the parent application as filed, either in the ansamycins, (ß-lactams, lincosamides, macrolides, present divisional application or in a further application nitrofurans, quinolones, sulfonamides, sulfones, tet- divided from the present divisional application. The racyclines, and any of their derivatives. claims of the parent application are not the claims of this 55 divisional application. 12. The biodegradable implant of clause 10 wherein the antibacterial agent comprises a ß-lactam.

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13. The biodegradable implant of clause 12 wherein the biodegradable matrix is a biodegradable polymer the (ß-lactam comprises a penicillin. matrix.

14. The biodegradable implant of clause 13 wherein 23. The biodegradable implant of clause 1 wherein the penicillin comprises amoxicillin. 5 the biodegradable matrix comprises a mucoadhe- sive polymer. 15. The biodegradable implant of clause 1 wherein the sustained release therapeutic agent is an anti- 24. The biodegradable implant of clause 23 wherein inflammatory agent. the mucoadhesive polymer is selected from the 10 group consisting of homopolymers of acrylic acid 16. The biodegradable implant of clause 15 wherein monomers and their pharmaceutically acceptable the anti-inflammatory agent is a nonsteroidal anti- salts; copolymers of acrylic acid and methacrylic ac- inflammatory agent or a steroidal anti-inflammatory id, styrene, or vinyl ethers; polyhydroxyethyl acr- agent. ylate; polyhydroxyethyl methacrylate ; polyvinyl al- 15 cohol; polyvinyl pyrrolidone; methyl cellulose; ethyl 17. The biodegradable implant of clause 1 wherein cellulose; hydroxyethyl cellulose; hydroxypropyl cel- the sustained release therapeutic agent comprises lulose; hydroxypropylmethyl cellulose; carboxyme- a steroidal anti-inflammatory agent. thyl cellulose; alginic acid; sodium alginate; traga- canth gum; collagen; gelatin; and any combination 18. The biodegradable implant of clause 17 wherein 20 thereof. the steroidal antiinflammatory agent is selected from the group consisting of 21- acetoxypregnenolone, 25. The biodegradable implant of clause 1 wherein alclometasone, algestone, amcinonide, beclometh- the biodegradable matrix comprises poly (lactic-co- asone, , budesonide, chloropred- glycolic) acid (PLGA) copolymer. nisone, clobetasol, clobetasone, clocortolone, clo- 25 prednol, corticosterone, cortisone, cortivazol, de- 26. The biodegradable implant of clause 25 wherein flazacort, desonide, , dexametha- the sustained release therapeutic agent comprises sone, diflorasone, diflucortolone, , amoxicillin. enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, , fluocinonide,30 27. The biodegradable implant of clause 25 wherein , fluocortolone, fluorometholone, flu- the sustained release therapeutic agent comprises perolone acetate, , flupred- budesonide. nisolone, flurandrenolide, , formocortal, , halobetasol propionate, 28. The biodegradable implant of clause 25 wherein halometasone, acetate, hydrocortama- 35 the sustained release therapeutic agent comprises te, hydrocortisone, etabonate, maz- mometasone furoate. ipredone, medrysone, , methylpred- nisolone, mometasone furoate, paramethasone, 29. The biodegradable implant of clause 25 wherein prednicarbate, prednisolone, prednisolone 25-di- the sustained release therapeutic agent comprises ethylamino-acetate, prednisolone sodium phos-40 beclomethasone. phate, prednisone, prednival, prednylidene, rimex- olone, tixocortol, triamcinolone, triamcinolone ace- 30. The biodegradable implant of clause 1 wherein tonide, triamcinolone benetonide, triamcinolone the biodegradable matrix comprises a poly (ortho es- hexacetonide, and any of their derivatives. ter). 45 19. The biodegradable implant of clause 18 wherein 31. The biodegradable implant of clause 1 wherein the steroidal antiinflammatory agent comprises the treatment period is about one week to about three budesonide. months.

20. The biodegradable implant of clause 18 wherein 50 32. The biodegradable implant of clause 1 wherein the steroidal antiinflammatory agent comprises the treatment period is about two weeks to about 4 mometasone furoate. weeks.

21. The biodegradable implant of clause 18 wherein 33. The biodegradable implant of clause 1 wherein the steroidal antiinflammatory agent comprises be- 55 the implant is of a form selected from the group con- clomethasone. sisting of rods, pellets, beads, strips, and micropar- ticles. 22. The biodegradable implant of clause 1 wherein

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34. The biodegradable implant of clause 1 wherein biodegradable implants in the lumen of the implant the implant is a microparticle. delivery device, the one or more biodegradable im- plants comprising a sustained release therapeutic 35. The biodegradable implant of clause 34 in a phar- agent dispersed within a biodegradable matrix and maceutically acceptable carrier. 5 having at least one characteristic that substantially prevents 36. The biodegradable implant of clause 35 wherein clearance of the one or more implants from a sinus the pharmaceutically acceptable carrier is a semi- during a treatment period after delivery of the one or solid gel. more implants into the sinus, wherein the one or 10 more implants are delivered into the sinus by distally 37. The biodegradable implant of clause 1 wherein advancing the pusher to slidably engage the one or the implant further comprises a series of predeter- more implants and move the one or more implants mined fracture lines such that after delivery into the through the opening in the distal portion of the con- sinus, the implant fractures into a plurality of seg- duit. ments. 15 48. The system of clause 47 wherein the biodegrad- 38. The biodegradable implant of clause 1 wherein able matrix is a biodegradable polymer matrix. the sinus is a maxillary sinus, a frontal sinus, an eth- moid sinus, or a sphenoidal sinus. 49. The system of clause 47 wherein the distal por- 20 tion of the conduit is angulated. 39. The biodegradable implant of clause 1 wherein the sinus is the maxillary sinus. 50. The system of clause 47 wherein the conduit is preloaded with a single implant. 40. A biodegradable implant for reducing inflamma- tion from a sinus procedure comprising a sustained 25 51. The system of clause 47 wherein the conduit is release therapeutic agent dispersed within a preloaded with a plurality of implants. biodegradable matrix, wherein the biodegradable implant has at least one characteristic that substan- 52. The system of clause 47 further comprising a tially prevents clearance of the implant from a sinus tool for visualizing the sinus ostium or sinus wall. during a treatment period after delivery of the implant 30 into the sinus. 53. The system of clause 52 wherein the tool is an endoscope. 41. The biodegradable implant of clause 40 wherein the sinus procedure is a sinus drainage procedure. 54. The system of clause 52 wherein the tool is a 35 computed tomography scanner. 42. The biodegradable implant of clause 40 wherein the sinus procedure enlarges a narrowed sinus os- 55. The system of clause 47 wherein the conduit is tium. a needle.

43. The biodegradable implant of clause 40 wherein 40 56. The system of clause 47 wherein the conduit is the sinus procedure is antral puncture and washout. a catheter.

44. The biodegradable implant of clause 40 wherein 57. The system of clause 47 wherein the conduit is the sinus procedure is intranasal antrostomy. malleable. 45 45. The biodegradable implant of clause 40 wherein 58. A method for delivering a biodegradable implant the biodegradable matrix is a biodegradable polymer into a sinus comprising: a) loading one or more bio- matrix. degradable implants into a conduit having a lumen, a distal portion, a side wall, a tip, and an opening in 46. The biodegradable implant of clause 40 wherein 50 the distal portion; b) accessing a sinus with the con- the sustained release therapeutic agent is mometa- duit; c) deploying the one or more biodegradable im- sone furoate. plants through the opening in the distal portion of the conduit into the sinus, wherein the one or more bio- 47. A system for treating sinusitis comprising: a) an degradable implants comprise a therapeutic amount implant delivery device, the implant delivery device 55 of an active agent for the treatment of sinusitis. comprising a conduit having a lumen, a distal portion, aside wall,a tip,and an openingin said distal portion; 59. The method of clause 58 wherein the step of and a pusher within the lumen; and b) one or more accessing comprises placing the conduit through a

10 17 EP 3 103 422 A1 18 sinus ostium. Claims

60. The method of clause 58 wherein the step of 1. A system comprising: accessing comprises placing the conduit through a sinus wall. 5 a conduit for providing access to a paranasal sinus cavity and an implant for treating sinusitis, 61. The method of clause 58 wherein the step of deploying comprises slidably engaging the one or wherein the implant comprises a therapeutic agent more biodegradable implants with a pusher and ad- dispersed within a biodegradable polymer, vancing the pusher within the conduit lumen. 10 wherein the implant is sized and configured to be at least partially placed within the conduit and is sized 62. The method of clause 58 wherein the step of and configured to be delivered from the conduit to a deploying comprises contacting the one or more bi- paranasal sinus cavity and is configured to have a odegradable implants with a pressurized gas. first solid form while in the conduit and a second solid 15 form in a paranasal sinus cavity, and 63. The method of clause 58 wherein the distal por- wherein the second form has at least one character- tion of the conduit is angulated. istic that substantially prevents clearance of the im- plant from the paranasal sinus cavity. 64. The method of clause 58 wherein the conduit is sharp-tipped. 20 2. The system of claim 1 wherein the at least one char- acteristic is: 65. The method of clause 58 wherein the opening is located in the side wall of the conduit. size of the implant; or shape of the implant; or 66. The method of clause 58 wherein the opening is 25 density of the implant; or located at the tip of the conduit. viscosity of the implant; or

67. The method of clause 58 wherein the biodegrad- mucoadhesiveness of the implant. able implant is a biodegradable polymeric implant. 30 3. The system of claim 1 wherein the therapeutic agent 68. A method for delivering a biodegradable implant is selected from the group consisting of anti-infective into a sinus comprising: a) loading one or more bio- agents, anti-inflammatory agents, and combinations degradable implants into a conduit having a lumen, thereof. a distal portion, a side wall, a tip, and an opening in the distal portion; b) accessing a sinus with the con- 35 4. The system of claim 1 wherein the therapeutic agent duit; c) deploying the one or more biodegradable im- comprises an anti-infective agent and the anti-infec- plants through the opening in the distal portion of the tive agent is selected from the group consisting of conduit into the sinus, wherein the one or more bio- antibacterial agents, antifungal agents, antiviral degradable implants comprise a therapeutic amount agents, and antiseptics. of an active agent for the reduction of inflammation 40 from a sinus procedure. 5. The system of claim 1 wherein the therapeutic agent comprises an anti-infective agent and the anti-infec- 69. The method of clause 68 wherein the step of tive agent comprises an antibacterial agent. accessing comprises placing the conduit through a sinus ostium. 45 6. Thesystem of claim 5wherein the antibacterial agent is selected from the group consisting of aminoglyco- 70. The method of clause 68 wherein the step of sides, amphenicols, ansamycins,β -lactams, lin- accessing comprises placing the conduit through a cosamides, macrolides, nitrofurans, quinolones, sul- sinus wall. fonamides, sulfones, tetracyclines, and any of their 50 derivatives. 71. The method of clause 68 wherein the biodegrad- able implant is a biodegradable polymeric implant. 7. Thesystem of claim 5wherein the antibacterial agent comprises a β-lactam. 72. The implant of clause 68 wherein the active agent comprises mometasone furoate. 55 8. The system of claim 7 wherein theβ -lactam com- prises a penicillin.

9. The system of claim 8 wherein the penicillin com-

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prises amoxicillin. about 0° to about 175°.

10. The system of claim 1 wherein the therapeutic agent: 17. The system of claim 1 wherein the conduit comprises a pusher located within a lumen. is an anti-inflammatory agent; or 5 comprises an anti-infective agent; or 18. The system of claim 1 wherein the conduit comprises comprises a steroidal anti-inflammatory agent; a distal portion and a proximal portion, and wherein or the distal portion of the conduit is stiffer than the prox- comprises budesonide; or imal portion of the conduit. comprises mometasone furoate. 10

11. The system of claim 1 wherein the therapeutic agent comprises a steroidal anti-inflammatory agent and wherein the steroidal anti-inflammatory agent is se- lected from the group consisting of 21-acetoxypreg- 15 nenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clobetasone, clocor- tolone, cloprednol, corticosterone, cortisone, corti- vazol, deflazacort, desonide, desoximetasone, dex- 20 amethasone, diflorasone, diflucortolone, diflupred- nate, enoxolone, fluazacort, flucloronide, flumetha- sone, flunisolide, fluocinolone acetonide, fluocinon- ide, fluocortin butyl, fluocortolone, fluorometholone, acetate, fluprednidene acetate, flupred- 25 nisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone,halopredone acetate, hydrocortama- te, hydrocortisone, loteprednol etabonate, maz- ipredone, medrysone, meprednisone, methylpred- 30 nisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-di- ethylamino-acetate, prednisolone sodium phos- phate, prednisone, prednival, prednylidene, rimex- olone, tixocortol, triamcinolone, triamcinolone ace- 35 tonide, triamcinolone benetonide, triamcinolone hexacetonide, and any of their derivatives.

12. The system of claim 11 wherein the steroidal anti- inflammatory agent comprises budesonide. 40

13. The system of claim 11 wherein the steroidal anti- inflammatory agentcomprises mometasone furoate.

14. The system of claim 11 wherein the steroidal anti- 45 inflammatory agent comprises beclomethasone.

15. The system of any one of the preceding claims wherein the biodegradable polymer is: 50 a biodegradable polymer matrix; or comprises a mucoadhesive polymer; or comprises poly(lactic-co-glycolic)acid (PLGA) copolymer. 55 16. The system of claim 1 wherein the conduit comprises a distal portion and a proximal portion, and wherein the distal portion of the conduit is angulated from

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 45491803 P [0001]

Non-patent literature cited in the description

•MINal.et Mucociliary Activity and Histopathology of • MIN et al. Application of Polylactic Acid Polymer in Sinus Mucosa in Experimental Maxillary Sinusitis: A the Treatment of Acute Maxillary Sinusitis in Rabbits. Comparison of Systemic Administration of Antibiotic Acta Otolaryngol, 1995, vol. 115, 548-552 [0005] and Antibiotic Delivery by Polylactic Acid Polymer. • Biodegradable Polymers in Controlled Drug Delivery. Laryngoscope, 1995, vol. 105, 835-342 [0005] HELLER. In: ’’CRC Critical Reviews in Therapeutic Drug Carrier Systems. CRC Press, 1987, vol. 1 [0030]

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