Novel system for non-invasive drug delivery

Abstract

The present invention relates to a novel drug delivery system using a monoparticulate solid carrier, in particular a co-processed excipient for the non-invasive administration of active pharmaceutical ingredients (APIs). The monoparticulate co-processed excipient comprises lactose and cellulose, or a derivative of cellulose (in particular Hydroxypropylmethylcellulose, HPMC), or comprises a polyol and cellulose, or a derivative of cellulose (in particular, HPMC). The invention relates in particular to the non-invasive administration of APIs using the coprocessed excipient as carrier into body cavities, in particular body cavities comprising a mucosal lining. More specifically, the invention relates to the administration of APIs by insufflation of the co-processed excipient carrying an API into such body cavities. The novel drug delivery system of the present invention relates in particular to the nasal administration of APIs.

Description

[0001] NOVEL SYSTEM FOR NON-INVASIVE DRUG DELIVERY

[0002] TECHNICAL FIELD

[0003] The present invention relates to a novel drug delivery system using a monoparticulate solid carrier, in particular a co-processed excipient for the non-invasive administration of active pharmaceutical ingredients (APIs). The monoparticulate co-processed excipient comprises lactose and cellulose, or a derivative of cellulose (in particular Hydroxypropylmethylcellulose, HPMC), or comprises a polyol and cellulose, or a derivative of cellulose (in particular, HPMC). The invention relates in particular to the non-invasive administration of APIs using the coprocessed excipient as carrier into body cavities, in particular body cavities comprising a mucosal lining. More specifically, the invention relates to the administration of APIs by insufflation of the co-processed excipient carrying an API into such body cavities. The novel drug delivery system of the present invention relates in particular to the nasal administration of APIs.

[0004] BACKGROUND ART

[0005] Modes for drug delivery encompass injectable administration routes and non-invasive administration. Non-invasive delivery systems generally refer to painless administration of drugs involving delivery across the biological barriers of the mucosal surfaces or the skin. Obviously, they offer advantages over injection so that non-invasive drug administration options are of special interest for the pharmaceutical industry. This applies in particular when considering that next to biologies, the class of small molecule drug candidates has rapidly proliferated but drug administration options currently often remain limited to injection. Further, conventional carriers used for non-invasive administration have been considered to result in a limited effectiveness of the treatment. In view of this, and since the majority of new chemical entities are highly potent and thus appropriate for low dose applications, there is a clear need for novel non-invasive drug delivery options.

[0006] Non-invasive drug delivery systems are categorized by the route of administration including, e.g., oral, nasal, pulmonary, ophthalmic, rectal, or transdermal delivery systems.

[0007] Nasal administration is a well-established route in drug delivery, typically using liquid formulation components together with an appropriate nasal device as platform. However, it may also demonstrate shortcomings, such as inaccurate dosage, non-uniform penetration into the nasal airspace, or stability challenges during storage. More specifically, the widespread use of liquid-based nasal sprays has been associated with limitations in the accessibility of targeted areas of absorption and tissue tolerability. Acoustic wave nebulization and other biological materials can compensate for these shortcomings. The use of polymers as mucosal vaccine carrier systems is developing rapidly because they provide the advantage of delivering antigens to specific target sites. Hence, polymers are usually studied for vaccine delivery through the nasal or oral cavity (Cho et al., 2021 , Tissue Eng. Regen. Med., Vol. 18:693-712). Polylactic-co-glycolic acid (PLGA) and polylactic acid (PLA) are considered to be the safest, most biodegradable, and most biocompatible polyester polymers currently available (Hadinoto et al., 2013, Eur. J. Pharm. Biopharm., Vol. 85:427- 443).

[0008] Research on new drug delivery systems such as nanoparticles and nanofibers for the delivery and controlled release of molecules is also in progress. Especially in the optimization of treatment delivery, nanoparticles are being studied as a hotspot in order to overcome the problems of biological barriers. Lipid-based nanoparticles are the most common nano-drug carriers approved by the FDA (Anselmo et al., 2019, Bioeng. Transl. Med., Vol. 4:e10143). Despite extensive research in this field, nanoparticle-based products for intranasal delivery are not yet available.

[0009] The present invention addresses the need for novel non-invasive drug delivery options, in particular novel drug delivery systems via nasal administration.

[0010] SUMMARY OF THE INVENTION

[0011] The inventors of the present application have developed a novel drug delivery for the non- invasive administration of pharmaceuticals. In particular, the present invention relates to a novel drug delivery system using a monoparticulate solid carrier, in particular a co-processed excipient, for the non-invasive administration of active pharmaceutical ingredients (APIs). The monoparticulate, co-processed excipient comprises lactose and cellulose or a derivative of cellulose, or comprises a polyol and cellulose or a derivative of cellulose. The invention relates in particular to the non-invasive administration of APIs using the co-processed excipient as carrier to body cavities, in particular body cavities comprising a mucosal lining. More specifically, the invention relates to the administration of APIs by insufflation of the coprocessed excipient carrying an API into such body cavities. The novel drug delivery system of the present invention relates in particular to the nasal administration of APIs.

[0012] The present inventors have surprisingly found that the excipient used in the present invention provides for beneficial effects in terms of drug targeting and accessibility of targeted areas of absorption. The advantageous effects associated with the non-invasive drug delivery system provided by the present invention are considered to be beneficial for the effectiveness of the treatment with the respective active pharmaceutical ingredient carried by the excipient. More specifically, the novel delivery system provided by the present invention is considered to provide for beneficial effects in terms of the in vivo bioavailability of the drugs. A faster onset of action is considered due to beneficial or enhanced penetration through the (nasal) mucosa.

[0013] In particular, the present invention is based, at least in part, on the surprising finding that insufflation of the excipient into a body cavity, in particular into the nasal cavity, allows an active pharmaceutical ingredient to penetrate the (nasal) mucosa at a rate, which is considered to be exceptional for non-invasive (nasal) administration of APIs. The excipient used in the present invention comprises co-processed lactose and cellulose or lactose and a derivative of cellulose (such as HPMC), or comprises co-processed polyol and cellulose or a polyol and a derivative of cellulose (such as HPMC).

[0014] The present invention is exemplified by a powder-based nasal application of the novel drug delivery system disclosed herein. In the novel approach of drug delivery disclosed herein, solid co-processed excipients are used for the first time in such an application. The co-processed excipients RetaLac® and RetaM® show the performance to overcome deficiencies of the use of the single components, HPMC, lactose, and mannitol. For instance, both RetaLac® and RetaM® have been shown by the present inventors to drastically speed up the wettability of HPMC. In a nasal application, co-processed excipients RetaLac® and RetaM® have been shown to exhibit positive effects as regards mucociliary clearance, which is one of the main factors affecting (nasal) delivery of drugs and vaccines. In particular, RetaLac® and RetaM® have led to the immediate formation of a barrier layer (due to swelling / erosion), which is considered to promptly reduce the strong activity of mucociliary clearance.

[0015] The combination of lactose and cellulose or a derivative of cellulose (in particular HPMC) creates a favorable environment for a molecule or an active (pharmaceutical) ingredient or an active substance, thereby facilitating or promoting its adhesion, solubility and permeability.

[0016] Likewise, the combination of a polyol, in particular mannitol, and cellulose or a derivative of cellulose (in particular HPMC) creates a favorable environment for a molecule or an active (pharmaceutical) ingredient or an active substance, thereby facilitating or promoting its adhesion, solubility and permeability.

[0017] The drug targeting, in particular (nasal) mucosal drug uptake, is verified by the penetration and permeation studies disclosed herein. The experimental data are considered to establish a proof-of-concept based on two active ingredients of discriminative nature, Budesonide (BUD) and Rhodamine B.

[0018] The present invention is defined by the appended claims. Aspects and embodiments of the invention include, but are not limited to: 1 . Use of a monoparticulate carrier in the preparation of a composition for insufflation of one or more active pharmaceutical ingredients into a body cavity, preferably a moist body cavity, in particular the nasal cavity, wherein the monoparticulate carrier comprises a combination, in particular a co-processed combination, of:

[0019] (a) lactose and cellulose, or lactose and a derivative of cellulose; or

[0020] (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0021] 2. The use of item 1 , wherein the monoparticulate carrier is a monoparticulate solid carrier.

[0022] 3. The use of item 1 or 2, wherein the polyol is any one of xylitol, mannitol, or sorbitol, preferably mannitol.

[0023] 4. The use of any one of items 1 to 3, wherein the monoparticulate carrier provides for an increase of the viscosity in the vicinity of the active pharmaceutical ingredient.

[0024] 5. The use of any one of items 1 to 4, wherein the body cavity is lined with a mucous membrane.

[0025] 6. The use of any one of items 1 to 5, wherein the active pharmaceutical ingredient is an active pharmaceutical ingredient to be insufflated into a body cavity, in particular the nasal cavity.

[0026] 7. The use of any one of items 1 to 6, wherein the composition, which preferably is a composition for therapeutic treatment, is (i) in powder form, in particular in dry powder form, or (ii) a liposomal-based composition, or (iii) a paste-like composition.

[0027] 8. A delivery system for insufflation of an active pharmaceutical ingredient into a body cavity, preferably a moist body cavity, in particular the nasal cavity, comprising an active pharmaceutical ingredient dispersed in, or encapsulated by, a monoparticulate carrier, wherein the monoparticulate carrier comprises a combination, in particular a co-processed combination, of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0028] 9. The delivery system for insufflation of one or more active pharmaceutical ingredients into a body cavity of item 8, comprising a formulation, in particular a blend, of the active pharmaceutical ingredient and the monoparticulate carrier.

[0029] 10. The delivery system for insufflation of one or more active pharmaceutical ingredients into a body cavity of item 9, wherein the formulation is a powder formulation, and wherein the blend is a powder blend. The powder (formulation or blend) may be a wettable powder that forms a suspension when mixed with a liquid, preferably a buffer or water, prior to insufflation. 11. The delivery system for insufflation of one or more active pharmaceutical ingredients into a body cavity of item 9 or 10, wherein the monoparticulate carrier is a monoparticulate solid carrier.

[0030] 12. The delivery system for insufflation of one or more active pharmaceutical ingredients into a body cavity of any one of items 8 to 11 , wherein the polyol is any one of xylitol, mannitol, or sorbitol, preferably mannitol.

[0031] 13. The delivery system of any one of items 9 to 12, wherein the monoparticulate carrier (comprising the active pharmaceutical ingredient) is in powder form. The powder may be a wettable powder that forms a suspension when mixed with water prior to insufflation.

[0032] 14. A pharmaceutical composition comprising an active pharmaceutical ingredient dispersed in, or encapsulated by, a monoparticulate carrier, wherein the monoparticulate carrier comprises a combination, in particular a co-processed combination, of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose. Preferably, the monoparticulate carrier is a monoparticulate solid carrier.

[0033] 15. The pharmaceutical composition of item 14, which is for (use in) insufflation of the active pharmaceutical ingredient into a body cavity, preferably a moist body cavity, in particular the nasal cavity.

[0034] 16. The pharmaceutical composition of item 14 or 15, which is in powder form. The powder may be a wettable powder that forms a suspension when mixed with water prior to insufflation.

[0035] 17. The pharmaceutical composition of any one of items 14 to 16, which is for use in therapy.

[0036] 18. Use of a monoparticulate carrier, or a composition or formulation comprising a monoparticulate carrier, wherein the monoparticulate carrier comprises a combination, in particular a co-processed combination, of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose, in technical applications, in particular technical applications comprising insufflation of the monoparticulate carrier into a body cavity, in particular a moist body cavity, preferably into the nasal cavity.

[0037] 19. The pharmaceutical composition of any one of items 14 to 17, or the use of item 18, wherein the pharmaceutical composition or the (composition comprising the) monoparticulate carrier, respectively, is in powder form. The powder may be a wettable powder that forms a suspension when mixed with water prior to insufflation.

[0038] 20. The pharmaceutical composition of any one of items 14 to 17 and 19, wherein the pharmaceutical composition is a blend of the active pharmaceutical ingredient and the monoparticulate solid carrier, preferably a powder blend, wherein the powder blend may be a wettable powder that forms a suspension when mixed with water prior to insufflation.

[0039] 21. The pharmaceutical composition of item 20, wherein the active pharmaceutical ingredient is dispersed in, or encapsulated by the monoparticulate (solid) carrier.

[0040] 22. The use of any one of items 1 to 7, or the delivery system of any one of items 8 to 13, or the pharmaceutical composition of any one of items 14 to 17, and 19 to 21 , or the use of item 18, wherein the monoparticulate carrier comprises: (i) equal parts of lactose and cellulose, or equal parts of lactose and a derivative of cellulose; or (ii) equal parts of a polyol and cellulose, or equal parts of a polyol and a derivative of cellulose.

[0041] 23. The use of any one of items 1 to 7 and 22, or the drug delivery system of any one of items 8 to 13 and 22, or the pharmaceutical composition of any one of items 14 to 17 and 19 to 22, or the use of item 18, wherein the derivative of cellulose is a cellulose ether, preferably a mixed alkyl-hydroxyalkyl cellulose ether (containing methoxyl and hydroxypropyl groups).

[0042] 24. The use of any one of items 1 to 7, 22 and 23, or the drug delivery system of any one of items 8 to 13, 22, and 23, or the pharmaceutical composition of any one of items 14 to 17 and 19 to 23, or the use of item 18 or 23, wherein the (cellulose or) cellulose ether is any one of hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) or a low-substituted hydroxypropyl ether of cellulose, and carboxymethylcellulose (CMC).

[0043] 25. The use of any one of items 1 to 7, 22, 23 and 24, or the drug delivery system of any one of items 8 to 13 and 22 to 24, or the pharmaceutical composition of any one of items 14 to 17 and 19 to 24, or the use of any one of items 18, 23, and 24, wherein the monoparticulate carrier comprises a binary combination of (i) lactose and cellulose, or lactose and a derivative of cellulose; or (ii) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0044] BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 : shows FT-IR-spectra of Reta M® fraction 63 - 100 pm_before (top) and after (bottom) application into a DLISA using a capsule-based device (RS01 from Plastiape®). Both spectra are identical, indicating transportation of Reta M® through the air.

[0046] Figure 2: shows Figure 2: FT-IR-spectra of Reta M® fraction 100 - 150 pm before (top) and after (bottom) application into a DLISA using a capsule-based device (RS01 from Plastiape®). Both spectra are identical, indicating transportation of Reta M® through the air. Figure 3: shows FT-IR-spectra of RetaLac® fraction 63 - 100 m before (top) and after (bottom) application into a DLISA using a capsule-based device (RS01 from Plastiape®). Both spectra are identical, indicating transportation of RetaLac® through the air.

[0047] Figure 4: shows FT-IR-spectra of RetaLac® fraction 100 - 150 pm before (above, purple line) and after (below, grey line) application into a DUSA using a capsule-based device (RS01 from Plastiape®). Both spectra are identical, indicating transportation of RetaLac® through the air.

[0048] Figure 5: shows a HPLC run of a Budesonide-RetaLac® blend (RetaLac® fraction 63-100 pm). The two stereo-isomers of Budesonide are detected at about 15min retention time at a wavelength of 240nm. HPLC UltiMate® 3000 from Thermo Fischer, equipped with Chromeleon® Software 7.2.10, Hypersil CDS C18 column, TF and an UV Variable Wavelenth Detector VWD-3400RS, TF.

[0049] Figure 6: shows a HPLC run of a Budesonide-Reta M® blend (Reta M® fraction 63 - 100 pm). The two stereo-isomers of Budesonide are detected at about 15min retention time at a wavelength of 240nm. HPLC UltiMate® 3000 from Thermo Fischer, equipped with Chromeleon® Software 7.2.10, Hypersil CDS C18 column, TF and an UV Variable Wavelenth Detector VWD-3400RS, TF.

[0050] Figure 7: shows in vitro permeation results of Rhodamine B in blends together with nasal delivery carriers RetaLac® and RetaM® at different particle size fractions. Particle size fractions are as follows: Fractions 63-100 pm: RetaLac® 63 and RetaM® 63, fractions 100-150 pm: RetaLac® 100 and RetaM® 100. All four applied carriers support a significant permeation of Rhodamine B as exemplary active ingredient.

[0051] Figure 8: shows in vitro penetration results of Rhodamine B in blends together with nasal delivery carriers RetaLac® and RetaM® at different particle size fractions. Particle size fractions are as follows: Fractions 63-100 pm: RetaLac® 63 and RetaM® 63, fractions 100-150 pm: RetaLac® 100 and RetaM® 100. All four applied carriers showed a significant intracellular penetration of Rhodamine B as exemplary active ingredient.

[0052] DEFINITIONS

[0053] As used herein, the use of the terms “a” or “an” connotes “one or more” or “at least one”, and the subsequent use of the definite articles “the” or “said” in an embodiment or a claim referring back to the same term does not change the general plural rule, but invokes that non-singular meaning, unless otherwise specified.

[0054] As used herein, the terms “active ingredient” and “active pharmaceutical ingredient” (“API”) refer to any ingredient that provides a biologically active effect or other direct effect in the diagnosis, cure, mitigation, therapy (including treatment and prevention) of a disease or (medical) condition, or that affects the structure or any function of the body of humans or animals.

[0055] As described herein, the term “active substance” may be used for natural products. A natural product is a compound or substance produced by a living organism, i.e., a compound or substance found in nature.

[0056] As described herein, a carrier or solid carrier, in particular a monoparticulate solid carrier, of the present invention is an excipient, in particular a co-processed excipient, more specifically, a co-processed excipient suitable for use in delivery systems for non-invasive administration of molecules or active ingredients or active substances. As will be appreciated by a person of ordinary skill in the art, the combination of excipients of the present invention is typically considered as a “co-processed excipient”. The terms “co-processed excipient” or “pharmaceutical excipient” or “co-processed pharmaceutical excipient” may be used interchangeably herein.

[0057] As described herein, and as appreciated by a person skilled in the art, a pharmaceutical excipient is basically everything other than the active pharmaceutical ingredient.

[0058] As described herein, the terms “pharmaceutical composition” and “composition for therapeutic treatment” may be used interchangeably herein.

[0059] The terms “mucosal lining” and “mucous membrane” may be used interchangeably herein.

[0060] DETAILED DESCRIPTION OF THE INVENTION

[0061] The present invention provides, in general, a co-processed combination of:

[0062] (a) lactose and cellulose, or lactose and a derivative of cellulose; or

[0063] (b) a polyol and cellulose, or a polyol and a derivative of cellulose, for use in non-invasive delivery, in particular nasal delivery, of a molecule or an active ingredient or an active substance.

[0064] Accordingly, the present invention provides a method of non-invasive delivery, in particular nasal delivery, of a molecule or an active ingredient or an active substance, comprising the use of a co-processed combination of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0065] In the present invention, the said co-processed combination acts as a carrier for the molecule or the active ingredient or the active substance. The co-processed combination of (a) lactose and cellulose, or lactose and a derivative of cellulose, or (b) a polyol and cellulose, or a polyol and a derivative of cellulose, may be considered as a carrier comprising (a) lactose and cellulose, or lactose and a derivative of cellulose, or (b) a polyol and cellulose, or a polyol and a derivative of cellulose. As described elsewhere herein, the carrier is typically a solid carrier, more specifically a monoparticulate solid carrier. Accordingly, a monoparticulate solid carrier used in the present invention comprises a (a) lactose and cellulose, or lactose and a derivative of cellulose, or (b) a polyol and cellulose, or a polyol and a derivative of cellulose. As described elsewhere herein, the monoparticulate solid carrier comprises the combination of (a) lactose and cellulose, or lactose and a derivative of cellulose, or (b) a polyol and cellulose, or a polyol and a derivative of cellulose, in co-processed form.

[0066] It has surprisingly been found that the co-processed pharmaceutical excipients of the present invention can be transported via air (Example 1 , Figures 1 to 4). Further, it has surprisingly been found that the co-processed pharmaceutical excipients of the present invention have the ability to transport active ingredients, in particular micronized APIs (Example 2, Figures 5 and 6). Thus, the present invention demonstrates, for the first time, that the co-processed pharmaceutical excipients of the present invention exhibit the important property of a solid excipient to be able to adhere and transport such fine API particles.

[0067] It has surprisingly been found in the present invention that the co-processed pharmaceutical excipients of the present invention provide for advantageous properties with regard to active pharmaceutical ingredients to penetrate the (nasal) mucosa at a rate, which is considered to be exceptional for non-invasive (nasal) administration of APIs, in particular administration into a body cavity, more specifically into the nasal cavity, as demonstrated in an in vitro nasal mucosa model (Example 3, Figures 7 and 8). The present invention demonstrates, for the first time, that the co-processed pharmaceutical excipients of the present invention are particularly suitable for the transportation of micronized APIs, in particular by insufflation, for the application into body cavities, in particular the nasal cavity.

[0068] In the present invention, the active ingredient is in particular an active pharmaceutical ingredient. An active ingredient or active pharmaceutical ingredient (API) may be considered as a compound or substance that is not found in nature, or that is a compound or substance present in isolated form not found in nature. In various embodiments of the present invention, an active ingredient or active pharmaceutical ingredient (API) is a synthetically or semi- synthetically produced compound or substance.

[0069] In the present invention, the said co-processed combination can act as a carrier for a natural product or a nutritional product. Accordingly, the present invention encompasses a delivery system for insufflation of a natural product into a body cavity, in analogy to the delivery system for insufflation of an active pharmaceutical ingredient into a body cavity described elsewhere herein. Accordingly, all aspects and embodiments described herein in relation to the insufflation of an active ingredient or API equally apply to the insufflation of a natural product. As described herein, a preferred natural product may be cannabinoids or a cannabis product. As further described herein, the term nutritional product encompasses all products, which either supplement the nutrition or provide part (or all) of the daily nutritional requirements.

[0070] In various embodiments of the present invention, a natural product may be considered as an active ingredient or API as described herein. For example, cannabinoids including cannabis are known and described as active ingredient or API in the treatment of several diseases and disorders, such as, without being limited thereto, cachexia, anorexia, cancer cachexia, cancer anorexia, cancer, severe pain, severe cancer pain, muscle spasms, severe nausea, post- traumatic stress disorder. Accordingly, in various embodiments of the present invention, cannabinoids or cannabis products may be considered as an active ingredient or API as described herein.

[0071] In the present invention, the carrier, in particular the monoparticulate (solid) carrier, is used (as an agent) for insufflation of a molecule or an active ingredient or an active substance into a body cavity, in accordance with the present invention. In accordance with the present disclosure, a non-invasive delivery, in particular a nasal delivery, of the present invention is a non-invasive delivery by insufflation, in particular a nasal delivery by insufflation. More specifically, a non-invasive delivery by insufflation according to the present invention is a non- invasive delivery by insufflation into a body cavity as described elsewhere herein. Accordingly, a nasal delivery by insufflation in the sense of the present invention is a nasal delivery by insufflation into the nasal cavity.

[0072] In accordance with the present disclosure, described herein is that an excipient, in particular a co-processed (pharmaceutical) excipient, as disclosed herein is used (as an agent) for insufflation of a molecule or an active ingredient or an active substance into a body cavity in accordance with the present invention.

[0073] The present invention provides the use of an agent for insufflation of a molecule or an active ingredient or an active substance into a body cavity, preferably a moist body cavity, in particular the nasal cavity, in the preparation of a (pharmaceutical) composition, wherein the agent comprises a combination, in particular a co-processed combination, of (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0074] Further, or alternatively, the present invention provides the use of a carrier, in particular a monoparticulate (solid) carrier, for insufflation of a molecule or an active ingredient or an active substance into a body cavity, preferably a moist body cavity, in particular the nasal cavity, in the preparation of a (pharmaceutical) composition, wherein the carrier, in particular the monoparticulate (solid) carrier, comprises a combination, in particular a co-processed combination, of (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose. As described elsewhere herein, the carrier, in particular the monoparticulate (solid) carrier, may be considered as a (pharmaceutical) excipient. Accordingly, a (pharmaceutical) excipient comprising a combination, in particular a co-processed combination, of (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose, is a co-processed (pharmaceutical) excipient, in particular a co-processed (pharmaceutical) excipient of, or comprising, (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0075] The present invention provides the use of a monoparticulate carrier in the preparation of a composition for insufflation of one or more active pharmaceutical ingredients into a body cavity, preferably a moist body cavity, in particular the nasal cavity, wherein the monoparticulate carrier comprises a combination, in particular a co-processed combination, of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose. The composition is preferably a composition for therapy. The composition may be considered as a pharmaceutical composition. As described elsewhere herein, the monoparticulate carrier can be used as an agent for insufflation of one or more active pharmaceutical ingredients into a body cavity, preferably a moist body cavity, in particular the nasal cavity. As such, the present invention provides the use of a monoparticulate carrier of the invention as an agent for insufflation of one or more active pharmaceutical ingredients into a body cavity, preferably a moist body cavity, in particular the nasal cavity, in the preparation of a composition for therapeutic treatment, or a composition for therapy.

[0076] While non-invasive delivery by insufflation, in particular nasal delivery by insufflation, is the preferred embodiment of the delivery system provided by the present invention, also disclosed herein, and encompassed by the present invention, is the use of the agent or carrier / excipient disclosed herein for non-invasive administration targeting body sites other than a body cavity. In particular, the delivery system of the present invention can be used for the non-invasive administration to the skin or any other surface of the body, which is not a body cavity.

[0077] Thus, the present invention provides a co-processed combination of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose, for use in non-invasive delivery of a molecule or an active ingredient or an active substance to the skin or any other surface of the body, which is not a body cavity. Accordingly, the present invention provides a method of non-invasive delivery of a molecule or an active ingredient or an active substance, to the skin or any other surface of the body, which is not a body cavity, comprising the use of a co-processed combination of: (a) lactose and cellulose, or lactose and a derivative of cellulose; or (b) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0078] Further disclosed herein, and encompassed by the present invention, is the use of the agent or carrier / excipient disclosed herein for (non-invasive) topical administration. Accordingly, the delivery system of the present invention can be used for the (non-invasive) topical administration of molecules or active ingredients or active substances disclosed herein. The present invention encompasses, as a separate part, all aspects and embodiments as disclosed herein, except that the non-invasive administration is specifically directed to a topical administration. This includes topical administration to the skin.

[0079] As a particular embodiment of topical administration, disclosed herein, and encompassed by the present invention, is the use of the agent or carrier / excipient disclosed herein for (non- invasive) transdermal administration. Accordingly, the delivery system of the present invention can be used for the (non-invasive) transdermal administration of molecules or active ingredients or active substances disclosed herein. The present invention encompasses, as a separate part, all aspects and embodiments as disclosed herein, except that the non-invasive administration is specifically directed to a transdermal administration.

[0080] In various embodiments of the present invention, a body cavity is a moist body cavity. In particularly preferred embodiments, the (moist) body cavity has a mucosal lining (is lined with a mucous membrane). The mucous membrane is a moist tissue layer that lines many body cavities and organs.

[0081] Target body cavities in the present invention include in particular, but are not limited to, the oral / buccal cavity, nasal cavity, ophthalmic / eye cavity, vaginal cavity, or rectal cavity. Preferred body cavities comprising a mucosal lining are the nose, ears, and mouth. The body cavity of particularly preferred interest in the present invention is the nasal cavity. In various embodiments, body cavities according to the present invention exclude the pulmonary or lung cavity. The terms pulmonary cavity, pleural cavity, and lung cavity may be used interchangeably herein.

[0082] In the co-processed combination of a polyol and cellulose, or a polyol and a derivative of cellulose, the polyol can be any one of xylitol, mannitol, or sorbitol. Mannitol is a preferred polyol in the co-processed combination of a polyol and cellulose, or the co-processed combination of a polyol and a derivative of cellulose, respectively.

[0083] With regard to the two embodiments of a co-processed combination of: (a) lactose and cellulose, or lactose and a derivative of cellulose and (b) a polyol and cellulose, or a polyol and a derivative of cellulose, the former one, i.e., the co-processed combination of lactose and cellulose, or lactose and a derivative of cellulose, respectively, may be preferred in the present invention over the co-processed combination of a polyol and cellulose, or a polyol and a derivative of cellulose, respectively.

[0084] As shown in the examples, carriers / excipients comprising co-processed lactose and (a derivative of) cellulose have led to the immediate formation of a barrier layer, which is considered to promptly reduce the strong activity of mucociliary clearance. Accordingly, in the aspects and embodiments of the present invention, the carrier / excipient is considered to provide for an increase of the viscosity in the vicinity of the molecule(s), active (pharmaceutical) ingredient(s), or active substance(s) to be administered by non-invasive administration, in particular to be administered by non-invasive administration to a (moist) body cavity (lined with a mucous membrane).

[0085] Accordingly, in the present invention, the molecules or active (pharmaceutical) ingredients or active substances, are particularly molecules or active (pharmaceutical) ingredients or active substances for non-invasive administration, in particular for non-invasive administration to a (moist) cavity (lined with a mucous membrane), preferably for non-invasive administration to the nose or nasal cavity. In certain embodiments, such molecules or active (pharmaceutical) ingredients or active substances, may be substances that may or may not be suitable for other administration routes, in particular injection. In other embodiments, such molecules or active (pharmaceutical) ingredients or active substances, may be substances, which are ineffective orally and which are only effective if administered by injection.

[0086] In the present invention, particularly preferred molecules or active (pharmaceutical) ingredients or active substances, are those that are considered or foreseen or prescribed for non-invasive administration, in particular for nasal administration. More specifically, particularly preferred molecules or active (pharmaceutical) ingredients or active substances, are those that are considered or foreseen or prescribed for non-invasive administration, in particular for nasal administration, and that may or may not be suitable for other administration routes, in particular injection.

[0087] In various embodiments of the present invention, active (pharmaceutical) ingredients are small molecules that are considered or foreseen or prescribed for non-invasive administration, in particular for nasal administration. More specifically, in various embodiments of the present invention, active (pharmaceutical) ingredients are small molecules that are considered or foreseen or prescribed for non-invasive administration, in particular for nasal administration, and that may or may not be suitable for other administration routes, in particular injection.

[0088] Accordingly, the present invention encompasses those molecules or active (pharmaceutical) ingredients or active substances, in particular small molecules, that can be carried by an agent or carrier / excipient disclosed herein. The unique connections between the nasal cavity and the brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. Accordingly, the drug delivery system of the present invention can help maximize brain-targeted drug delivery and may allow for high pharmacological activity at lower drug dosages. Accordingly, the present invention provides a method for brain-targeted drug delivery of molecules or active (pharmaceutical) ingredients or active substances, in particular small molecules, as described herein, comprising the insufflation of an agent or carrier / excipient disclosed herein comprising a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, as described herein, to the nasal cavity.

[0089] The present invention is considered to provide a highly promising drug delivery system for the treatment of diseases or conditions of the central nervous system. As described herein, central nervous system diseases include brain tumors and neurodegenerative diseases such as stroke, Parkinson’s disease, and Alzheimer’s disease. Accordingly, the present invention encompasses molecules or active (pharmaceutical) ingredients or active substances that are used in the therapy (i.e., treatment or prevention) of diseases or (medical) conditions of the central nervous system. More specifically, the present invention provides a method for brain- targeted delivery of molecules or active (pharmaceutical) ingredients or active substances, in particular small molecules, as described herein, comprising the insufflation of an agent or carrier / excipient described herein comprising a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, as described herein, to the nasal cavity. The molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, is a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, for the treatment of a disease or condition of the central nervous system, in particular a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, for the treatment of a brain tumor or a neurodegenerative disease, including but not limited to, stroke, Parkinson’s disease, and Alzheimer’s disease.

[0090] In a further aspect, the present invention provides, in general, an agent or carrier / excipient disclosed herein comprising a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, as described herein, for use in therapy or medicine. In a further aspect, the present invention provides, in general, a (pharmaceutical) composition as disclosed elsewhere herein for use in therapy or medicine.

[0091] The novel delivery system provided by the present invention can be used to administer a wide range of molecules or active (pharmaceutical) ingredients or active substances. Examples of an active pharmaceutical ingredient include, but are not limited to: analgesics, antihistamines, decongestants, hormones (e.g., insulin, oxytocin), and vaccines. In various embodiments, the (nasal) delivery system provided by the present invention may exclude the administration of the same molecule(s) or active (pharmaceutical) ingredient(s) or active substance(s), by other invasive routes of administration, e.g., injection.

[0092] In various embodiments, the (nasal) delivery system provided by the present invention may comprise the combined administration of the same molecule(s) or active (pharmaceutical) ingredient(s) or active substance(s), by different or separate non-invasive routes of administration according to the present invention.

[0093] In various embodiments, the (nasal) delivery system provided by the present invention may comprise the combined administration of different molecules and / or active (pharmaceutical) ingredients and / or active substances, by the same or different / separate non-invasive routes of administration according to the present invention.

[0094] Non-invasive delivery according to the present invention, including but not limited to nasal administration, topical administration and transdermal administration, preferably nasal administration, can be used for the systemic administration of molecules or active (pharmaceutical) ingredients or active substances, in particular small molecules. Accordingly, the present invention provides a method for the systemic delivery of molecules or active (pharmaceutical) ingredients or active substances, in particular small molecules, as described herein, comprising the use of an agent or carrier / excipient described herein comprising such a molecule or active (pharmaceutical) ingredient or active substance, in particular a small molecule, as described herein. In various (preferred) embodiments, the method for systemic delivery disclosed herein is a method for systemic delivery by nasal administration, topical administration, or transdermal administration, preferably nasal administration.

[0095] In preferred embodiments of the present invention, the (pharmaceutical) composition to be administered by non-invasive administration according to the present invention is in powder form, in particular in dry powder form. Further, the (pharmaceutical) composition as disclosed herein may be a blend of the molecule or active (pharmaceutical) ingredient or active substance, and the agent or carrier / excipient, preferably a powder blend, wherein the powder blend may be a wettable powder that forms a suspension when mixed with water prior to insufflation. In various or preferred embodiments, the molecule or active (pharmaceutical) ingredient or active substance may be considered to be dispersed in, or encapsulated by, the agent or carrier / excipient.

[0096] In accordance with the present invention, the (pharmaceutical) composition comprises the agent or carrier / excipient, which comprises / carries the molecule or active (pharmaceutical) ingredient or active substance, as disclosed herein. More specifically, the molecule or active (pharmaceutical) ingredient or active substance may be dispersed in, or encapsulated by, the agent or carrier I excipient comprised by the (pharmaceutical) composition. The (pharmaceutical) composition disclosed herein is for (use in) non-invasive administration of the molecule or active (pharmaceutical) ingredient or active substance in accordance with the present invention.

[0097] The present invention encompasses that the molecule or active (pharmaceutical) ingredient or active substance, as disclosed herein, is co-processed together with the components of the agent or carrier / excipient. Accordingly, the present invention encompasses a pharmaceutical composition comprising a molecule or active (pharmaceutical) ingredient or active substance, as described herein, co-processed together with the components of the agent or carrier / excipient, i.e., co-processed together with (a) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or (b) mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose, as described elsewhere herein.

[0098] The powder (form), in particular the dry powder (form), may be a wettable powder (form) that can form, or forms, a suspension / solution when mixed with water prior to non-invasive administration according to the present invention.

[0099] Water activity, or Aw, is the isothermal ratio of a vapor pressure of a product, as opposed to pure water. A powder (formulation) or dry powder (formulation) according to the present invention may have a water activity (Aw) typical for the most common pharmaceutical dosage form, compressed tablets, i.e., in the range of 0.3 to 0.4. Likewise, a powder blend according to the present invention may have a water activity (Aw) typical for the most common pharmaceutical dosage form, compressed tablets, i.e., in the range of 0.3 to 0.4. Further, a (pharmaceutical) composition according to the present invention may also have a water activity (Aw) in the range of 0.3 to 0.4.

[0100] In various embodiments of the present invention, the composition to be administered by non- invasive administration according to the present invention may be a liposomal(-based) composition, or may be a gel-like composition or a paste-like composition. In accordance with the present invention, such a (liposomal-)based composition or gel-like composition or pastelike composition comprises the agent or carrier / excipient, which comprises / carries the molecule or active (pharmaceutical) ingredient or active substance, as disclosed herein. The molecule or active (pharmaceutical) ingredient or active substance may be dispersed in, or encapsulated by, the agent or carrier / excipient comprised by the (liposomal-)based composition, or may be a gel-like composition or a paste-like composition. The liposomalbased) composition, or the gel-like composition or the paste-like composition disclosed herein is for (use in) non-invasive administration of the molecule or active (pharmaceutical) ingredient or active substance in accordance with the present invention. According to one aspect of the present invention, disclosed herein is a delivery system for the non-invasive administration of a molecule or active (pharmaceutical) ingredient or active substance according to the present invention, comprising an agent or carrier / excipient as disclosed herein comprising a molecule or active (pharmaceutical) ingredient or active substance as disclosed herein. In various or preferred embodiments, the molecule or active (pharmaceutical) ingredient or active substance may be considered to be dispersed in, or encapsulated by, the agent or carrier / excipient.

[0101] Specifically disclosed herein is a delivery system for the insufflation of a molecule or active (pharmaceutical) ingredient or active substance into a body cavity, preferably a moist body cavity, in particular the nasal cavity, comprising an agent or carrier / excipient as disclosed herein comprising a molecule or active (pharmaceutical) ingredient or active substance as disclosed herein. In various or preferred embodiments, the molecule or active (pharmaceutical) ingredient or active substance may be considered to be dispersed in, or encapsulated by, the agent or carrier / excipient.

[0102] In the present invention, a delivery system of the present invention, in particular a delivery system for insufflation of a molecule or active (pharmaceutical) ingredient or active substance as disclosed herein, may comprise a formulation, in particular a blend, of the molecule or active (pharmaceutical) ingredient or active substance as disclosed herein and the agent or carrier / excipient as disclosed herein. In various embodiments, the formulation may be a powder formulation, and the blend may be a powder blend. The powder (formulation or blend) may be a wettable powder that can form, or forms, a suspension / solution when mixed with water prior to insufflation.

[0103] From a drug targeting point of view, the active ingredient or API comprised by any agent or carrier / excipient disclosed herein, or comprised by any (pharmaceutical) composition or other formulation disclosed herein, may have an aerodynamic particle size suitable for, or adjusted to, the respective non-invasive administration. For example, for nasal applications the active ingredient or API comprised by any agent or carrier / excipient disclosed herein, or comprised by any (pharmaceutical) composition or other formulation disclosed herein, may have an aerodynamic particle size suitable for, or adjusted to, nasal administration, which preferably excludes an overlap to magnitudes used for inhalation into the lungs. In various preferred embodiments of the present invention, the particle size of an active ingredient or API is about 1-10 pm. More specifically, the particle size of an active ingredient or API may be about 1-5 pm, or may be about 2-8 pm. This applies to embodiments according to the present invention, where medication for (local) nasal application may be contraindicated to inhalation therapy. In various embodiments, any (pharmaceutical) composition or other formulation disclosed herein for nasal administration is typically defined by particle dimensions between about 10 pm and about 160 m, and may be in the range of about 10-150 pm. This applies in particular to nasal administration of any (pharmaceutical) composition or other formulation disclosed herein in powder form. This 10-150 pm range of particle dimensions applies to a formulation, in particular a blend, of an agent or carrier / excipient disclosed herein and an active ingredient or API. In preferred embodiments, the particle size fraction of the agent or carrier / excipient may be in the range of about 60 to 100 pm, or may be in the range of about 100 to 150 pm.

[0104] Accordingly, in case of an active ingredient or API with a particle size of about 10 pm, the particle dimensions of a formulation, in particular a blend, of the present invention may be between about 70 pm and about 110 pm, or may be between about 110 pm and about 160 pm.

[0105] According to another aspect of the present invention, disclosed herein is the use of an agent or carrier / excipient as disclosed herein, which comprises a molecule or active (pharmaceutical) ingredient or active substance disclosed herein, in technical applications, in particular technical applications comprising a non-invasive administration or delivery of the agent or carrier / excipient according to the present invention, preferably a non-invasive administration into a body cavity, in particular a moist body cavity, preferably into the nasal cavity.

[0106] In various embodiments, the ratio of lactose to cellulose, or lactose to a derivative of cellulose, respectively, ranges from about 1 :1 to about 10:1 by weight (wt. %). Preferably, the ratio of lactose to cellulose, or lactose to a derivative of cellulose, respectively, ranges from about 75:25 to about 50:50 by weight (wt. %). In various embodiments, the ratio of lactose to cellulose, or lactose to a derivative of cellulose, respectively, ranges from about 75:25 to about 25:75 by weight (wt. %). Particularly preferred is a ratio of lactose to cellulose, or lactose to a derivative of cellulose, respectively, which ranges from about 50:50.

[0107] Likewise, in various embodiments, the ratio of polyol to cellulose, or polyol to a derivative of cellulose, respectively, rages from 1 :1 to 10:1 by weight (wt. %). Preferably, the ratio of polyol to cellulose, or polyol to a derivative of cellulose, respectively, rages from about 75:25 to about 50:50 by weight (wt. %). In particularly preferred embodiments of the present invention, the agent or carrier / excipient comprises: (i) equal parts of lactose and cellulose, or equal parts of lactose and a derivative of cellulose; or (ii) equal parts of a polyol and cellulose, or equal parts of a polyol and a derivative of cellulose. In particularly preferred embodiments, the ratio of lactose to cellulose, or lactose to a derivative of cellulose, respectively, is about 50:50 by weight (wt. %). Likewise, in particularly preferred embodiments, the ratio of the polyol, in particular mannitol, to cellulose, or the polyol, in particular mannitol, to a derivative of cellulose, respectively, is about 50:50 by weight (wt. %). As described herein, “wt. %” refers to, or preferably refers to, the dry mass (more specifically the total dry mass), in particular the (total) dry mass of the composition. In this regard, the composition preferably means the composition of the monoparticulate solid carrier or excipient of the present invention, which comprises a co-processed combination of: (a) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or (b) mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose.

[0108] As described herein, the term “dry mass” in relation to components of the carrier or excipient of the present invention typically denominates the dry mass including water content, if any, in its compendial limits for water in regard to the respective components of the composition. The water content means water that may be present as a hydrate, e.g. in crystal form, as well as in an adsorbed form on the surface of a given component. Accordingly, and as will be appreciated by a person of ordinary skill in the art, the term “dry mass” in relation to, e.g., (alpha) lactose monohydrate, typically denominates the dry mass of the lactose including the hydrate water, and may further include surface water, if any. These considerations apply likewise also to the cellulose and mannitol components of the monoparticulate solid carrier or excipient of the present invention.

[0109] The monoparticulate solid carrier or excipient of the present invention encompasses hydrated components as well as anhydrous forms of the components.

[0110] The terms “dry mass” and “dry weight”, or “dry matter” may be used interchangeably herein.

[0111] In further or other preferred embodiments of the present invention, the agent or carrier / excipient comprises a binary (co-processed) combination of (i) lactose and cellulose, or lactose and a derivative of cellulose; or (ii) a polyol and cellulose, or a polyol and a derivative of cellulose.

[0112] The present invention encompasses embodiments, wherein the agent or carrier / excipient comprises a co-processed combination of (i) lactose and one or more derivatives of cellulose; or (ii) a polyol (preferably mannitol), and one or more derivatives of cellulose. For example, the present invention encompasses embodiments, wherein the agent or carrier / excipient comprises a co-processed combination of (i) lactose and one or more of HPMC, HEC (Hydroxyethylcellulose), and / or CMC (Carboxymethylcellulose); or (ii) a polyol, preferably mannitol, and one or more of HPMC, HEC, and / or CMC. In such combinations, the ratio of lactose to one or more derivatives of cellulose, may range from about 75:25 to 50:50 by weight (wt. %). Likewise, the ratio of polyol to one or more derivatives of cellulose, may range from 75:25 to 50:50 by weight (wt. %). Preferably, in such combinations, the ratio of lactose to one or more derivatives of cellulose, is about 50:50 by weight (wt. %). Likewise, preferably the ratio of polyol (in particular mannitol) to one or more derivatives of cellulose, is about 50:50 by weight (wt. %). For example, the ratio of lactose to a first derivative of cellulose (e.g., HPMC) and a second derivative of cellulose (e.g., HEC), is about 50:25:25, or the ratio of polyol (in particular mannitol) to a first derivative of cellulose (e.g., HPMC) and a second derivative of cellulose (e.g., HEC), is about 50:25:25.

[0113] The present invention also encompasses embodiments, wherein the agent or carrier / excipient comprises a co-processed combination of (i) lactose, cellulose, and one or more derivatives of cellulose; or (ii) a polyol (preferably mannitol), cellulose, and one or more derivatives of cellulose. For example, the present invention encompasses embodiments, wherein the agent or carrier / excipient comprises a co-processed combination of (i) lactose, cellulose, and one or more of HPMC, HEC and / or CMC; or (ii) a polyol, preferably mannitol, cellulose, and one or more of HPMC, HEC, and / or CMC.

[0114] As described herein, the one or more derivatives of cellulose may be one or more derivatives of cellulose classified into the same group of cellulose derivatives. The derivatives of cellulose can be classified as either cellulose ethers or cellulose esters. Cellulose ethers are preferred in the present invention and include methylcellulose (MC), ethylcellulose (EC), HPMC and HEC. The present invention encompasses embodiments, in which the agent or carrier / excipient comprises a binary (co-processed) combination of (i) lactose and one or more derivatives of cellulose that are classified into the same group of cellulose derivatives as described above; or (ii) a polyol (in particular mannitol) and one or more derivatives of cellulose that are classified into the same group of cellulose derivatives as described above. In such embodiments, the binary aspect is reflected by the lactose or polyol on the one hand, and the group of cellulose derivatives on the other hand. In such embodiments, cellulose ethers are preferred as one of the two components of the binary (co-processed) combination described herein above.

[0115] The agent or carrier / excipient can be prepared by co-processing lactose and cellulose, or coprocessing of lactose and a derivative of cellulose, in the desired ratio. The co-processed agent or carrier / excipient can be formulated as a (dry) powder or as a gel, in particular for nasal administration. A co-processed excipient is typically produced by a manufacturing process such as high-shear dispersion, granulation, spray drying, or melt extrusion. In the present invention, spray drying is a preferred manufacturing process for the co-processed excipients of the present invention. As will be appreciated by a person of ordinary skill in the art, a coprocessed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing. In other or further preferred embodiments of the present invention, the derivative of cellulose is a cellulose ether, preferably a mixed alkyl-hydroxyalkyl cellulose ether (containing methoxyl and hydroxypropyl groups). More specifically, the (cellulose or) cellulose ether may be any one of hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) or a low-substituted hydroxypropyl ether of cellulose, and carboxymethylcellulose (CMC). HPMC K4M (e.g., METHOCEL™ K4M) is a water-soluble cellulose ether polymer that may be used in the present invention.

[0116] In preferred embodiments, the agent or carrier / excipient can comprise alpha-lactose or betalactose, in particular alpha-lactose, preferably alpha-lactose monohydrate, more specifically milled alpha-lactose monohydrate, and hypromellose (HPMC).

[0117] A preferred agent or carrier / excipient according to the present invention follows the known excipients RetaLac® or RetaM®, which are composed of equal parts of lactose and hypromellose (RetaLac®), or equal parts of mannitol and hypromellose (RetaM®). The lactose preferably is alpha-lactose, in particular alpha-lactose monohydrate, more specifically milled alpha-lactose monohydrate.

[0118] As will be appreciated by a person skilled in the art, co-processed excipients are by definition more than simple mixtures of two or more components. As commonly known in the art, a coprocessed excipient is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing, and without significant chemical change. Thus, co-processed excipients are made by combining two or more excipients or components, which interact at the sub-particle level to provide synergistic properties, which are considered superior as compared to the individual excipients or components of the co-processed excipient.

[0119] Aspects and embodiments of the present invention include:

[0120]

[0001] A delivery system for insufflation of an active pharmaceutical ingredient into the nasal cavity, comprising an active pharmaceutical ingredient dispersed in a monoparticulate solid carrier, wherein monoparticulate solid carrier comprises a co-processed combination of:

[0121] (a) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or

[0122] (b) mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose.

[0123] [2] The drug delivery system of [1], wherein the monoparticulate solid carrier comprising the active pharmaceutical ingredient is in powder form.

[0124] [3] Use of a monoparticulate solid carrier in the preparation of a composition for insufflation of an active pharmaceutical ingredient into the nasal cavity, wherein the monoparticulate solid carrier comprises a co-processed combination of:

[0125] (a) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or (b) mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose.

[0126] [4] The use of [3], wherein the composition for insufflation is in powder form.

[0127] [5] A pharmaceutical composition comprising an active pharmaceutical ingredient dispersed in a monoparticulate solid carrier, wherein the monoparticulate solid carrier comprises a coprocessed combination of:

[0128] (a) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or

[0129] (b) mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose.

[0130] [6] The pharmaceutical composition of [5], which is for use in insufflation of the active pharmaceutical ingredient into the nasal cavity.

[0131] [7] The pharmaceutical composition of [5] or [6], which is in powder form.

[0132] [8] The pharmaceutical composition of any one of [5] to [7], which is for use in therapy.

[0133] [9] The drug delivery system of [1] or [2], or the use of [3] or [4], or the or the pharmaceutical composition of any one of [5] to [7], or the pharmaceutical composition for use in therapy of [8], wherein the monoparticulate solid carrier comprises:

[0134] (i) equal parts of lactose and cellulose, preferably equal parts of lactose and hydroxypropylmethylcellulose; or

[0135] (ii) equal parts of mannitol and cellulose, preferably equal parts of mannitol and hydroxypropylmethylcellulose.

[0136]

[0010] The drug delivery system of any one of [1], [2], and [9], or the use of any one of [3], [4], and [9], or the pharmaceutical composition of any one of [5] to [7] and [8], or the pharmaceutical composition for use in therapy of [8] or [9], wherein the monoparticulate solid carrier comprises a co-processed binary combination of:

[0137] (i) lactose and cellulose, preferably lactose and hydroxypropylmethylcellulose; or

[0138]

[0011] mannitol and cellulose, preferably mannitol and hydroxypropylmethylcellulose.

[0139] EXAMPLES

[0140] The examples verify and confirm that a monoparticulate solid carrier as disclosed herein is a suitable carrier for nasal drug delivery, in particular nasal powder drug delivery. This is exemplified by studies showing that two pharmaceutical excipients according to the present invention, RetaLac® and RetaM®, can be delivered through air using a corresponding model device (RS01 from Plastiape®); Example 1. Significantly, it is shown that RetaLac® and RetaM® as exemplary pharmaceutical excipients of the present invention are also qualified to carry micronized APIs (like Budesonide), as detected by a corresponding Dosage Unit Sampling Apparatus (DUSA, Copley®); Example 2. Moreover, surprising effects of the pharmaceutical excipients according to the present invention as reflected by the two pharmaceutical excipients RetaLac® and RetaM®, are shown in an in vitro nasal mucosa model system for permeation and penetration studies, in which Budesonide and Rhodamine B have been applied as exemplary drug molecules; Example 3.

[0141] Materials and Methods

[0142] For all trials, two different particle fractions of RetaLac® and RetaM® have been applied: Fraction I (63-100pm) and fraction II (100-150pm). As example API micronized Budesonide (Lot 2110OM 10030733, Farmavios S.p.A.) was used.

[0143] Dosage unit properties were investigated via a Dosage Unit Sampling Apparatus (DUSA, Copley®) using the scheme according to USP NF <601 > (Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders - Performance Quality Tests, as of September 2024).

[0144] The scheme according to USP NF <601 > is shown in Figure 9.

[0145] The flow rate applied is 4 kPa pressure difference throughout the applied device (RS01 from Plastiape®) at an air volume of 4I (P3 / P2 < 0.5). For delivered dose evaluation CITDAS (Copley®) software is used.

[0146] Formulation Set-up:

[0147] The following set-up is kept constant during all tests: 3-5 shots per material / fraction / formulation utilizing capsules with 25 mg content (capsule filling), and in case of a drug load, 1.5% Budesonide is applied.

[0148] Analytics:

[0149] Drug identification and quantification was performed by HPLC for Budesonide, and by FT-IR- spectrophotometry for the two excipients, respectively.

Claims

1. A delivery system for insufflation of an active pharmaceutical ingredient into the nasal cavity, comprising an active pharmaceutical ingredient dispersed in a monoparticulate solid carrier, wherein the monoparticulate solid carrier comprises a co-processed combination of:(a) lactose and hydroxypropylmethylcellulose (HPMC); or(b) mannitol and hydroxypropylmethylcellulose (HPMC).

2. The drug delivery system of claim 1 , wherein the monoparticulate solid carrier comprising the active pharmaceutical ingredient is in powder form.

3. Use of a monoparticulate solid carrier in the preparation of a composition for insufflation of an active pharmaceutical ingredient into the nasal cavity, wherein the monoparticulate solid carrier comprises a co-processed combination of:(a) lactose and hydroxypropylmethylcellulose (HPMC); or(b) mannitol and hydroxypropylmethylcellulose (HPMC).

4. The use of claim 3, wherein the composition for insufflation is in powder form.

5. A pharmaceutical composition comprising an active pharmaceutical ingredient dispersed in a monoparticulate solid carrier, wherein the monoparticulate solid carrier comprises a co-processed combination of:(a) lactose and hydroxypropylmethylcellulose (HPMC); or(b) mannitol and hydroxypropylmethylcellulose (HPMC).

6. The pharmaceutical composition of claim 5, which is for use in insufflation of the active pharmaceutical ingredient into the nasal cavity.

7. The pharmaceutical composition of claim 5 or 6, which is in powder form.

8. The pharmaceutical composition of any one of claims 5 to 7, which is for use in therapy.

9. The drug delivery system of claim 1 or 2, or the use of claim 3 or 4, or the pharmaceutical composition of any one of claims 5 to 7, or the pharmaceutical composition for use in therapy of claim 8, wherein the monoparticulate solid carrier comprises:(i) equal parts of lactose and hydroxypropylmethylcellulose (HPMC); or(ii) equal parts of mannitol and hydroxypropylmethylcellulose (HPMC).

10. The drug delivery system of any one of claims 1, 2, and 9, or the use of any one of claims 3, 4, and 9, or the pharmaceutical composition of any one of claims 5 to 7 and 8, or the pharmaceutical composition for use in therapy of claim 8 or 9, wherein the monoparticulate solid carrier comprises a co-processed binary combination of:(i lactose and hydroxypropylmethylcellulose (HPMC); or(ii) mannitol and hydroxypropylmethylcellulose (HPMC).[0001]Submitted herewith are amended claims 1 to 10.[0002]The amendments remove the amendments introduced with the PCT Direct Letter dated September 23, 2025, with the exception of retaining the specification of cellulose as hydroxypropyl methylcellulose (HPMC).[0003]Accordingly, the PCT Article 19 amended claims correspond to aspects [1] to [10] disclosed on pages 22 and 23 of the application as originally filed, except for specifying the cellulose as hydroxypropyl methylcellulose (HPMC).[0004]Hence, the amendments do not go beyond the disclosure in the international application as filed and therefore meet the requirements of Article 19(2) PCT.

Images