Biodegradable intranasal system for sustained release of active ingredients in the nasal cavity

Abstract

The present invention relates to a biodegradable intranasal system for the sustained release of fluticasone propionate in the nasal cavity, said system comprising a biodegradable polyester matrix containing fluticasone propionate as an active ingredient to be released into the nasal cavity, the polyester being selected from the list of poly(L,D-lactic acid) (PLA), poly(caprolactone) (PCL), their copolymers such as PLA-PCL, and mixtures thereof, a biodegradable intranasal system, and a method for preparing said system. The present invention also relates to a kit comprising the system of the present invention and means for inserting the system into the nasal cavity. The present invention further relates to fluticasone propionate for use in treating chronic rhinitis or chronic sinusitis, which is in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention.

Description

Technical Field

[0001] The present invention relates to a biodegradable intranasal system for the sustained release of fluticasone propionate in the nasal cavity.

Background Art

[0002] Chronic rhinitis is a long-term inflammation of the nasal mucosa that typically lasts for more than four consecutive weeks. Chronic rhinitis can be non-allergic or allergic rhinitis. Allergic rhinitis is caused by an allergic response to specific allergens such as pollen, dust, or pet dander. During an allergic response, the body's immune system overreacts to the presence of one of these allergens in the air. Non-allergic rhinitis is a form of rhinitis in which the body's immune system is not involved. It is often induced by environmental problems such as air pollution, tobacco smoke, or strong odors. In some cases, the cause cannot be identified.

[0003] Chronic sinusitis is a long-term sinus inflammation that typically lasts for more than 12 consecutive or non-consecutive weeks. Chronic sinusitis is different from recurrent sinusitis because the symptoms of chronic sinusitis never actually disappear for a long time. In recurrent sinusitis, there can be more than four episodes of sinusitis per year, but there can also be asymptomatic periods in between.

[0004] The treatment of chronic rhinitis or chronic sinusitis usually involves a combination of pharmaceuticals such as antihistamines, antibiotics, saline nasal sprays, decongestants, corticosteroids, and / or anticholinergics. These pharmaceuticals include oral medications and nasal sprays. If pharmaceutical treatment fails, energy-based solutions such as laser, radio wave, or cryotherapy may be proposed for chronic rhinitis. Surgery, such as sinus surgery in the case of chronic sinusitis, or surgery on the inferior turbinate in the case of chronic rhinitis such as turbinectomy or turbinate bone resection (the latter causes serious adverse events), may also be considered as an option.

[0005] Fluticasone propionate is a corticosteroid commonly used to reduce allergic or non-allergic nasal symptoms such as nasal congestion / rhinorrhea, itching, and sneezing. It acts on the nose to block the effects of allergy-causing substances (pollen, pet dander, dust mites, mold, etc.) and reduce swelling. In these applications, fluticasone propionate is administered topically several times a day by nasal spray.

[0006] Therefore, there is a need for easier administration of this pharmaceutical and improved compliance with the dosing schedule. Sustained-release administration of this pharmaceutical for a period of at least 6 months for chronic rhinitis or at least 12 months for chronic sinusitis is also needed.

[0007] International application WO2006 / 107957 discloses an apparatus for treating sinus conditions, including a cavity member and one or more active agents for sustained release into the nasal cavity and sinuses. The disclosed apparatus is configured to deliver the active agent for a period of about one week to about one month (about 35 days).

[0008] U.S. Patent Application US2013 / 281982 discloses an implantable device and a method for delivering a substance to a location within or an opening into the nasal cavity or sinuses of a human or animal subject for treating disorders such as sinusitis and other ear, nose, and throat disorders.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0010] However, there is a positive need for a device that can be easily placed in the nasal cavity and that can release an active agent into the nasal cavity for a long period of time, typically at least 3 months, preferably at least 6 months, for treating or preventing chronic rhinitis or chronic sinusitis.

Means for Solving the Problems

[0011] In this situation, the inventors have discovered a biodegradable nasal system that can release fluticasone propionate into the nasal cavity for a period of at least 6 months, preferably between 6 and 12 months. In particular, the inventors have found that a biodegradable system comprising a polyester matrix containing poly(L,D-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA) such as PLA-PCL, or a mixture thereof, and fluticasone propionate (FP) enables the release of FP into the nasal cavity for a period of at least 3 months, preferably at least 6 months, for example between 6 and 12 months. The inventors have shown that the degradation time of such a biodegradable system exceeds 12 months, which means that there is no significant loss of mechanical properties during at least 12 months, and thus an effective amount of FP is released, and thus a sufficient residence time in the nasal cavity for treating chronic sinusitis or chronic rhinitis is ensured. Therefore, such a system is particularly suitable for treating or preventing chronic sinusitis or chronic rhinitis. It has been shown that other polymers such as poly(L-lactic acid) (PLLA) or copolymers such as PLA-PEG-PLA, when used alone, cannot provide such release or such degradation time.

[0012] Accordingly, the present invention relates to a biodegradable intranasal system for the sustained release of fluticasone propionate in the nasal cavity, said system comprising a biodegradable polyester matrix containing fluticasone propionate as the active ingredient to be released into the nasal cavity, wherein the polyester is selected from the list of poly(L,D-lactic acid) (PLA), poly(caprolactone) (PCL), their copolymers such as PLA-PCL, and mixtures thereof, a biodegradable intranasal system.

[0013] The present invention also relates to a kit comprising at least the system of the present invention and means for inserting said system into the nasal cavity.

[0014] The present invention further relates to fluticasone propionate for use in treating chronic allergic or non-allergic rhinitis, in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention.

[0015] The present invention also relates to fluticasone propionate for use in treating chronic sinusitis, in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention.

[0016] The present invention further relates to a method for preparing the biodegradable intranasal system of the present invention, comprising the step of forming the system by a process selected from extrusion, solvent evaporation (e.g., using dichloromethane), hot pressing, hot injection, freeze drying, electrospinning, molding or 3D printing.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0018] The inventors have developed a biodegradable intranasal system for the sustained release of fluticasone propionate in the nasal cavity, which has mechanical and chemical properties particularly suitable for use in the medical field, and in particular for treating or preventing chronic disorders of the nasal cavity such as chronic rhinosinusitis or chronic rhinitis over a long period of time.

[0019] Definition In the context of the present invention, the term "biodegradable system" refers to a system that is degradable in an aqueous or moist medium, particularly a biological medium such as the nasal cavity, over a specific or controlled period of time. Degradation leads to a loss of the mechanical properties of the system. In the context of the present invention, the degradation of the system can be due to the progressive hydrolysis of ester bonds in the polyester matrix. In a particular embodiment of the present invention, the biodegradable system is resorbable.

[0020] In the context of the present invention, the term "resorbable system" refers to a biodegradable system as defined above, in which the degradation products are metabolized.

[0021] According to the present invention, an "aqueous medium" refers to a medium having an osmolarity similar to that of a biological fluid. Phosphate buffered saline (PBS), which is considered representative of biological fluids, is generally used as an aqueous medium.

[0022] According to the present invention, a "moist medium" refers to a medium equivalent to an aqueous medium, i.e., a medium having an osmolarity similar to that of a biological fluid, but the moist medium is non-liquid and / or viscous. The nasal cavity can be characterized as a non-liquid moist medium.

[0023] In the context of the present invention, the term "intranasal" or "nasal cavity" refers to the narrow, mucosa-lined space extending from the nostrils to the pharynx (posterior nares). It is divided by the nasal septum into two cavities, also known as fossae (right and left). On both sides of the nasal cavity are the nasal turbinates: inferior, middle, and superior turbinates.

[0024] In the context of the present invention, the terms "molecular mass", "molar mass" and "molecular weight" are used interchangeably to denote the number average molecular weight / molar mass (Mn), unless otherwise specified. According to the present invention, Mn is determined by size exclusion chromatography performed in dimethylformamide as the analytical solvent using polystyrene in the standard range.

[0025] In the context of the present invention, the terms "biodegradable intranasal system of the present invention", "intranasal system of the present invention" or "system of the present invention" can be used interchangeably. Similarly, the terms "biodegradable polyester matrix" and "polyester matrix" can be used interchangeably.

[0026] In the context of the present invention, the term "about" means plus or minus 10% of a given value.

[0027] In the context of the present invention, the expression "between x and y" means that the values x and y are included.

[0028] Biodegradable intranasal system The present invention relates to a biodegradable intranasal system for the sustained release of fluticasone propionate in the nasal cavity, the system comprising a biodegradable polyester matrix containing fluticasone propionate as an active ingredient to be released into the nasal cavity, wherein the polyester is selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), copolymers such as PLA-PCL of poly(caprolactone) (PCL) and poly(lactic acid) (PLA), and mixtures thereof.

[0029] The term "polyester" refers to a polymer whose repeating unit in the main chain contains an ester functional group and can be used in the medical field. In particular, "polyester" means aliphatic polyesters such as poly(lactic acid), poly(glycolic acid), poly(caprolactone) (PCL), poly(butyrolactone) (PBL), poly(hydroxyalkanoate) (PHA), and their copolymers. In the context of the present invention, the polyester is selected from poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), and a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA).

[0030] Poly(lactic acid) (PLA) may be poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA) or poly(D,L-lactic acid) (PDLLA). In the context of the present invention, poly(D,L-lactic acid) and poly(D-lactic acid), especially poly(D,L-lactic acid), are preferably used. In the case of poly(D,L-lactic acid) (PDLLA), PLA preferably contains at least 50% L-lactic acid, especially L-lactic acid between 50% and 99%. Typically, poly(D,L-lactic acid) (PDLLA) may contain 50% L-lactic acid (PLA50), 55% L-lactic acid (PLA55), 60% L-lactic acid (PLA60), 65% L-lactic acid (PLA65), 70% L-lactic acid (PLA70), 75% L-lactic acid (PLA75), 80% L-lactic acid (PLA80), 85% L-lactic acid (PLA85), 90% L-lactic acid (PLA90), 95% L-lactic acid (PLA95), 96% L-lactic acid (PLA96), or 99% L-lactic acid (PLA99). Preferably, PDLLA contains L-lactic acid between 50% and 85%, more preferably between 50% and 65%. In fact, by changing the percentage of L-lactic acid in relation to D-lactic acid, it is possible to adjust the release of fluticasone propionate.

[0031] Copolymers of PLA and PCL include PLA-PCL diblocks, or PLA-PCL-PLA or PCL-PLA-PCL triblock copolymers, or statistical distributions (in various ratios) of both monomers, or mixtures thereof, especially [PLA-PCL-PLA and PCL-PLA-PCL], [PLA-PCL and / or PCL-PLA-PCL], [PLA-PCL or PLA-PCL-PLA], [PLA-PCL-PLA and PCL-PLA-PCL and PCL]. Preferably, the system according to the invention comprises only copolymers of PLA and PCL. Preferably, the system according to the invention comprises only block copolymers of PLA and PCL. In these copolymers, the PLA used is preferably PDLLA or PDLA, more preferably PDLLA. In certain embodiments, the system according to the invention comprises only PLA-PCL diblock copolymers, preferably only PLA85-PCL or PLA50-PCL diblock copolymers. In certain embodiments, the PLA-PCL copolymer has a PLA / PCL molar ratio between 95 / 5 and 50 / 50. In certain embodiments, the PLA-PCL diblock copolymer has a PLA / PCL molar ratio between 90 / 10 and 50 / 50, preferably between 90 / 10 and 70 / 30, more preferably 85 / 15. The PLA / PCL molar ratio can be measured by proton nuclear magnetic resonance (1H NMR).

[0032] In certain embodiments, the PLA-PCL copolymer has a PLA / PCL molar ratio between 95 / 5 and 50 / 50. In certain embodiments, the PLA-PCL copolymer has a PLA / PCL molar ratio between 90 / 10 and 50 / 50, preferably between 90 / 10 and 70 / 30, more preferably 85 / 15. The PLA / PCL molar ratio can be measured by proton nuclear magnetic resonance (1H NMR).

[0033] In certain embodiments of the present invention, the biodegradable polyester matrix may comprise a mixture of polyesters selected from the list of PCL and copolymers of PCL and PLA such as PDLLA, PDLA, PCL, and copolymer PLA-PCL. Preferably, the biodegradable polyester matrix comprises a mixture of PCL and at least one polyester selected from the list of PCL and copolymers of PCL and PLA such as PDLLA, PDLA, and copolymer PLA-PCL. For example, the biodegradable polyester matrix may comprise a mixture of PCL and a copolymer of PLA and PCL, preferably a mixture of PCL and copolymer PLA-PCL.

[0034] In certain embodiments, the biodegradable polyester matrix preferably comprises a mixture of PCL and copolymer PLA-PCL with a PLA-PCL content of 0.1% to 60% based on the total mass of the system. In this context, the content of PCL in the biodegradable polyester matrix is preferably at least 20% by mass, more preferably at least 40% by mass, particularly between 20% by mass and 99.89% by mass, preferably between 40% by mass and 99.89% by mass, with respect to the total mass of the system.

[0035] In certain embodiments, the biodegradable polyester matrix comprises a mixture of PCL and copolymer PLA-PCL with a PCL / copolymer ratio ranging from 10 / 90 to 90 / 10, preferably from 40 / 60 to 90 / 10, more preferably from 50 / 50 to 80 / 20, even more preferably from 50 / 50 to 75 / 25. The inventors have observed that the higher the content of copolymer PLA-PCL in the mixture, the slower the release of fluticasone propionate.

[0036] In the context of the present invention, when the biodegradable polyester matrix contains PCL as the only polyester, the content of PCL in the biodegradable polyester matrix is preferably at least 80% by mass, preferably at least 85% by mass, more preferably at least 90% by mass, particularly between 80% and 99.99% by mass, preferably between 85% and 99.99% by mass, more preferably between 90% and 99.99% by mass, based on the total mass of the system.

[0037] Preferably, the biodegradable polyester matrix contains PCL, or a mixture of PCL and PLA-PCL. More preferably, the biodegradable polyester matrix contains only PCL as the polyester.

[0038] In a preferred embodiment, PCL has a molar mass (number average) between 25,000 g / mol and 250,000 g / mol, preferably between 35,000 g / mol and 250,000 g / mol, preferably between 80,000 g / mol and 250,000 g / mol, preferably between 100,000 g / mol and 250,000 g / mol, more preferably between 120,000 g / mol and 250,000 g / mol, more preferably between 120,000 and 200,000 g / mol. The molar mass can be measured by means known to those skilled in the art. For example, the number average molar mass can be determined by size exclusion chromatography (SEC, Shimadzu SIL-20A HT) using two mixed media columns PLgel 5μm MIXED-C (300×7.8 mm), a Shimadzu RI detector 20-A and a Shimadzu UV detector SPD-20A (260 and 290 nm) (constant temperature analysis cell at 40°C). DMF can be used as the mobile phase with a flow rate of 1 mL / min at 40°C (column temperature). PCL can be dissolved in DMF until a concentration of 5 mg / mL is reached, and then the solution can be filtered through a 0.45 μm Millipore filter before injection. The average molecular weight can be expressed according to calibration using polystyrene standards.

[0039] Preferably, the polyester of the matrix is in an uncrosslinked form.

[0040] In the context of the present invention, the polyester matrix further comprises fluticasone propionate. This means that fluticasone propionate is dispersed in the polyester matrix. Preferably, fluticasone propionate is not covalently bonded to the polyester in the polyester matrix.

[0041] Advantageously, the content of fluticasone propionate in the intranasal system according to the invention is at most 20% by weight, preferably at most 15% by weight, preferably at most 10% by weight, preferably between 0.01% by weight and 15% by weight, preferably between 0.01% by weight and 10% by weight, preferably between 0.1% by weight and 10% by weight, more preferably between 1% by weight and 10% by weight, based on the total mass of the system.

[0042] In a particular embodiment of the present invention, the polyester matrix consists of a polyester selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA), and mixtures thereof, and fluticasone propionate. Typically, fluticasone propionate is incorporated into the structure of a polyester matrix comprising a polyester selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA), and mixtures thereof.

[0043] In certain embodiments, the intranasal system of the present invention is preferably made of a biodegradable polyester matrix. This means that the system of the present invention preferably consists of a biodegradable polyester matrix. Thus, the system of the present invention preferably comprises fluticasone propionate and a polyester selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA), and mixtures thereof, or consists of such a polyester matrix.

[0044] Accordingly, in certain embodiments, the present invention relates to a composition comprising a polyester matrix according to the present invention as defined above. More specifically, the composition of the present invention comprises or consists of a polyester matrix comprising fluticasone propionate and a polyester selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), a copolymer of poly(caprolactone) (PCL) and poly(lactic acid) (PLA), and mixtures thereof. More specifically, the composition of the present invention comprises or consists of a polyester matrix comprising fluticasone propionate and a polyester selected from the list of poly(caprolactone) (PCL) and a mixture of poly(caprolactone) (PCL) and a PLA-PCL copolymer.

[0045] In a preferred embodiment, the intranasal system of the present invention does not comprise a coating containing an active ingredient such as fluticasone propionate. In particular, fluticasone propionate is only dispersed within the polyester matrix constituting the system of the present invention. Preferably, the intranasal system of the present invention does not comprise a coating.

[0046] In certain embodiments, the polyester matrix consists of fluticasone propionate and a polyester selected from the list of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), copolymers of poly(caprolactone) (PCL) and poly(lactic acid) (PLA) such as PLA-PCL copolymers, and mixtures thereof.

[0047] In certain embodiments, the polyester matrix consists of fluticasone propionate and a polyester selected from the list of poly(caprolactone) (PCL) and mixtures of poly(caprolactone) (PCL) and PLA-PCL copolymers.

[0048] In another particular embodiment, the nasal system of the present invention may further comprise at least one homopolymer such as a polyester or poly(ethylene glycol) (PEG). The homopolymer may be dispersed in the polyester matrix or may be in the form of a coating of the system. Preferably, the homopolymer is not covalently bonded to either the polyester matrix or fluticasone propionate. This homopolymer may be added to the polyester matrix before or during the forming process, for example, so as to be dispersed in the polyester matrix. Otherwise, it is possible to impregnate or coat the system or the polyester matrix with the homopolymer after the forming process. The addition of the homopolymer can provide better control of the release of fluticasone propionate or the mechanical properties of the system of the present invention. Preferably, the homopolymer may be poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(caprolactone) (PCL), poly(butyrolactone) (PBL), poly(hydroxyalkanoate) (PHA), poly(ethylene glycol) (PEG), poly(oxyethylene) (PEO), or mixtures thereof. The homopolymer may have, for example, a molar mass (per number) between 1 kDa and 300 kDa. Advantageously, the system of the present invention comprises additional homopolymer between 0.1% and 30% by weight relative to the total weight of the system.

[0049] In another embodiment, the system of the present invention may include additional additives or active ingredients, such as antihistamines, other corticosteroids or anti-inflammatory drugs, in addition to the polyester matrix. This additive or active ingredient may be added to the polyester matrix before or during the formation of the matrix, for example, so as to be dispersed in the polyester matrix. Otherwise, after the forming process, it is possible to impregnate or coat the system with this active ingredient or additive. Preferably, the active ingredient can diffuse from the polymer matrix / coating into the external environment when it is in an aqueous or wet medium.

[0050] In certain embodiments, the polyester matrix of the present invention, more specifically the intranasal system of the present invention, has a Young's modulus that is included between 350 MPa and 1000 MPa, preferably between 350 MPa and 850 MPa, more preferably between 350 MPa and 650 MPa, and even more preferably between 450 MPa and 650 MPa. The Young's modulus can be measured by any method known to those skilled in the art. For example, the Young's modulus can be determined by performing a classical tensile assay and then determining the value using OriginLab software. In certain embodiments, when the polyester matrix contains PCL as the only polyester, the Young's modulus is included between 350 MPa and 1000 MPa, preferably between 350 MPa and 850 MPa, more preferably between 350 MPa and 650 MPa, and even more preferably between 450 MPa and 650 MPa.

[0051] In certain embodiments, the polyester matrix of the present invention, more specifically the intranasal system of the present invention, has a breaking strain that is between 100% and 700%, preferably between 300% and 500%, more preferably between 350% and 450%. The breaking strain can be measured by any method known to those skilled in the art. For example, the breaking strain can be determined by performing a classical tensile assay and then using OriginLab software to determine the value. In certain embodiments, when the polyester matrix contains PCL as the sole polyester, the breaking strain is between 100% and 700%, preferably between 300% and 500%, more preferably between 350% and 450%.

[0052] In certain embodiments, the polyester matrix of the present invention, more specifically the intranasal system of the present invention, may have a thickness between a few microns and several hundred microns, particularly between 10 μm and 700 μm. Preferably, the intranasal system of the present invention has a thickness between 100 μm and 700 μm, more preferably between 100 μm and 500 μm, for example between 100 μm and 400 μm. In certain embodiments, the polyester matrix of the present invention, more specifically the intranasal system of the present invention, may have a thickness between 100 μm and 350 μm. Generally, the thickness of the resulting system depends on the amount of polyester matrix used and the surface area of the substrate or mold used in the forming process. The thickness can be measured by methods generally known in the art such as optical microscopy. Control of the thickness of the system can result in better control of the release of fluticasone propionate. For example, the inventors have observed that the thicker the system, the slower the release of fluticasone propionate.

[0053] Accordingly, the system according to the present invention may take the form of a film, a tube, or other 2D or 3D matrix forms, etc. In particular, the system of the present invention has a form adapted to the anatomical structure within the nasal cavity, preferably adapted to be placed near or around the inferior and / or middle nasal conchae.

[0054] "Film" means, for example, a two-dimensional material obtained from the evaporation on a plane of a solvent in which a polyester matrix according to the present invention is dissolved. The thickness of such a film is advantageously between a few microns and several hundred microns, in particular between 10 μm and 700 μm. In certain embodiments, the film has a thickness between about 100 μm and 700 μm, more preferably between 100 μm and 500 μm, between 100 μm and 400 μm, etc. The thickness of such a film is advantageously between 100 μm and 350 μm. "Thickness" means "dry thickness" in the sense that it is measured under anhydrous conditions (e.g., by optical microscopy) after formation and complete evaporation of the solvent in which the polyester matrix is dissolved. The dimensions of the film can be adapted as needed, in particular by cutting a film of larger dimensions to the desired dimensions.

[0055] The film can be folded to form a tube or sleeve and may be closed by stitching or adhesion as needed. The tube can also be obtained directly by forming it around a cylinder or by extrusion.

[0056] In the context of the present invention, "tube" refers to a hollow three-dimensional cylinder whose wall is formed of a polyester matrix according to the present invention. Preferably, the diameter of such a tube is between 5 mm and 30 mm. In certain embodiments, the tube has a wall thickness between 100 μm and 700 μm and a diameter between 5 mm and 30 mm.

[0057] In certain embodiments, the biodegradable intranasal system of the present invention enables sustained release of fluticasone propionate in the nasal cavity for at least 90 days, preferably at least 105 days, preferably at least 120 days, preferably at least 135 days, preferably at least 150 days, preferably at least 165 days, preferably at least 180 days (i.e., 6 months). In certain embodiments, the system of the present invention can release fluticasone propionate in the nasal cavity for at least 180 days, preferably between 180 days and 365 days. In another certain embodiment, the system of the present invention can release fluticasone propionate in the nasal cavity for at least 360 days, preferably between 360 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0058] In certain embodiments, the biodegradable intranasal system of the present invention can release at least 15% by weight, preferably at least 25% by weight, more preferably at least 40% by weight of the fluticasone propionate initially present in the system 180 days (i.e., 6 months) after introduction of the system into an aqueous or moist medium. In more particular embodiments, the biodegradable intranasal system of the present invention can release at least 50% by weight, preferably at least 70% by weight, more preferably at least 80% by weight of the fluticasone propionate initially present in the system 180 days (i.e., 6 months) after introduction of the system into an aqueous or moist medium.

[0059] In another specific embodiment, the biodegradable intranasal system of the present invention can release at least 25% by mass, preferably at least 35% by mass, more preferably at least 45% by mass of fluticasone propionate initially present in the system 360 days (i.e., 12 months) after introduction of the system into an aqueous or moist medium. In a more specific embodiment, the biodegradable intranasal system of the present invention can release at least 50% by mass, preferably at least 70% by mass, more preferably at least 80% by mass of fluticasone propionate initially present in the system 360 days (i.e., 12 months) after introduction of the system into an aqueous or moist medium. In the context of the present invention, the amount of fluticasone propionate released at each release time can be measured by HPLC with a UV detector, a fluorescence detector or a mass spectrometer.

[0060] An additional particularly advantageous feature of the system according to the invention is that the system is degradable in an aqueous or moist medium (such as a biological medium) after a residence time of at least 360 days, preferably at least 550 days. The loss of the mechanical properties of the system according to the invention is directly related to its degradation. Degradability can be evaluated, for example, by measuring the decrease in the molecular weight of the system over time, for example by size exclusion chromatography, after immersion in a physiological saline medium (PBS 1×) at 37°C with stirring. In order to allow the release of fluticasone propionate in the nasal cavity for a sufficient period before the mechanical properties of the system are unduly affected by degradation, the degradation of the system, i.e., the solubilization of the polyester matrix in the nasal cavity, is gradual and controlled. Thus, the removal of the system according to the invention may be by natural removal (after degradation or by resorption), or by removal by a healthcare professional. In a specific embodiment of the present invention, the intranasal system is resorbable.

[0061] Method for preparing the intranasal system of the present invention The preparation of the intranasal system according to the present invention can be carried out by any means known to those skilled in the art, in particular by incorporating fluticasone propionate in the required content during the preparation of the polyester matrix.

[0062] Accordingly, the present invention relates to a method for preparing the biodegradable intranasal system of the present invention, which comprises a step of forming the system by a process selected from extrusion, solvent evaporation (e.g., using dichloromethane), hot pressing, hot injection, lyophilization, electrospinning, molding or 3D printing, and preferably a preliminary step of mixing the polyester and fluticasone propionate together before the process.

[0063] For example, the preliminary step defined above may be, for example: - impregnating / swelling the polyester of the polyester matrix in a solution containing fluticasone propionate, - mixing dry powders of the polyester and fluticasone propionate, - mixing dry powders of the polyester and fluticasone propionate in a liquid solvent (such as dichloromethane) to obtain a suspension or solution, - mixing by melting or softening the powders of the polyester and fluticasone propionate, - mixing a solution of the polyester and a powder of fluticasone propionate to form a suspension or solution, and - mixing a solution of the polyester and fluticasone propionate, optionally with a liquid solvent, to form a suspension or solution etc., and can be prepared by incorporating fluticasone propionate during the preparation of the polyester matrix by means generally known to those skilled in the art.

[0064] Preferably, the preliminary step comprises mixing dry powders or solutions of the polyester and fluticasone propionate in a liquid solvent. The liquid solvent may be, for example, dichloromethane.

[0065] Next, the system according to the invention can be formed from a mixture comprising a polyester and fluticasone propionate, in particular from the solution / suspension obtained during the preliminary steps, by means known to those skilled in the art, in particular by a process selected from extrusion, solvent evaporation (e.g. using dichloromethane), hot pressing, hot injection, freeze drying, electrospinning, moulding or 3D printing.

[0066] In a preferred embodiment, the intranasal system of the invention is prepared by mixing a polyester and fluticasone propionate in a liquid solvent (such as dichloromethane) to obtain a suspension or solution, and extruding the resulting suspension or solution while evaporating the liquid solvent.

[0067] In certain embodiments, additional steps can be performed, such as cutting and / or assembling means for intranasal insertion.

[0068] After the manufacturing process, the system of the invention can be sterilized by means known to those skilled in the art, such as gamma ray sterilization, beta ray sterilization or ethylene oxide sterilization. In a preferred embodiment, the system of the invention is sterilized by gamma rays, in particular gamma rays between 15 and 45 kGy.

[0069] Kit The invention also relates to a kit comprising at least the biodegradable intranasal system of the invention and means for inserting the system into the nasal cavity.

[0070] The kit according to the invention, in particular the means of insertion, enables the biodegradable intranasal system according to the invention to be reliably introduced and placed into the nasal cavity of the human body, preferably on a biological protrusion present in the nasal cavity, more preferably near or around the inferior and / or middle nasal concha.

[0071] The kit according to the invention can be used in particular in subjects suffering from chronic disorders of the nasal cavity, including chronic allergic or non-allergic rhinitis and chronic sinusitis.

[0072] Drug delivery system The biodegradable intranasal system of the present invention is particularly suitable for its use in treating or preventing chronic allergic or non-allergic rhinitis and / or chronic sinusitis in a subject in need thereof.

[0073] In the context of the present invention, the terms "subject", "individual" or "patient" are interchangeable and refer to an animal, preferably a mammal, more preferably a human. As defined herein, the subject suffers from chronic allergic or non-allergic rhinitis and / or chronic sinusitis. The subject may be of either sex and of any age.

[0074] According to the present invention, the biodegradable intranasal system is preferably intended to be inserted into the nasal cavity of the human body. Thus, the system of the present invention is preferably suitable for being reliably inserted and installed into the nasal cavity of the human body, preferably on a biological protrusion present in the nasal cavity, for example, near or around the inferior and / or middle nasal conchae.

[0075] Thus, the present invention also relates to fluticasone propionate for use as an active ingredient in treating and / or preventing chronic disorders of the nasal cavity in a subject in need thereof, in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention.

[0076] Thus, the present invention also relates to fluticasone propionate for use as an active ingredient in treating and / or preventing chronic allergic or non-allergic rhinitis in a subject in need thereof, in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate into the nasal cavity for at least 120 days, preferably at least 180 days, particularly between 120 days and 240 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0077] Accordingly, the present invention also relates to fluticasone propionate for use as an active ingredient for treating and / or preventing chronic rhinosinusitis in a subject in need thereof, in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 240 days, preferably at least 360 days, particularly between 240 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0078] The present invention also relates to a composition of the present invention for use in treating and / or preventing chronic disorders of the nasal cavity in a subject in need thereof, in a form suitable for intranasal administration.

[0079] Accordingly, the present invention also relates to a composition of the present invention for use in treating and / or preventing chronic allergic or non-allergic rhinitis in a subject in need thereof, in a form suitable for intranasal administration. In this embodiment, the composition of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 120 days, preferably at least 180 days, particularly between 120 days and 240 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0080] Accordingly, the present invention also relates to a composition of the present invention for use in treating and / or preventing chronic rhinosinusitis in a subject in need thereof, in a form suitable for intranasal administration. In this embodiment, the composition of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 240 days, preferably at least 360 days, particularly between 240 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0081] The present invention also relates to a method for treating and / or preventing chronic disorders of the nasal cavity in a subject in need thereof, the method comprising administering an effective amount of fluticasone propionate intranasally to the subject by the biodegradable intranasal system of the present invention.

[0082] The present invention also relates to a method for treating and / or preventing chronic allergic or non-allergic rhinitis in a subject in need thereof, the method comprising administering an effective amount of fluticasone propionate intranasally to the subject by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 120 days, preferably at least 180 days, particularly between 120 days and 240 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0083] The present invention also relates to a method for treating and / or preventing chronic sinusitis in a subject in need thereof, the method comprising administering an effective amount of fluticasone propionate intranasally to the subject by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 240 days, preferably at least 360 days, particularly between 240 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0084] The present invention also relates to a method for treating and / or preventing chronic disorders of the nasal cavity in a subject in need thereof, the method comprising administering the biodegradable intranasal system of the present invention intranasally to the subject.

[0085] The present invention also relates to a method for treating and / or preventing chronic allergic or non-allergic rhinitis in a subject in need thereof, the method comprising the step of administering an intranasal biodegradable system of the present invention intranasally to the subject. In this embodiment, the intranasal biodegradable system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 120 days, preferably at least 180 days, particularly between 120 days and 240 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0086] The present invention also relates to a method for treating and / or preventing chronic sinusitis in a subject in need thereof, the method comprising the step of administering an intranasal biodegradable system of the present invention intranasally to the subject. In this embodiment, the intranasal biodegradable system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 240 days, preferably at least 360 days, particularly between 240 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0087] The present invention also relates to the use of fluticasone propionate in a composition according to the present invention for the manufacture of a medicament for treating and / or preventing chronic disorders of the nasal cavity in a subject in need thereof, wherein the composition is in a form suitable for intranasal administration by an intranasal biodegradable system of the present invention.

[0088] The present invention also relates to the use of fluticasone propionate in the composition according to the invention for the manufacture of a medicament for treating and / or preventing chronic allergic or non-allergic rhinitis in a subject in need thereof, wherein the composition is in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 120 days, preferably at least 180 days, particularly between 120 days and 240 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0089] The present invention also relates to the use of fluticasone propionate in the composition according to the invention for the manufacture of a medicament for treating and / or preventing chronic sinusitis in a subject in need thereof, wherein the composition is in a form suitable for intranasal administration by the biodegradable intranasal system of the present invention. In this embodiment, the biodegradable intranasal system of the present invention is preferably suitable for releasing fluticasone propionate intranasally for at least 240 days, preferably at least 360 days, particularly between 240 days and 550 days. Advantageously, the sustained release of fluticasone propionate is a continuous sustained release.

[0090] The present invention will be described below using the following examples, which are provided for illustrative purposes and do not limit the present invention in any way.

Examples

[0091] (Example 1) Preparation of a polyester film containing fluticasone propionate The polymers are · Poly(lactic acid) (PLA50) containing 50% L-lactic acid: RESOMER® R 207 S - supplier Evonik (Mn ≈ 185,000 g / mol), · Poly(lactic acid) (PLA85) containing 85% L-lactic acid: RESOMER® LR 704 S - supplier Evonik (Mn ≈ 262,000 g / mol), · Poly(lactic acid) (PLA96) containing 96% L-lactic acid: PURASORB® PLD 9620 - supplier Corbion (Mn ≈ 136,800 g / mol), · Poly(L-lactic acid) (PLLA): RESOMER® L 207 S - supplier Evonik (Mn ≈ 141,000 g / mol supplier data), · Poly(caprolactone) (PCL): molar mass (number average) of approximately 180,000 g / mol - RESOMER® C 217 - supplier Evonik (Mn ≈ 135,000 g / mol), · Copolymer PLA-PEG-PLA: copolymer containing 96% PLA85 and 4% poly(ethylene glycol) (PEG) - RESOMER® LRP t 7046 - supplier Evonik (Mn ≈ 158,000 g / mol), and · Copolymer PLA-PCL: copolymer containing 85% (w / w) PLA85 and 15% (w / w) PCL - PURASORB® PLC 8516 - supplier Corbion (Mn ≈ 149,000 g / mol) are used.

[0092] The molar molecular weight was determined according to the above method.

[0093] The active ingredient is fluticasone propionate: CAS: 80474-14-2, Mw = 500.58 g / mol.

[0094] During the experimental tests, glass materials such as glass pipettes, glass containers / vessels, etc. are used.

[0095] 1-1) Preparation by solvent evaporation Circular films containing 10% (w:w) of the active ingredient (fluticasone propionate) are a) Prepared by uniformly mixing fluticasone propionate with a polymer (PLA-PEG-PLA, PLA50, PLA85, PLA96, PLA-PCL, PLLA, or PCL): 1 g of fluticasone propionate is added to 9 g of the polymer in a vial. 90 mL of analytical grade dichloromethane is added. The mixture is solubilized to obtain a solution; b) forming a film by solvent evaporation: A precisely calculated volume of the solution is deposited onto a substrate and the solvent is slowly evaporated to form a film; then c) cutting the film into 6 mm squares prepared by.

[0096] 1 - 2) Preparation by hot press Circular films containing 10% (w:w) active ingredient (fluticasone propionate) are a) mixing fluticasone propionate uniformly with a polymer (PLA - PEG - PLA, PLA50, PLLA, or PCL): 1 g of fluticasone propionate is added to 9 g of the polymer in a vial. 90 mL of analytical grade dichloromethane is added. Once the mixture is solubilized, the dichloromethane is evaporated under vacuum for 20 - 30 minutes using a rotary evaporator. Then, the vial is left under vacuum for 3 days (the solvent trap is immersed in liquid nitrogen connected between the vial and the vacuum pump) to remove the residual solvent. When the mass of the vial reaches the mass it initially had, a trace amount of residual solvent is considered removed. The obtained film is removed with a spatula, cut into very small pieces with a scalpel, and placed at 4 °C; b) forming a film by hot press: A heat press, model Carver 41200E, is used for this study. A Teflon paper mold (SS Shovan) is custom - made in the laboratory to obtain circular films with a diameter of 7 cm and a thickness of 200 μm. Once the assembly is in place, a specific amount of the previously prepared film is placed at the center of the mold and then pressed. The parameters of temperature, amount of material, pressure, and time under pressure vary depending on the type of polymer selected and are thus optimized for each polymer under study (Table 1); c) Laser cutting: The film thus obtained is laser cut to form a stick with a thickness of 200 μm having the following dimensions: 1.5 mm * 24 mm. The thickness is measured with a micrometer (1866 HELIOS PREISSER); d) Sterilizing by gamma rays Prepared by

[0097]

Table 1

[0098] 1 - 3) Preparation by extrusion Tubes containing 10% (w:w) of the active ingredient (fluticasone propionate) are a) Mixing fluticasone propionate homogeneously with a polymer (PLA - PEG - PLA, PLA50, PLLA, or PCL): 1 g of fluticasone propionate is added to 9 g of the polymer in a vial. 90 mL of analytical dichloromethane is added. The mixture is solubilized to obtain a solution; b) Forming a film by extrusion The solution is injected into an extruder (with evaporation of the solvent during extrusion) to produce a tube with a thickness of 200 μm (inner diameter of 9 mm); e) Laser cutting: The tube thus obtained is laser cut to form a stick with a thickness of 200 μm having the following dimensions: 1.5 mm * 24 mm. The thickness is measured with a micrometer (1866 HELIOS PREISSER) or calculated using the mass of the sample; f) Sterilizing by gamma rays Prepared by

[0099] 1 - 4) Molar mass measurement The average molar mass was determined by size exclusion chromatography (SEC, Shimadzu SIL-20A HT) using two mixed media columns PLgel 5μm MIXED-C (300×7.8 mm), a Shimadzu RI detector 20-A and a Shimadzu UV detector SPD-20A (260 and 290 nm) (constant temperature analysis cell at 40 °C). DMF was the mobile phase with a flow rate of 1 mL / min at 40 °C (column temperature). The polymer was dissolved in DMF until a concentration of 5 mg / mL was reached, and then the solution was filtered through a 0.45 μm Millipore filter before injection. The average molecular weight was expressed according to calibration using polystyrene standards. Figure 1 shows the evolution of the molar mass of the matrix PCL + 10% FP as a function of time.

[0100] 1 - 5) Characterization of mechanical properties Samples of matrix PCL + 10% FP were used to examine the evolution of mechanical properties during degradation. The shape of the samples (rectangle: 24 mm * 1.5 mm) enabled them to be used in tensile assays. At defined times, the samples were removed from the release medium and dried using absorbent paper. For all samples (performed with a repetition number of 3 for each time point):

[0101] Once completely dry, the thickness of the samples was measured using a Helios-Preisser 1866-Basic 0 - 25 mm micrometer. The samples were placed on an Instron 3344L8422 tensile bench with a 500 Newton jaw. The length of the sample between the two jaws was measured using a Helios-Preisser 2403 1850472 300 mm (12 inches) 0.01 mm (0.0005 inches) micrometer. A classical tensile assay was performed at a speed of 10 mm / min. OriginLab software was used to calculate stress and strain and to determine Young's modulus, breaking stress and strain.

[0102] Figure 2 shows the evolution of Young's modulus as a function of time. Figure 3 shows the evolution of breaking strain as a function of time.

[0103] (Example 2) Release profile of fluticasone propionate from the film or tube obtained in Example 1 Release medium: Vial containing 20 mL of PBS (phosphate buffered saline (pH 7.4)) containing 0.1% (w:v) SDS (sodium dodecyl sulfate), stirred at 37 °C (100 rpm).

[0104] Sample collection conditions: At the time of sample collection in the first week, 1 mL of the medium is taken and replaced with 1 mL of fresh medium, and then the medium is completely renewed after each 1 mL sample collection every 7 days. Then, the collected samples are analyzed by HPLC.

[0105] 2-1) Results of release of fluticasone propionate from the film of Example 1-1): Each formulation (10% fluticasone propionate w:w; 200 μm thickness) was tested with a repetition number of 3. The release profile is shown in Figure 4 (Figure 4). The cumulative percent release of FP increases over time for all films except the PLA-PEG-PLA film (the effect observed after 190 days is thought to be due to rupture of the sample) and the PLLA film which is not thought to release FP.

[0106] The PLA50 and PLA-PCL films show the same release profile. The PLA85 and PLA96 films are close to each other and also have a release profile close to that of PLA50 and PLA-PCL. The PCL film releases the most: about 80% of the total dose in about 12 months. It can be hypothesized that fluticasone propionate has a higher affinity for lactic acid monomer than for caprolactone monomer.

[0107] These results support that a polyester matrix containing fluticasone propionate and a polyester selected from PLA, PCL, and their copolymers enables sustained release of fluticasone propionate in an aqueous medium. These results also seem to support a greater affinity of fluticasone propionate for lactic acid monomers than for caprolactone. Therefore, a PCL matrix is preferred for the present invention.

[0108] 2-2) Results of release of fluticasone propionate from the films of Example 1-2) and 1-3): Each formulation (10% fluticasone propionate w:w; 200 μm thickness) was tested with a repetition number of 3. The release profiles are shown in Figure 5 (Figure 5). It is noteworthy that the formulations produced by extrusion seem to have a higher release kinetics than those prepared by hot pressing. Therefore, from these results, it is considered that the temperature and mechanical constraints involved in the two manufacturing processes induce different distribution mechanisms of fluticasone propionate in the polymer matrix.

[0109] 2-3) Influence of gamma sterilization on the release of fluticasone propionate from the PCL film of Example 1-3): Each formulation (10% fluticasone propionate w:w; 200 μm thickness) was tested with a repetition number of 3. The release profiles are shown in Figure 6 (Figure 6). It seems that the higher the gamma dose, the lower the release rate. This may be the result of the reticulation of PCL chains at higher gamma doses. However, this effect seems to be low. Therefore, gamma sterilization can be a suitable sterilization process.

[0110] 2-4) Influence of thickness on the release of fluticasone propionate from the PCL film of Example 1.3: Each formulation (10% w:w fluticasone propionate) was tested with a repetition number of 3. The release profiles are shown in Figure 7 (Figure 7). The results indicate that the higher the film thickness, the slower the release. Therefore, it can be considered that the mechanisms of diffusion and degradation involved in the release of the active molecule become slower with an increase in thickness.

[0111] 2-5) Influence of the FP percentage on the release of fluticasone propionate from the PCL film of Example 1.3: Each formulation (with a thickness of 300 μm) was tested with a repetition number of 3. The release profiles are shown in Figure 8 (Figure 8). The results indicate that the higher the FP percentage, the slower the release. Therefore, as described above, it can be considered that the mechanisms of diffusion and degradation involved in the release of the active molecule become slower with an increase in the percentage of FP.

[0112] (Example 3) Comparison of the release profiles of fluticasone propionate from different blends of PLA-PCL copolymers, PCL films, and PLGA tubes 3-1) Purpose of the study This study reports the cumulative release profiles of fluticasone propionate (FP) performed with different blends of PLA-PCL copolymers containing 10% FP, PCL films, and PLGA tubes containing 6% FP.

[0113] 3-2) Materials and methods Materials Ten formulations containing 10% FP (w:w) were produced using the polymers listed in Table 2 below (Table 2). Their average molecular weights are of the same order (approximately 100 kg / mol per number). Except for PCL (Resomer C 217), which is a linear homopolymer, the polymers are linear statistical copolymers, and the monomer distribution is random within each polymer.

[0114]

Table 2

[0115] PLGA tubes containing 6% FP were cut with scissors and accurately weighed. These tubes could not be sterilized.

[0116] HPLC is performed on a Shimadzu model. The SPD-M20A IVDD photodiode array measures the absorbance of the eluted compounds on a Kinetex® 2.6 μm C18 100 Å LC column 100×4.6 mm. Release media samples are analyzed according to the parameters of the "DEV-REC-protocol for fluticasone propionate dosage by HPLC".

[0117] FP (CAS number: 80474-14-2) is obtained from Sterling, batch n° FT-007 / 21, phosphate buffered saline (PBS) is from Sigma-Aldrich, in tablet form (P4417-100TAB), batch numbers SLCF6818 and SLCH0989, and sodium dodecyl sulfate (SDS) is from Sigma-Aldrich (436143-100G), batch n° number MKCJ9719.

[0118] HPLC grade acetonitrile, industrial grade ethanol and purified water are used in this protocol. The solvents (acetonitrile and water) used as the mobile phase contain 0.1% trifluoroacetic acid.

[0119] A 20 ml volume glass vial is used to incubate the test article in the release media.

[0120] A 1.5 ml volume glass vial is used for release media sample analysis. A dedicated 1 ml glass graduated pipette is used to transfer the release media sample from the incubation vial to the analysis vial. A dedicated 10 ml glass graduated pipette is used to transfer fresh release media to the incubation vial. This pipette never comes into contact with the solution containing FP.

[0121] Use the Drummond Pipet-Aid XP as a pipettor for all sample collections (1 and 10 ml pipettes).

[0122] Incubate the released samples in a heating shaker (Unimax 1010 and Incubator 1000 models manufactured by Heidolph).

[0123] Method Preparation of released samples In the following studies, all conditions are performed with a repetition number of 3 for the samples shown in Table 3 below.

[0124]

Table 3

[0125] A film with an average thickness of 330 μm is prepared by the hot pressing method as disclosed in Example 1. The film is sterilized by gamma irradiation at 25 kGy by Ionisos, laser cut into 24 mm × 1.5 mm sticks, and then accurately weighed.

[0126] Eight blend formulations, two "controls" (CopoEvo70 alone and PCL alone), and PLGA formulations were tested in two different release media: PBS supplemented with 0.1% SDS, pH 7.4 and PBS supplemented with 0.5% SDS, pH 7.4.

[0127] Blanks with a repetition number of 3 were used for each release medium (0.1% SDS and 0.5% SDS).

[0128] Release study parameters

[0129]

Table 4

[0130] 3-3) Results 0.1% SDS release medium The results in Figure 9 and the following Table 5 show that after the initial burst, the release of FP is low and, in the case of the PLGA polymer, is up to 3.3% released after 90 days.

[0131] Formulations of the pure PLA-PCL copolymer "CopoEvo70" show significantly slower release than PCL and the copolymer / PCL blends.

[0132] The copolymer / PCL blends and PCL alone show fairly similar release profiles and their standard deviations are large.

[0133] In the last 40 days (50 - 90 days), the 25% copolymer / 75% PCL blends with Copo70 and CopoEvo70 tend to release more FP than PCL in 0.1% SDS, but the standard deviations still overlap.

[0134] Under the 0.1% SDS condition, the addition of the PLA-PCL copolymer at both study ratios has little or no effect on the release profiles of the samples formulated with 10% FP. 0.5% SDS, which is considered an accelerated condition, shows a clearer difference and this is shown in the following section.

[0135]

Table 5

[0136] 0.5% SDS release medium The 0.5% SDS results shown in Figure 10 show a release profile with little overlap with 0.1% SDS (Figure 9). This tends to indicate that the 0.5% SDS condition is clearer in terms of the release of the formulations evaluated in this study.

[0137] As expected, all formulations release a larger proportion of FP faster in 0.5% SDS than in 0.1% SDS. This is due to the surfactant property of SDS that increases the solubility of FP in water.

[0138] The difference in the ratio of SDS in the release medium has a low impact on the PLGA formulation, and it was observed that the cumulative FP percentage released on day 50 was less than 4% and less than 5% after 90 days (see the rounded results in Table 3 and 4), which supports the inappropriateness of the PLGA polymer for the ARIS specification.

[0139] Under this condition, formulations containing the pure PLA-PCL copolymer "CopoEvo70" (0.5%-CopoEvo70") also show a significantly slower release profile compared to other formulations. It can be observed that the difference in the ratio of SDS in the release medium has a low impact on this formulation for the first two months: on day 50, 10% of the total FP was released in 0.1% SDS and 13% of the total FP was released in 0.5% SDS. However, the gap between the two SDS conditions becomes more apparent after two months: on day 91, 16% of the total FP was released in 0.1% SDS and on day 91, 24% of the total FP was released in 0.5% SDS (data are shown in Table 3 and 4). Comparing this formulation with the PCL / PLA-PCL blend and PCL, formulating FP with the CopoEvo70 polymer is shown to significantly reduce the release profile of FP.

[0140] Blends containing more copolymer (50-50 blend) show a slower release profile than PCL and the 25-75 blend. It shows that decreasing the proportion of PCL reduces the release profile of FP in PBS, pH 7.4 + 0.5% SDS.

[0141] After 50 days, the release profiles of the 25-75 blends of Copo95 and Copo70 are different. The release of FP from the Copo95 blend is reduced compared to all others.

[0142] The FP release from the pure CopoEvo70 formulation seems to be catching up with the cumulative % of the released FP from the 50-50 blend. Its release profile is observed to be more linear and not showing as large a burst as PCL and all other formulations containing PCL (where the burst corresponds to the large amount of FP released in the first 14 days).

[0143] Visual aspects of the test articles On day 7, all PLGA samples had swollen greatly and split in half. This indicates a significant water uptake, although the water uptake has not been quantified as their FP release is still under evaluation. As a result, the samples became softer but maintained their integrity. All other samples showed no visual changes.

[0144] Up to day 91, the other samples showed no visual changes and no rupture or water uptake was detected.

[0145] With the 91-day release, the following can be concluded: PLGA is not a suitable polyester for the sustained release of FP over the long term. Its FP release is not sufficient and it is difficult to fit into minimally invasive implants due to its significant water uptake.

Claims

1. A biodegradable intranasal system for sustained release of fluticasone propionate in the nasal cavity, wherein the system comprises a biodegradable polyester matrix containing fluticasone propionate as an active ingredient released into the nasal cavity, the polyester being selected from a list consisting of poly(D,L-lactic acid) (PDLLA), poly(D-lactic acid) (PDLA), poly(caprolactone) (PCL), PLA-PCL copolymers, and mixtures thereof.

2. The biodegradable intranasal system according to claim 1, wherein the polyester is selected from the list consisting of poly(caprolactone) (PCL), poly(D,L-lactic acid) (PDLLA) containing at least 50% L-lactic acid, PLA-PCL copolymer, and mixtures thereof.

3. The biodegradable intranasal system according to claim 1, wherein the polyester is poly(caprolactone)(PCL) or a mixture of poly(caprolactone)(PCL) and PLA-PCL copolymer, preferably poly(caprolactone)(PCL) or a mixture of poly(caprolactone)(PCL) and PLA-PCL copolymer.

4. The biodegradable intranasal system according to claim 1, wherein the polyester is poly(caprolactone) (PCL).

5. The biodegradable intranasal system according to claim 1, wherein poly(caprolactone) (PCL) has a molar mass between 25,000 g / mol and 250,000 g / mol.

6. The biodegradable intranasal system according to claim 1, wherein the content of fluticasone propionate is at most 20% by mass, preferably at most 15% by mass, preferably at most 10%, preferably between 0.1% and 10% by mass, and more preferably between 1% and 10% by mass, based on the total mass of the system.

7. The biodegradable intranasal system according to claim 1, comprising a biodegradable polyester matrix containing fluticasone propionate as an active ingredient released into the nasal cavity.

8. A biodegradable intranasal system according to claim 1, which does not include a coating.

9. The biodegradable intranasal system according to claim 1, wherein at least 15% by mass, preferably at least 25% by mass, and more preferably at least 40% by mass of fluticasone propionate initially present in the system is released 180 days after the introduction of the system into an aqueous or wetted medium.

10. The biodegradable intranasal system according to claim 1, which releases fluticasone propionate into the nasal cavity for at least 120 days, preferably at least 180 days.

11. The biodegradable intranasal system according to claim 1, which releases fluticasone propionate into the nasal cavity for at least 240 days, preferably at least 360 days.

12. A kit comprising at least the system according to any one of claims 1 to 11, and means for inserting the system into the nasal cavity.

13. Fluticasone propionate for use in treating chronic allergic or non-allergic rhinitis, in a form suitable for intranasal administration by a biodegradable intranasal system according to any one of claims 1 to 11.

14. Fluticasone propionate for use in treating chronic sinusitis, in a form suitable for intranasal administration by a biodegradable intranasal system according to any one of claims 1 to 11.

15. A method for preparing a biodegradable intranasal system according to any one of claims 1 to 11, comprising the step of forming the system by a process selected from extrusion, solvent evaporation (using, for example, dichloromethane), hot pressing, hot injection, freeze-drying, electrospinning, molding or 3D printing.

16. The method according to claim 15, comprising a preliminary step of mixing polyester and fluticasone propionate together before processing.

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