Drug eluting compositions and methods of making and using the same

Abstract

The current invention encompasses a steroid eluting biodegradable nasal implant. Aspects of the invention are drawn towards compositions of the nasal implant, methods of producing the steroid eluting biodegradable nasal implant, methods of use, and methods of treatment thereof.

Description

DRUG ELUTING COMPOSITIONS AND METHODS OF MAKING AND USING THE SAME

[0001] This application claims priority to U. S. Provisional Application No. 63 / 716,004 filed on November 04, 2024, the entire contents of which are incorporated herein by reference.

[0002] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

[0003] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure as it appears in the U. S. Patent and Trademark Office patent file or records but otherwise reserves any and all copyright rights.GOVERNMENT SUPPORT

[0004] This invention was made with government support under STTR Award No. 2305502 from the National Science Foundation. The government has certain rights in the invention.FIELD OF THE INVENTION

[0005] The present invention relates to a drug eluting composition, methods of making the drug eluting composition, and methods of using the drug eluting composition.BACKGROUND OF THE INVENTION

[0006] Rhinitis, nasal congestion and nasal polyposis are significant medical issues that affect millions of people around the world. It has been estimated that 77 million people in the United States suffer from some form of rhinitis. Rhinitis can be either allergic (AR) or non-allergic (NAR). Symptoms include nasal congestion, runny nose, sneezing, and itching. Nasal turbinates are one of the major causes of nasal obstruction and are directly involved in the etiology of rhinitis. Turbinates can become hypertrophied and produce increased amounts of mucous when irritated by environmental allergens, hormones in the body, or some medicines. Steroids can decrease the reactivity of turbinates to allergens, hormones, and other non-allergic stimulants. Steroids can be delivered in multiple ways to the human body. For example, steroids can be injected into veins or muscles to decrease inflammation. A problem that can be associated with the injection of steroids into veins or muscles is that there can be side effectsto the entire body when this is done. Another way that steroids, antihistamines, and / or anticholinergics can be delivered to the human body is via an aqueous solution containing the molecules that is sprayed into the nose to help decrease inflammation and hypertrophy. This method of treatment can be administered daily, or twice daily. There are also some aerosol preparations available. However, it can be difficult for a patient to comply with a rigorous application schedule, and the application may not be done as prescribed. This can lead to treatment failures. There can also be a significant amount of nasal bleeding because the sprays can thin the mucosa on the septum.

[0007] The application of steroids to the inferior turbinate decreases the size of the turbinate therefore decreasing nasal obstruction and allowing the patient to breath better. They also reduce the overall inflammatory symptoms in the nose, associated with rhinitis. In the past, physicians would sometimes inject aqueous solutions of steroid directly into the turbinates over a span of two weeks. In many cases this worked well for controlling rhinitis and reduced the symptoms of rhinitis for up to 12 months. However, this practice has been all but abandoned because some patients developed blindness after injection within about twenty -four hours of injection, and usually within one hour of injection. It is hypothesized that the small size of the particle in an aqueous solution would travel within an artery in the turbinate back to the artery going to the eye and cause blindness.

[0008] Other treatments for rhinitis are surgical in nature and reduce the size of the turbinate, mechanically (“submucosal reduction”) or with ablation. Studies have shown efficacy with these techniques for 3 years and 6 months respectively. While these techniques are effective, especially the submucosal resection, they are employed less frequently on this large population due to their surgical nature.

[0009] Another treatment for rhinitis is allergy desensitization therapy (also called immunotherapy), and posterior nasal nerve ablation (PNN), but ENTs are unhappy with these procedures because it can months for a patient to begin to see improvement and take up to three years to complete treatment.SUMMARY OF THE INVENTION

[0010] Aspects of the disclosure are drawn towards a composition comprising a biodegradable polymer and a steroid. In embodiments, the composition comprises no more that about 30 wt. % of the steroid, and the biodegradable polymer comprises about 5.0 wt. % to about 25 wt. % of poly(DL-lactide-co-glycolide) acid end (PLGA), wherein the PLGA comprises a lactide to glycolide ratio of about 50:50 and a molecular weight of about 40 kDa to about 65kDa. Inembodiments, the steroid comprises a systemic bioavailability of no more than 10%. In embodiments, the compositions described herein comprises about 5.0 wt. % to about 85.0 wt. % of at least one hydroxypropyl-methylcellulose (HPMC), wherein the at least one HPMC comprises a molecular weight of about 550 kDa to about 1,000 kDa. In embodiments, the compositions described herein further comprises about 5.0 wt.% to about 35.0 wt. % of polyethylene glycol (PEG) 3350, about 1.0 wt.% to about 2.0 wt. % of polyethylene glycol (PEG) 400, about 34.0 wt. % to about 68.0 wt. % of a polyethylene oxide (PEO), wherein the PEO comprises a molecular weight of about 600 kDa, 0 wt. % to about 20 wt. % of polyvinyl pyrrolidone (PVP), wherein the PVP comprises a molecular weight of about 1,350 kDa, or any combination thereof. In embodiments described herein, the steroid comprises mometasone furoate, fluticasone, ciclesonide, or any combination thereof. In embodiments, the compositions described herein comprise about 10 wt. %, about 11 wt. %, about 12 wt. %, about 13 wt. %, about 14 wt. %, about 15 wt. %, about 16 wt. %, about 17 wt. %, about 18 wt. %, about 19 wt. %%, or about 20 wt. % of the steroid. In embodiments, the compositions described herein comprise formula F1, formula F8, formula F12, formula F20, formula F29, formula F30, formula F31, formula F32, formula F33, formula F34, formula F35, formula F36, formula F37, formula F38, formula F39, or formula F40. In embodiments, the compositions described herein elutes about 80% of the steroid to a target tissue in about 30 days. In embodiments, the target tissue comprises a nasal tissue. In embodiments, the nasal tissue comprises a nasal polyp or a nasal turbinate. In embodiments, the composition is a monolithic structure. In embodiments described herein, the monolithic structure is a cylinder comprising a length of about 40mm and a diameter of about 1 mm to about 2 mm.

[0011] Aspects of the disclosure are drawn towards a method of treating rhinitis, turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof, the method comprising administering any one of the compositions described herein to the nasal tissue of a subject in need thereof. In embodiments, the nasal tissue comprises a nasal polyp or a nasal turbinate. In embodiments, the rhinitis comprises allergic rhinitis or non-allergic rhinitis.

[0012] Aspects of the disclosure are drawn towards use of any one of the compositions described herein to treat a subject afflicted with rhinitis, turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof.

[0013] Aspects of the disclosure are drawn toward a method of preparing a steroid-eluting nasal implant, wherein the method comprises blending a steroid and at least one biodegradable polymer, thereby forming a steroid-polymer blend, processing the steroid-polymer blend, thereby producing a steroid-eluting nasal implants, and cooling the processed steroid-polymerblend in a geometry, thereby forming a steroid-eluting nasal implant. In embodiments, the steroid-polymer blend comprises any one of the compositions described herein. In embodiments, the processing comprises feeding the steroid-polymer blend into a hot melt extruder, extruding the steroid-polymer blend through a screw and a die, wherein the die comprises a diameter of about 0.5 mm to about 2.5 mm, and wherein the extruding comprises a feed rate of about 0.5 g / min to about 2.0 g / min, a processing speed of about 40 rpm to about 80 rpm, a processing temperature of about 80°C to about 200°C, or any combination thereof. In embodiments, the processing comprises mixing the steroid-polymer blend at a temperature of about 150°C to about 200°C, depositing the steroid-polymer blend in a plurality of layers, wherein the plurality of layers forms a 3D infill pattern. In embodiments, the infill pattern is selected from the group consisting of a grid, a line, an octet, a quarter cubic, a gyroid, a zigzag, or any combination thereof. In embodiments, the infill pattern comprises a density of less than about 25% to about 100%. In embodiments of any one of the methods described herein, the infill pattern and infill density are configured to vary the drug release profile. In embodiments, the geometry is a cylinder.

[0014] Other objects and advantages of this invention will become readily apparent from the ensuing description.BRIEF DESCRIPTION OF THE FIGURES

[0015] FIG. 1 illustrates a nasal space, under an embodiment.

[0016] FIG. 2 illustrates a delivery mechanism for a drug eluting implant, under an embodiment.

[0017] FIG. 3 illustrates a delivery mechanism for a drug eluting implant, under an embodiment.

[0018] FIG. 4 illustrates components of a delivery mechanism for a drug eluting implant, under an embodiment.

[0019] FIG. 5 illustrates a delivery mechanism for a drug eluting implant, under an embodiment.

[0020] FIG. 6 illustrates a delivery mechanism for a drug eluting implant, under an embodiment.

[0021] FIG. 7 illustrates components of a delivery mechanism for a drug eluting implant, under an embodiment.

[0022] FIG. 8 illustrates components of a delivery mechanism for a drug eluting implant, under an embodiment.

[0023] FIG. 9 illustrates components of a delivery mechanism for a drug eluting implant, under an embodiment.

[0024] FIG. 10 illustrates a nasal space, under an embodiment.

[0025] FIG. 11 illustrates a nasal space, under an embodiment.

[0026] FIG. 12 illustrates a nasal space, under an embodiment.

[0027] FIGS. 13-18 show images of an implant inserted into the subcutaneous tissue in the back of a rat, under an embodiment. The present studies were completed to evaluate in vivo steroid elution.

[0028] FIG. 19 shows implant formations comprising mometasone furoate, PLGA 5005 A, and HPMC K35M, under an embodiment.

[0029] FIG. 20 shows implant formations comprising mometasone furoate, PLGA 5005A, HPMC K35M, HPMC K100M, and Affinisol HME 4M, under an embodiment.

[0030] FIG. 21 shows implant formations comprising mometasone furoate, PLGA 5005A, HPMC K35M, PEG 3350, and PEG 400, under an embodiment.

[0031] FIG. 22 shows implant formations comprising mometasone furoate, PLGA 5005A, HPMC K35M, and PEO 205, under an embodiment.

[0032] FIG. 23 shows implant formations comprising mometasone furoate, PLGA 5005A, HPMC K35M, HPMC K100M, PEG 3350, PEO 205, and Affinisol HME 4M, under an embodiment.

[0033] FIG. 24A - 24B shows non-limiting, exemplary percentages of implant material components, under an embodiment indicating the day upon which the percentage drug release exceeds 80 percent.

[0034] FIG. 25 shows percentages of proposed implant material components, under an embodiment.

[0035] FIG. 26A shows a non-limiting, exemplary graph of water uptake in formulations Fl, F2, F27, and F28. and mass remaining study of mometasone furoate implants.

[0036] FIG. 26B shows a non-limiting, exemplary graph of mass remaining study for formulations Fl, F2, F27, and F28.

[0037] FIG. 27A shows a non-limiting, exemplary graph of cumulative % drug release of formulations with PLGA and HPMC K35M.

[0038] FIG. 27B shows a non-limiting, exemplary graph of cumulative % drug release of formulations with PLGA, HPMC, and Affinisol™ HPMC HME.

[0039] FIG. 27C shows a non-limiting, exemplary graph of cumulative % drug release of formulations with PLGA and HPMC K35M and PEG.

[0040] FIG. 27D shows a non-limiting, exemplary graph of cumulative % drug release of formulations with PLGA and HPMC K35M with and without PEG (Fl and F2 without PEG and F7 and F18 with PEG).

[0041] FIG. 28 shows a non-limiting, exemplary schematic outlining the workflow of the process for producing and testing drug eluting implants in an embodiment. Without wishing to be bound by theory, we will evaluate drug elution in vivo in rats; foreign body response in vivo in rabbits; and a safety study in vivo in sheep to evaluated systemic absorption of steroid from implants by looking for cortisol levels in the sheep.

[0042] FIG. 29 shows a non-limiting, exemplary schematic of the experimental set-up for the Repka-Zhang test.

[0043] FIG. 30 shows non-limiting, exemplary images of texture analysis apparatus for evaluation of bioadhesion.

[0044] FIG. 31A shows a non-limiting, exemplary image of a rotating bottle method set-up for study of in-vitro release.

[0045] FIG. 31B shows a non-limiting, exemplary image of an in-line diffusing set-up for study of in-vitro release.

[0046] FIG. 32 shows a non-limiting, exemplary image of a IVIS® Lumina K Series III imaging system.

[0047] FIG. 33A shows non-limiting, exemplary in vitro-in vivo data comparison for Fl.

[0048] FIG. 33B shows non-limiting, exemplary in vitro-in vivo data comparison for F28.

[0049] FIG. 34 shows a non-limiting, exemplary flow diagram for preparation and characterization of hot-melt extruded implants.

[0050] FIG. 35 shows a non-limiting, exemplary digital image of MF impends made with various combinations of polymers under embodiments.

[0051] FIG.36 shows non-limiting, exemplary SEM images of formulations Fl, F5, F18, and F28 at 20x and 50x magnification.

[0052] FIG. 37A shows non-limiting, exemplary DSC thermograms of MF, Fl, F5, F18, and F28 and their polymers.

[0053] FIG. 37B shows non-limiting, exemplary FTIR spectra of Fl and its components.

[0054] FIG. 37C shows non-limiting, exemplary FTIR spectra of F28 and its components.

[0055] FIG. 37D shows non-limiting, exemplary FTIR spectra of F18 and its components.

[0056] FIG. 38 shows non-limiting, exemplary breaking force data for implant formulations.

[0057] FIG. 39 shows non-limiting, exemplary images of in-vivo rat studies including implantation, sample collection, and implants harvested.

[0058] FIG. 40 shows non-limiting, exemplary graphs comparing in-vitro and in-vivo drug release behavior of formulations Fl and F28.

[0059] FIG. 41 shows non-limiting, exemplary images and data of 3D printing infill patterns, designs, and infill densities.DETAILED DESCRIPTION OF THE INVENTION

[0060] Detailed descriptions of one or more embodiments are provided herein. It is to be understood, however, that the invention can be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the invention in any appropriate manner.

[0061] The singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification can mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0062] Wherever any of the phrases “for example,” “such as,” “including” and the like are used herein, the phrase “and without limitation” is understood to follow unless explicitly stated otherwise. Similarly, “an example,” “exemplary” and the like are understood to be nonlimiting.

[0063] The term “substantially” allows for deviations from the descriptor that do not negatively impact the intended purpose. Descriptive terms are understood to be modified by the term “substantially” even if the word “substantially” is not explicitly recited.

[0064] The terms “comprising” and “including” and “having” and “involving” (and similarly “comprises”, “includes,” “has,” and “involves”) and the like are used interchangeably and have the same meaning. Specifically, each of the terms is defined consistent with the common United States patent law definition of “comprising” and is therefore interpreted to be an open term meaning “at least the following,” and is also interpreted not to exclude additional features, limitations, aspects, etc. Thus, for example, “a process involving steps a, b, and c” means that the process includes at least steps a, b and c. Wherever the terms “a” or “an” are used, “one or more” is understood, unless such interpretation is nonsensical in context.

[0065] As used herein, the term “about” can refer to approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the statedvalue by a variance of 20 percent up or down (higher or lower). In embodiments, the term “about” can be denoted

[0066] As used herein, the term “substantially the same” or “substantially” can refer to variability typical for a particular method is taken into account.

[0067] The terms “sufficient” and “effective”, as used interchangeably herein, can refer to an amount (e.g., mass, volume, dosage, concentration, and / or time period) needed to achieve one or more desired result(s).

[0068] Before explaining at least one embodiment of the disclosure in detail, it is to be understood that the disclosure is not necessarily limited in its application to the details set forth in the following description or exemplified by the examples. The disclosure can be used for other embodiments or of being practiced or carried out in various ways. Other compositions, compounds, methods, features, and advantages of the disclosure will be or become apparent to one having ordinary skill in the art upon examination of the following drawings, detailed description, and examples. All such additional compositions, compounds, methods, features, and advantages can be included within this description, and be within the scope of the disclosure.

[0069] The term "alkyl" refers to the radical of saturated aliphatic groups, including straightchain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkylsubstituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.

[0070] In some embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), 20 or fewer, 12 or fewer, or 7 or fewer. Likewise, in some embodiments cycloalkyls have from 3-10 carbon atoms in their ring structure, e.g., have 5, 6 or 7 carbons in the ring structure. The term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims can include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having one or more substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents include, but are not limited to, halogen, hydroxyl, carbonyl (such as a carboxyl, alkoxycarbonyl, formyl, or an acyl), thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, a hosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0071] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein can refer to an alkyl group, as defined herein, but having from one to ten carbons, or from oneto six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In some embodiments, alkyl groups are lower alkyls. In some embodiments, a substituent described herein as alkyl can be a lower alkyl.

[0072] It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl can include halogen, hydroxy, nitro, thiols, amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Cycloalkyls can be substituted in the same manner.

[0073] The term “heteroalkyl”, as used herein, can refer to straight or branched chain, or cyclic carbon-containing radicals, or combinations thereof, containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P, Se, B, and S, wherein the phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined herein for alkyl groups.

[0074] The term "alkylthio" can refer to an alkyl group, as defined herein, having a sulfur radical attached thereto. In some embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, and -S-alkynyl. Representative alkylthio groups include methylthio, and ethylthio. The term “alkylthio” also encompasses cycloalkyl groups, alkene and cycloalkene groups, and alkyne groups. “Arylthio” refers to aryl or heteroaryl groups. Alkylthio groups can be substituted as defined herein for alkyl groups.

[0075] The terms "alkenyl" and "alkynyl", refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described herein, but that contain at least one double or triple bond respectively. As used herein, the term “alkenyl” can refer to an unsaturated branched, straight-chain, or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group can be in either the cis or trans conformation about the double bond(s). In embodiments described herein, the alkenyl group can be C2-C13 alkenyl. Nonlimiting examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, etc.

[0076] The terms "alkoxyl" or "alkoxy" as used herein can refer to an alkyl group, as defined herein, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, and tert-butoxy. An "ether," for example, can be two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, and -O-alkynyl. Aroxy can be represented by -O-aryl or O-heteroaryl, wherein aryl and heteroaryl are as defined herein. The alkoxy and aroxy groups can be substituted as described herein for alkyl.

[0077] As used herein, the term “halogen” can refer to -F, -Cl, -Br or -I; the term "sulfhydryl" can refer to -SH; the term "hydroxyl" can refer to -OH; and the term "sulfonyl" can refer to -SO2-.

[0078] The term “substituted” as used herein, can refer to permissible substituents of the compounds described herein. In the broadest sense, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, but are not limited to, halogens, hydroxyl groups, or any other organic groupings containing any number of carbon atoms, for example 1-14 carbon atoms, and optionally include one or more heteroatoms such as oxygen, sulfur, or nitrogen grouping in linear, branched, or cyclic structural formats. Representative substituents include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, phenylthio, substituted phenylthio, arylthio, substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, sulfonyl, substituted sulfonyl, sulfonic acid, phosphoryl, substituted phosphoryl, phosphonyl, substituted phosphonyl, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid, peptide, and polypeptide groups. As used herein in reference to an “R” group, the name used to describe said “R” group can be the chemical name prior to the removal of a hydrogen. For example, wherein “R” is described as an “alkane” can refer to an “alkyl” group.

[0079] Heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. It is understood that “substitution” or “substituted” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0080] In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. The permissible substituents can be one or more and the same or different for appropriate organic compounds. The heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.

[0081] In various aspects, the substituent can be selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, each of which optionally is substituted with one or more suitable substituents. In some embodiments, the substituent is selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone, wherein each of the alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone can be further substituted with one or more suitable substituents.

[0082] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, thioketone, ester, heterocyclyl, -CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, alkylthio, oxo, acylalkyl, carboxy esters, carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, carboxamidoalkylaryl, carb oxami doaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like. In some embodiments, the substituent is selected from cyano, halogen, hydroxyl, and nitro.

[0083] As used herein, the term hydroxy alkyl can refer to a hydroxy terminated alkyl. For example, the hydroxyalkyl can be any hydroxyalkyl known in the art. In embodiments the hydroxyalkyl can be C1-C12 hydroxyalkyl. For example, the hydroxyalkyl can be hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.

[0084] Aspects of the disclosure are drawn towards a composition comprising a biodegradable polymer and a steroid. In embodiments the composition comprises no more than 30 wt. % of the steroid. For example the composition can comprise less than about 1.0 wt.%, about 1.5 wt.%, about 2.0 wt.%, about 2.5 wt.%, about 3.0 wt.%, about 3.5 wt.%, about 4.0 wt.%, about 4.5 wt.%, about 5.0 wt.%, about 5.5 wt.%, about 6.0 wt.%, about 7.0 wt.%, about 7.5 wt.%, about 8.0 wt.%, about 9.0 wt.%, about 9.5 wt.%, about 10.0 wt.%, about 10.5 wt.%, about 11.0 wt.%, about 11.5 wt.%, about 12.0 wt.%, about 12.5 wt.%, about 13.0 wt.%, about 13.5 wt.%, about 14.0 wt.%, about 14.5 wt.%, about 15.0 wt.%, about 16.0 wt.%, about 17.0 wt.%, about 18.0 wt.%, about 19.0 wt.%, about 20.0 wt.%, about 21.0 wt.%, about 22.0 wt.%, about 23.0 wt.%, about 24.0 wt.%, about 25.0 wt.%, about 26.0 wt.%, about 27.0 wt.%, about 28.0 wt.%, about 29.0 wt.%, or about 30 wt.% of the steroid. In some embodiments, the composition comprises about 12.5 wt.% to about 20 wt.% of the steroid. In embodiments, the composition comprises no more than 15 wt. % of the steroid. In some embodiments, for example, the composition comprises 15.0 wt. % of the steroid.

[0085] In embodiments the steroid can comprise a systemic bioavailability of no more than 10%. For example, the systemic bioavailability of the steroid can be less than about 1.0 %, about 1.25 %, about 1.50 %, about 1.75 %, about 2.0 %, about 2.25 %, about 2.50 %, about 2.75 %, about 3.0 %, about 3.25 %, about 3.50 %, about 3.75 %, about 4.0 %, about 4.25 %, about 4.75 %, about 5.0 %, about 5.25 %, about 5.50 %, about 5.75 %, about 6.0 %, about 6.25 %, about 6.50 %, about 6.75 %, about 7.0 %, about 7.25 %, about 7.50 %, about 7.75 %, about 8.0 %, about 8.25 %, about 8.75 %, about 9.0 %, about 9.25 %, about 9.50 %, about 9.75 %, or about 10.0 %.

[0086] In embodiments the steroid can comprise mometasone furoate (MF), fluticasone, fluticasone propionate, fluticasone furoate, triamcinolone acetonide, budesonide, ciclesonide, or any combination thereof.

[0087] As used herein, the term “biodegradable” and “dissolvable” can be used interchangeably and can refer to a material that is capable of being broken down by a living thing and reabsorbed by its natural environment. For example, the biodegradable implants offer the advantage of not having the need to be removed after treatment.

[0088] As used herein, the term “systemic bioavailability” can refer to a metric indicating the amount of active drug available to produce a therapeutic effect at the intended site of action, or the extent to which the drug enters the systemic circulation. For example, mometasone' s systemic bioavailability is measured at <0.1%-0.46%. Systemic bioavailability, as used herein, can be measured using pharmacokinetic studies. For example, the systemic bioavailability of asteroid can be determined using the area under the plasma concentration-time curve (AUC). This method can measure the concentration of the unchanged steroid and its metabolites in the plasma at various time intervals after administration.

[0089] In some embodiments the biodegradable polymer comprises about 5.0 wt.% to about 25 wt.% of a poly(DL-lactide-coglycolide) acid endcap (PLGA), wherein the PLGA comprises a lactide to glycolide ratio of about 50:50 and a molecular weight of about 40kDa to about 65kDa. In some embodiments, for example, the PLGA can comprise about 5.0 wt. %, about 5.50 wt.%, about 6.0 wt.%, about 6.5 wt.%, about 7.0 wt.%, about 7.5 wt.%, about 8.0 wt.%, about 8.5 wt.%, about 9.0 wt.%, about 9.5 wt.%, about 10.0 wt.%, about 10.5 wt.%, about 11.0 wt.%, about 11.5 wt.%, about 12.0 wt.%, about 12.5 wt.%, about 13.0 wt.%, about 13.5 wt.%, about 14.0 wt.%, about 14.5 wt.%, about 15.0 wt.%, about 15.5 wt.%, about 16.0 wt.%, about 16.5 wt.%, about 17.0 wt.%, about 17.5 wt.%, about 18.0 wt.%, about 18.5 wt.%, about 19.0 wt.%, about 19.5 wt.%, about 20.0 wt.%, about 20.5 wt.%, about 21.0 wt.%, about 21.5 wt.%, about 22.0 wt.%, about 22.5 wt.%, about 23.0 wt.%, about 23.5 wt.%, about 24.0 wt.%, about 24.5 wt.%, or about 25.0 wt.%.

[0090] In embodiments, the composition described herein can comprise about 5.0 wt. % to about 75.0 wt.% of a hydroxypropyl-methylcellulose (HPMC), wherein the HPMC comprises a molecular weight of less than about 550 kDa to about 1,000 kDa. In some embodiments the HPMC can comprise, for example, 5.0 wt. %, about 5.50 wt.%, about 6.0 wt.%, about 6.5 wt.%, about 7.0 wt.%, about 7.5 wt.%, about 8.0 wt.%, about 8.5 wt.%, about 9.0 wt.%, about 9.5 wt.%, about 10.0 wt.%, about 10.5 wt.%, about 11.0 wt.%, about 11.5 wt.%, about 12.0 wt.%, about 12.5 wt.%, about 13.0 wt.%, about 13.5 wt.%, about 14.0 wt.%, about 14.5 wt.%, about 15.0 wt.%, about 15.5 wt.%, about 16.0 wt.%, about 16.5 wt.%, about 17.0 wt.%, about 17.5 wt.%, about 18.0 wt.%, about 18.5 wt.%, about 19.0 wt.%, about 19.5 wt.%, about 20.0 wt.%, about 20.5 wt.%, about 21.0 wt.%, about 21.5 wt.%, about 22.0 wt.%, about 22.5 wt.%, about 23.0 wt.%, about 23.5 wt.%, about 24.0 wt.%, about 24.5 wt.%, or about 25.0 wt.%, 26.0 wt. %, about 27.0 wt.%, about 28.0 wt.%, about 29.0 wt.%, about 30.0 wt.%, about 31.0 wt.%, about 32.0 wt.%, about 33.0 wt.%, about 34.0 wt.%, about 35.0 wt.%, about 36.0 wt.%, about 37.0 wt.%, about 38.0 wt.%, about 39.0 wt.%, about 40.0 wt.%, about 41.0 wt.%, about 42.0 wt.%, about 43.0 wt.%, about 44.0 wt.%, about 45.0 wt.%, about 46.0 wt.%, about 47.0 wt.%, about 48.0 wt.%, about 49.0 wt.%, about 50.0 wt.%, about 51.0 wt.%, about 52.0 wt.%, about 53.0 wt.%, about 54.0 wt.%, about 55.0 wt.%, about 56.0 wt.%, about 57.0 wt.%, about 58.0 wt.%, about 59.0 wt.%, about 60.0 wt.%, about 61.0 wt.%, about 62.0 wt.%, about 63.0 wt.%, about 64.0 wt.%, about 65.0 wt.%, about 66.0 wt.%, about 67.0 wt.%, about 68.0 wt.%, about69.0 wt.%, about 70.0 wt.%, about 71.0 wt.%, about 72.0 wt.%, about 73.0 wt.%, about 74.0 wt.%, or about 75.0 wt.%.

[0091] In some embodiments, for example, the composition described herein can comprise about 34.0 wt. % to about 73.0 wt. % of a HPMC comprising a molecular weight of about 675 kDa. In some embodiments, for example, the composition described herein can comprise about 60 wt. % to about 75 wt. % of a HPMC comprising a molecular weight of about 1,000 kDa. In some embodiments, for example, the composition described herein comprises about 5.0 wt. % to about 73.0 wt. % of a HPMC comprising a molecular weight of about 550 kDa.

[0092] In embodiments the composition described herein can further comprise about 5.0 wt.% to about 35.0 wt.% of a polyethylene glycol (PEG) 3350. As used herein PEG 3350 can refer to PEG with an average molecular weight of about 3,350 g / mol. In some embodiments, for example, the PEG 3350 can comprise about 5.0 wt.%, about 6.0 wt.%, about 7.0 wt.%, about 8.0 wt.%, about 9.0 wt.%, about 10.0 wt.%, about 11.0 wt.%, about 12.0 wt.%, about 13.0 wt.%, about 14.0 wt.%, about 15.0 wt.%, about 16.0 wt.%, about 17.0 wt.%, about 18.0 wt.%, about 19.0 wt.%, about 20.0 wt.%, about 21.0 wt.%, about 22.0 wt.%, about 23.0 wt.%, about 24.0 wt.%, about 25.0 wt.%, about 26.0 wt.%, about 27.0 wt.%, about 28.0 wt.%, about 29.0 wt.%, about 30.0 wt.%, about 31.0 wt.%, about 32.0 wt.%, about 33.0 wt.%, about 34.0 wt.%, or about 35.0 wt.%.

[0093] In embodiments, the composition described herein can further comprise about 1.0 wt.% to about 2.0 wt.% of a polyethylene glycol (PEG) 400. As used herein, PEG 400 can refer to a PEG with an average molecular weight of about 400. In some embodiments, the PEG 400 can comprise about 1.0 wt.%, 1.1 wt.%, 1.2 wt.%, 1.3 wt.%, 1.4 wt.%, 1.5 wt.%, 1.6 wt.%, 1.7 wt.%, 1.8 wt.%, 1.9 wt.%, or about 2.0 wt.%.

[0094] In embodiments, the composition described herein can further comprise about 34.0 wt.% to about 68.0 wt.% of a polyethylene oxide (PEO), wherein the PEO comprises a molecular weight of about 600 kDa. In some embodiments, for example the PEO can comprise about 34.0 wt.%, about 35.0 wt.%, about 36.0 wt.%, about 37.0 wt.%, about 38.0 wt.%, about 39.0 wt.%, about 40.0 wt.%, about 41.0 wt.%, about 42.0 wt.%, about 43.0 wt.%, about 44.0 wt.%, about 45.0 wt.%, about 46.0 wt.%, about 47.0 wt.%, about 48.0 wt.%, about 49.0 wt.%, about 50.0 wt.%, about 51.0 wt.%, about 52.0 wt.%, about 53.0 wt.%, about 54.0 wt.%, about 55.0 wt.%, about 56.0 wt.%, about 57.0 wt.%, about 58.0 wt.%, about 59.0 wt.%, about 60.0 wt.%, about 61.0 wt.%, about 62.0 wt.%, about 63.0 wt.%, about 64.0 wt.%, about 65.0 wt.%, about 66.0 wt.%, about 67.0 wt.%, or about 68.0 wt.%.

[0095] In embodiments, the composition described herein, can further comprise 0.0 wt.% to about 20 wt.% of a polyvinyl pyrrolidone (PVP), wherein the PVP comprises a molecular weight of about 1,350 kDa. In some embodiments, for example, the PVP can comprise 0.0 wt.%, about 1.0 wt.%, about 2.0 wt.%, about 3.0 wt.%, about 4.0 wt.%, about 5.0 wt.%, about 6.0 wt.%, about 7.0 wt.%, about 8.0 wt.%, about 9.0 wt.%, about 10.0 wt.%, about 11.0 wt.%, about 12.0 wt.%, about 13.0 wt.%, about 14.0 wt.%, about 15.0 wt.%, about 16.0 wt.%, about 17.0 wt.%, about 18.0 wt.%, about 19.0 wt.%, or about 20.0 wt.%.

[0096] In some embodiments, the composition described herein can further comprise any combination described herein of a polyethylene glycol (PEG) 3350, a polyethylene glycol (PEG) 400, a polyethylene oxide (PEO), or a polyvinyl pyrrolidone (PVP).

[0097] In some embodiments, the composition described herein can comprise 15% MF, 5% of a PLGA, 5% of an HPMC wherein the molecular weight is 675 kDa, and 75 % of an HPMC wherein the molecular weight is 1,000 kDa.

[0098] In some embodiments, the composition described herein can comprise 15 wt.% MF, 5 wt.% of a PLGA, 10 wt.% of an HPMC wherein the molecular weight is 675 kDa, and 70 wt.% of an HPMC wherein the molecular weight is 1,000 kDa.

[0099] In some embodiments, the composition described herein can comprise 15 wt.% MF, 7 wt.% of a PLGA, 5 wt.% of an HPMC wherein the molecular weight is 675 kDa, and 73 wt.% of an HPMC wherein the molecular weight is 1,000 kDa.

[0100] In some embodiments, the composition described herein can comprise 15 wt.% MF, 7 wt.% of a PLGA, 10 wt.% of an HPMC wherein the molecular weight is 675 kDa, and 68 wt.% of an HPMC wherein the molecular weight is 1,000 kDa.

[0101] In some embodiments, the composition described herein can comprise 15 wt.% MF, 10 wt.% of a PLGA, 5 wt.% of an HPMC wherein the molecular weight is 675 kDa, and 70 wt.% of an HPMC wherein the molecular weight is 1,000 kDa.

[0102] In some embodiments, the composition described herein can comprise 15% MF, 10 wt.% of a PLGA, 10 wt.% of an HPMC wherein the molecular weight is 675 kDa, and 65 % of an HPMC wherein the molecular weight is 1,000 kDa.

[0103] In some embodiments, the composition described herein can comprise 15% MF, 5 wt.% of a PLGA, 75 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 5 % of an HPMC wherein the molecular weight is 550 kDa.

[0104] In some embodiments, the composition described herein can comprise 15% MF, 5 wt.% of a PLGA, 70 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 10 % of an HPMC wherein the molecular weight is 550 kDa

[0105] In some embodiments, the composition described herein can comprise 15% MF, 7 wt.% of a PLGA, 73 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 5 % of an HPMC wherein the molecular weight is 550 kDa.

[0106] In some embodiments, the composition described herein can comprise 15% MF, 7 wt.% of a PLGA, 68 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 10 % of an HPMC wherein the molecular weight is 550 kDa.

[0107] In some embodiments, the composition described herein can comprise 15% MF, 10 wt.% of a PLGA, 70 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 5 % of an HPMC wherein the molecular weight is 550 kDa.

[0108] In some embodiments, the composition described herein can comprise 15% MF, 10 wt.% of a PLGA, 65 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 10 % of an HPMC wherein the molecular weight is 550 kDa.

[0109] In some embodiments, the composition described herein can comprise 15% MF, 34 wt.% of a PLGA, 40.8 wt.% of an HPMC wherein the molecular weight is 1000 kDa, and 10.2 % of an HPMC wherein the molecular weight is 550 kDa.

[0110] In some embodiments, the composition described herein can comprise 15% MF, 17 wt.% of a PLGA, and 68 wt.% of an HPMC wherein the molecular weight is 675 kDa.

[0111]

[0112] In some embodiments the about 80% of the steroid elutes to a target tissue in about 7 days to about 45 days. For example, 80% of the steroid elutes to a target tissue in about about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, or about 45 days. For example, these formulations produced implants that exhibited in vitro drug release for 20-45 days while maintaining adequate mechanical strength.

[0113] In embodiments, the target tissue can comprise a nasal tissue. In some embodiments, the nasal tissue can comprise a nasal polyp or a nasal turbinate. Non-limiting, exemplary nasal polyps can be Ethmoidal Polyps, Antrochoanal Polyps, Sphenoidal Polyps, Frontal Sinus Polyps, Allergic Fungal Sinusitis Polyps, Cystic Fibrosis-Associated Polyps, Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), Neoplastic Nasal Polyps, Unilateral Nasal Polyps. The term nasal turbinate, as used herein, refers to a long, narrow, curled boneshelf inside the nasal cavity covered by soft tissue and mucous membrane. Non-limiting, exemplary nasal turbinates can be inferior turbinate, middle turbinate, superior turbinate, or supreme turbinate. For example, a steroid-eluting dissolvable implant can be placed in the inferior turbinates (Figure 1) using an in-office delivery system shown in Figure 6.

[0114] In embodiments the composition is a monolithic structure. In some embodiments the monolithic structure can comprise a cylinder. In some embodiments the cylinder can comprise a length of about 40mm and a diameter of about 1mm to about 2mm. As used herein, the terms “monolith” and “monolithic structure” can be used interchangeably and are defined as a structure made from a single, continuous material or formed as one solid piece, rather than assembled from multiple parts. For example, using hot melt extrusion, the steroid and biodegradable polymers were blended and processed into a single, continuous cylindrical filament, forming a monolithic implant capable of sustained drug release over 30 days.

[0115] An embodiment of the disclosure is drawn towards a method of treating rhinitis, turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof. In some embodiments the method can comprise administering the composition described herein to the nasal tissue of a subject in need thereof.

[0116] In some embodiments, non-limiting, exemplary indications of rhinitis can be allergic rhinitis, non-allergic rhinitis, rhinitis medicamentosa, idiopathic rhinitis, or sinusitis. Non-limiting, exemplary indications of turbinate hypertrophy can be acute turbinate hypertrophy, chronic turbinate hypertrophy, soft tissue turbinate hypertrophy, bony turbinate hypertrophy, mixed turbinate hypertrophy, inferior turbinate hypertrophy, middle turbinate hypertrophy, or superior turbinate hypertrophy.

[0117] An embodiment of the disclosure is drawn towards the use of the composition described herein to treat a subject afflicted with rhinitis turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof.

[0118] An embodiment of the disclosure is drawn towards a method of preparing a steroid-eluting nasal implant. In some embodiments the steroid-eluting implant can comprise blending a steroid and at least one biodegradable polymer described herein, thereby forming a steroid-polymer blend. In some embodiments the processed steroid-polymer blend can be cooled into a geometry thereby forming a steroid-eluting nasal implant. As used herein, the geometry can comprise a cylinder, a tube, a prism, a block, a cube, or any geometry known to those skilled in the art.

[0119] In embodiments the steroid-polymer blend can comprise anyone of the biodegradable polymers, or steroid described herein. In some embodiments the processing cancomprise feeding the steroid-polymer blend into a hot melt extruder. Further, the steroidpolymer blend can be extruded through a screw and a die, wherein the die can comprise a diameter of about 0.5 mm to about 2.5 mm. In some embodiments the extruding can comprise a feed rate of about 0.5 g / min to about 2.0 g / min, a processing speed of about 40 rpm to about 80 rpm, a processing temperature of about 80°C to about 200°C, or any combination thereof.

[0120] For example, the die can comprise a diameter of about 0.5 mm, about 0.55 mm, about 0.6 mm, about 0.65 mm, about 0.7 mm, about 0.75 mm, about 0.8 mm, about 0.85 mm, about 0.9 mm, about 0.95 mm, about 1.0 mm, about 1.05 mm, about 1.1 mm, about 1.15 mm, about 1.2 mm, about 1.25 mm, about 1.3 mm, about 1.35 mm, about 1.4 mm, about 1.45 mm, about 1.5 mm, about 1.55 mm, about 1.6 mm, about 1.65 mm, about 1.7 mm, about 1.75 mm, about 1.8 mm, about 1.85 mm, about 1.9 mm, about 1.95 mm, about 2.0 mm, about 2.05 mm, about 2.1 mm, about 2.15 mm, about 2.2 mm, about 2.25 mm, about 2.3 mm, about 2.35 mm, about 2.4 mm, about 2.45 mm, or about 2.5 mm,

[0121] For example, the extruding can comprise a feed rate of about 0.5 g / min, about 0.55 g / min, about 0.6 g / min, about 0.65 g / min, about 0.7 g / min, about 0.75 g / min, about 0.8 g / min, about 0.85 g / min, about 0.9 g / min, about 0.95 g / min, about 1.0 g / min, about 1.05 g / min, about 1.1 g / min, about 1.15 g / min, about 1.2 g / min, about 1.25 g / min, about 1.3 g / min, about 1.35 g / min, about 1.4 g / min, about 1.45 g / min, about 1.5 g / min, about 1.55 g / min, about 1.6 g / min, about 1.65 g / min, about 1.7 g / min, about 1.75 g / min, about 1.8 g / min, about 1.85 g / min, about 1.9 g / min, about 1.95 g / min, or about 2.0 g / min.

[0122] For example, the extruding can comprise a processing speed of about 40 rpm, about 42 rpm, about 44 rpm, about 46 rpm, about 48 rpm, about 50 rpm, about 52 rpm, about 54 rpm, about 56 rpm, about 58 rpm, about 60 rpm, about 62 rpm, about 64 rpm, about 66 rpm, about 68 rpm, about 70 rpm, about 72 rpm, about 74 rpm, about 76 rpm, about 78 rpm, or about 80 rpm.

[0123] For example, the extruding can comprise a processing temperature of about 80 °C, about 85 °C, about 90 °C, about 95 °C, about 100 °C, about 105 °C, about 110 °C, about 115 °C, about 120 °C, about 125 °C, about 130 °C, about 135 °C, about 140 °C, about 145 °C, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, about 175 °C, about 180 °C, about 185 °C, about 190 °C, about 195 °C, of about 200 °C.

[0124] In some embodiments of the method described herein, the processing can comprise mixing the steroid-polymer blend at a temperature of about 150 °C to about 200 °C. In some embodiments the processed steroid-polymer blend can be deposited in a plurality of layers wherein the plurality of layers forms a 3D infill pattern. In some embodiments the infillpattern can consist of a grid, a line, and octet, a quarter cubic, a gyroid, a zigzag, any geometry known in the art, or any combination thereof.

[0125] As used herein, the terms 3D printing “pattern” and “infill geometry” can be used interchangeably. The infill geometry and infill density are two design parameters that influence the drug release behavior of extended-release 3D-printed implants. The infill pattern determines the internal structure and how the filament or material is deposited layer by layer. The 3D printing patterns can have different porosity and density. Each 3D printing infill pattern creates an internal microstructure that affects the surface area-to-volume ratio (SA / V), diffusion pathways, mechanical strength, and erosion behavior of 3D printed implants. On the other hand, infill density determines how much of the internal volume is filled with material (3D printing feedstock). At low infill density, rapid erosion or diffusion of 3D printed implants occurs. While at high infill density, the swelling / erosion is reduced. One of the advantages of 3D printing is that we can tailor the release profile without (or with minimal) changes to the formulation composition, but by changing the printing pattern or infill parameters.

[0126] In an embodiment of the method described herein, the infill pattern can comprise a density of about less than 25% to about 100%. For example, the infill density can comprise less than about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%.

[0127] In some embodiments, the infill pattern can comprise a line and the infill density can comprise 100%. In some embodiments, the infill pattern can comprise a line and the infill density can comprise 50%. In some embodiments, the infill pattern can comprise a line and the infill density can comprise 25%. In some embodiments the infill pattern can comprise a grid and the infill density can comprise 100%. In some embodiments, the infill pattern can comprise a grid and the infill density can comprise 50%. In some embodiments, the infill pattern can comprise a zigzag and the infill density can comprise 80%. In some embodiments, the infill pattern can comprise a zigzag and the infill density can comprise 50%. In some embodiments,the infill pattern can comprise a zigzag and the infill density can comprise 25%. In some embodiments, the infill pattern can comprise a gyroid and the infill density can comprise 100%. In some embodiments, the infill pattern can comprise a gyroid and the infill density can comprise 75%. In some embodiments, the infill pattern can comprise a gyroid and the infill density can comprise 50%. In some embodiments, the infill pattern can comprise a quartic-cubic and the infill density can comprise 100%. In some embodiments, the infill pattern can comprise a quartic-cubic and the infill density can comprise 50%. In some embodiments, the infill pattern can comprise an octet and the infill density can comprise 100%. In some embodiments, the infill pattern can comprise an octet and the infill density can comprise 50%.

[0128] In embodiments, the infill pattern and density of the methods described herein are configured to vary drug release profile. In some embodiments of the method described here the geometry can be a cylinder.EXAMPLES

[0129] Examples are provided herein to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are for purposes of illustration only, since alternative methods can be utilized to obtain similar results.EXAMPLE 1

[0130] Biodegradable nasal implants can be effective in delivering controlled and prolonged drug release for local action. The use of hot-melt extrusion can be a tool for implant development. Described herein, we prepare mometasone furoate implants for the treatment of rhinitis using controlled-release biodegradable poly (lactic-co-glycolic acid) (PLGA) in combination with the hydrophilic swellable hydroxypropyl methylcellulose (HPMC). Different HPMC viscosity grades and PLGA with different ratios were extruded using 15% w / w drug loading. The extruded formulations were evaluated in terms of extrudability, pore morphology, compatibility, thermal behavior, adhesion, drug release, mass remaining, and water uptake. From the in-vitro drug release studies, Fl and F28 formulations demonstrated promising controlled drug delivery for 30 days. Further, these two formulations were investigated for in-vivo drug release and mass remaining studies using the rat model.

[0131] Background

[0132] Rhinitis, which means inflammation of the nose, is a condition that causes inflammation of the nasal cavity and associated mucous membranes, leading to a runny nose, sneezing, and congestion. It has a significant effect on an individual’s quality of life and society. Rhinitis is classified as allergic or non-allergic, where the non-allergic one is caused due to a viral infection or exposure to irritants. Rhinitis may be acute or chronic. Acute rhinitis commonly results from viral infections but may also be a result of allergies, bacteria, or other causes. Chronic rhinitis usually occurs with chronic sinusitis (chronic rhinosinusitis). In general, the treatment of rhinitis is based on the patient's age and the severity of symptoms. Optimal treatment includes allergen avoidance, targeted symptom control, immunotherapy, and asthma evaluation, when appropriate. Intranasal corticosteroids are the most effective treatment and should be the first-line therapy for mild to moderate disease. Among the various approaches, corticosteroid injection of the turbinates was proven as the most effective way to relieve rhinitis symptoms but led to visual impairment. Hence, the present study is designed to develop a steroid-eluting dissolvable thread to place in the inferior turbinates (nasal implant), which is aimed to deliver controlled drug release for a month to improve the therapeutic efficiency and eliminate the side effects.

[0133] Nasal implants can be either biodegradable or non-biodegradable. Biodegradable implants are made from polymeric materials that break down in the body over time (biodegradable polymers), eliminating the need for surgical removal after treatment. Implants are defined as drug delivery systems or devices composed of a drug-polymer matrix that can provide a localized and efficient controlled drug release with minimal side effects, achieving desired therapeutic outcomes with low drug loadings. These implantable systems can bypass the first-pass effect and avoid enzymatic or chemical degradation in the gastrointestinal tract, thereby enhancing drug bioavailability. Various manufacturing techniques can be used to prepare implants, including compression, injection molding, solvent casting, and hot-melt extrusion (HME).

[0134] HME is a process where raw materials are melted and extruded to create solid dispersions or matrices, which is significant for improving the solubility and bioavailability of poorly water-soluble drugs and for designing controlled and site-specific drug delivery systems. HME offers several advantages over conventional methods, such as solvent-based techniques. First, it eliminates the need for organic solvents, reducing negative environmental impacts and potential toxicity issues. Thus, HME is considered a solvent-free and eco-friendly technique. Second, it allows for a continuous processing approach, enhancing efficiency and scalability in production. Third, HME facilitates better control over the physical and chemicalproperties of the final product, leading to improved stability and performance. Moreover, the technique enables the incorporation of a wide range of excipients and active pharmaceutical ingredients (APIs) in a single step, promoting uniform distribution and enhanced therapeutic effectiveness.

[0135] Embodiments described herein are drawn toward the development of a prolonged-release nasal implant for mometasone furoate using PLGA (poly (lactic-co-glycolic acid)) and HPMC (hydroxypropyl methylcellulose) through a hot-melt extrusion technique. Mometasone furoate (MF) can be used to manage postoperative inflammation due to its strong anti-inflammatory effects and low systemic absorption when applied locally. It is effective in reducing mucosal swelling, polyp size, and the recurrence of nasal polyps in patients with chronic rhinosinusitis. PLGA is a biodegradable polymer that can be used for nasal implants, with a long track record of safety and efficacy in humans. PLGA is a hydrophobic polymer, extensively utilized in the fabrication of controlled-release implants to achieve prolonged release for 3-6 months by maintaining a relatively solid structure in a wide range of biological conditions. Its hydrolytic degradation and matrix erosion are important factors that influence the drug release rates. The combination of different polymers with different physicochemical features can improve the control over the drug release and properties of the polymer matrix such as solubility, viscosity, and glass transition temperature. HPMC, a type of cellulose ether, is a hydrophilic, biodegradable, and biocompatible polymer that can swell upon hydration, making it feasible for drug escape / release based on viscosity grade. By combining HPMC with PLGA in various ratios, the resulting implant can provide controlled release from 15 days to 2 months.

[0136] Methodology

[0137] MF implants were fabricated using a Process 11 co-rotating twin-screw extruder (Thermo Scientific, Waltham, MA, USA), equipped with a die fitted with a 1.50 mm nozzle. The drug-polymer blend (Table 10 shows the composition of the various formulations) was prepared using a V-cone blender to achieve a homogeneous mixture. The blend was fed into the extruder at a constant rate of 0.5-1 g / min while maintaining a temperature of 150 to 185°C to extrude the filament. Each formulation targeted an implant size of <40.00 mm in length and <2.00 mm in diameter, with a drug loading of 15% w / w, resulting in implants weighing 60 mg, each containing 9 mg of MF.

[0138] Table 7: Non-limiting, exemplary formulation composition of Mometasone furoate implants

[0139] The resulting implants were evaluated for physical appearance, dimensions, drug content, and content uniformity. The drug's thermal behavior was examined using a differential scanning calorimeter and the drug-polymer compatibility was analyzed using FTIR. The surface morphology and breaking force of the filaments were assessed using scanning electron microscopy and a TA-XT2i texture analyzer, respectively. The prepared implants of definite size and weight equivalent to 9 mg of MF in triplicate were evaluated for in vitro drug release in pH 7.4 phosphate buffer with 2% sodium lauryl sulfate (SLS) dissolution media. The implants were also evaluated for bioadhesion, water uptake, and in vitro mass remaining. The samples were analyzed for drug content and drug release using HPLC at 254 nm. Based on the in vitro drug release profile and other evaluation parameters, Fl and F28 formulations were selected for in vivo rat mass remaining and drug release studies for 30 days (n=3).

[0140] Non-Limiting Results and Discussion

[0141] MF implants were successfully fabricated using the Process 11 co-rotating twin-screw extruder (Figure 34). The resulting filaments were white colored with a smooth surface and had sufficient brittleness / flexibility needed for implantation. HME process parameters, specifically feed rate & screw speed and configuration were adjusted during preliminary trials, and the same parameters were used for performing all experiments. Filament extrusion was carried out with a single mixing zone with an offset angle of 30° at a constant speed (50 rpm) and feed rate (0.5 g / min-1.0 g / min) to maintain the die pressure below 100 bar for smoothrunning with a single mixing zone featuring 90°, 60°, and 30° offset angles near zone-6 for all the formulations based on the preliminary trials. The barrel temperature gradually increased from zones 2 to 4 and maintained at 180 °C from zone 5 to the die to ensure a smooth extrusion process. Lowering the die temperature resulted in extrusion failure due to a die pressure increase of over 100 bar.

[0142] Figure 35 displays digital images of MF implants made with various combinations of polymers as shown in Table 7. The diameter is primarily determined by the size of the die (1.5 mm die was used) and the length of the implants was calculated based on the target dosage weight and manually cut from the extrudate strands. The images confirm that all implants have a cylindrical and rod-shaped solid form, featuring well-defined diameters and lengths. The final implant size is around 25.00 mm in length (23.26-24.82 mm) and 1.6 mm in diameter (1.60-1.64 mm), featuring a drug loading of 15%, resulting in a 60 mg weight implant (59.61±0.87 to 60.45±1.51 mg) equivalent to 9 mg of MF. All the formulations were evaluated for drug content (90.82±0.87 to 95.76±0.45) and content uniformity (91.36±2.45 to 95.42±2.20), and the results were found to be satisfactory. The uniform distribution of MF in the polymer blend was confirmed by the very low standard deviations. Without wishing to be bound by theory, the difference between the theoretical drug loading and the determined drug content is indicative of process losses and drug adsorption onto the inner surface of the extruder barrel. Hence, the HME fabrication technology and processing conditions were deemed suitable for implant fabrication.

[0143] Scanning electron microscopy (SEM) studies were conducted to examine the morphological changes on the surface of the prepared MF implants. Figure 36 shows the respective SEM images of Fl, F5, Fl 8, and F28 formulations at 20x and 50x magnifications. SEM images at 50x magnification show a relatively smooth surface with some surface irregularities. Small pores and cracks are distributed across the surface, indicating that the polymer matrix has retained its integrity post-extrusion. The pitting or voids observed on the surface could indicate areas where MF is dispersed. Without wishing to be bound by theory, these surface irregularities can be related to the drug-polymer interaction or air pockets formed during the extrusion process. The small inclusions scattered across the surface can be residual crystalline particles of MF that did not fully disperse within the PLGA and HPMC K35M matrix. At a lower magnification (20x), the overall structure of the implant is visible. The surface appears slightly rough, with visible pitting across the length of the filament. These rough areas, in combination with some irregularities, indicate that the formulation has structural integrity but can also have small pores due to the extrusion process. Despite thetexture, the filament shows a homogenous structure with no significant macroscopic phase separation. Among the Fl, F5, and F18 implants, F5 exhibits a relatively smooth surface due to its lower PLGA content, while F18 has a rougher surface because it contains 34% PLGA. When comparing Fl and F28, F28 displays a rougher and more porous surface than Fl, attributed to the inclusion of HPMC KI OOM and HME 4M grades instead of the K35 grade.

[0144] The thermal properties of pure drug, polymers, and drug-loaded implants (Fl, F5, F18, and F28) were analyzed using differential scanning calorimetry (DSC) to assess the physical states of each component in the prepared implants. Figure 37A presents the corresponding thermograms. The DSC thermogram for MF reveals a distinct endothermic peak at approximately 230°C, corresponding to the crystalline drug's melting point. PLGA 5005A exhibits a glass transition temperature (Tg) around 50°C, indicating the polymer's transition from a glassy to a rubbery state. The DSC thermograms for HPMC K35M, K100M, and HME 4M show a broad endothermic event in the range of 60-80°C, which corresponds to the moisture loss or dehydration from the polymer. No sharp melting point is observed as HPMC is an amorphous polymer. Additionally, the thermogram for PEG 400 displays characteristic thermal behavior.

[0145] The DSC thermogram of the implant formulations shows a combination of thermal events from the individual components. The Tg of PLGA is observed around 50°C, consistent with the PLGA alone, indicating that the polymer's glass transition is maintained within the final formulation. The moisture loss event from HPMC is still observed around 60-80°C, showing that the polymer retains its characteristic behavior in the final formulation. However, the sharp endothermic peak for MF at 230°C is either significantly reduced or absent in the final formulation, indicating that the API has transitioned into an amorphous state or has undergone molecular dispersion within the polymer matrix. The absence or reduction of the API's melting peak indicates interaction between MF and the polymers (HPMC and PLGA), which can result in improved solubility and stability in the prepared formulation. The thermogram for the MF and the formulations show irregular fluctuations beyond 230°C, which can indicate thermal degradation. After the API melts, continued heating can cause the breakdown of the polymer matrix, leading to exothermic or endothermic events characteristic of polymer degradation. The absence of sharp thermal events after this point suggests that any transitions occurring after 230°C are related to degradation, as the components decompose or lose their structural integrity.

[0146] FTIR spectra for the implant samples were studied in reference to their components to evaluate and confirm the compatibility of the components of the prepared MFimplant formulations. The analysis of MF, HPMC K35M, and PLGA 5005A through FTIR spectroscopy provides insights into their structural integrity within formulations. MF exhibits characteristic peaks, including a carbonyl stretching band at around 1720 cm1and O-H stretching between 3500-3200 cm confirming its presence. HPMC displays a broad O-H stretch at 3400 cm1and C-0 stretching between 1300-1000 cm indicating stable hydrogen bonding typical of cellulose derivatives. Similarly, PLGA shows strong C=O stretching vibrations at approximately 1750confirming its structure remains intact. In the Fl physical mixture, the FTIR spectrum showcases all components, with distinct C=O stretching peaks for both MF and PLGA, alongside HPMC’s O-H stretch, with no significant peak shifts, indicating a lack of chemical interactions. The Fl placebo extrudate, consisting only of HPMC and PLGA, confirms the absence of MF peaks while retaining the characteristic polymer peaks, indicating successful formulation. Finally, the Fl final formulation shows all three components' peaks, affirming their presence without significant shifts, thus indicating no covalent interactions. However, a slight broadening of the O-H stretch of HPMC can indicate hydrogen bonding with MF, which can enhance formulation stability by limiting API mobility (Figure 37B). Overall, FTIR analysis indicates that the structural integrity of the active pharmaceutical ingredient and polymers is maintained throughout the formulation processes.

[0147] The FTIR analysis of F28 (Figure 37C) indicates that MF remains chemically intact throughout the formulation process, as its characteristic functional groups (C=O and O-H) are preserved in the final extruded formulation. The slight broadening of the O-H band in the final formulation can indicate hydrogen bonding interactions between MF and HPMC, which can improve the physical stability of the formulation. This interaction helps embed the API more effectively within the polymer matrix, which can prevent recrystallization or phase separation of the API. In the FTIR spectrum of the F18 formulation (Figure 37D), Mometasone's characteristic C=O stretching vibration at 1720 cm1is retained, along with the C=O stretch of PLGA at 1750 cmThe O-H stretch from HPMC is still visible at 3400 cmthough slightly broader than in the physical mixture. This broadening of the O-H band indicates weak hydrogen bonding interactions between Mometasone and HPMC, which can contribute to improved stability of the API within the polymer matrix. In conclusion, The FTIR analysis confirms that MF is compatible with HPMC K35M, PLGA 5005 A, and PEG 400 in the Fl 8 formulation. Overall, the absence of significant peak shifts in all final formulations indicates that no strong covalent interactions have occurred between the API and the excipients.

[0148] The breaking force of the filaments was evaluated to determine the force required to break them. Significant variation was observed among the formulations, withbreaking force ranging from 87.0 g for F7 to 390.6 g for F27 (Figure 38). This variability indicates that the mechanical properties of the implants are influenced by the formulation composition, particularly the type and amount of polymers used. Formulations with higher PLGA contentexhibited greater breaking force. For instance, F2 (34% PLGA) had a breaking force of 290.9 g, F27 (34% PLGA) reached 390.6 g, and F18 (34% PLGA) showed 333.7 g. In contrast, formulations with lower PLGA concentrations, such as Fll (12.75% PLGA) with 259.5 g and F5 (14.9% PLGA) with 182.4 g, exhibited lower breaking forces. These results indicate that PLGA significantly enhances the structural integrity / mechanical strength of the filaments.

[0149] HPMC K35M, a hydrophilic polymer, also affects the flexibility and mechanical strength of the filaments. The data indicates there may be an optimal range for HPMC K35M content, as seen in Fl (68% K35M) and F2 (51% K35M), which had moderate breaking forces of 247.7 g and 290.9 g, respectively. However, formulations such as F7 (63% K35M, 5% PEG 3350) and F6 (51% HPMC K35M, 34% PEG 3350) demonstrated the lowest breaking forces at 87.0 g and 128.1 g, respectively, indicating that the inclusion of PEG 3350 can reduce the mechanical strength of the filaments. In contrast, Fl 8, which contains 34% PLGA, 49.5% HPMC K35M, and 1.5% PEG 400, maintained a high breaking force of 333.7 g, showing that minimal amounts of PEG 400 do not significantly decrease breaking force.

[0150] Incorporating other polymers, such as PEG 3350, PEG 400, and HPMC HME 4M, also influenced the breaking force. For instance, F6, which contained 34% PEG 3350, had a breaking force of 128.1 g, indicating that PEG 3350 does not enhance the breaking force. Conversely, F18, which included 1.5% PEG 400, maintained a high breaking force of 333.7 g, indicating that small amounts of PEG 400 do not adversely affect mechanical properties. Moreover, F27 and F28, containing 5.1% and 13.6% HPMC HME 4M, achieved high breaking forces of 390.6 g and 343.0 g, respectively, indicating that HPMC HME 4M can positively contribute to the structural integrity of the filaments when used in suitable proportions.

[0151] Before starting the drug release study, a solubility study was conducted to identify a suitable dissolution medium. Since MF is a poorly soluble drug, pH 7.4 phosphate buffer (PBS) was tested both with and without SLS for the solubility studies. In the absence of SLS, the solubility of MF was low and below the detection level. With 1% SLS, the solubility increased to 73.77 pg / mL, and with 2% SLS, it reached 144.36 pg / mL. Given that the target dose of 9 mg for a 30-day release corresponds to a required solubility of 300 pg per day, pH 7.4 PBS with 2% SLS was selected as the dissolution medium. The in-vitro drug release study of MF implants was conducted in an orbital water bath shaker at 37 ± 2°C and 250 rpm, usingpH 7.4 PBS with 2% SLS as the dissolution media for 30 days. 9.0 mg of drug-equivalent implants were placed in scintillation vials containing 10 mL of the dissolution media. The entire volume of the medium was replaced with fresh buffer solutions, and the study continued until over 80% of the drug was released from the formulations. Collected samples were analyzed using HPLC, and daily drug release and percentage cumulative drug release were calculated. In vitro drug release behavior of various formulations is shown in Figure 27A -27D.

[0152] Formulations Fl, F2, F4, F5, and Fll exhibit distinct drug release profiles, reflecting the influence of PLGA and HPMC K35M ratios. F5 and Fl 1 show significant initial burst releases, with over 40% released in the first week and an additional 40% in the second week, due to lower PLGA concentrations and higher HPMC K35M ratios. In contrast, Fl has a moderate release rate (239.3 mcg / day on day 1), with 30% drug release in the first week, 20-25% in the second, and only 10-13% in week 3. F2 offers a more controlled profile, starting with a lower burst of 103.3 mcg / day on day 1 and sustaining consistent release due to its higher PLGA content (34%). F4, containing 51% PLGA, demonstrates the most stable release pattern, with an initial burst of 92.7 mcg / day and steady release throughout the study, making it ideal for prolonged delivery. The PLGA ratio significantly affects initial burst release. Higher PLGA content results in slower degradation through hydrolysis of its ester linkages, leading to more gradual drug release. Conversely, higher HPMC K35M content (as in F5 and Fll) accelerates drug release due to its hydrophilic nature, which enhances matrix porosity and facilitates quicker diffusion of drug molecules.

[0153] Formulations F27 and F28 illustrate the impact of AFFINISOL™ HPMC HME 4M on drug release profiles. F27 has a higher initial burst release due to the combination of HPMC HME 4M, HPMC K35M, and a greater PLGA content. This formulation creates a matrix that initially resists water penetration because of the hydrophobic nature of PLGA. However, once water infiltrates, the HPMC components facilitate rapid drug diffusion, resulting in a quick release. The interaction of high PLGA with low-viscosity HPMC HME 4M and K35M allows for this initial burst, followed by a more gradual, sustained release. In contrast, F28, which contains higher- viscosity HPMC (KI OOM) and lower PLGA content alongside HPMC HME 4M, shows a reduced initial burst. The viscous HPMC K100M forms a thicker, more cohesive gel layer upon hydration, creating a stronger barrier to drug diffusion. Consequently, the initial drug release is slower, with 49.6% of the drug released by day 7. This thicker gel matrix provides better control over the drug release rate, ensuring a slower and more sustained release.

[0154] Formulations F7 and F18 illustrate the impact of PEG on drug release profiles. Specifically, F7, which contains 5% PEG 3350, shows a pronounced initial burst release compared to formulation Fl, which has the same composition but lacks PEG. By day 6, F7 had released 49.5% of the drug, nearly double the 26.1% released by Fl, maintaining a higher release rate throughout the study. The presence of PEG 3350 in F7 accelerates drug release by dissolving and leaching out, creating additional pores within the matrix that enhance the surface area for diffusion. Similarly, formulation Fl 8, which contains 34% PLGA, also exhibited faster drug release with just 1.5% PEG 400. These findings highlight PEG'S crucial role in promoting burst release from implants, regardless of PLGA content, and highlighting its impact on modifying drug release dynamics.

[0155] The bioadhesion test was carried out using a TA-XT2i Texture Analyzer Stable Micro System (Texture Technologies Corp, NY, USA) equipped with a slotted die-cut fixture (TA-303 Indexable Adhesive Test Rig), a 7 mm diameter circular steel probe (TA-57R), and Texture Expert™ software. The bioadhesion study evaluates the adhesion properties of drug-loaded implants to biological tissues, which enhances drug retention and efficacy at the target site. Adhesion quality is quantified using the Work of Adhesion (WoA), which represents the energy required to separate two adjacent surfaces and is determined by the area under the curve in the adhesion graph. The order of WoA for different levels of PLGA and HPMC K35M was F5 > Fl > F18, reflecting increasing PLGA content and decreasing HPMC K35M levels in these formulations. In the case of F27 and F28, different grades of HPMC were used, resulting in the highest WoA. Without wishing to be bound by theory, this increased adhesion was attributed to the presence of HPMC HME 4M, a low-viscosity grade that is more easily hydrated compared to HPMC K35M and K100M (Table 8).

[0156] Table 8: Work of Adhesion (WoA) of implant formulations

[0157] Implants with a defined drug dose (9 mg) were exposed to 20 mL of pH 7.4 phosphate buffer. To prevent saturation, the total medium is replaced two times a week. Samples were withdrawn each week for one month, and the excess medium was carefullyremoved with Kimtech precision wipes before weighing to obtain the wet mass (t). The samples were then dried for at least two days until reaching a stable weight to determine the dry mass (t). The wet and dry mass at different time points were used to calculate the implant’s % water uptake and % of mass remaining.

[0158] From the water uptake study, the results revealed differences in water absorption among various implant formulations based on their composition (Figure 26A). This study was conducted for 4 weeks in pH 7.4 phosphate buffer. From the results, Fl formulation reached its maximum weight in the first week, but F2 formulation exhibited a gradual weight increase over the entire four-week period, attributed to a higher percentage of PLGA. Significant water uptake was observed in formulations F28 and F27 due to the presence of HPMC HME 4M. In the third and fourth weeks, water uptake decreased because of the erosion of the HPMC HME 4M. In formulation F27, swelling gradually increased until the fourth week due to a higher percentage of PLGA presence, whereas in formulation F28, the swelling was at its maximum in the first week and started to erode in the third week.

[0159] From the results of the mass remaining study (Figure 26B), formulation Fl with low PLGA and high HPMC, weight reduction was observed gradually. In the F2 and F27 formulations with high PLGA, the implant showed significant weight reduction in the first week, but negligible further weight loss was observed in subsequent weeks. In contrast to F2, the higher values of the F27 formulation are attributed to the presence of HPMC HME 4M. Formulation F28 which contains HPMC HME 4M and KI OOM along with PLGA showed slow erosion due to the formation of a K100M high viscous gel around the implant matrix.

[0160] Male Sprague-Dawley rats (250 ± 10 g) were utilized for in-vivo experiments. Initially, the rats were anesthetized by injecting 5% isoflurane into an induction chamber, and the dorsal side was shaved prior to implantation and suturing. Implants Fl and F28 were then placed (n=3) on the rats’ backs (Figure 39). Animals were anesthetized and euthanized by injecting excess isoflurane into an induction chamber at 3-, 7-, 14-, 21-, and 30- days postimplantation. To retrieve the threads, an incision was made parallel to their location on the dorsal side, near the shoulders. This incision was subsequently enlarged into a skin flap, allowing for the isolation of the thread, surrounding tissue, and any associated fluid (Figure 39). The remaining implant samples were carefully collected and transferred to a container with 50 ml acetone. Then the samples were homogenized, filtered, diluted with 50:50:1 ratio acetonitrile: water: glacial acetic acid and analyzed using HPLC to estimate the percentage of remaining drug content (Table 9).

[0161] Table 9: Determination of residual drug content from MF implants inserted in rats

[0162] The in-vivo drug release behavior of the MF implants is illustrated in Figure 40. In-vivo drug release was calculated by subtracting the amount of residual drug from the total drug content in the implants. The results show that the Fl implant, containing PLGA and HPMC K35M, maintained its integrity and exhibited a slow-release profile. In contrast, the F28 implant, which included HPMC HME 4M, experienced a loss of integrity. Additionally, the high-viscosity HPMC KI OOM and PLGA contributed to forming a viscous gel that hindered drug release. Overall, the in-vivo drug release was slower compared to the in-vitro release, due to limited fluid availability in the rats, which led to a saturated drug solution.

[0163] PLGA is typically supplied in granular form, which requires size reduction before it can be blended with drugs and other polymers for formulation purposes. We attempted to mill the PLGA using a mixer. However, we encountered a significant issue during this process: the temperature of the PLGA increased due to its low glass transition temperature (Tg). PLGA's Tg is relatively low, meaning that even slight temperature increases can cause the material to soften, leading to potential changes in its properties during milling. The heat generated during the milling process caused the material to partially melt or become sticky, making it difficult to achieve uniform sizing and posing a risk to the stability of the formulation.

[0164] To overcome this problem, we shifted to cryo-milling for subsequent trials. Cryo-milling involves the use of liquid nitrogen, which cools the PLGA to very low temperatures during the milling process. This cooling effect prevents the generation of heat and ensures that the material remains brittle, allowing for efficient size reduction without compromising its integrity. Cryo-milling also offers more consistent particle sizing and preserves the material's physicochemical properties, ensuring that the final formulation can be accurately blended with the drug and other polymers.

[0165] Non-limiting Conclusion

[0166] Controlled-release MF implants for nasal application using PLGA and HPMC were formulated and produced by hot-melt extrusion methodology. The prepared implantswere characterized by SEM, DSC, FTIR, breaking force, bioadhesion, and water uptake behavior. In vitro drug release studies and in vivo rat studies proved the controlled-release behavior of prepared implants. Without wishing to be bound by theory, hot-melt extruded PLGA-HPMC implant production was determined to be a promising approach for achieving controlled delivery of MF for nasal applications. Furthermore, there are plans for future studies using rabbit and sheep models to investigate in-vivo drug release behavior and histology.

[0167] Described herein are steroid eluting implants that can provide MF controlled release for one month. Different polymers and ratios were screened to achieve this objective. The physical, mechanical, and thermal behavior of formulations were evaluated and then studied for in vitro drug release studies. From these results, Fl and F28 formulations were selected for in vivo rat studies. From the in vivo studies, both formulations showed controlled release, but slow when compared to the in vitro results. Without wishing to be bound by theory, this can be an indication of the availability of less fluid in rats leading to saturation of the drug in the fluid and thus inhibited drug diffusion.

[0168] We can investigate additional animal models. Studies can involve in vivo rat experiments on additional developed formulations. We can use a rabbit model to study the implants’ drug release and immune response. We can conduct a toxicity study in vivo using a sheep model. We can also use fluorescent-based imaging techniques to evaluate drug release and distribution in vivo. This allows imaging technologies to monitor the drug distribution around the implant's application site. By scanning the area surrounding the implant, we can visualize the dispersion of the drug and better understand how it interacts with surrounding tissues.EXAMPLE 2

[0169] Non-limiting Results of the Development of extended-release steroid implants

[0170] Described herein is an extended-release, biodegradable, nasal implant comprising mometasone furoate homogenously mixed with a multi-polymer system of poly (lactic-co-glycolic acid) (PLGA, 5005A) (Viatel™ DLG 5005 A, 40-65 KDa) and seven other polymers including hydroxypropyl methylcellulose (HPMC K100M, K35M, Affinisol HME 4M), polyethylene glycol (PEG 3350 and PEG 400), polyvinylpyrrolidone (PVP K90, -1,350,000 g / mol), and polyethylene oxide (PEO WSR 205) using a hot-melt extrusion technique. In some embodiments, mometasone furoate (MF) was selected as the active ingredient in nasal implants due to its potent anti-inflammatory effects and low systemic absorption when applied locally in the nasal cavity (18,19). It is effective in reducing mucosalswelling, polyp size, and the recurrence of nasal polyps in patients with chronic rhinosinusitis (20,21).

[0171] Hot-melt extrusion (HME) was selected as the method of manufacture of the nasal implants because it is an environmentally friendly process that can be used as a platform manufacturing technology for a variety of pharmaceutical dosage forms to enhance the water solubility and oral bioavailability of drug substances and to design extended release and sitespecific drug delivery systems. Also, HME can be tailored to have a more linear release than currently in use sprayable manufacturing techniques, which deliver the drug in an asymmetric pattern with most drug eluting in the very early stages of release.

[0172] Eight different polymers with different physicochemical properties were used in the studies because the combination can be utilized to tailor the drug release rate and the physical properties of the polymer carrier such as solubility, viscosity, erosion rate, and glass transition temperature. PLGA, HPMC, PEG, PVP, and PEO were selected as polymeric carriers for the nasal implants because these polymers are biodegradable with a long history of safety and efficacy in FDA approved drug and device products (22-25). PLGA is a hydrophobic polymer, extensively utilized in drug-loaded implants to achieve extended release of drug substances in a wide range of pharmacological conditions for 3 to 6 months by maintaining a relatively solid structure. The rate of hydrolytic degradation and matrix erosion influence the drug release rate (22). HPMC, a cellulose ether polymer, is a hydrophilic, biodegradable, and biocompatible polymer that swells upon hydration (23). The extent of swelling of the polymer depends on the molecular weight grade. A higher molecular weight yields a greater viscosity of the swollen gel and a slower drug release rate (26). Without wishing to be bound by theory, different molecular weight grades of HPMC can be combined with PLGA in various ratios to prepare drug-loaded implants that will extend the release of a drug from 15 to 60 days.

[0173] Mometasone furoate implants were fabricated using a Process 11 co-rotating twin-screw extruder (Thermo Scientific, Waltham, MA, USA), equipped with a die fitted with a 1.50 mm nozzle. Twenty-eight different formulations were extruded and evaluated comprising 8 different polymers with different physicochemical properties. Table 1 shows the composition of some of the various 28 formulations chosen for further study, which were found acceptable from a mechanical and drug content perspective. The acceptable filaments were white with a smooth surface and exhibited a sufficient brittleness / flexibility balance needed for proper implantation. These drug / polymer blends were prepared using a V-cone blender to achieve a homogeneous mixture. The blend was fed into the extruder at a constant rate of 0.5-1 g / min while maintaining a temperature of 150°C to 185°C to extrude the filament. Eachformulation targeted an implant size of <40.00 mm in length and <2.50 mm in diameter, with a drug loading of 15% w / w, resulting in implants weighing 60 mg, each containing 9 mg of MF. The MF implants were evaluated and characterized by a battery of physical and chemical tests: physical appearance, dimensions, drug content, drug content uniformity, thermal behavior, drug-polymer compatibility, surface morphology, breaking force, in vitro drug release, bioadhesion, water uptake, and erosion / mass remaining.

[0174] Table 1: Formulation composition of Mometasone furoate implants

[0175] The water uptake and mass remaining studies revealed distinct differences in water absorption among formulations, as illustrated in Figure 26A and Figure 26B. Formulation Fl reached its maximum weight in the first week, while F27 and F28 exhibited significant water uptake due to it comprising HPMC HME 4M. Water uptake decreased in weeks three and four due to erosion of HPMC HME 4M. Formulation Fl showed gradual weight loss, while F2 and F27 experienced initial weight reduction followed by minimal loss. F28 demonstrated slow erosion due to a viscous gel formed by HPMC K100M surrounding the implant matrix.

[0176] In vitro drug release behavior of various formulations is shown in Figure 27A -27D. Formulations F5 and F11 showed rapid drug release, with over 40% released in the first week due to lower PLGA concentrations and higher HPMC K35M ratios.

[0177] By increasing PLGA concentration, formulation Fl exhibited a slower release, while the F4 formulation demonstrated consistent extended release for about 90 days. The addition of HPMC HME 4M in the F27 formulation resulted in an initial burst release, whereas the F28 formulation, with higher viscosity HPMC K100M, showed a slower release. PEGpresence in formulations F7 and F18 significantly accelerated drug release. Based on the findings from the in vitro drug release study, formulations Fl and F28 were selected for in vivo studies. These formulations were selected because they provided a sustained in vitro drug release over a 30-day period with Fl providing a slower, more consistent release profile, and F28 providing a faster release.

[0178] Male Sprague-Dawley rats (250±10 g) were used for in vivo experiments. After anesthetizing the rats (n=3), formulations Fl and F28 were implanted on their backs. The animals were euthanized at 7-, 14-, 21-, and 30-days post-implantation. The remaining implant samples were collected, homogenized, filtered, and analyzed by HPLC to estimate the percentage of remaining drug content (Table 2). In-vivo drug release was calculated by subtracting the amount of residual drug from the total drug content in the implants. The results show that the Fl implant, containing PLGA and HPMC K35M, maintained its integrity and exhibited a slow-release profile. In contrast, the F28 implant, which included HPMC HME 4M, experienced a loss of integrity. Additionally, the high-viscosity HPMC K100M and PLGA in F28 contributed to forming a viscous gel that hindered drug release.

[0179] The rat implantation model was selected to provide evidence that the implants would degrade slowly over time and release MF in a controlled manner. Without wishing to be bound by theory, the in vivo drug release was slower compared to the in vitro release due to limited fluid availability in the rat implantation site, which led to a saturated drug solution. A limitation of the rat model is the low water / fluid content at the site of implantation (the back of the animal) as compared to the higher water content that would be present in the mucosal membrane in the nasal cavity. Another challenge encountered was the removal of the residual implant at the predetermined time points to evaluate residual drug content and erosion of the implant. Over time, the implant swelled and fragmented into small pieces which adhered to the surrounding tissues. This made it difficult to remove an intact implant, and some fragments were contaminated with tissue. This affected the accuracy of drug quantification.

[0180] Table 2: Estimated drug elution in a rat model.

[0181] Without wishing to be bound by theory, we can use fluorescent-based imaging techniques to evaluate drug release and implant distribution in vivo. By scanning the area surrounding the implant via imaging technologies, we can significantly improve the residual implant retrieval process, which can provide a more accurate in vivo drug release profile.

[0182] Despite these challenges, the in vivo study yielded promising results, demonstrating that, the implants were degrading, MF was released in a controlled manner, and 40% of the MF dose was released over the 30-day period. Without wishing to be bound by theory, further modification of the implant formulation and modified surgical extraction techniques assisted by imagining technology, we can achieve our target release profile of 80-100% MF released in 30 days.

[0183] In summary, extended-release MF implants for insertion into the nasal turbinates comprising PLGA, HPMC, PEO, PEG, and PVP were formulated and successfully produced by hot-melt extrusion methodology. We developed nasal implants that can provide extended release of MF in nasal turbinates for 30 days. Combinations of different types and grades of biodegradable polymers were screened using HME processing. These formulations produced implants that exhibited in vitro drug release for 20-45 days while maintaining adequate mechanical strength. A battery of physicochemical tests was used to select two formulations for an in vivo study using rats as an animal model. Both formulations exhibited slow degradation over time and a controlled extended release of MF. We can produce a dissolvable, multi-polymer, Hot Melt Extruded, steroid-eluting turbinate implant.

[0184] We can investigate different viscosity grades of PLGA and HPMC and adjust the ratios of HPMC to PLGA to further optimize the drug release profiles. For example, reducing the PLGA ratio to below 10% can enable faster drug release. Additionally, using lower-viscosity grades of PLGA and / or HPMC, and adding plasticizers / pore-forming agents to the polymer matrix can increase the drug release rate.

[0185] Technical Objectives, Approach and Work Plan

[0186] Background

[0187] The number of research articles on hot melt extrusion (HME) has skyrocketed in the past 20 years (25). Compared to conventional pharmaceutical formulation and processing methods, HME provides a number of distinct advantages (26). It is a solvent-free method thatcan be utilized to improve solubility, stability and bioavailability especially for poorly water-soluble drugs (25). HME can operate continuously (requiring fewer processing steps) and doesn't require significant downstream processing such as compression (27). HME has therefore emerged as a technique that can address a wide range of problems facing the pharmaceutical industry. Even though the fabrication of solid dispersions has been the main use for HME, new applications are constantly being found and applied in pharmaceutical product development.

[0188] Implants can be classified as biodegradable and non-biodegradable (28). Biodegradable implants offer the advantage of not having the need to be removed after treatment (29). HME has emerged as a critical technology in the development of biodegradable implants for drug delivery. This process enables the production of implants with controlled drug release profiles by combining active pharmaceutical ingredients (APIs) with biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polylactic acid (PLA) (30). In HME, APIs and polymers are heated, mixed, and extruded through a mold, creating an implantable device that gradually biodegrades in the body, releasing the drug at a controlled rate over an extended period (30).

[0189] Implantable drug delivery systems benefit greatly from HME as they regulate the extrusion parameters, processing temperature, and polymer composition. These elements have a direct impact on the implant's drug release profile, mechanical characteristics, and rate of degradation (31,32). By modifying these factors, manufacturers can develop implants that deliver drugs over a predetermined time frame, from days to months, satisfying the therapeutic requirements of long-term drug delivery. The solvent-free nature of HME also minimizes residual solvent risks and eliminates the need for drying steps, enhancing both product safety and process efficiency. Moreover, HME-produced implants offer a steady, localized drug release, reducing systemic side effects and improving patient compliance (33). Due to its flexibility and scalability, HME continues to be a promising platform for advancing biodegradable implant technology in modern medicine.

[0190] Fabrication of biodegradable implants using HME has been reported by various research groups. Li et al. (2013) developed an implant drug delivery system composed of Dexamethasone, PLA, and F68 using an HME method. A new biodegradable implant was successfully prepared by HME for controlled release of the immunosuppressive drug to the implantation site. In vitro release studies showed up to 18% of drug released from the implants over a period of 4 months (34), while in vivo release studies demonstrated up to 50% of drug released over a period of 1 month (35). The study indicated that the PLA / F68 / Dexamethasoneimplant can be capable of suppressing inflammatory reactions for at least 1 month. Dharmayanti et al. (2020) investigated the use of drug-eluting biodegradable implants prepared using HME for the sustained release of bisphosphonates for the treatment of osteoporosis. Bioerodible PLA and PLGA implants loaded with bisphosphonate alendronate sodium were prepared via HME. Prepared implants showed sustained drug release in vitro between 25 to 130 days, where implants of greater glycolide to lactide composition and higher drug loadings released drug more rapidly. All PLGA implants showed a sigmoidal release profile, while the PLA implants showed a logarithmic release profile (36). Zheng et al. (2021) reviewed the use of hot melt extrusion as an emerging manufacturing method for slow and sustained protein delivery implantable devices (37). Ghalanbor et al. (2010) used lyophilized lysozyme as a model protein to first assess the feasibility of HME to prepare implants based on protein / endcapped 50:50 PLGA formulations. Implants reached full release in 60-80 days. Released lysozyme maintained its integrity and reached complete release, showing HME as a promising manufacturing method for protein / polymer implantable delivery devices (38). Salmoria et al. (2017) evaluated the structure and properties of poly caprolactone (PCL) / ibuprofen implant rods prepared using hot-melt extrusion. In some embodiments, a single-screw extruder was used. The PCL / ibuprofen implant rods prepared using different processing temperatures showed different release profiles, with fast or slow drug release depending on ibuprofen distribution (39).

[0191] In some embodiments, we use a hot-melt extrusion technology platform to develop and evaluate a biodegradable implant that elutes steroids to treat rhinitis.

[0192] Initial Product Specifications

[0193] Introducing tool

[0194] A sterile, 1 cm diameter, 10 cm syringe device with 1.2 mm obturator with 10cm cannulated beveled sharp tip with 1.5 mm inner diameter

[0195] Implant

[0196] A steroid-eluting biodegradable / dissolvable implant, cylindrical in shape with an approximate diameter of 1 mm to 2 mm and length of 40 mm for the treatment of rhinitis in adult patients can be formulated. The implant will be manufactured by HME technology consisting of an appropriate steroid drug load incorporated in one or more biodegradable polymers.

[0197] R& D Objectives

[0198] Objective 1. Optimize the formulation of a biodegradable / dissolvable implant by HME and / or 3D printing techniques.

[0199] Objective 2. In vitro and In vivo characterization of HME and 3D printed implants for mechanical properties, drug content, water uptake, mass remaining, in vitro drug release studies and in vivo release pattern.

[0200] Objective 3. Evaluate the immune response and safety of the biodegradable / dissolvable implants.

[0201] Objective 4. Develop all of the specifications of the introducing tool for placement of the implant into the inferior turbinate.

[0202] Figure 28 shows a non-limiting, exemplary schematic outlining the workflow of the process for producing and testing drug eluting implants in an embodiment.

[0203] Non-Limiting, Exemplary R& D Approach

[0204] Optimize the formulation of a biodegradable / dissolvable implant by HME and / or 3D printing techniques.

[0205] Without wishing to be bound by theory, we can reduce the PLGA ratio in the implant formulation composition to less than 10%. This can enable a quicker and more thorough release of the medication within 30 days. Moreover, employing lower-viscosity PLGA or HPMC (K4M or KI 5M) can improve drug release rates in contrast to higher- viscosity polymers, which swell more slowly and preserve implant integrity for better drug release. In summary, we can produce the formulations for the implants.

[0206] In vitro and in vivo characterization studies.

[0207] The HME Prototype drug-loaded threads can be assessed with the following evaluation tests.

[0208] Implant Dimensions, Appearance, Thermal, Mechanical, Analytical and Drug Release Properties:

[0209] A digital caliper (VWR1, PA, U. S. A) can be used to determine the length and diameter / thickness of the implants.

[0210] Differential Scanning Calorimetry (DSC):

[0211] Differential Scanning Calorimetry (DSC) is an essential analytical method in the pharmaceutical industry that determines the physical state of drugs. DSC can reveal crystallinity, polymorphic forms, and glass transition temperatures (Tg) in drug substances by measuring heat fluxes associated with phase transitions. These factors influence stability and bioavailability. DSC also helps to analyze drug-excipient compatibility by finding interactions that may impact drug performance (40). DSC will be utilized to evaluate the physical state of the steroidal drug and polymeric carriers in the HME drug-loaded threads. A 5-10 mg samplewill be sealed in a Tzero lid and then will be loaded into the DSC along with a reference empty pan. TA Instruments TRIOS software will be used to analyze data.

[0212] Analytical method:

[0213] An HPLC method can be used to determine the mometasone furoate content as well as the drug release profile studies of the drug-loaded threads.

[0214] Mechanical Properties

[0215] The flexibility, brittleness, and stiffness of the threads can be using a three-point bend test using a texture analyzer (TA-XT2i Texture Analyzer by Stable Micro Systems, UK). This evaluation method was developed in our laboratories at the University of Mississippi (41). A schematic experimental set-up of the test is shown in Figure 29. A thread sample of 6 cm will be placed on a TA-95N probe set with a 25 mm supporting gap. The test processing parameters such as trigger force, blade pre-test speed, test speed, and post-test speed will be optimized.

[0216] Surface morphology

[0217] The drug release profile and degradation rate of implants can be influenced by their surface morphology (42). This morphology has an impact on how the body and implant interact. Because they provide biological fluids with additional entry points, rough or porous surfaces can degrade more rapidly through swelling and / or erosion mechanisms. Smoother surfaces, on the other hand, can deteriorate more slowly. We can modify the drug release kinetics and degradation timeline of the mometasone furoate threads by examining the surface morphology of the various implants. The threads’ surface morphology will be analysed using scanning electron microscopy (SEM) using a JSM-7200FLV Field-Emission Scanning Electron Microscope (JOEL, Peabody, MA, USA) with an accelerating voltage of 5 kV. The samples will be mounted on a carbon pad placed on an aluminium stub and sputter-coated with platinum under argon atmosphere using a fully automated Denton Desk V TSC Sputter Coater (Denton Vacuum, Moorestown, NJ, USA) prior to imaging.

[0218] Water uptake and mass remaining study

[0219] Because it is crucial in controlling the rates at which biodegradable polymers degrade, assessing implants' water absorption capability is important. Because water interacts with the substance and causes hydrolysis or enzymatic reactions that break down the polymer, water absorption affects how rapidly the polymer degrades (43). Thus, controlling the water uptake capacity, which ensures that the implant retains its structural integrity for the intended amount of time (30 days) while releasing the drug gradually is paramount. Water absorption and mass retention studies will be conducted for the mometasone furoate threads produced withHME. After determining the initial weight of each mometasone furoate thread, it will be placed in 10 millilitres of phosphate buffer with a pH of 6.4, which is the average baseline pH for the back of the nose. The implants will be removed from the medium at certain intervals, any excess medium will be wiped away, and the implant's wet weight will be measured. Afterward, the samples will be allowed to dry at room temperature in a vacuum desiccator or at 40°C until their dry weight remains constant. Water uptake and mass remaining will be calculated using the following equations:

[0220] Equation 1: Water uptake (%) = ([Wet wt - Dry wt] / Dry wt) x 100

[0221] Equation 2: Mass remaining (%) = (Dry wt / Initial wt) x 100

[0222] Bioadhesion:

[0223] Because the threads need to have the ability to stay attached to the turbinate, a bioadhesive test will be performed to evaluate their adhesive strength and ensure that they can maintain sufficient contact over time. This test will mimic conditions found in the nasal environment, testing how well steroid threads adhere to moisture, mucosal secretions, or mechanical forces. The test will quantify adhesive forces to assess whether the implant's bonding qualities are suitable for long-term adhesion to the turbinate, which is crucial for effective drug delivery. The threads will be hydrated with a phosphate buffer of pH 6.4 for ten seconds. The bioadhesion characteristics of the threads will be assessed utilizing a texture analyzer (TA. XT2i) in conjunction with a TA-57R probe and a slotted die-cut fixture (TA-303 Indexable Adhesive Test Rig) (Figure 30). The results of several formulations will be compared to understand the impact of the formulation compositions' adhesiveness properties. The bioadhesive test results will be used to enhance thread formulation, hence boosting retention and performance in vivo.

[0224] In vitro Release Studies:

[0225] The drug release profile of the drug-loaded threads will be performed using different methods including the rotating bottle method (Figure 31 A) and the in-line diffusion method (Figure 3 IB). For the rotating bottle method, each thread will be placed in a 20 mL scintillation vial containing 10 mL phosphate buffer, pH 6.4 with and without surfactant. The bottles will be incubated in a controlled temperature bio-shaker at 37 ± 2 °C and rotated at 100 rpm. The drug release test will be performed for up to 30 days. At each time interval (daily for the first 15 days and weekly until the end of the experiment), the entire volume will be withdrawn, and 10 mL of fresh medium will be added to the sample. For the in-line diffusion method, PermeGear in-line diffusion cells will be used with a dissolution media of phosphate buffer, pH 6.4 with and without surfactant. The flow rate will be adjusted, and samples will becollected using a fraction collector at predetermined time points. The samples will be analyzed using HPLC, and the cumulative drug release will be calculated. To understand the drug release mechanism (e.g., diffusion vs. diffusion / erosion), the drug release data will be fitted to different release models. Without wishing to be bound by theory, the release rates can vary with some of the formulations sustaining the release of the mometasone furoate for at least 30 days.

[0226] In vivo Release Studies:

[0227] The in vivo release profile of MF will be determined using male Sprague-Dawley rats (200-250 g). Initially, a reduced dose of the Fl formulation from Phase I will be implanted as per the previous method in one group of rats (n=3) and analyzed for drug release to determine if drug release is dependent on formulation composition or saturation of the drug at the implant application site. Based on these results, the dose of the implant will be finalized for future animal studies.

[0228] Based on the results of the in vitro characterization studies, five prototypes with varying in vitro release profiles (e.g., >80% drug release in 15 days and >85% drug release in 30 days) will be used for the in vivo release study. A total of 60 rats will be randomized and divided into five groups of 12. The threads for the animal study will be extruded with fluorescent dye and will be surgically implanted into the dorsolateral subcutaneous tissue of each rat. At each subsequent time interval (7, 14, 21, and 30 days), rats will be euthanized with 5% isoflurane. Residual implant will be harvested by making an incision parallel to its location on the dorsal side of the rat (near the shoulders). The incision will then be widened into a skin flap from which the thread, tissue, and fluid around the thread will be isolated. Real-Time Fluorescent and Bioluminescent in vivo Imaging will be used to track the thread's erosion and drug release (in vivo). The quantity of drug remaining in the collected thread through homogenization of the remaining thread in a suitable solvent system (acetone) will be determined via HPLC analysis. The observed in vivo thread erosion and drug release data will be used to determine the correlation between the in vitro and in vivo results. In addition, if an individual rat loses more than 20% of its initial weight, the rat will be sacrificed, and the remaining drug will be quantified at that particular time point.

[0229] Real-Time Fluorescent and Bioluminescent In vivo Imaging: The IVIS® Lumina K Series III from PerkinElmer (Figure 32) is a cutting-edge imaging system that allows for real-time capture of biologically relevant events within milliseconds. This versatile system can perform both quantitative luminescence and fluorescence imaging, functioning as both a standard high signal-to-noise imager and a high-speed imager. It features a highly sensitiveEMCCD camera that enhances signal detection and reduces exposure times, enabling rapid kinetic studies.

[0230] Evaluate the immune response and safety of the biodegradable / dissolvable implants

[0231] Rabbit Study:

[0232] New Zealand white rabbits weighing 2.5-3.5 kg can be used to test the immunological response to the three most promising biodegradable implants. Three implant prototypes will be tested based on the results of the erosion and drug release of the threads in vitro and in vivo. A total of 36 rabbits will be randomly divided into three groups, with each group consisting of 12 rabbits. Before implantation, the prototype threads will undergo a sterilization process to eliminate potential contaminants. The surgical procedure will involve administering anesthesia to ensure that the rabbits are adequately sedated and pain-free during the surgery. The implants will be inserted into the dorsolateral subcutaneous tissue, allowing for easy access to the implant site for later analysis. After a designated observation period, the rabbits will be euthanized at 1, 2, 3 and 4 weeks to facilitate collection of tissue samples from the implant sites. This tissue will be subjected to histological analysis, to evaluate immune cell response and implant degradation.

[0233] Sheep study:

[0234] MF drug products are FDA approved for nasal administration. MF exerts a local effect on the nasal mucosal with minimal systemic absorption. If MF is used at high doses, over large surface areas, or for prolonged periods, some systemic absorption may occur. This absorption can lead to measurable suppression of the hypothalamic-pituitary-adrenal (HP A) axis. When absorbed systemically, MF mimics cortisol in the bloodstream, signaling the pituitary and hypothalamus to reduce their secretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). With decreased ACTH stimulation, the adrenal glands reduce cortisol production, potentially leading to lower circulating cortisol levels. Thus the studies in sheep will ensure that there is no HPA suppression and provide a safety profile for the implanted MF thread.

[0235] The lead formulation will be selected from the two previous animal studies, and it will be implanted into one set of 6 sheep in the nasal turbinates. One week prior to the insertion of the implant, cortisol levels will be monitored to determine baseline levels in each respective sheep. After implant insertion, systemic MF and cortisol levels will be quantified at twice-weekly intervals for one month. Thus, the data obtained in this large animal study will serve as a basis for the MF implant’s safety profile for humans.

[0236] Develop of the specifications of the introducing tool for placement of the implant into the inferior turbinate.

[0237] After the downselection of the implants during the foreign body response animal study, a final specification for the implant will be developed for the safety study in sheep. In embodiments, this implant can comprise dimensions of about 2.0mm x 40mm. Given the differences in anatomy between sheep and humans, prototypes for each introducing tool can be developed and tested for functionality using techniques known in the art. While off-the-shelf spinal needles were described in embodiments, no current devices accommodate these implant specifications and will need to be special ordered from a supplier. The human introducing prototype tools will be evaluated in a human cadaver model for anatomical correctness and functionality. The sheep introducing tool will be used during the previously described sheep study.

[0238] Broader Impacts

[0239] Without wishing to be bound by theory, the implant described herein will replace the need for chronic, daily administration of nasal sprays and / or long-term immunotherapy, with a simple, 10-minute, in-office implant placement, which should last for 6-12 months. This controlled drug release thread can provide improved patient care, addressing a very large health problem that affects 77 million Americans (1). ENTs are currently treating an estimated 6 million of these patients today (6) and this platform will drive the standard of care for the remaining 71 million patients. Effective treatment of this massive group of people results in a commensurate reduction in lost workdays, increased productivity, and improved quality of life.

[0240] References Cited Herein

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[0268] Section 201(g) of the FD& C Act (21 USC 321(g))

[0269] Section 201(h)(1) of the Food, Drug, and Cosmetic Act

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[0289] Kamel, R., and H. Abbas, "PLGA-based monolithic filaments prepared by hot-melt extrusion: In-vitro comparative study." Annales pharmaceutiques frangaises. Vol. 76. No.2. Elsevier Masson, 2018.EXAMPLE 3

[0290] Rhinitis has a tremendous effect on individual quality of life (QOL) and on society (1,2,3). Its symptoms include itching, sneezing, runny nose, and nasal obstruction. Etiology is divided into Non-Allergic Rhinitis (NAR) and Allergic Rhinitis (AR). AR is an immunoglobulin E (IgE)-mediated inflammatory nasal condition resulting from allergen introduction in a sensitized individual. Triggers of NAR symptoms vary and can include certain odors or irritants in the air, weather changes, some medications, certain foods, and chronic health conditions (4). Settipane et al estimated 19 million and 58 million NAR and AR patients, respectively, in the U. S. (5).

[0291] While many physicians treat rhinitis patients, including allergists and family practice physicians, Otolaryngologists - Ear, Nose, and Throat surgeons (ENTs) - bear the brunt of treatment for AR and NAR and have the fullest armamentarium for treatment. Of the 77 million U. S. patients, ENTs are treating nearly 6 million (Table 3) and drive the standard of care (6). In the U. S., there are approximately 6,000 ENTs with 5,000 treating sinus disease. To treat rhinitis, ENTs may prescribe oral and topical decongestants or steroids, perform allergy testing and treatment (approximately 2,700 of these 5,000 have been trained for allergy testing and treatment) (7), and occasionally, they will perform surgery to treat rhinitis. Our market research, including 20 direct interviews with ENTs and an online market survey tool of 100 ENTs indicates that ENTs are generally unhappy with their options for treating this very common problem. In a non-limiting, exemplary market survey, on a scale of 1 to 7, with “7” being the highest score, none of their current options rated higher than “5” (Table 4) (6). This is the result of several issues: Allergy desensitization therapy takes three years. Topical therapy is chronic and only mildly effective and poorly complied with. Several surgical approaches have been shown to treat severe rhinitis relatively well including vidian neurectomy, turbinoplasty, and posterior nerve ablation. Nevertheless, ENTs are only willing to surgically treat (or patients are only willing to be treated surgically) in less than 400,000 of these 6 millioncases, mostly for “severe” rhinitis (8). The rest are relegated to daily medical therapy or longterm allergy desensitization therapy.

[0292] Table 3 - Rhinitis patients treated by ENTs (1,000’s) (6)

[0293] Table 4 - Satisfaction of therapies for AR among U. S. ENTs (6)

[0294] Corticosteroid injections of the turbinates were shown to relieve rhinitis symptoms for at least 6 months and in many cases, up to one year (9,10,11). This approach to rhinitis treatment was popular, until reports emerged of cases of visual impairment. As a result, this practice was largely abandoned (12-15) and is “not recommended” in guidelines (4). In summary, ENTs are unhappy with the treatment options in their armamentarium in what is a large market.

[0295] Described herein is a steroid-eluting dissolvable implant that can be placed in the inferior turbinates (Figure 1) using an in-office delivery system shown in Figure 6 (16). The implant will be inserted during a 10-minute in-office procedure and will deliver the steroid in a controlled fashion for over 1 month with expected symptom relief of at least 6 months and up to 12 months. The disclosure provides several non-limiting, exemplary innovative advantages. First, it takes advantage of past research, showing that short-term delivery of steroids can ameliorate rhinitis symptoms for 6-12 months (11). Unlike steroid injections, however, the risk of blindness is eliminated, as there is no risk of steroids being injected retrograde into the ophthalmic artery. Finally, it utilizes Hot Melt Extrusion (HME). Becausedissolvable polymers are melted, and then extruded, with powdered drug components, drug delivery is more uniform. The utilization of HME of a turbinate implant can relieve patients of daily topical therapy or palliate symptoms immediately during the initiation of allergy desensitization therapy.

[0296] Described herein, we use emerging HME technology to deliver steroids in a controlled and longer-term fashion (at least one month in vivo). In some embodiments, 28 different dissolvable, drug delivery prototypes were developed, using a combination of 9 different dissolvable polymers. All were tested in vitro for rate of drug elution and mechanical properties. In some embodiments, 9 of these prototype formulas eluted at least 80% (of 9 mg total load) of mometasone furoate in the target range - between 12 and 44 days. Two of these implants were evaluated in vivo (rat model) to attempt to correlate in vitro elution profiles to in vivo elution profiles.

[0297] Described herein are non-limiting, exemplary formulas for steroid-eluting implant. We can use animal models to evaluate these formulas. In embodiments, a rat model can be used to evaluate in vivo elution properties. Most of these polymers are currently used in humans. Systemic absorption can be assessed with blood cortisol levels.

[0298] Non-Limiting, Exemplary Broader Impact

[0299] The compositions described herein can substitute chronic, daily, topical sprays and / or long-term immunotherapy with a simple, 10-minute, in-office implant placement and should last for 6-12 months. An impact of this controlled drug release is improved patient care, addressing a very large health problem that affects 77 million Americans (1). ENTs are currently treating an estimated 6 million of these patients today (6) and drive the standard of care for the remaining 71 million patients.

[0300] Described herein is a steroid eluting implant. In embodiments, the implant can be used to treat rhinitis while eliminating risks associated with steroid injections of the turbinate. Without wishing to be bound by theory, the compositions and methods described herein can benefit patients who weren’t successful with topical therapy and, for those patients who were beginning allergy desensitization therapy, as a palliative measure to reduce symptoms for the first six months when the desensitization therapy had not taken effect.

[0301] Table 5 - Non-Limiting, Exemplary Features and Benefits of the Disclosure

[0303] Without wishing to be bound by theory, the placement of the device described herein into the inferior turbinate can be non-invasive and straight forward, and the likelihood of major adverse outcomes is small. Without wishing to be bound by theory, the delivery of steroids into the nasal lining can reduce tissue inflammation and thus ameliorate symptoms. Additionally, because the device is implanted, patient compliance factors will not be an issue.

[0304] This treatment offers a new paradigm in the treatment of chronic rhinitis. Without wishing to be bound by theory, the compositions and methods described herein allow for treatment that can be used in lieu of daily nasal sprays (something patients do not like to use regularly) as well as a bridge between initiation and efficacy of immunotherapy, which can take years to work. This addresses the unmet market needs with daily nasal spray compliance and immunotherapy palliation.EXAMPLE 4

[0305] Formulation development of steroid-eluting dissolvable thread for treatment of Rhinitis

[0306] In embodiments, a steroid-eluting biodegradable / dissolvable implant, cylindrical in shape with an approximate diameter of 1 mm to 2 mm for the treatment of rhinitis in adult patients can be formulated. In embodiments, the implant can be manufactured by HME and / or 3D printing technology consisting of an appropriate steroid (e.g., mometasone furoate) drug load incorporated in one or more biodegradable polymers. Extruded products can also be molded post processing into a variety of implant shapes.

[0307] There are treatments for rhinitis that involve multiple steroid injections over a short period of time. This practice was effective in treating allergic and non-allergic rhinitis (AR and NAR) with durability for 6-12 months. Unfortunately, a small number of case reports emerged where temporary or permanent blindness ensued. On rare occasions, steroids were injected retrograde into the ophthalmic artery. Consequently, Otolaryngologists largely abandoned the practice.

[0308] This disclosure describes a steroid-eluting implant designed to treat rhinitis with submucosal steroids in the turbinates while obviating the complication of blindness in its delivery. Several corticosteroids products in the form of nasal sprays such as fluticasone propriate (Flonase®), mometasone furoate (Nasonex®), budesonide (Rhinocort Aqua®), and triamcinolone (Nasacort AQ®) are prescribed for patients with rhinitis. One benefit of second-generation steroids, such as mometasone, is the lower systemic bioavailability or the extent to which the drug enters the systemic circulation. Mometasone' s systemic bioavailability is measured at <0.1%-0.46%, compared to budesonide, measured at 31-34%. For this reason, it has been recommended to use a steroid with low bioavailability, such as mometasone, especially in patients who are also administering inhaled steroids to treat asthma. Polymers such as poly (lactic-co-glycolic acid) (PLGA), Polyethylene Glycol, hydroxypropyl methylcellulose (HPMC), Polyvinyl pyrrolidone (PVP), Polyethylene Oxide (PEO) will be used alone, and in combination as polymeric carriers, and / or with other additives. The selected steroidal API (mometasone furoate) will be investigated to produce the hot-melt extruded implant or feedstock for 3D printing with steroid elution for at least a month.

[0309] Background: Rhinitis has a tremendous effect on individual quality of life (QOL) and on society (1). 62% of rhinitis patients have (mostly seasonal) Allergic Rhinitis (AR) with the remaining 38% suffering from Non- Allergic Rhinitis (NAR) (2). In terms of the overall economic burden of illness, AR ranks fifth among chronic conditions in the UnitedStates (3,4,5). Several surgical approaches have been shown to treat severe rhinitis relatively well including vidian neurectomy, turbinoplasty, and posterior nerve ablation. Nevertheless, Otolaryngologists (Ear, Nose, and Throat surgeons - ENTs) reserve surgery to treat only some cases of severe rhinitis, where the rest are relegated to chronic medical therapy, including immunotherapy and topical sprays. Corticosteroid injections of the turbinates were shown many years ago to relieve rhinitis symptoms for at least 6 months but in many cases, up to one year (6, 7, 8). This approach to rhinitis treatment was popular, until reports emerged of cases of visual impairment, and then was largely abandoned (9-12). Described herein is a steroid-eluting dissolvable thread and delivery device to be placed in the turbinates that can reduce the hypertrophy and drainage associated with rhinitis, but through usage of the new thread and delivery technique, avoid the visual impairment previously reported. ENTs treat approximately 6 million rhinitis patients per year (2). This quick, in-office procedure will give them an option for treating rhinitis with something other than surgery, chronic drug therapy, or immunotherapy.

[0310] Summary of Idea: Use of HME and 3D printing in the development of shortterm (<= 30 days) biodegradable implants for treatment of rhinitis as biodegradable implants offer the advantage of not having the need to be removed after treatment. Biodegradable polymers such as poly (lactic-co-glycolic acid) (PLGA), Polyethylene Glycol, hydroxypropyl methylcellulose (HPMC), Polyvinyl pyrrolidone (PVP) will be used alone, and in combination with different ratios as polymeric carriers, and / or with other additives. The selected steroidal API (mometasone furoate) will be investigated to produce the hot-melt extruded implant or feedstock for 3D to develop mometasone-eluting dissolvable implant.EXAMPLE 5

[0311] Non-Limiting, Exemplary Method and Apparatus for Delivery of a Drug

[0312] BACKGROUND

[0313] Rhinitis, nasal congestion and nasal polyposis are significant medical issues that affect millions of people around the world. It has been estimated that 77 million people in the United States suffer from some form of rhinitis. Rhinitis can be either allergic or non-allergic. Symptoms include nasal congestion, runny nose, sneezing, and itching. The nasal turbinates are one of the major causes of nasal obstruction and are directly involved in the etiology of rhinitis. The turbinates can become hypertrophied and produce increased amounts of mucous when irritated by environmental allergens, hormones in the body, or some medicines. Steroids can decrease the reactivity of the turbinates to allergens, hormones, and other non-allergicstimulants. Steroids can be delivered in multiple ways to the human body. For example, steroids can be injected into veins or muscles to decrease inflammation.

[0314] A problem with the injection of steroids into veins or muscles is that there can be side effects to the entire body (i.e., systemic effects). Another way that steroids can be delivered to the human body is via an aqueous solution containing steroid molecules that are sprayed, for example daily or twice daily, into the nose to help decrease inflammation and hypertrophy. There are also some aerosol preparations. However, it can be difficult for a patient to comply with a daily or twice daily application schedule, and the application may not be done as prescribed. This can lead to treatment failures. There can also be a significant amount of nasal bleeding because the sprays can thin the mucosa on the septum.

[0315] The application of steroids to the inferior turbinate decreases the size of the turbinate therefore decreasing nasal obstruction and allowing the patient to breath better. They also reduce the overall inflammatory symptoms in the nose, associated with rhinitis. In the past, physicians have injected aqueous solutions of steroid directly into the turbinates over a span of two weeks. However, this practice has been all but abandoned because some patients developed blindness after injection within about twenty-four hours of injection, and usually within one hour of injection. Researchers believe that the small size of the particle in an aqueous solution would travel within an artery in the turbinate back to the artery going to the eye and cause blindness.

[0316] Other treatments for rhinitis are surgical in nature and reduce the size of the turbinate, mechanically (“submucosal reduction”) or with ablation. Studies have shown efficacy with these techniques for 3 years and 6 months respectively. While these techniques are effective, especially the submucosal resection, they are employed less frequently in this large population due to their surgical nature.

[0317] Described herein are non-limiting, exemplary embodiments of the present invention. Referring to the drawings, beginning with FIGS. 1 to 9, an exemplary embodiment of a method and apparatus for delivering a drug into nasal tissue, such as into the nasal turbinate or intranasal polyp, is shown and described. In an embodiment, a drug eluting material is implanted into a nasal turbinate or nasal polyp. The drug eluting material can be one or more implants 2 that are implanted into a nasal turbinate 4 and / or nasal polyp 6 (shown in FIGS. 10 to 12). In an embodiment, the drug can include one or more steroids, corticosteroids, antihistamines, and / or other drugs. The method and apparatus can be used to treat a number of conditions, including but not limited to turbinate hypertrophy (shown in the left half of FIG.11 ), nasal congestion, allergic and nonallergic rhinitis, and nasal polyposis.

[0318] In an embodiment, the delivery apparatus can include a syringe 10, such as a 3-5 cc medical syringe. In an embodiment, the needle 12 is a 5 cc sterile Luer-Lok tip syringe, product number 309646.

[0319] The syringe 10 is attached to a needle 12, such as a hollow bore 10-27 gauge spinal needle. In an embodiment, the needle 12 has a length of between about 1.5 inches and 7 inches. However, embodiments are not so limited, and dimensions may vary according to need and applications. In an embodiment the needle 12 is a Spinocan product number S22475 or S2735, with a gauge of between 18 and 27. The needle 12 can have a bend 14 which can allow for easier placement of a drug into the nasal tissue.

[0320] As shown in FIG. 2, a plunger 16 is connected to an ejector 18. The ejector 18 can be an obturator, flexible metal wire, or other suitable structure. The plunger 16 can be connected to the ejector 18 by a number of means, including but not limited to gluing, welding, fusing, or any other manner suitable for connecting the ejector 18 to the plunger 16. The plunger 16 and ejector 18 can also be formed into a single integrated component during manufacturing. In an embodiment, medical grade adhesive is used to glue the ejector 18 to the plunger 16. The ejector 18 is longer than the needle 12 so that when the ejector 18 is inserted through the syringe 10 and into the hollow bore needle 12 and the plunger 16 is then fully plunged into the syringe 10, the ejector 18 will reach the tip 20 of the needle 12 (as shown in FIG. 9). In FIGS. 8 and 9, the needle 12 has been made transparent so that the ejector 18 (in FIGS. 8 and 9) and drug eluting implant 2 (in FIG. 8) can be seen inside of the needle 12.

[0321] Referring now to FIGS. 1, 7-9, and 12, the method and apparatus described herein can utilize or include an implant, such as a drug eluting implant 2. In an embodiment, the drug eluting implant 2 can be or can contain a bio absorbable material and / or slow-release material that, once inserted into the nasal turbinate 4 or nasal polyp 6, allows one or more drugs to be released over a period of time. The drug eluting implant 2 can, over various periods of time depending on the drug and formulation, release the drug(s) into the local tissue. For example, if the drug eluting implant 2 is a steroid eluting implant that is implanted into the turbinate 4, the steroid will shrink the reactive tissue in the turbinate 4 and decrease the reactiveness of the tissue to allergens in a manner similar to nasal sprays. Similarly, if the drug eluting implant 2 is a steroid eluting implant that is implanted into a nasal polyp 6, the steroid will shrink the reactive tissue in the polyp 6 and decrease the reactiveness of the tissue to allergens, also in a manner similar to nasal sprays.

[0322] However, unlike nasal sprays, the drug eluting implant 2 is often implanted into the patient by another person, such as by a physician in a physician's office. In further contrastto nasal sprays, the drug eluting implant 2 can be left implanted in the patient for weeks or months, and the drugs of the drug eluting implant 2 can be slowly released over this extended period of time. The extended time period of drug release of the drug eluting implant 2 can obviate the need for a patient to use a nasal spray once per day or even multiple times per day.

[0323] In an embodiment, the drug eluting implant 2 is made of a bio absorbable material, such that the drug eluting implant 2 is eventually absorbed into the tissue of the patient (for example, once all of the drugs of the drug eluting implant 2 have been released). In an alternative embodiment, the drug eluting implant 2 can be removed after a period of time if desired.

[0324] The time period of drug release of the drug eluting implant 2 can be an extended period of time, and can be at least one day, at least one week, at least one month, or at least one year. In an embodiment, the drug eluting implant 2 can be or can include a slow release poly(lactic-co-glycolic acid) scaffold that can include one or more drugs that can be wrapped or printed onto it.

[0325] The drug eluting implant 2 can contain or can be composed of one or more types of drugs, including but not limited to steroids, corticosteroids, antihistamines, hormones, antibiotics, anticholinergic agents, and / or other types of drugs. As used herein, the term “drug” includes drugs, medicines, active ingredients, and the like. In an embodiment, the drug eluting implant 2 contains both a slow-release steroid as well as a slow-release antihistamine, thus making it both a steroid eluting implant as well as an antihistamine eluting implant.

[0326] The drug eluting implant 2 can be of various sizes and shapes. In the embodiment shown in FIGS. 1, 7-9, and 12, the drug eluting implant 2 is in the shape of a rod and may resemble a piece of monofilament fishing line. In an embodiment the drug eluting implant can have a length of 15-40 mm and can have a diameter of 1.0-2.55 mm. In an embodiment the drug eluting implant 2 can be flexible, while in another embodiment the drug eluting implant 2 can be rigid. The drug eluting implant can also be of a spherical shape, such as one or more small beads of drug eluting material, as is shown by drug eluting implant 40 in FIG. 12.

[0327] Referring to FIG. 1, the nasal turbinates include the superior turbinate 30, middle turbinate 32, and inferior turbinate 34. Although in FIG. 1 the drug eluting implant 2 is shown implanted in the inferior turbinate 34, the drug eluting implant 2 can also be implanted in the superior turbinate 30 or the middle turbinate.

[0328] In operation of an embodiment, a drug eluting implant 2 is implanted into a nasal turbinate 4. The syringe 10, needle 12, plunger 16, and ejector 18 can be used in concertto implant a drug eluting implant 2 into a nasal tissue. In FIG. 1, a drug eluting implant 2 is implanted into a nasal turbinate 4. More particularly, the drug eluting implant 2 of FIG. 1 is implanted into the submucosal plane of the inferior turbinate 34. In operation, this can be accomplished by connecting the plunger 16 to the ejector 18. The ejector 18 can then be passed through the syringe 10 and inserted into the hollow bore of the needle 12. If the drug eluting implant 2 is to be implanted at a later time, the plunger 16 can be fully depressed into the syringe 10, and the syringe 10, needle 12, plunger 16 and ejector 18 assembly can be stored until it is ready to be used.

[0329] When the syringe 10, needle 12, plunger 16 and ejector 18 assembly is ready to be used to implant a drug eluting implant 2 into the turbinate of a patient, the plunger 16 is first fully retracted as shown in FIG. 5. This partially backs the ejector 18 out of the hollow bore needle 12, thus creating a void within a portion of the hollow bore needle 12 beginning at the tip 20 of the hollow bore needle 12. The drug eluting implant 2 is then placed into this void in the needle 12 by inserting the drug eluting implant 2 into the tip 20 of the needle 12 until the drug eluting implant 2 is fully contained within the hollow bore of the needle 12 (as shown in FIG. 8 ).

[0330] Next, the tip 20 of the needle 12 is inserted at the anterior end of the turbinate 4, and then further inserted into the submucosal plane of the inferior turbinate. Once the needle 12 is properly positioned within the turbinate 4, the plunger 16 is depressed into the syringe 10, thus forcing the ejector 18 towards the tip 20 of the needle 12. As the plunger 16 is fully depressed, the drug eluting implant 2 is ejected (as shown in FIG. 9). As the plunger 16 is depressed, the needle 12 is simultaneously withdrawn from the turbinate 4. Depressing the plunger 16 until the plunger 16 is fully depressed while simultaneously withdrawing the needle 12 from the turbinate 4 ejects the drug eluting implant 2 from the needle 12 and implants the drug eluting implant 2 into the tract of the turbinate 4 that was formed by the insertion of the needle 12. The drug eluting implant 2 then remains in the turbinate 4 and slowly releases its drugs over a period of time. The method of implanting a drug eluting implant 2 into the turbinate 4 can be periodically repeated, such as once a month or once every three to four months when the drug eluting implant's supply of drugs is depleted. Doing so can create a relatively permanent form of treatment for a patient without the need for the daily use of a nasal spray.

[0331] In operation of another embodiment, a drug eluting implant 2 is implanted into a nasal polyp 6. As shown in FIG. 12, drug eluting implants 2 and 40 are implanted into nasal polyps 6. In operation, this can be accomplished by connecting the plunger 16 to the ejector18. The ejector 18 can then be passed through the syringe 10 and inserted into the hollow bore of the needle 12. If the drug eluting implant 2 is to be implanted at a later time, the plunger 16 can be fully depressed into the syringe 10, and the syringe 10, needle 12, plunger 16 and ejector 18 assembly can be stored until it is ready to be used.

[0332] When the syringe 10, needle 12, plunger 16 and ejector 18 assembly is ready to be used to implant a drug eluting implant 2 or 40 into the nasal polyp of a patient, the plunger 16 is first fully retracted as shown in FIG. 5. This partially backs the ejector 18 out of the hollow bore needle 12, thus creating a void within a portion of the hollow bore needle 12 beginning at the tip 20 of the hollow bore needle 12. The drug eluting implant 2 is then placed into this void in the needle 12 by inserting the drug eluting implant 2 into the tip 20 of the needle 12 until the drug eluting implant 2 is fully contained within the hollow bore of the needle 12 (as shown in FIG. 8).

[0333] Next, the tip 20 of the needle 12 is inserted into the nasal polyp 6. Once the needle 12 is properly positioned within the polyp 6, the plunger 16 is depressed into the syringe 10, thus forcing the ejector 18 towards the tip 20 of the needle 12. As the plunger 16 is fully depressed, the drug eluting implant 2 and / or 40 is ejected. As the plunger 16 is depressed, the needle 12 is simultaneously withdrawn from the polyp 6. Depressing the plunger 16 until the plunger 16 is fully depressed while simultaneously withdrawing the needle 12 from the polyp 6 ejects the drug eluting implant 2 and / or 40 from the needle 12 and implants the drug eluting implant 2 and / or 40 into the tract of the polyp 6 that was formed by the insertion of the needle 12. The drug eluting implant 2 and / or 40 then remains in the polyp 6 and slowly releases its drugs over a period of time. The method of implanting a drug eluting implant 2 and / or 40 into the polyp 6 can be periodically repeated, such as once a month or once every three to four months when the drug eluting implant's supply of drugs is depleted. Doing so can create a relatively permanent form of treatment for a patient without the need for the daily use of a nasal spray.

[0334] In still other embodiments, instead of using the syringe 10, needle 12, plunger 16 and ejector 18 assembly to implant the drug eluting implant into the turbinate 4 or polyp 6, the drug eluting implant can be implanted into the turbinate 4 or polyp 6 in a number of other ways. For example, the drug eluting implant can be a long and rigid spear like rod that is sharpened at one end. The rod can be sufficiently long so that it can be held at one end while inserting the opposite sharpened end into the turbinate or polyp. The rod can then be snapped or cut off, for example flush with the turbinate or polyp, such that a drug eluting portion of therod remains implanted in the turbinate or polyp. Additional mechanisms of delivery may be used depending on dimensions and target locations of the implant.

[0335] Rhinitis has a tremendous effect on individual quality of life (QOL) and on society (1). 62% of rhinitis patients have (mostly seasonal) Allergic Rhinitis (AR) with the remaining 38% suffering from Non- Allergic Rhinitis (NAR) (2). In terms of the overall economic burden of illness, AR ranks fifth among chronic conditions in the United States (3,4,5). Several surgical approaches have been shown to treat severe rhinitis relatively well including vidian neurectomy, turbinoplasty, and posterior nerve ablation. Nevertheless, Otolaryngologists (Ear, Nose, and Throat surgeons - ENTs) reserve surgery to treat only some cases of severe rhinitis, where the rest are relegated to chronic medical therapy, including immunotherapy and topical sprays. Corticosteroid injections of the turbinates were shown many years ago to relieve rhinitis symptoms for at least 6 months but in many cases, up to one year (6, 7, 8). This approach to rhinitis treatment was popular, until reports emerged of cases of visual impairment, and then was largely abandoned (9-12). A different approach implements a steroid-eluting dissolvable thread and delivery device to be placed in the turbinates. Like previous steroid injections, it should reduce the hypertrophy and drainage associated with rhinitis, but through usage of the novel thread and delivery technique, avoid the visual impairment previously reported. ENTs treat approximately 6 million rhinitis patients per year (2). This quick, in-office procedure will give them an option for treating rhinitis with something other than surgery, chronic drug therapy, or immunotherapy.

[0336] Use of HME and 3D printing in the development of short-term (<= 30 days) biodegradable implants for treatment of rhinitis as biodegradable implants offer the advantage of eliminating the need for removal after treatment. Biodegradable polymers such as poly (lactic-co-glycolic acid) (PLGA), Polyethylene Glycol, hydroxypropyl methylcellulose (HPMC), Polyvinyl pyrrolidone (PVP) will be used alone, and in combination with different ratios as polymeric carriers, and / or with other additives. The selected steroidal API (mometasone furoate) will be investigated to produce the hot-melt extruded implant or feedstock for 3D to develop mometasone-eluting dissolvable implant.

[0337] Under an embodiment, a steroid-eluting biodegradable / dissolvable implant, cylindrical in shape with an approximate diameter of 1 mm to 2 mm for the treatment of rhinitis in adult patients is formulated. The implant is manufactured by Hot Melt Extrusion (HME) and / or 3D printing technology consisting of an appropriate steroid (mometasone furoate) drug load incorporated in one or more biodegradable polymers. Extruded product can also be molded post processing.

[0338] This disclosure describes a steroid-eluting implant designed to similarly treat rhinitis with submucosal steroids in the turbinates while obviating the complication of blindness (described above) in its delivery. A number of corticosteroids products in the form of nasal sprays such as fluticasone propriate (Flonase®), mometasone furoate (Nasonex®), budesonide (Rhinocort Aqua®), and triamcinolone (Nasacort AQ®) are prescribed for patients with rhinitis. One benefit of second-generation steroids, such as mometasone, is the lower systemic bioavailability or the extent to which the drug enters the systemic circulation. Mometasone' s systemic bioavailability is measured at <0.1%-0.46%, compared to budesonide, measured at 31-34%. For this reason, it is recommended to use a steroid with low bioavailability, such as mometasone, especially in patients who are also administering inhaled steroids to treat asthma. Polymers such as poly (lactic-co-glycolic acid) (PLGA), Polyethylene Glycol, hydroxypropyl methylcellulose (HPMC), Polyvinyl pyrrolidone (PVP) will be used alone, and in combination as polymeric carriers, and / or with other additives. The selected steroidal API (mometasone furoate) is used to produce the hot-melt extruded implant or feedstock for 3D printing with steroid elution for at least a month.

[0339] FIGS. 13-18 show images of an implant (as described above) inserted into rats, under an embodiment.

[0340] FIGS. 19 -25 show images of in vitro drug release behavior of various implant formulations

[0341] The present invention employs a High-Performance Liquid Chromatography (HPLC) method for the analysis of samples and the establishment of a standard graph. The slope derived from the standard graph is utilized to calculate drug concentrations at various time points. Based on these concentrations, cumulative percentage drug release (CDR) is determined for each respective time point, thereby enabling the generation of time versus CDR graphs (FIGS 19-25).EXAMPLE 6

[0342] Biodegradable nasal implants can be effective in delivering controlled and prolonged drug release for local action. The use of hot-melt extrusion can be a tool for implant.

[0343] Introduction

[0344] Topical corticosteroids, such as mometasone furoate (MF), play a crucial role in managing postoperative inflammation due to their potent anti-inflammatory properties and minimal systemic absorption when administered locally. Mometasone furoate hasdemonstrated efficacy in reducing mucosal edema, polyp size, and the recurrence of nasal polyps. Despite its benefits, conventional delivery methods like nasal sprays or drops often fail to provide sustained drug levels at the site of action, limiting their therapeutic effectiveness (3,4).

[0345] Nasal implants have emerged as a promising method for delivering corticosteroids directly to the sinus mucosa. These implants could improve the effectiveness of the drugs, decrease the need for frequent administration, and enhance patient compliance by providing controlled and sustained release. Previous studies have explored various implantable devices for delivering corticosteroids in the postoperative setting, which have shown promising results in reducing inflammation, preventing adhesions, and maintaining sinus patency (5,6).

[0346] The present study describes the formulation development and evaluation of mometasone furoate nasal implants. This study aims to develop an implantable prolonged-release system using a single-step continuous manufacturing technique (hot-melt extrusion) to optimize local drug concentration with PLGA [Poly (lactic-co-glycolic acid)] and HPMC (hydroxypropyl methylcellulose). PLGA is one of the widely used biodegradable and biocompatible polymers for controlled-release drug delivery applications. The formulation process involved selecting appropriate biocompatible materials, determining the optimal drug loading, and assessing the in-vitro and in-vivo performance of the implants.

[0347] Materials and Methods

[0348] Materials: MF was purchased from Flavine North America, Inc. (New Jersey, USA). Viatel™ bioresorbable polymer Poly (D, L-lactide-co-glycolide) 5005 A (Viatel™ DLG 5005 A / E) purchased from Ashland Specialty Ingredients (Wilmington, DE), Benecel™ K35M hydroxypropyl methylcellulose was gifted by Ashland Specialty Ingredients (Wilmington, DE), Kollidon® 90 F was received as a generous gift from BASF Chemical Co. (Ludwigshafen, Germany), Polyethylene Glycol (PEG 3350, PEG 400), AFFINISOL™ HPMC HME 4M gifted by Colorcon. All other chemicals and solvents utilized in the current investigation were of analytical grade and were purchased from Fischer Scientific (St. Louis, MO, USA).

[0349] Analytical method: Mometasone Furoate was analyzed by HPLC with UV detection at 254 nm. Isocratic elution was used with 65 / 35 Methanol / water, flow 1.7 mL / min, and a 25 cm Waters Symmetry C8 column (5 pm silica). MF eluted in approximately 9 min. Samples were diluted 50:50:1 in acetonitrile: water: glacial acetic acid. Mometasone Furoate was quantified using an Agilent HPLC-UV system (AGILENT TECHNOLOGIES,) with a UV / VIS detector. Samples were injected at a volume of 20 pl. For calibration purposes,standards were prepared by dissolving Mometasone furoate in Methanol and diluting the stock solution with diluent 50:50:1 in acetonitrile: water: acetic acid across a concentration range of 2-10 pg / ml.

[0350] Preparation of Nasal Implants using Hot Melt Extrusion (HME): The composition of the different formulations prepared is given in Table 7. Process 11 co-rotating Twin-Screw Extruder (Thermo Scientific, Waltham, MA, USA) was used to fabricate the implants. The Process 11 HME screws were configured, with one kneading zone featuring 90°, 60°, and 30° offset angles near zone-6, and a die fitted with a 1.50 mm nozzle. As the PLGA material was received in granular form, it underwent freezer-milling (SPEX 6700) using liquid nitrogen and was subsequently sieved through a #40 ASTM mesh. The drug, PLGA, and other polymers were sieved through a #40 ASTM mesh and blended in a V-cone blender for 10 minutes to achieve a homogenous mixture. The resulting homogenous physical mixture (PM) was then fed into the feeding zone of the extruder at a constant feeding rate of 0.5 g / min. The temperature between 150 and 185°C was maintained throughout the barrel (zones 2 to 8) and the die. The screw speed was kept at 75-100 rpm to maintain a die pressure of 30-50 bar. Following extrusion, the filament was cooled down to room temperature on a belt conveyor (Thermo Scientific) to solidify the extruded filament. The target implant should be <40.00 mm long and <2.00 mm in diameter per the implant applicator requirement. Hence all the formulations were prepared with 15% drug loading, resulting in each implant with 60 mg weight containing an equivalent dose of 9 mg of mometasone furoate.

[0351] Blend Uniformity: The physical mixtures of all formulations were evaluated for blend uniformity before extrusion to ensure uniform distribution of the drug in the filaments. MF 9 mg equivalent PMs (60 mg) were weighed and dissolved in acetone and sonicated for 30 minutes until a clear solution was formed. It was then further diluted with Milli-Q water and analyzed for the drug using HPLC at a specific wavelength of 254 nm

[0352] Dimensions: Extruded filaments were analyzed for appearance and dimensions to check for uniformity. Each filament was cut into 9 mg equivalent dose (60 mg) implants, measured for weight (mass), diameter, and length, and reported in the table with standard deviation values (7).

[0353] Content Uniformity: Content Uniformity was estimated for all extruded filaments to ensure the uniform distribution of MF within the filament. The implants were randomly selected from each batch of the first, middle, and last parts of the filament, and cut into 60 mg (9.0 mg equivalent to the drug) of the filament. Dissolved the implant in acetone and sonicated for 30 minutes. The obtained clear solution was centrifuged at 10,000 rpm for10 minutes and the supernatant was further diluted with Milli-Q water and analyzed using HPLC at 254 nm for the drug.

[0354] Assay: Extruded filaments were analyzed to determine the drug quantity in the filament. Small pieces m length equivalent to 600 mg of filament were cut from the different locations of the extruded filament and mixed together. 60 mg (9.0 mg equivalent to the drug) of the cut filaments were taken and dissolved in 50 mL of acetone and sonicated for 30 minutes. The obtained clear solution was centrifuged at 10,000 rpm for 10 minutes and further diluted with 50:50:1 in acetonitrile: water: glacial acetic acid and analyzed using HPLC at 254 nm for the drug, of two assay results were calculated.

[0355] DSC: The drug's thermal behavior was examined using a differential scanning calorimeter, i.e., a Discovery instrument (DSC 25, TA Instruments, DE, USA). The pure API, Excipients (Polymers and Plasticizers), PMs, and extruded filaments were analyzed. T-zero aluminum pans with 5-10 mg of sample were sealed with aluminum pans, and the test was carried out with a 10 °C / minute heating rate from 25 to 250 °C and with 50 mL / minute of nitrogen purge flow.

[0356] FTIR: The pure API, excipients (polymers and plasticizers), PMs, and extruded filaments were analyzed for drug incompatibility with the excipients using an Infrared spectroscopy Cary 660 FTIR spectrophotometer (Agilent Technologies, Santa Clara, California, USA) combined with an ATR apparatus (Pike Technologies MIRacle, Madison, WI, USA) attached with a single-bounce diamond-coated ZnSe internal reflection element. A spectrum of 4000-650 cm-1was recorded with 32 scans.

[0357] Tensile Strength: After the extrusion, extruded implants (n=3) were analyzed for their strength and flexibility for easy insertion using an implant applicator. The TA-XT2i Texture Analyzer (Stable Micro Systems Ltd., Godaiming, England), fitted with a TA-92 adjustable 3-point bend / snap fixture module, was utilized for the test. The parameters set for the test included a 10 mm gap between the clamps, a pre-test speed of 2 mm / s, a test speed of 2 mm / s, a post-test speed of 10 mm / s, and a probe moving distance of 10 mm. Extruded filaments were positioned on the sample support clamps, while a 3 mm thick, rounded-end, bell lock-shaped knife was mounted on the holder at the upper part of the texture analyzer. The blades moved 10 mm from their starting point until they were close to the filament. The Exponent software (version 6.1.5.0, Stable Micro Systems Ltd., Godaiming, UK) was used to monitor and plot the resistance force over the distance or time.

[0358] Scanning Electron Microscopy (SEM): To assess the surface morphologies of pure drugs, polymers, and fabricated implants, SEM analysis was conducted using a JSM7200FLV scanning electron microscope (JEOL, Peabody, MA, USA) with a 5kV accelerating voltage. Samples were affixed to SEM stubs with double-sided adhesive tape. Prior to imaging, all samples were sputter-coated with platinum using the Denton Desk V TSC sputter coater (Denton Vacuum, Moorestown, NJ, USA) and kept in an argon atmosphere.

[0359] Implant swelling and erosion: Implants with a defined drug dose (9 mg) were exposed to 20 mL of pH 6.8 phosphate buffer (simulated nasal fluid) as the medium. To prevent saturation, the total medium is replaced two times a week. At specified time intervals (every week for two months), specimens were withdrawn, and the excess medium was gently removed using Kimtech precision wipes (Kimberly-Clark, Rouen, France) and weighed to obtain the wet mass (t). The samples were then freeze-dried for three days and reweighed to determine the dry mass (t). Using the following calculations implant swelling and erosion behavior are calculated.• Wet mass (%) (t) = (wet mass (t) / initial weight) x 100%• Water content (%) (t) = [(wet mass (t) - dry mass (t)) / wet mass (t)] x 100%• Dry mass loss (%) (t) = [(initial weight - dry mass (t)) / initial weight] x 100%

[0360] Here, the initial weight refers to the weight of the implants before exposure to the release medium (t = 0). All experiments were conducted in triplicate, and the results are presented as mean values with + / - standard deviations. (7)

[0361] In-vitro drug release study: The in-vitro drug release study of MF implants was conducted in a horizontal water bath shaker at 37 ± 2°C using pH 7.4 phosphate buffer with 2% SLS as dissolution media. The drug release study was performed for the drug-loaded implants over 30 days. The horizontal water bath shaker was set to 250 rpm to ensure uniform mixing of the media. Based on the assay results, 9.0 mg of drug equivalent implant samples (n=3) were placed in 20 mL scintillation vials containing 10 mL of dissolution media. The whole media (10 mL) was replaced with fresh buffer every 24 h and collected samples (n=3) were analyzed for drug released from the implant using HPLC at 254 nm.

[0362] In-vivo rat studies: In-vivo rat studies were conducted for Fl and F28 formulations for 30 days.

[0363] Non-Limiting, Exemplary Results and Discussion

[0364] Preparation of Nasal Implants using Hot Melt Extrusion (HME):Formulations with combinations of PLGA and HPMC, PLGA, HPMC and AFFINISOL™ HPMC HME 4M, PLGA, HPMC K35M, PEG producing white colored, smooth surface, brittle filaments. As the PLGA ratio increases die pressure is lower (3-50 bar) and as the HPMCK35M ratio increases die pressure is higher (70-90 bar). When AFFINISOL™ HPMC HME 4M is introduced into the formulations irrespective of HPMC K35M ratio die pressure is maintained in between 20-40 bar. Initial trials were made with lower die temperature i.e., 100-150 °C die pressure increased >100 bar, and the equipment stopped working. When the die temperature increases >170 °C die pressure is reduced to <90 bar by extruding a soft filament, upon cooling the filament on the conveyor turns brittle. As the feed rate increases >1.0g / minute die pressure increases>100 bar and leading to failure in the extrusion process. If the feed rate was maintained at 0.5 g - 1.0 g extruded the filament without an increase in the die pressure.

[0365] Blend Uniformity: The blend uniformity analysis was conducted on a single batch, given that the drug loading remained constant at 15% across all formulations and the blending procedure was standardized. Furthermore, the consistency in drug distribution was assured by measuring the content uniformity in the final filament. This approach is justified by the consistency in drug concentration and processing methods. For the evaluated batch, blend uniformity was assessed using 10 distinct samples. The results demonstrated a high degree of homogeneity, with the Relative Standard Deviation (RSD) maintained below 5.0% for all samples. Additionally, the mean drug content exceeded 95%, indicating excellent uniformity in the blend. Given these robust results from the representative batch, it was deemed unnecessary to perform blend uniformity tests for subsequent formulations. The low RSD and high mean drug content suggest that the blending process is reliable and reproducible, capable of consistently producing uniform mixtures across different polymer combinations. This approach streamlines the formulation development process by reducing redundant testing while maintaining confidence in the blend quality. It assumes that the established blending procedure is sufficiently robust to accommodate minor variations in polymer composition without significantly impacting drug distribution within the blend.

[0366] Dimensions: Following the extrusion process, filaments were cut into ~24 mm (23 - 25 mm range) lengths in different locations and tested for uniformity of weight and diameter to find the consistency of the filament throughout the process. Average dimensional measurements of the implant were reported in the table with SD values. The average dimensions (weight / mass, diameter, and length) of the implants were consistent across all the formulations with lower SD values.

[0367] Assay: The analysis of MF loadings revealed a consistent discrepancy between the estimated and initially loaded quantities, with extracted amounts being lower than expected. This variance suggests potential drug loss during the extrusion process, possibly due to drugadsorption on the extruder barrel's interior or incomplete extraction from the implants. These findings emphasize the need to refine both the manufacturing process and extraction methods to achieve more accurate drug loading and maintain consistent implant quality. Notably, increasing the batch size could potentially address the issue of lower assay values, as the proportion of material adhering to the barrel would be relatively smaller in larger batches. This scaling-up approach might mitigate the impact of drug loss on overall content uniformity, thereby improving the accuracy of drug loading in the final implants. Also, adjustments to drug loading calculations may be necessary to account for process-related losses. The lower assay values observed for F4 and F6 could be attributed to the higher ratio of PLGA (51%) in these formulations. During the extrusion process, the granular portion of PLGA may segregate, which is reflected in the assay results. Additionally, for F6, another hypothesis is that the PEG 3350 content (34%) may soften or convert into a liquid form at higher temperatures, leading it to extrude out first, thus impacting the assay results.

[0368] Content Uniformity and Assay: The evaluation of drug content uniformity in the implants provided crucial insights into the extrusion process efficiency and consistency of drug loading or distribution. A comprehensive analysis was conducted by performing total drug extraction and quantification via HPLC on three samples (start, middle, and end) from each filament / implant type. This approach aimed to determine the average content uniformity between implants, and the assay of filaments with results compiled in a table. All the formulations were seemingly homogenous, as indicated by the low standard deviations in MF-loading observed between implants of the same formulation.

[0369] Table 10: Physical evaluation of MF implantsdetermine the force required to break them. Each formulation's tensile strength was measured three times, with the results reported alongside standard deviation (SD) values. The tensile strength varied significantly among the formulations, ranging from 87.0 g for F7 to 390.6 g for F27. This variability indicates that the mechanical properties are heavily influenced by the formulation composition.

[0371] Formulations with higher PLGA content generally exhibited greater tensile strength. F2 (34% PLGA) had a tensile strength of 290.9 g, F27 (34% PLGA) reached 390.6 g, and F18 (34% PLGA) showed 333.7 g. In contrast, formulations with lower PLGA concentrations, such as Fll (12.75% PLGA) with 259.5 g and F5 (14.9% PLGA) with 182.4 g, had lower tensile strengths. These findings suggest that PLGA significantly enhances the structural integrity of the filaments.

[0372] HPMC K35M, a hydrophilic polymer, also affects the flexibility and mechanical strength of the filaments. The data indicates there may be an optimal range for HPMC K35M content, as seen in Fl (68% K35M) and F2 (51% K35M), which had moderate tensile strengths of 247.7 g and 290.9 g, respectively. However, formulations such as F7 (63% K35M, 5% PEG 3350) and F6 (51% HPMC K35M, 34% PEG 3350) demonstrated the lowest tensile strengths at 87.0 g and 128.1 g, respectively, indicating that the inclusion of PEG 3350 can reduce the mechanical strength of the filaments. In contrast, Fl 8, which contains 34% PLGA, 49.5% HPMC K35M, and 1.5% PEG 400, maintained a high tensile strength of 333.7 g, showing that minimal amounts of PEG 400 do not significantly decrease tensile strength.

[0373] The incorporation of other polymers, such as PEG 3350, PEG 400, and AFFINISOL™ HPMC HME, also influenced tensile strength. For instance, F6, which contained 34% PEG 3350, had a tensile strength of 128.1 g, suggesting that PEG 3350 may not enhance tensile strength. Conversely, Fl 8, which included 1.5% PEG 400, maintained a high tensile strength of 333.7 g, indicating that small amounts of PEG 400 do not adversely affect mechanical properties. Moreover, F27 and F28, containing 5.1% and 13.6% AFFINISOL™ HPMC HME 4M, achieved high tensile strengths of 390.6 g and 343.0 g, respectively, demonstrating that AFFINISOL™ HPMC HME 4M can positively contribute to the structural integrity of the filaments when used in suitable proportions.

[0374] In-vitro drug release study:

[0375] Before the start of the drug release study, a solubility study is carried out to find the suitable release medium. As MF is a low soluble drug, in pH 7.4 PBS without SLS and with SLS were selected for solubility studies. As the target dose of 9 mg filament for 30 days of release is equivalent to 300 pg / day solubility is required in 24 hours. Based on the solubility data, pH 7.4 PBS with 2% SLS was selected as the release medium. The drug release from various polymer ratios was studied in 10 mL of pH 7.4 PBS with 2% SLS at 34-36 °C in an orbital shaker and sampling will be done every 24 hours. The total quantity of medium was replaced with fresh buffer solutions and the study continued till >80% of the drug was released from the formulations. Collected samples were analyzed using HPLC and calculated for daily release and % cumulative drug release.

[0376] The formulations exhibit distinct drug release profiles, highlighting the impact of PLGA and HPMC K35M ratios on the release profile. Formulation Fll and F5 show a significant initial burst release, with > 40% in 1stweek and another 40% drug release (i.e., > 80%) release in 2ndweek due to the lower concentration of PLGA and a higher ratio of HPMC K35M. In contrast, Fl starts with moderate release rates (239.3 mcg / day on day 1) and features several peaks and troughs, with 30% drug release in the first week and 20-25% in the second week and further slow release from week 2 (week 3 only 10-13%). F2 demonstrates a more controlled release profile, with a lower initial burst of 103.3 mcg / day on day 1 and sustained, consistent release with smaller peaks over time due to more PLGA (34%) than Fll, F5, and Fl formulations. F4 with higher PLGA (51%) provides the most stable release pattern, with a low initial burst of 92.7 mcg / day on day 1, maintaining a steady, sustained release throughout the testing period, making it suitable for prolonged drug delivery applications. These observations highlight how the PLGA ratio is impacting the initial burst release. The degradation of PLGA involves hydrolysis of its ester linkages, which is a relatively slowprocess. Therefore, higher PLGA content in the implant formulations results in a more gradual release of the drug. This is because the polymer matrix takes longer to break down, slowly releasing the drug entrapped within. In formulations with PLGA and HPMC K35M, as the PLGA ratio increases, drug release is slower when compared with a lower ratio of PLGA. In contrast, formulations with higher HPMC K35M content (Fll and F5) showed faster drug release due to the hydrophilic nature of HPMC K35M, this occurs as the polymer swells, increasing the porosity of the matrix, which in turn facilitates a quicker diffusion of the drug molecules out of the matrix.

[0377] F27 shows a higher initial burst due to the use oflower viscosity HPMC (K35M) combined with a higher PLGA content. This combination creates a matrix that initially resists water penetration due to the hydrophobic nature of PLGA. However, once water enters, the presence of HPMC K35M allows for rapid drug diffusion, resulting in a quick release of the drug. The interaction of high PLGA and low- viscosity HPMC K35M enables an initial burst release, followed by a more gradual, sustained release.

[0378] In contrast, F28, which contains higher viscosity HPMC (K100M) and a lower PLGA content, exhibits a reduced initial burst. The more viscous HPMC K100M forms a thicker, more cohesive gel layer upon hydration, which creates a stronger barrier to drug diffusion. As a result, the initial drug release is slowed, with F28 releasing 49.6% of the drug by day 7. This thicker gel matrix provides more effective control over the drug release rate, ensuring a slower, more sustained release.

[0379] The study investigated the impact of incorporating PEG into formulations containing PLGA and HPMC K35M on drug release profiles. The results demonstrated that the addition of PEG significantly enhances drug release. Specifically, formulation F7, which includes 5% of PEG 3350, exhibited a pronounced initial burst release compared to formulation Fl, which has the same composition but without PEG. During the early phase of the study (up to day 6), F7 consistently showed a higher cumulative percentage of drug release, nearly doubling that of FL By day 6, Fl had released 26.1% of the drug, whereas F7 had released 49.5%, a difference of approximately 20%. This increased release rate in F7 was maintained throughout the duration of the study.

[0380] The inclusion of PEG 3350 in F7 accelerates the drug release process by dissolving and leaching out, which creates additional pores and channels within the matrix. This enhances the surface area available for drug release, facilitating a more rapid diffusion of the drug. Moreover, even formulations with a higher PLGA ratio, such as F18 (containing 34% PLGA), showed faster drug release when only a minimal amount of PEG 400 (1.5%) waspresent. These findings underscore the significant role of PEG in promoting burst release from implants, irrespective of the PLGA ratio, highlighting its impact on modifying drug release dynamics.

[0381] Table 10: Non-Limiting, Exemplary FormulationsEQUIVALENTS

[0382] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific substances and procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims.

Claims

CLAIMSWhat is Claimed:

1. A composition comprising a biodegradable polymer and a steroid, wherein the composition comprises no more than about 30 wt. % of the steroid; andthe biodegradable polymer comprises about 5.0 wt. % to about 25 wt. % of poly(DL-lactide-co-glycolide) acid endcap (PLGA), wherein the (PLGA) comprises a lactide to glycolide ratio of about 50:50 and a molecular weight of about 40 kDa to about 65 kDa.

2. The composition of claim 1, wherein the steroid comprises a systemic bioavailability of no more than 10%.

3. The composition of claim 1 or claim 2, wherein the composition comprises:about 5.0 wt. % to about 85.0 wt. % of at least one hydroxypropylmethylcellulose (HPMC), wherein the at least one HPMC comprises a molecular weight of about 550 kDa to about 1,000 kDa.

4. The composition of any one of claims 1-3, further comprising:about 5.0 wt.% to about 35.0 wt. % of polyethylene glycol (PEG) 3350; about 1.0 wt.% to about 2.0 wt. % of polyethylene glycol (PEG) 400; about 34.0 wt. % to about 68.0 wt. % of a polyethylene oxide (PEO), wherein the PEO comprises a molecular weight of about 600 kDa;0 wt. % to about 20 wt. % of polyvinyl pyrrolidone (PVP), wherein the PVP comprises a molecular weight of about 1,350 kDa; orany combination thereof.

5. The composition of any one of claims 1-4, wherein the steroid comprises mometasone furoate, fluticasone, ciclesonide, or any combination thereof.

6. The composition of any one of claims 1-5, wherein the composition comprises about 10 wt. %, about 11 wt. %, about 12 wt. %, about 13 wt. %, about 14 wt. %, about 15wt. %, about 16 wt. %, about 17 wt. %, about 18 wt. %, about 19 wt. %, or about 20 wt. % of the steroid.

7. The composition of any one of claims 1-6, wherein the composition comprises formula Fl, formula F8, formula F12, formula F20, formula F29, formula F30, formula F31, formula F32, formula F33, formula F34, formula F35, formula F36, formula F37, formula F38, formula F39, or formula F40.

8. The composition of any one of claims 1-7, wherein the composition elutes about 80% of the steroid to a target tissue in about 30 days.

9. The composition of any one of claims 1-8, wherein the target tissue comprises a nasal tissue.

10. The composition of any one of claims 9, wherein the nasal tissue comprises a nasal polyp or a nasal turbinate.

11. The composition of any one of claims 1-10, wherein the composition is a monolithic structure.

12. The composition of any one of claims 1-11, wherein the monolithic structure is a cylinder comprising a length of about 40mm and a diameter of about 1 mm to about 2mm.

13. A method of treating rhinitis, turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof, the method comprising administering the composition of any one of claims 1-12 to the nasal tissue of a subject in need thereof.

14. The method of claim 13, wherein the nasal tissue comprises a nasal polyp or a nasal turbinate.

15. The method of claim 14, wherein rhinitis comprises allergic rhinitis or non-allergic rhinitis.

16. Use of a composition of any one of claims 1-15 to treat a subject afflicted with rhinitis, turbinate hypertrophy, nasal congestion, nasal polyposis, or any combination thereof.

17. A method of preparing a steroid-eluting nasal implant, wherein the method comprises:blending a steroid and at least one biodegradable polymer, thereby forming a steroid-polymer blend;processing the steroid-polymer blend, thereby producing a steroid-eluting nasal implant; andcooling the processed steroid-polymer blend in a geometry, thereby forming a steroid-eluting nasal implant.

18. The method of claim 17, wherein the steroid-polymer blend comprises the composition of any one of claims 1-12.

19. The method of claim 17, wherein the processing comprises:feeding the steroid-polymer blend into a hot melt extruder;extruding the steroid-polymer blend through a screw and a die, wherein the die comprises a diameter of about 0.5 mm to about 2.5 mm; andwherein the extruding comprises:a feed rate of about 0.5 g / min to about 2.0 g / min,a processing speed of about 40 rpm to about 80 rpm, a processing temperature of about 80°C to about 200°C, or any combination thereof.

20. The method of claim 17, wherein the processing comprises:mixing the steroid-polymer blend at a temperature of about 150°C to about 200°C;depositing the steroid-polymer blend in a plurality layers, wherein the plurality of layers forms a 3D infill pattern.

21. The method of claim 20, wherein the infill pattern is selected from the group consisting of a grid, a line, an octet, a quarter cubic, a gyroid, a zigzag, or any combination thereof.

22. The method of claim 21, wherein the infill pattern comprises a density of less than about 25% to about 100%.

23. The method of any one of claims 20-22, wherein the infill pattern and infill density are configured to vary the drug release profile.

24. The method of claim 17, wherein the geometry is a cylinder.

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