Dry powder formulations

Abstract

The present disclosure relates to a method of forming dry powder formulations (100) for the nasal delivery of an active pharmaceutical ingredient (API), e.g. a peptide API, by agglomerating a solid formulation (10) of particles (1) comprising an API and further particles (2) comprising an excipient into agglomerated particles (3) and also dry powder dosage forms comprising the agglomerated particles (3).

Description

[0001] Dry Powder Formulations

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to powder (especially dry powder) formulations, which are preferably for the nasal delivery, of an active pharmaceutical ingredient (API). Such an API can comprise one or more peptides. The present disclosure further relates to dosage forms containingthe same.

[0004] BACKGROUND

[0005] Oral and injectable dosage forms are known for delivery of an active pharmaceutical ingredient (API). Yet the poor bioavailability and high cost entailed by such dosage forms can make patient access a challenge. Meanwhile, complicated administration requirements can make compliance poor. These issues can be especially problematic for peptide APIs. Furthermore, oral and injectable products can elicit severe side effects for at least some APIs, especially peptide APIs. In addition, the poor stability of some APIs, and peptides in particular, in solution can make them unsuitable for delivery via liquid formulations such as injectable solutions or droplets for nasal delivery or inhalation.

[0006] There is a need for alternative dosage forms that reduce or alleviate some or all of the above drawbacks to current liquid and tablet dosage forms, especially for peptide APIs.

[0007] The present inventors have realised that dry powder nasal delivery may avoid side effects associated with current injectable and tablet dosages; and may improve affordability, thereby widening the patient population able to receive the benefits that APIs, especially peptide APIs, may offer. Additionally or alternatively, such dry powder nasal dosage forms may offer an easy administration route, thereby enhancing compliance. Inhalable formulations may be an alternative way of achieving such benefits.

[0008] In order to be suitable for nasal administration, a dry powder dosage form advantageously has a relatively narrow particle size distribution, e.g. with the majority of particles being in the range of 20 to 150 pm, with a low proportion of particles, e.g. as a percentage by volume, having a diameter of less than 10 pm. Freeze drying processes produce a wide particle size distribution with a high proportion of particles of less than 10 pm in diameter. In addition, freeze drying processes typically produce a dry powder with a density that is too low for use as a dosage form for nasal delivery that typically requires a density of 0.2 to 0.6 g / cm3. Thus, lyophilised APIs are unsuitable for nasal delivery without further processing.

[0009] Micronisation of a drug substance can be used to prepare formulation for nasal delivery. While that process can be employed for some small molecule APIs, the high energy and heat applied in the process is damaging to more sensitive molecules like peptides. Spray drying can be used to more effectively control particle size distribution. However, the conversion of a lyophilised dry powder to a powder having a particle size distribution suitable for nasal delivery by a spray drying process would involve redissolving the lyophilised dry powder to form a further liquid formulation. Re-dissolving an API a second time increases the risk of degradation. Thus, the formulation of powders for nasal delivery via spray drying processes may not be ideal for API’s that are either difficult to fully solubilize or are unstable in solution.

[0010] There is a need for alternative means of producing dry powder formulations of APIs, especially peptide APIs, that are suitable for nasal administration that may be formed in good yields and with a particle size distribution appropriate for nasal delivery. There is also a need for dry powder delivery platforms which are well suited to handling and processing, such as having low static, good flowability and / or other advantageous features.

[0011] SUMMARY OF THE DISCLOSURE

[0012] The dry powder formulations accordingto the present disclosure and prepared according to the methods of the present disclosure can usefully provide a delivery platform for nasal administration. Dry powder formulations according to the present disclosure can incorporate a range of APIs, especially APIs with poor stability in aqueous environments, such as peptides, and therefore serve as a useful drug delivery vehicle for otherwise difficult to administer APIs.

[0013] The present inventors have found an efficient way of producing a dry powder that is a solid particulate powder having appropriately sized particles for nasal delivery, ideally wherein no more than 10% of the particles by volume have a diameter of less than 10 pm, from an API starting material that is in a form which is not suitable for nasal delivery, such as a lyophilized API starting material.

[0014] In addition, the powders of the present disclosure and produced by the methods of the disclosure have one or more of the following advantageous properties: the dry powder is well suited to collection (e.g. in terms of static charge, aggregation, flowability, adhesion to vessel); has a low moisture (especially, low water) content (ideally less than 5% w / w; e.g. analysed by Karl Fischer colorimetry); a good yield (ideally, the yield is more than 50%, especially more than 80%); and / or has an appropriate glass transition temperature (e.g. analysed by modulated differential scanning calorimetry, mDSC). In addition the method of the present disclosure has been found to enable mixing of excipients / APIs that would normally be incompatible together in solution (e.g. feedstocks for spray drying). Furthermore, as the method of the disclosure can be carried out at room temperature, it has been found to be effective in preparing dry powder dosage forms that are suitable for nasal delivery form from excipients / APIs that are sensitive to heat. In a first aspect, the present disclosure provides a method of forming a dry powder formulation of particles suitable for nasal delivery using moisture activated dry granulation (MADG). The dry powder formulation comprises an API, at least one binder and optionally one or more further excipients. The method comprises the steps of:

[0015] (a) fluidizing a dry composition comprisingthe API;

[0016] (b) adding water to the fluidized dry composition as a mist of droplets to form a solid formulation; and

[0017] (c) agglomerating the solid formulation using moisture activated dry granulation (MADG) to form agglomerated particles comprising the API.

[0018] The agglomerated particles formed in step (c) typically comprise the API and the at least one binder. One or more binders can advantageously be included in the dry composition priorto fluidization in step (a); added duringfluidization of the dry composition, i.e. during step (a); added separately to or simultaneously with the addition of the water in step (b); or added after the water is added in step (b), either during or prior to the agglomeration step (c). Preferably, one or more binders are included in the dry composition together with the API, i.e. prior to addition of the water. The at least one binder can, for example, be present in the solid formulation in a total amount of from 1 to 12 percent by weight based on the total weight of the solid formulation. Advantageously, the at least one binder is present in the solid formulation in a total amount of from 1 to 10 percent by weight, preferably in a total amount of from 1 to 6 percent by weight, based on the total weight of the solid formulation.

[0019] The water may be added as a constituent of an aqueous mixture. Water may, for example, be present in the solid formulation in an amount of up to 20 percent by weight based on the total weight of the solid formulation. Preferably, water is present in the solid formulation in an amount of up to 10 percent by weight based on the total weight of the solid formulation. Advantageously, water is present in the solid formulation in an amount of up to 9 percent by weight, preferably of up to 6 percent by weight, based on the total weight of the solid formulation.

[0020] Preferably, the method comprises the steps of:

[0021] (a) fluidizing a dry composition comprisingthe API;

[0022] (b) adding water to the fluidized dry composition as a mist of droplets to form a solid formulation; and

[0023] (c) agglomerating the solid formulation using moisture activated dry granulation (MADG) to form agglomerated particles comprising the API, wherein the at least one binder is present in the solid formulation in a total amount of from 1 to 6 percent by weight based on the total weight of the solid formulation, and wherein water is present in the solid formulation in an amount of up to 6 percent by weight based on the total weight of the solid formulation. The method of the first aspect of the disclosure has been found to provide access to a dry powder formulation comprising agglomerated particles of a size suitable for nasal delivery, for example, having a Dv50 in the range of 10 to 500 pm and including less than 15 % by volume, preferably less than 10% by volume of particles having a diameter of less than 10 pm.

[0024] The agglomerated particles are secondary particles formed of clusters of primary particles bound to each other. It will be appreciated that primary particles are smaller than secondary particles. The API is typically included in a primary particle. Primary particles can have a Dv50 of less than 15 pm , a Dv90 less than 40 pm and / or a Dv10 less than 5 pm.

[0025] Previously known methods of producing particles of a size suitable for nasal delivery, such as spray drying techniques, have required the constituents to be combined or redissolved as an aqueous solution or suspension. Hence, spray drying may not be particularly suited for use with water sensitive APIs, such as peptides, for use with combinations of incompatible APIs / excipients, or for use with poorly soluble APIs / excipients. While freeze dried powders have previously been bound together into granules of a size suitable for tableting, e.g. by wet granulation in which a formulation comprising at leasts percent by weight of water, typically more than 10 percent by weight, of water, is granulated to form a wet mass, it has not previously been recognised that MADG can be used to form agglomerated particles of a size suitable for nasal administration orthat by using a MADG process a low amount of binder may be employed and a small amount of water may be introduced as a fine mist.

[0026] In a second aspect, the present disclosure provides a dry powder formulation of particles suitable for nasal delivery, the dry powder formulation comprising an active pharmaceutical ingredient (API) and at least one binder. The dry powder formulation may optionally comprise one or more further excipients. The particles of the dry powder formulation include agglomerated secondary particles that include primary particles comprisingthe API, the primary particles being bound to each other with the at least one binder. The dry powder formulation optionally contains no more than 10 percent by weight, advantageously no more than 9 percent by weight, especially no more than 6 percent by weight of water, based on the total weight of the dry powder formulation. The total amount of binder(s) present in the dry powder formulation is optionally from 1 to 12 percent by weight, advantageously from 1 to 10, percent by weight, especially from 1 to 6 percent by weight, based on the total weight of the dry powder formulation.

[0027] The dry powder formulation of particles can have a Dv50 in the range of 10 to 500 pm, wherein less than 15% by volume, preferably less than 10% by volume of its particles have a diameter of less than 10 pm. Advantageously, less than 15% by volume, preferably less than 10% by volume, of the agglomerated particles that include the API have a diameter of less than 10 pm.

[0028] The dry powder formulation typically comprises one or more further excipients in addition to the binder. The agglomerated particles that include constituent primary particles that contain the API may include further additional primary particles that lack the API (i.e. an additional constituent particle that includes an excipient other than the binder) both bound together with the at least one binder. Thus, the agglomerated secondary particles, described herein, can include first primary particles that contain the API and second primary particles that lack the API, wherein the first and second primary particles are bound together with in clusters the at least one binder.

[0029] The dry powder formulation of the second aspect of the disclosure is advantageously obtained by the method of the first aspect of the disclosure. The dry powder formulation of the second aspect of the disclosure can be formed by the method of the first aspect of the disclosure.

[0030] A third aspect the present disclosure provides a nasal dosage form comprising the dry powder formulation of the second aspect of the disclosure and / or a dry powder formulation formed in the method of the first aspect of the disclosure.

[0031] The agglomerated particles formed in step (c) of the method of the first aspect of the invention may be suitable for incorporation into the final nasal dosage form, or an intermediate from which the nasal dosage form is produced in one or more subsequent steps, such as a drying step orthe step of mixingwith an additional carrier excipient.

[0032] The nasal dosage form of the third aspect of the disclosure can comprise the dry powder formulation of the second aspect of the disclosure. The nasal dosage form of the third aspect of the disclosure can, for example, comprise the dry powder formulation of the second aspect of the disclosure together with a dispensing device.

[0033] Preferably, the dry powder formulation is for the delivery of a peptide active pharmaceutical ingredient (API). Thus, the powder formulation can comprise an API that is or comprises one or more peptides.

[0034] The present disclosure can be as defined in the following numbered clauses:

[0035] 1. A method of forming a dry powder formulation of particles using moisture activated dry granulation (MADG), suitable for nasal delivery, the dry powder formulation comprising an API and one or more excipients, wherein the one or more excipients comprise or consist of at least one binder, the method comprising the steps of:

[0036] (a) fluidizing a dry composition comprisingthe API;

[0037] (b) adding waterto the fluidized dry composition as a mist of droplets to form a solid formulation; and (c) agglomerating the solid formulation using moisture activated dry granulation (MADG) to form the agglomerated particles comprising the API, wherein the one or more binders are advantageously: included in the dry composition prior to fluidization; added during fluidization of the dry composition; added separately to or simultaneously with the addition of the water; or added after the water either during or prior to the agglomeration step.

[0038] 2. The method according to clause 1 , wherein at least one binder is present in the solid formulation in a total amount of from 1 to 12 percent by weight based on the total weight of the solid formulation, preferably in a total amount of from 1 to 10 percent by weight, based on the total weight of the solid formulation.

[0039] 3. The method accordingto clause 1 or clause 2, wherein water is present in the solid formulation in an amount of up to 10 percent by weight based on the total weight of the solid formulation, preferably in an amount of up to 9 percent by weight, based on thetotal weight of the solid formulation.

[0040] 4. The method according to clause 1 , wherein at least one binder is present in the solid formulation in a total amount of from 1 to 6 percent by weight based on the total weight of the solid formulation, and wherein water is present in the solid formulation in an amount of up to 6 percent by weight based on the total weight of the solid formulation.

[0041] 5. The method of any one of clauses 1 to 4, comprising adding a mist of liquid from an ultrasonic nozzle.

[0042] 6. The method of any preceding clause, wherein the dry composition is fluidized using resonant acoustic mixing (RAM) prior to addition of the water.

[0043] 7. The method of clause 6, wherein steps (a) to (c) are carried out in an acoustic mixer.

[0044] 8. The method of any preceding clause, wherein the density of the solid formulation increases by at least 3-fold, especially at least 5-fold over steps (a) to (c).

[0045] 9. The method of any preceding clause, wherein the water is added to the solid formulation as a mist of droplets having a median volume droplet size (Dv50) of less than 100 pm.

[0046] 10. The method of any preceding clause, wherein the binder is present in the dry composition or is added to the fluidized dry composition with the water, e.g. as an aqueous solution.

[0047] 11. The method of any preceding clause, wherein the dry composition comprises particles comprising the API having a Dv50 of less than 15 pm, a Dv90 less than 40 pm and / or a Dv10 less than 5 pm. 12. The method of any preceding clause, wherein the dry composition includes one or more excipients other than the at least one binder.

[0048] 13. The method of any preceding clause, further comprising the step of sieving the agglomerated particles to reduce the proportion of particles present having a diameter of less than 10 pm.

[0049] 14. The method of any preceding clause, wherein the API is a peptide, especially a GLP-1 receptor agonist.

[0050] 15. The method of any preceding clause, wherein the binder is water-activated binder.

[0051] 16. The method of any preceding clause, wherein the binder is a polymeric binder formed from N-vinylpyrrolidone monomer, a cellulose binder or a combination of a polymeric binder formed from N-vinylpyrrolidone monomer, and a cellulose binder.

[0052] 17. The method of any preceding clause, wherein the one or more excipients includes a sugar alcohol.

[0053] 18. The method of any preceding clause, wherein the one or more excipients includes a cyclodextrin.

[0054] 19. The method of any one of clauses 1 to 16, wherein the one or more excipients includes a sugar alcohol and / or a cyclodextrin, wherein the total amount of sugar alcohol(s) and / or a cyclodextrin(s) is from 30 to 85 % w / w, such as 40 to 75 % w / w or 45 to 65 % w / w, based on the total weight of the solid formulation.

[0055] 20. The method of clause 19, wherein the Dv50 of the sugar alcohol(s) and cyclodextrin(s) present is greater than 40 pm.

[0056] 21 . The method of any preceding clause, wherein the one or more excipients includes a permeability enhancer.

[0057] 22. The method of clause 21 , wherein the permeation enhancer is selected from the group consisting of dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC), and sodium salcaprozate (SNAC), especially DPC.

[0058] 23. The method of any preceding clause, wherein the density of the dry powder formulation of particles produced is from 0.2 to 0.6 g / cm3.

[0059] 24. The method of any preceding clause, wherein the particles of the dry powder formulation have a Dv10 of above 10 pm, especially a Dv10 of above 15 pm, and / or a Dv90 of below 500 pm, especially a Dv90 of below 250 pm.

[0060] 25. The method of any preceding clause, wherein the particles of the dry powder formulation have a Dv50 in a range of 20-200 pm, especially in the range of from 25-120 pm. 26. A dry powder formulation of particles suitable for nasal delivery, the dry powder formulation comprising: an active pharmaceutical ingredient (API) and one or more excipients that comprise or consist of at least one binder, wherein the particles include agglomerated secondary particles that include constituent primary particles comprising the API bound to each other with the at least one binder; and wherein the particles optionally have a Dv50 in the range of 10 to 500 pm and less than 10% by volume of particles having a diameter of less than 10 pm.

[0061] 27. The dry powder formulation of clause 26, wherein the total amount of binder(s) present is from 1 to 6 percent by weight based on the total weight of the dry powder formulation, and no more than 6 percent by weight of water, based on the total weight of the dry powder formulation, is present in the dry powder formulation.

[0062] 28. The dry powder formulation of clause 26, which is obtained using the method of any one of clauses 1 to 25 or which is obtainable usingthe method of any one of clauses 1 to 25.

[0063] 29. The dry powder formulation of clause 26 or clause 1 , wherein the agglomerated particles include first primary particles that contain the API, and second primary particles that lack the API, wherein the first and second primary particles are bound together with the at least one binder.

[0064] 30. The dry powder formulation of any one of clauses 26 to 29, wherein the API is a peptide, especially a GLP-1 receptor agonist.

[0065] 31 . The dry powder formulation of any one of clauses 26 to 30, wherein the binder is water-activated binder.

[0066] 32. The dry powder formulation of any one of clauses 26 to 31 , wherein the binder is a polymeric binder formed from N-vinylpyrrolidone monomer, a cellulose binder or a combination of a polymeric binder formed from N-vinylpyrrolidone monomer, and a cellulose binder.

[0067] 33. The dry powder formulation of any one of clauses 26 to 32, wherein the one or more excipients includes a sugar alcohol.

[0068] 34. The dry powder formulation of any one of clauses 26 to 32, wherein the one or more excipients includes a cyclodextrin.

[0069] 35. The dry powder formulation of any one of clauses 26 to 32, wherein the one or more excipients includes a sugar alcohol and / or a cyclodextrin, wherein the total amount of sugar alcohol(s) and / or a cyclodextrin(s) is from 30 to 85 % w / w, such as 40 to 75 % w / w or 45 to 65 % w / w, based on the total weight of the solid formulation.

[0070] 36. The dry powder formulation of clause 35, wherein the Dv50 of the sugar alcohol(s) and cyclodextrin(s) present is greater than 40 pm.

[0071] 37. The dry powder formulation of any one of clauses 26 to 36, wherein the one or more excipients include a permeability enhancer.

[0072] 38. The dry powder formulation of clause 37, wherein the permeation enhancer is selected from dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC), and sodium salcaprozate (SNAC).

[0073] 39. The dry powder formulation of any one of clauses 26 to 38, wherein the density of the formulation is from 0.2 to 0.6 g / cm3.

[0074] 40. The dry powder formulation of any one of clauses 26 to 39, wherein the solid particulate powder has a Dv10 of above 10 pm, especially a Dv10 of above 15 pm, and a Dv90 of below 500 pm, especially a Dv90 of below 250 pm.

[0075] 41 . The dry powder formulation as defined in any one of clauses 26 to 40, wherein the solid particulate powder having a Dv50 in a range of 20-200 pm, especially in the range of from 25-120 pm.

[0076] 42. A dosage form for nasal delivery or inhalation, comprising the dry powder formulation as defined in any one of clauses 26 to 41 .

[0077] DESCRIPTION OF THE DRAWINGS

[0078] Fig. 1 shows a schematic view of a MADG process of the disclosure in which a solid formulation is converted to a dry powder formulation of the disclosure comprising agglomerated particles.

[0079] Fig. 2 shows a schematic view of a MADG process of the disclosure in which an alternative solid formulation is converted to a dry powder formulation of the disclosure comprising agglomerated particles.

[0080] DETAILED DESCRIPTION

[0081] While the subject-matter of the present disclosure is described and illustrated below with reference to particular embodiments, it will be appreciated by those skilled in the art that the subject-matter lends itself to many different variations not specifically illustrated herein. Byway of example only, certain possible variations will now be described.

[0082] The powder components disclosed herein can be present in amounts defined by % w / w. It will be appreciated that the % w / w amounts of components, when combined, will not sum to a value of more than 100. The active pharmaceutical ingredient (API)

[0083] The formulations and dosage forms of the disclosure contain an active pharmaceutical ingredient (API). The API can be or comprise any ingredient for the diagnosis, mitigation, treatment, or prevention of disease.

[0084] It has been found that the method of the disclosure can be used with combinations of APIs and excipients that would otherwise be incompatible in solution, e.g. because the API is unstable or sparingly soluble at the pH at which the excipient is stable or readily dissolves.

[0085] The API can be or comprise one or more peptides. The term “peptide” can mean a chain of amino acid residues covalently linked by peptide bonds. Thus, a peptide can be a compound consisting of two or more amino acid residues linked in a chain, the carboxyl group of each acid being joined to the amino group of the next by a bond of the type -OC- NH-. The peptide APIs present in the formulations of the disclosure typically have from 15 to 80 amino acid residues.

[0086] Peptides and proteins tend to be very unstable in aqueous environments due to hydrolysis, oxidation, or aggregation. Their half-life in water at neutral pH and at room temperature can range from minutes to hours, depending on conditions.

[0087] The peptide can be a glucagon-like peptide-1 (GLP-1 ) receptor agonist. GLP-1 receptor agonists are a class of medications utilized to treat type 2 diabetes mellitus (T2DM) and obesity. Examples of GLP-1 receptor agonists include: Liraglutide, Semaglutide, Albiglutide and Dulaglutide, which are classified as long-acting agonists, and Exenatide, Beinaglutide and Lixisenatide, which are classified as short-acting agonists. Tirzepatide is a long-acting dual glucose-dependent insulinotropic polypeptide (GIP) receptor and GLP-1 receptor agonist. The GLP-1 receptor agonist can be a peptide optionally having from 15 to 80 amino acid residues, such as from 20 to 50 amino acid residues. Preferred GLP-1 receptor agonists include: liraglutide, semaglutide, albiglutide, dulaglutide, exenatide, beinaglutide, lixisenatide and tirzepatide. The GLP-1 agonist can be selected from liraglutide and semaglutide, especially semaglutide.

[0088] Poor bioavailability of GLP-1 receptor agonists and high cost of GLP-1 receptor agonist dosages make patient access a challenge and complicated administration requirements make compliance poor, especially after initial weight loss. Furthermore, oral and injectable products can elicit severe side effects. The dry powder formulations of the present disclosure provides an effective means of delivering GLP-1 receptor agonists nasally.

[0089] When the API is a peptide, water is preferably present in the solid formulation in an amount of up to 10 percent by weight based on the total weight of the solid formulation. Advantageously, when the API is a peptide, water is present in the solid formulation in an amount of up to 9 percent by weight, preferably of up to 6 percent by weight, based on the total weight of the solid formulation.

[0090] When the API is other than a peptide, water content of greater than 10 percent by weight may be advantageous, for example, water contents of up to 20 percent by weight may be advantageous.

[0091] The API is typically present in an amount of at least 0.1 % w / w, such as an amount of at least 1 % w / w, for example an amount of at least 5 % w / w, based on the total weight of the dry powder formulation.

[0092] The method of the present disclosure can be used to form dry powder formulations with a high portion of API and / orwithout outthe need to include significant levels of excipients as bulking agents or fillers. Accordingly, the API can be present in high amounts, such as an amount of up to 95%, such as an amount of up to 90 % w / w, for example an amount of up to 80 % w / w, based on the total weight of the dry powder formulation. The API can, for example, be present in an amount in a range of 0.1-95 % w / w, such as 1-80 % w / w, especially 5-80 % w / w, based on the total weight of the dry powder formulation.

[0093] The API can advantageously constitute a substantial proportion of the dry powder formulation, for example, an amount of at least 10 % w / w, such as at least 20 % w / w, or at least 40 % w / w, based on the total weight of the dry powder formulation. Thus, API can, for example, be present in an amount in a range of 10-95 % w / w, such as 20-80 % w / w, especially 40-80 % w / w, based on the total weight of the dry powder formulation.

[0094] When the dry powder formulation includes no excipients other than the binder, the API can be present in an amount of from 88 to 99 percent by weight, especially from 94 to 99 percent by weight, based on the total weight of the formulation other than water.

[0095] It has been found that when an API, especially a peptide API, constitutes more than 50% of the formulation achieving dry powder formulation in which no more than 10% of the particles by volume have a diameter of less than 10 pm can be challenging. For example, it may be necessary to repeat steps (b) and (c) in order to reduce the level of fine material in the formulation. However, when the amount of API, especially peptide API, constitutes less than 50% of the formulation, a dry powder formulation in which no more than 10% of the particles by volume have a diameter of less than 10 pm may be produced with a single agglomeration step.

[0096] The API present in the dry composition used in the method of the first aspect of the disclosure, can be present in particles having a Dv50 of less than 15 pm, for examples having a Dv50 of less than 10 pm. The API can be present in particles having a Dv90 less than 40 pm. The API can be present in particles having a Dv10 less than 5 pm. More than 10 % by volume of the particles that include the API can have a diameter of less than 10 pm, for example, more than 25 % by volume of the particles that include the API can have a diameter of less than 10 pm. The primary particles that include the API that are present in the agglomerated secondary particles of the second aspect of the present disclosure can have the dimensions described above.

[0097] The bulk density of the particles of the dry composition that include the API can be less than 0.1 g / cm3, for example less than 0.05 g / cm3. It has been found that the method of the invention can advantageously be effective in producing a solid particulate powder having appropriately sized particles for nasal delivery from dry compositions that have such low bulk densities, e.g. lyophilised particles comprising the API. However, it will be appreciated that the method can also be effective in producinga solid particulate powder having appropriately sized particles for nasal delivery bulk density of the particles of the dry composition that include the API are greater than 0.1 g / cm3.

[0098] Moisture activated dry granulation (MADG)

[0099] The method of the first aspect of the disclosure uses moisture activated dry granulation (MADG) to form the dry powder formulation of particles suitable for nasal delivery.

[0100] A MADG process is a process that involves the steps of (a) dry mixing a composition of dry ingredients, including the API, to form a mixture, (b) moisture activation in which a small amount of water is sprayed onto the mixture, e.g. in the form of an aqueous mixture such as an aqueous solution, to activate a binder and create a slightly damp mass, and (c) agglomeration in which the damp mass is briefly to allow the particles to agglomerate into agglomerated secondary particles. The binder may be included in the composition of dry ingredients or included with the water, e.g. as a constituent of an aqueous solution, that is sprayed onto the mixture or added after the water. A MADG process can also include (d) a drying step in which agglomerated particles or granules are then dried using low heat or ambient air drying to remove excess moisture and / or (e) a sizing step in which agglomerated particles or granules are typically passed through a mill or sieve to achieve uniform size. Steps (b) and (c) can optionally be repeated. When optional step (d) is carried out, steps (b) and / or (c) can optionally be repeated before optional step (d) or after step (d). When steps (b) and / or (c) are repeated after optional step (d), step (d) can optionally be repeated after the repeat of steps (b) and / or (c), for example, prior to carrying out optional step (e). MADG is typically used to produce uniformly sized particles or granules for compression into tablets.

[0101] In the method of the present disclosure, the dry mixing step (a) includes fluidizing a dry composition comprising the API, and the moisture activation step (b) includes the addition of water to the fluidized dry composition as a mist of droplets. In the method of the present disclosure the binder can be present in the dry composition or added to the fluidized dry composition with the water, e.g. as an aqueous solution. Step (c) may directly follow step (b). Each of steps (a) to (c) may, for example, be carried out in an acoustic mixer. All steps may be carried out at room temperature, i.e. an ambient temperature of approximately 22 °C.

[0102] Typically, in the method of the present disclosure, at no point does the water content of the solid formulation exceed 20 percent by weight. Advantageously, in the method of the present disclosure, at no point does the water content of the solid formulation exceed 10 percent by weight, preferably nor more than 9 percent by weight, especially no more than 6 percent by weight, based on the total weight of the solid formulation. Therefore, advantageously, at no point during the adding step (b) nor during the agglomeration step (c) does the solid formulation include water at an amount that exceeds 20 percent by weight, advantageously 10 percent by weight, preferably 6 percent by weight. The method of the disclosure can include (d) a drying step in which agglomerated secondary particles are dried. However, as the method of the disclosure uses a low amount of water (e.g. no more than 6 percent by weight of the solid formulation that is agglomerated is water), drying may not be necessary.

[0103] The method of the present disclosure can include (e) a sizing step in which agglomerated secondary particles are sieved to achieve uniform size suitable for nasal delivery.

[0104] Dry mixing

[0105] A dry composition comprising the API is fluidized prior to the addition of water in the method of the present disclosure. The dry composition can consist of the API as the sole ingredient or include excipients in addition to the API. Prior to the addition of water, the API and optionally at least one excipient are combined as a dry composition. The dry composition advantageously comprises no more than 2 percent water by weight, preferably no more than 1 .5 percent by weight water, and more preferably no more than 0.5 percent by weight water.

[0106] One or more binders can be included in the dry composition prior to fluidization, i.e. prior to step (a); added separately during fluidization of the dry composition, i.e. during step (a); added separately or simultaneously with the addition of the water, e.g. in solution with the water or as a further dry ingredient during step (b) ; or added after the water either during or prior to the agglomeration step, i.e. during step (c) or after step (b) but before step (c). Preferably, one or more binders are included in the dry composition together with the API, i.e. prior to addition of the water. Preferably, one or more binders are included in the dry composition together with the API before the RAM step.

[0107] The API that is present in the dry composition can be in the form of a lyophilised powder. The dry composition can be formed by combining the API and at least one excipient as dry ingredients. For example, first primary particles comprising the API can be combined with second primary particles that comprise at least one excipient but with lack the API, as dry ingredients prior to agglomerating the first and second primary particles together into agglomerated secondary particles. Alternatively, the API and at least one excipient can be combined in a wet environment, such as in solution or suspension or a combination of a solution and suspension and then dried, e.g. freeze dried, and then combined with any remaining constituents of the dry composition. For example, the API and an excipient can be combed in a wet environment, such as in solution or suspension or a combination of a solution and suspension and then dried, e.g. freeze dried, and then further combined with the binder, any other remining excipients, and any other remaining constituents of the dry composition. Typically, the binder is combined with the other constituents of the dry composition as a dry ingredient. For example, when the API and one or more of the excipients are mixed in solution or suspension and dried, typically freeze dried, to form dry particles that include both the API and one or more excipients, the one or more excipients that are mixed with the API in solution or suspension do not include any binder, which is instead combined with the dry particles as a dry ingredient.

[0108] After or during the combination of the constituents of the dry composition, the constituents of the dry composition are advantageously mixed. Resonance acoustic mixing (RAM) can be used to mix the dry ingredients. Advantageously the constituents of the dry composition are mixed priorto addition of water. For example, the constituents of the dry composition can be mixed by RAM prior to addition of water.

[0109] RAM typically involves placing dry materials in a resonant chamber and exposing the mixture of dry materials to sound waves to generate oscillating pressure changes in the material, leadingto a fluid-like motion. The dry composition can, for example, be mixed by exposure to sound waves at a frequency of between 20 kHz and 200 kHz, such as between 20 kHz and 100 kHz, in a resonant chamber.

[0110] It has been found that RAM can increase the density of the dry composition, for example at least 2-fold, typically at least 3-fold. Thus, the density of the solid formulation may increase by at least 2-fold, such as at least 3-fold, over step (a).

[0111] Water addition

[0112] Prior to or during the step of agglomerating the solid formulation in the method of the present disclosure, water is added to a dry composition comprising an API and optionally one or more excipients to form a solid formulation. The water is added as a constituent of a liquid that includes water. The liquid, may, for example, be an aqueous mixture comprising water and further constituents, such as a mixture of water and a water miscible solvent, an aqueous solution or an aqueous suspension. Water may constitute at least 50 weight percent of the liquid. The liquid may be pure or substantially pure water, e.g. wherein water constitutes at least 95 percent by weight of the liquid. Water may comprise (i.e. constitute) no more than about 20 percent by weight of the solid formulation during the agglomeration step. Water advantageously comprises (i.e. constitutes) no more than about 10 percent by weight, preferably no more than about 9 percent by weight and especially no more than about 6 percent by weight of the solid formulation during the agglomeration step, typically from 0.5 to 5.0 percent by weight, and such as from 1 .0 to 4.5 percent by weight. Total liquids (e.g. water and any further liquids such as water-miscible solvent) may, for example, constitute no more than about 20 percent by weight, preferably no more than about 10 percent, advantageously no more than about 9 percent by weight and especially no more than about 6 percent by weight of the solid formulation during the agglomeration step, typically from 0.5 to 5.0 percent by weight, and such as from 1 .0 to 4.5 percent by weight.

[0113] In the method of the disclosure, water is added to the dry composition as a mist of droplets, or as a constituent of a mist of droplets. The droplets can, for example, have a median volume droplet size (Dv50) of less than 100 pm, typically as a Dv50 of less than 50 pm, and such as a Dv50 of from 10 to 50 pm.

[0114] The fine mist of droplets can be produced by an atomizer, for example, by an ultrasonic transducer in which an ultrasonic nozzle produces a very fine mist of liquid with droplet sizes as described above. This fine mist is created through the high-frequency vibrations of an ultrasonic transducer, which atomizes the liquid by breaking it into small droplets. The ultrasonic nozzles can operate at a frequency between 20 Hz and 2 MHz, typically a frequency from about 20 kHz to about 200 kHz, e.g. about 130 kHz, with higher frequencies producing finer mists. It has been found that operating at frequencies above 20 kHz is advantageous in producing a suitably fine mist of water droplets. The atomizer advantageously generates a plume of water droplets. A plume of water droplets is typically obtained by operating the atomizer in the above frequency ranges at a power output of between 2 and 3 watts, such as at approximately 2.4 watts The use of ultrasonic transducers to create fine mists of liquid is known from applications like humidification, medical nebulizers, and precise coating processes, where uniform and controlled droplet sizes are important. Water may be added in step (b) using an atomizer, for example, operating at a flow rate of 150 pl / min with the ultrasonic nozzle optionally at 130 Hz.

[0115] During the addition of the water, the dry composition is in a fluidized state. The dry composition can, for example, be fluidized using resonant acoustic mixing (RAM). As discussed above, RAM can be used to mix the constituents of the dry composition prior to addition of the water, thus RAM can be used both to mix the constituents of the dry composition prior to addition of the water and to fluidize the dry composition during addition of water. The water can be added to the dry composition while the dry composition is exposed to sound waves at a frequency of between 20 kHz and 200 kHz or between 20 kHz and 100 kHz in a resonant chamber of an acoustic mixer.

[0116] Otherforms of fluidization can be used. For example, a fluidized bed can be used in which air or another gas is passed upward through a dry powder to generate a fluid-like behaviour. Afluidized bed can be more practical than RAM when agglomerating the solid formulation on a large scale, e.g. when the solid formation has a mass of greater than 5 kg. The water can be added to the dry composition while the dry composition is fluidized by the flow of gas in a fluidized bed.

[0117] As discussed elsewhere herein, the binder can be incorporated into the solid formulation together with the water. For example, the binder may be added dissolved in the water or a liquid that includes water, e.g. as an aqueous solution. Thus, the mist of droplets added to the solid formulation can be an aqueous solution comprising the binder. Alternatively, the binder may be added as a further dry ingredient or as a solution in a non-aqueous solvent. It has been found that adding the binder as an aqueous solution may limit the choice of binder to those which are highly soluble in water. It has also been found that adding the binder together with the water is constrained by the need for the viscosity of the aqueous solution or suspension to be controlled when adding water as a mist of droplets. Thus, it is preferred that the binder is added separately to the water. When binder is added simultaneously with the addition of the water in step (b), is it preferred that the binder is added as a further dry ingredient or as a solution in a non-aqueous solvent.

[0118] Agglomeration

[0119] Moisture activated dry granulation (MADG) is used to agglomerate particles present in the solid formulation to form agglomerated secondary particles comprising the API and binder. The agglomerated particles typically comprise one or more further excipients in addition to the binder. During MADG, constituent primary particles comprising the API become bound together into larger agglomerated secondary particles.

[0120] Agglomeration is typically carried out in the same equipment used to fluidize the dry composition in step (a). Agglomeration step (c) is typically carried out in an acoustic mixer, for example following (a) fluidization of the dry composition and (b) the addition of water in the same acoustic mixer. As discussed above, RAM can be used to mix the constituents of the dry composition prior to addition of the water, thus RAM can be used both to mix the constituents of the dry composition prior to addition of the water, fluidize the dry composition during addition of water and agglomerate the solid formulation in the MADG process of the invention. Alternatively, the entire MADG process may, for example, be carried out in a fluidized bed.

[0121] Agglomeration step (c) may, advantageously, be carried out in an acoustic mixer, for example, operated at an acceleration of 35 G for a duration of 2-5 minutes. MADG is carried out at room temperature, e.g. at approximately 22 °C.The agglomerated secondary particles are clusters of primary particles that are bound to each other by the at least one binder. The primary particles (which can also be referred to as “constituent particles”) are the smaller particles of various sizes that together make up the larger agglomerated particles (which can be referred to as “agglomerated secondary particles”, or “secondary particles”). In agglomerated form, the primary particles do not lose their individual identity. Agglomeration may be ascertained by microscopy, such as by scanning electron microscopy (SEM). As used herein, the term agglomerated particle may mean a secondary particle made up of constituent primary particles which are attached to each other by binder, as may be ascertained by microscopy, such as by scanning electron microscopy (SEM). The binder can be in the form of a matrix holding together the secondary particle. The solid formulation (i.e. prior to agglomeration) can comprise a single type of particle comprising the API or a combination of two or more different types of particles, e.g. one type of particle comprising the API and another type of particle comprising an excipient without the API. When the solid formulation contains a single type of particle comprising the API, or a combination of two types of particles wherein one comprises the API and another consists solely of binder, the resulting agglomerated secondary particles will comprise a single type of constituent primary particles, with the single-type of primary particles being bound to each other by binder, e.g. by a matrix of binder. When the solid formulation contains two different types of particles, one type of particle comprising the API and one type of particle comprising an excipient other than the binder but lacking the API, the agglomerated particles will comprise multiple types of different constituent particles bound together by binder, e.g. by a matrix of the binder. The primary particles containing the API (i.e. first primary particles) can, for example, be agglomerated togetherwith other primary particles that lack the API (i.e. second primary particles) that are present in the solid formulation. The primary particles containing the API (i.e. first primary particles) can, for example, be agglomerated togetherwith multiple different other primary particles (i.e. at least second and third primary particles) that lack the API that are present in the solid formulation. The other constituent primary particles that lack the API can, for example, include a filler and / or a permeation enhancer. The constituent primary particles that lack the API may, for example, include a second primary particle that includes a filler and a third primary particle that includes a permeation enhancer. The binder can be included in the solid formulation in particles that comprise the API, or be included in particles that include constituents of the dry powder formulation other than the API (e.g. primary particles that comprise excipients other than binder but no API), or be included as separate solid particles that consist, or consist essentially, of the binder, or be included in solution with the water.

[0122] Fig.1 shows a schematic representation of a MADG process in a solid formulation (10) in which multiple types of particles are present, including particles containing the API (1 ) and other particles that lack the API (2). The particles containing the API (1 ) and the other particles that lack the API (2) are agglomerated together with a binder (not shown) into a dry powder formulation (100) that include agglomerated secondary particles (3) that comprise both first primary particles containingthe API (1) and second primary particles that lack the API (2) bound together with the binder (not shown). The individual agglomerated secondary particles (3) produced by binding together the first primary particles containing the API (1 ) and second primary particles that lack the API (2) with the binder (not shown) are substantially larger that the first and second primary particles (1 , 2) prior to agglomeration. Thus, the average particle size Dv50 is increased, the proportion of the particles present in the agglomerated formulation (100) having a diameter greater than 10 pm has been raised and the density of the solid formulation has been increased, by the MADG process.

[0123] While in the example shown in Fig. 1 the solid formulation (10) includes two types of particles, a first type containing the API (1 ) and a different, second type lacking the API (2), it is to be understood that the solid formulation of the present disclosure can comprise more than two types of particle (1 , 2). For example, the solid formulation can comprise particles consisting of the API, particles consisting of a filler, and particles consisting of a permeation enhancer. Accordingly, the dry powder formulation of the disclosure can, comprise agglomerated secondary particles that comprise multiple types of constituent primary particles, for example first primary particles consisting of the API, second primary particles consisting of a filler, and third primary particles consisting of a permeation enhancer, all bound together with the binder.

[0124] Fig. 2 shows a schematic representation of a MADG process in which an alternative solid formulation (20) containing particles (4), comprising the API and optionally an excipient other than a binder, that are agglomerated together with the binder (not shown) into a dry powder formulation (200) containing agglomerated secondary particles (5). The binder can be included in the particles (4) containing the API and the optional excipient other than a binder, such that only a single type of constituent primary particle is present in the solid formulation (20); or the binder can be included in the solid formulation (20) as separate particles (not shown).

[0125] The solid formulations (10, 20), prior to agglomeration, can include particles of varying sizes. As shown in Fig. 2, a portion of the particles (4) in the solid formulations (20) can be relatively large particles (4a), e.g. of 40 pm or more in diameter, while a significant proportion of the particles can be smaller particles (4b) that are too small for nasal delivery, i.e. less than 10 pm in diameter. Following the MADG process, a dry powder formulation (200) is produced in which constituent primary particles (4) have been incorporated into agglomerated secondary particles (5), which are of a size suitable for nasal delivery, i.e. 10 pm or more in diameter, e.g. 20 pm or more in diameter. The proportion by volume of small particles (4b) having a diameter of 10 pm or less that remain in the dry powder formulation (200) is substantially less than in the solid formulation (20) and is typically less than 10% by volume. The proportion of small particles (4b) can be reduced further by sieving dry powder formulation (200), if desired.

[0126] Preferably, the agglomerated secondary particles of the formulations of the invention includes multiple types of primary particle, i.e. the solid formulation of the invention is a formulation (10) of type schematically illustrated in Fig. 1 that includes two types of primary particles (1 ,2), Types of primary particles typically differ from each another at least in their constituents, e.g. one type of particles (1 ) comprises the API and another type (2) comprises only excipient(s).

[0127] The density of the agglomerated particles is greater than the density of the fluidized dry composition. It has been found that the agglomeration step can further increase the density of the fluidized dry composition. For example, the agglomeration step can increase the density of the fluidized dry composition by a further 1.1-fold, such as a further 1.2-fold, in addition to any increase in density achieved in the fluidization step. The density of the agglomerated particles can optionally be at least 2 times the density of the solid formulation prior to fluidization, such as at least 3 times, for example at least 5 times, the density of the solid formulation prior to fluidization. Thus, the density of the solid formulation may increase by at least 2-fold, such as at least 3-fold, especially at least 5-fold, over steps (a) to (c).

[0128] The agglomeration step has been found to significantly decrease the proportion of fine particles that are less than 10 pm in diameter. For example, the volume of particles that are less than 10 pm in diameter, which are present in the dry powder formulation followingthe agglomeration step (c), compared to the amount present in the fluidized dry composition following step (a) can be reduced by 20% or more, especially 30% or more. While the MADG process has been found to substantially increase the proportion of particles that have a size suitable for nasal delivery, some particles of a size that are too small or too large for nasal delivery may remain following the MADG process.

[0129] The method of the first aspect of the disclosure can include a step of sieving the agglomerated particles to remove residual particles of a size that are too small for nasal delivery. For example, the method can include the step of sieving the agglomerated particles to reduce the proportion of particles present that have a diameter of less than 10 pm.

[0130] The method of the first aspect of the disclosure can include a step of sieving the agglomerated particles to remove residual particles of a size that is too large for nasal delivery. For example, the method can include the step of sieving the agglomerated particles to reduce the proportion of particles present that have a diameter of more than 200 pm.

[0131] Subsequent to the agglomeration step, some or all of the water added may become bound into the particles. The amount of free, unbound water in the particles may be altered, typically decreased, subsequent to the agglomeration step. The water content of the agglomerated particles can be reduced in a dryingstep, for example, using a vacuum. When the water is added as together with additional liquids, e.g. mixed with water- miscible solvents, subsequent to the agglomeration step, some or all of the total liquids added may become bound into the particles. The amount of free, unbound liquid in the particles may be altered, typically decreased, subsequent to the agglomeration step. The liquid content of the agglomerated particles can be reduced in a drying step, for example, using a vacuum.

[0132] The amount of free, unbound water present in the dry powder formulation of the disclosure can be less than 5 percent by weight, typically less than 4 percent by weight, such as from 0.5 to 5.0 percent by weight or from 1 to 4 percent by weight. The total amount of free, unbound liquid, including water and other liquids such as water-miscible solvents, present in the dry powder formulation of the disclosure can be less than 5 percent by weight, typically less than 4 percent by weight, such as from 0.5 to 5.0 percent by weight or from 1 to 4 percent by weight.

[0133] The method of the invention have been found to provide access to dry powder formulations having a particle size distribution suitable for nasal delivery that have hitherto being difficult to prepare by conventional methods including micronisation or spray drying, e.g. due to the API being unsuitable for dissolving in solution or being processed by other micronisation techniques. Dry powder formulations of the invention, including those that are obtained by the method described herein, have a distinct morphology that differs from dry powder formulations formed by other methods, such as spray drying.

[0134] The distinct structure can, for example, be identified using scanning electron microscopy (SEM). SEM may, for example, be used to visually identify the presence of multiple constituent particles that are bound together in the secondary agglomerated particles present in the dry powder formulations of the present invention. Spray dried particles typically have solid interiors, whereas the agglomerated particles produced by the present method may have spaces throughout the particle core between primary particles, as is shown schematically in Fig.1 and Fig. 2. Spaces between primary particles (1 ,2, 4a, 4b) have been found to provide porosity to the agglomerated secondary particles (3, 5). Particles produced by the described methods are typically irregularly shaped with rough surfaces. Particles produced by spray drying tend to be more spherical with smoother surfaces than those produced by the present method. Particles produced by the described methods typically have non-homogeneous surfaces. SEM images of the agglomerated particles of the invention may be used to identify regions formed from the different constituent primary particles that together make up the agglomerated secondary particles. Typically, more than one type of primary particle is present at the surface of the secondary agglomerated particles leading to a variation in the surface of the particles. Secondary agglomerated particles (3) formed from multiple different primary particles (1 ,2) are schematically illustrated in Fig. 1 in which it can be seen that some surface regions are formed of the first primary particles (1 ) and other surface regions formed from the second primary particles (2). Particles of the prior art that are produced from solutions typically have homogeneous surfaces with an even distribution of constituents on the surface. Binders

[0135] The solid formulation agglomerated in the method of the first aspect of the disclosure comprises one or more binders. The dry powder formulation of the second aspect of the disclosure comprises one or more binders.

[0136] Binders can be present to assist in forming and holding together the other solid constituents of the agglomerated particles. The binders are typically water-activated polymeric binders that require moisture to activate their binding properties. When mixed with water, the water-activated binder may swell and form a viscous gel that helps bind the particles together. The binders are typically hydrophilic molecules comprising multiple protic groups, e.g. multiple hydroxy groups. Examples of suitable binders include: polymeric binders, for example polymeric binders formed from N- vinylpyrrolidone monomer such as povidone (polyvinylpyrrolidone) and copovidone (a 3:2 copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate); carbohydrate molecules comprising a plurality of saccharide units linked together, e.g. cellulose binders such as hydroxypropyl methylcellulose (HPMC) and sodium carboxymethyl cellulose (CMC); and natural binders such as starches and gelatins; especially, polymeric binders formed from N-vinylpyrrolidone monomer and cellulose binders, such as povidone and HPMC.

[0137] Binders are often crucial for formulating tablets that require sufficient hardness and mechanical strength to withstand handling and transport. Water-activated binders are commonly used in wet granulation processes in which the binder is mixed with powders and water is added to form a damp mass, which is then granulated. The present inventors have surprisingly found that if binders, especially water-activated polymeric binders are included in a solid formulation comprising the API in lower quantities (such as in an amount of from 1 to 6 percent by weight based on the total weight of the solid formulation) than are typically employed in wet granulation processes, and then the solid formulation is agglomerated using a MADG process, particles with a size distribution suitable for nasal delivery can be produced.

[0138] The binder can be included in the solid formulation in a solid or liquid form. The binder can be included in the solid formulation as separate solid particles that consist, or consist essentially, of the binder. The binder can be included in the solid formulation as a component of particles that also comprise the API and / or as a component of particles that also comprise a non-binder excipient. The binder can be included in solution with the water, e.g. incorporated into the droplets. Thus, the mist of droplets added to the solid formulation can be an aqueous solution comprising the binder.

[0139] The binder is present in the solid formulation in an amount of from 1 to 6 percent by weight, such as in an amount of from 1 .5 to 5.0 percent by weight, such as from 2.0 to 4.0 percent by weight, based on the total weight of the solid formulation. The binder is presentin the dry powder formulation of the second aspect of the disclosure an amount of from 1 to 6 percent by weight, such as in an amount of from 1 .5 to 5.0 percent by weight, such as from 2.0 to 4.0 percent by weight, based on the total weight of the dry powder formulation.

[0140] Optional Further Excipients

[0141] In addition to the binder, the dry powder formulation typically comprises one or more excipients other than the at least one binder. Typically, the solid formulation that is formed into agglomerated particles using MADG comprises one or more excipients other than the at least one binder.

[0142] The one or more optional excipients other than the at least one binder may function as bulking agents that add to the volume of a powder to enable easier processing thereof and / or to make the powder up to a volume suitable for nasal delivery.

[0143] The one or more optional excipients other than the at least one binder can be present in the dry powder formulation in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w or 20 to 65 % w / w, based on the total weight of the dry powder formulation. Typically, excipients other than binders constitute at least 30 % w / w, such as at least 40 % w / w or at least 45 % w / w of the dry powder formulation, based on the total weight of the dry powder formulation.

[0144] The one or more optional excipients other than the at least one binder can be present in the solid formulation in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w or 20 to 65 % w / w, based on the total weight of the solid formulation. Typically, excipients other than binders constitute at least 30 % w / w, such as at least 40 % w / w or at least 45 % w / w of the solid formulation, based on the total weight of the solid formulation.

[0145] Optional Fillers

[0146] The one or more optional excipients other than the at least one binder can include a filler whose primary or sole purpose is to add volume and / or mass to the powder, stabilize the powder and promote ease of manufacturing. Alternatively or additionally, the one or more optional excipients other than the at least one binder may perform a function when present in the dry powder formulation or dosage form, e.g. when administered nasally, such as enhancing the permeability of the API. The one or more optional excipients other than the at least one binder may perform a function during earlier stages of processing the API and then merely act as a filler in the dry powder formulation. For example, the one or more optional excipients other than the at least one binder can include constituents that function to modify the viscosity of a solution or suspension that includes the API priorto lyophilisation, and which subsequently functions as a filler in a solid formulation.

[0147] Suitable excipients other than binders for inclusion in the dry powder formulation of the present disclosure include sugar alcohols such as mannitol, sorbitol and erthritol, especially mannitol. A sugar alcohol may function primarily as a filler in the dry powder formulation.

[0148] The sugar alcohol or other filler advantageously has a particle size distribution with a Dv 50 of 40 pm or greater. As demonstrated in the data presented in the experimental section below, the particle size distribution of dry powders produced in the invention using a mannitol filler having an average particle size of 50 pm, i.e. 50C grade (Dv106 pm, Dv50 55 pm, Dv 90 130 pm) is superior to that producing using a mannitol filler having an average particle size of 25 pm, i.e. 25C grade (Dv103.5 pm, Dv5024 pm, Dv 9055 pm).

[0149] The one or more optional filler excipients can be present in the dry powder formulation in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w or 20 to 65 % w / w, based on the total weight of the dry powder formulation. Typically, fillers are present in the dry powder formulation in an amount of at least 30 % w / w, such as at least 40 % w / w or at least 45 % w / w, based on the total weight of the dry powder formulation.

[0150] The one or more optional filler excipients can be present in the solid formulation in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w or 20 to 65 % w / w, based on the total weight of the solid formulation. Typically, fillers are present in the solid formulation in an amount of at least 30 % w / w, such as at least 40 % w / w or at least 45 % w / w, based on the total weight of the solid formulation.

[0151] The amounts of fillers mentioned above relate to the amounts of compounds whose primary function is as a filler, such as mannitol, and compounds that due to the quantities present function as a bulking agent, i.e. compounds which contribute more than 10 % w / w of the total formulation, but which have a dual function, e.g. cyclodextrins such as betadex, discussed below in the section concerning permeation enhancers.

[0152] Optional permeation enhancers

[0153] Optional excipients present in the dry powder formulation may function to enhance the permeability of the API. Some APIs, including peptides, such as semaglutide, do not easily cross endothelial membranes. Permeability enhancers are used to increase the bioavailability of APIs, especially peptide APIs. The permeability enhancer present in the formulation of the disclosure can be a single compound or a combination of more than one permeability enhancer compounds.

[0154] Preferred permeability enhancers include: cyclodextrins, e.g. with 5 to 10 glucose units, such as p-cyclodextrin (IUPAC name: cyclomaltoheptaose, also known as “Betadex”) and 2-hydroxypropyl-p- cyclodextrin (also known as “HP-Betadex”); phosphocholines such dodecylphosphocholine (DPC);

[0155] - fatty acid esters of carnitine, such as lauroyl-L-carnitine (LLC); and - salts of a fatty acid having a chain length of from 6 to 22-carbon atoms optionally substituted an aromatic group, such as sodium salcaprozate (SNAC) (IUPAC name: A / -[8(2-hydroxylbenzoyl) amino] caprylate) or sodium caprate.

[0156] Other suitable permeability enhancers can include N-(5-chlorosalicyloyl)-8- aminocaprylic acid (5-CNAC), 1 -phenylpiperazine (PPZ) and sodium deoxycholate (SDC).

[0157] It has been found that the inclusion of DPC as a permeation enhancer enables dry powders with a particularly advantageous particle size distribution to be produced in the methods of the present invention.

[0158] The permeability enhancer is optionally selected from one or more of: a cyclodextrin; a phosphocholine; a fatty acid ester of carnitine; and a salt of a fatty acid having a chain length of from 6 to 22-carbon atoms optionally substituted with an aromatic group.

[0159] The optional excipients can comprise or consist of one or more cyclodextrins. Thus, one or more cyclodextrins, such as those having 5 to 10 glucose units, such as p-cyclodextrin (IUPAC name: cyclomaltoheptaose, also known as “Betadex”) and 2-hydroxypropyl-p- cyclodextrin (also known as “HP-Betadex”) can be included in the formulations and dosage forms of the disclosure. Cyclodextrins may be included in order to function purely as a filler. However, as discussed in more detail below, cyclodextrins may function as a permeability enhancer in addition to functioning as a filler. Thus, one or more cyclodextrin excipients can be present to function solely as a filler, or to function both a filler and a permeability enhancer. When large quantities of cyclodextrins are present, e.g. they constitute more than 10 % wt / wt of the total formulation, they typically function primarily as a filler.

[0160] Cyclodextrins, such as p-cyclodextrin and 2-hydroxypropyl-p-cyclodextrin, can form inclusion complexes with peptides, improving their solubility and stability in aqueous environments. By enhancing solubility, they facilitate better absorption across biological membranes and protect peptides from enzymatic degradation. Preferred cyclodextrins include 5 to 10 glucose units.

[0161] The one or more optional excipients other than binders present can consist of cyclodextrins or can comprise cyclodextrins in combination with other excipients other than binders, such as a sugar alcohol, e.g. mannitol. When the one or more excipients other than binders consists of or comprises one or more cyclodextrins, the cyclodextrins can be present in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w, or 20 to 65 % w / w, based on the total weight of the dry powder formulation.

[0162] Phosphocholines can be included in the formulation as optional excipients that function as a permeability enhancer in addition to functioning as a filler. Phosphocholines can function to disrupt lipid bilayers and enhance membrane permeability. The disruption of lipid structure allows APIs, especially peptide APIs, to pass through more easily thereby enhancing the transport of the APIs through membrane barriers. Phosphocholines include lysophosphatidylcholines having one fatty acid chain on a glycerol group attached to phosphate, phosphatidylcholines having two fatty acid chains on a glycerol group attached to phosphate, and alkylated phosphocholines having an alkyl chain directly attached to the phosphate of the phosphocholine head group. The alkyl or fatty acid chain length is typically of from 6 to 22-carbon atoms and may be saturated or unsaturated, for example with one or two C=C unsaturated groups.

[0163] Examples of phosphocholine permeability enhancers include dodecylphosphocholine (DPC) having a saturated 12-carbon alkyl chain, hexadecylphosphocholine (miltefosine) having a saturated 16-carbon alkyl chain attached to a phosphocholine head group, oleylphosphocholine (OlPC) having an unsaturated 18-carbon oleyl chain linked to a phosphocholine head group, and octadecylphosphocholine having an 18-carbon saturated alkyl chain attached to a phosphocholine head group.

[0164] When the one or more optional excipients includes a phosphocholine, the excipients typically also include at least one other excipient other than a binder, such as a sugar alcohol, e.g. mannitol, in addition to the phosphocholine. When the one or more excipients comprise one or more phosphocholines, the phosphocholines can be present in an amount of 2 to 30 % w / w, based on the total weight of the formulation.

[0165] Fatty acid esters of carnitine can be included in the formulation as excipients that function as a permeability enhancer in addition to functioningas a filler. Fatty acid esters of carnitine, where carnitine is conjugated with fatty acids of varying chain lengths, e.g. with a fatty acid chain length of 6 to 22-carbon atoms, can enhance membrane fluidity and transport mechanisms due to their amphiphilic nature. They may facilitate passive diffusion and active transport of APIs, especially peptide APIs, across cellular membranes, increasing their absorption. The mechanism of action is similar across these esters, as they tend to interact with the lipid bilayer of biological membranes, enhancing permeability by alteringthe membrane structure.

[0166] The optional excipients other than a binder can thus include one or more of the following fatty acid esters of carnitine: caproyl-L-carnitine (CLC) having a C6 chain; lauroyl-L- carnitine (LLC) having a C12 chain; myristoyl-L-carnitine (MLC) having a C14 chain; palmitoyl-L-carnitine (PLC) having a C16 chain; and stearoyl-L-carnitine (SLC) having a C18 chain. A preferred fatty acid ester of carnitine is lauroyl-L-carnitine (LLC).

[0167] When the optional excipients include one or more fatty acid ester of carnitines, the one or more optional excipients typically also includes at least one other excipient other than a binder, such as a sugar alcohol, e.g. mannitol, in addition to the one or more fatty acid ester of carnitines. When the optional excipients comprise one or more one or more fatty acid ester of carnitines, the one or more fatty acid ester of carnitines can be present in an amount of 2 to 30 % w / w, based on the total weight of the formulation.

[0168] Salts of fatty acids can be included in the formulation as bulking agents that function as a permeability enhancer in addition to functioning as a filler. Salts of fatty acids may act as permeability enhancers by increasing the solubility of and / or stabilizing APIs, especially peptide APIs, in the gastrointestinal tract; while also enhancing permeability. Suitable salts of fatty acids typically include a fatty acid chain of from 6 to 22-carbon atoms, optionally substituted with an aromatic group such as a benzoyl group, e.g. a (hydroxybenzoyl)amino group. They may act as carriers that help in the transport of APIs, especially peptide APIs, across the intestinal barrier, thereby improving their systemic availability.

[0169] The optional excipients can include one or more of the following unsubstituted fatty acid salt molecules: sodium caprylate, the sodium salt of caprylic acid (C8); sodium caprate, the sodium salt of capric acid (C10); and sodium laurate, the sodium salt of lauric acid (C12).

[0170] The optional excipients can include one or both of the following substituted fatty acid salt permeability enhancers: sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC-8); and sodium N-[8-(2-hydroxybenzoyl)amino]caproate (SNAC, or sodium salcaprozate), both of which include the (hydroxybenzoyl)amino substituent on the fatty acid chain.

[0171] The optional excipients other than the binder(s) can consist of one or more salts of fatty acids or comprise one or more salts of fatty acids in combination with other excipients other than the binder(s), such as a sugar alcohol, e.g. mannitol. When the excipients other than the binder(s) consists of or comprises one or more one or more salts of fatty acids, the one or more salts of fatty acids may be present in an amount of 5 to 85 % w / w, such as 10 to 75 % w / w, or 20 to 65 % w / w, based on the total weight of the dry powder formulation.

[0172] Another class of optional excipient that can function as permeability enhancers are medium-chain fatty acid ester having a chain length of from 6 to 22 carbon atoms in the fatty acid portion, such as from 6 to 14 carbon atoms in the fatty acid portion. Mediumchain fatty acid esters, with 6 to14 carbon atoms in the fatty acid portion, can improve mucosal permeability and are often used in formulations for nasal delivery. Examples of a suitable medium-chain fatty acid ester permeability enhancer is a lauric acid (C12) ester such as glycerol monolaurate and glycerol dilaureate and a caprylic acid (C10) ester such as glycerol monocaprylate and caprylic acid triglycerides.

[0173] In preferred embodiments, the one or more optional excipients include one or more of: a sugar alcohol, especially mannitol; a cyclodextrin, such as p-cyclodextrin (“Betadex”) or 2-hydroxypropyl-p- cyclodextrin (“HP-Betadex”); and at least one permeability enhancer selected from dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC) and sodium salcaprozate (SNAC).

[0174] The optional excipients can, for example, comprise both lauroyl-L-carnitine (LLC) and sodium salcaprozate (SNAC) as permeability enhancers or can include sodium salcaprozate (SNAC) as a permeability enhancer.

[0175] In especially preferred embodiments, the one or more optional excipients include one or both of: a sugar alcohol, especially mannitol; a cyclodextrin, such as p-cyclodextrin (“Betadex”) or 2-hydroxypropyl-p- cyclodextrin (“HP-Betadex”).

[0176] A further class of optional excipients that can be present in addition to the binder is an amino acid component. The amino acid component can be or comprise one or more different amino acids. Suitable amino acids include a-amino acids with non-polar, aliphatic side groups, such as glycine, alanine, leucine, valine and isoleucine. Preferred amino acids include leucine, valine and isoleucine, especially leucine, most especially L-leucine.

[0177] Amino acids have been found to be useful in stabilising peptides. Furthermore, an amino acid component can be present as a hydrophobic agent to assisting in coating particles of dry powder formulations.

[0178] Without wishing to be bound by theory, it has also been found that an amino acid, especially leucine, may help to coat the API, especially a peptide API, thereby protecting it from moisture. When the powder comprises a cyclodextrin (which can be hydrophilic) the presence of an amino acid such as leucine may be especially advantageous.

[0179] The amino acid, if present, can advantageously be present in an amount of 2-15 % w / w, such as 5-15 % w / w, especially 8-12 % w / w, based on the total weight of the dry powder formulation.

[0180] It has been found that the presence of surfactants is not required duringthe formulations and dosage forms of the disclosure. For example, it has been found that the presence of surfactants is not necessary to prevent the API and other constituents from adhering to equipment such as glassware, stainless steel and silicone tubing.

[0181] Formulations and dosage forms of the disclosure advantageously include essentially no surfactant, for example no more than 0.01 wt% of surfactant, especially no more than 0.001 wt% of surfactant, based on the total weight of the powder formulation or dosage form. The formulations and dosage forms of the disclosure advantageously include essentially no non-ionic surfactant, for example no more than 0.01 wt% of non-ionic 1 surfactant, especially no more than 0.001 wt% of non-ionic surfactant, based on the total weight of the powder formulation or dosage form. The formulations and dosage forms of the disclosure advantageously include essentially no emulsifier, for example no more than 0.01 wt% of emulsifier, preferably no more than 0.001 wt% of emulsifier, based on the total weight of the powder formulation or dosage form. The powder formulations and dosage forms of the disclosure advantageously include essentially no polysorbate surfactant, for example no more than 0.01 wt% of polysorbate surfactant, preferably no more than 0.001 wt% of polysorbate surfactant, based on the total weight of the powder formulation or dosage form.

[0182] Preferably the formulations and dosage forms of the disclosure advantageously include essentially no surfactant selected from a polysorbate, sodium laurylsulphate, cremophor EL (Polyoxyl 35 Castor Oil) and oleic acid, for example no more than 0.01 wt% of such surfactants, preferably no more than 0.001 wt% of such surfactants, based on the total weight of the powder formulation or dosage form.

[0183] For the avoidance of doubt, permeability enhancers that have surfactant properties can be present in the powder formulation.

[0184] Dry Powder Formulation

[0185] As used herein, the term “dry composition” or “dry powder” can mean that the composition or powder has a moisture (e.g. water) content of below 10 % w / w, advantageously below 6 % w / w, preferably below 4, 3 or 2 % w / w, based on the total weight of the composition or powder. The moisture content of the dry composition or powder can be at least 0.5 or at least 1 % w / w, for example, to prevent handling problems associated with static.

[0186] Moisture content may be measured by any suitable method in the art, such as by a colorimetric method. Suitably, the method may be a Karl Fischer method as is known in the art.

[0187] The dry composition comprising the API that is fluidized in step (a) of the method of the first aspect of the present disclosure will have a lower moisture content than the solid formulation formed in step (b). The dry composition can, for example, have a water content of less than less than 3 % w / w or less than 2 % w / w. The dry composition typically has a water content of from 0.5 to 3 % w / w, such as from 1 to 2 % w / w.

[0188] The dry powderformulation formed in the method of thefirst aspect of the disclosure and the dry powder formulation of the second aspect of the disclosure is in the form of a solid particulate powder.

[0189] The dry powder formulation has separate defined particles. The powder formulation can be a free-flowing dry powder formulation. In addition to the agglomerated particles that include the API together with the binder, the dry powder formulation can optionally further comprise additional particles that lack the API. The optional additional particles that lackthe API include at least one excipient other than the binder.

[0190] Each or substantially each of the particles of the dry powder formulation can contain the API. Alternatively, agglomerated particles comprisingthe API may be mixed with particles comprising no API. A substantial proportion of the particles (e.g. at least 20% w / w), the majority of the particles (e.g. at least 50% w / w), or most of the particles (e.g., at least 70 % w / w) can be agglomerated particles that comprise the API and any remaining particles may lack the API. Particles of excipients without the API may serve as carrier particles for agglomerated particles containing the API. The particles lacking the API can be nonagglomerated, singular particles.

[0191] The particles that include the API can be formed by freeze drying a solution of the API and optionally a further excipient, especially a viscosity modifier, to form lyophilized solid particles, which are then agglomerated in the presence of the binder, and optionally a filler, using the MADG process, to form the agglomerated secondary particles. When further optional excipients otherthan the binder are present in a dry powder formulation of the disclosure, such as a filler, the additional excipients are typically present in the solid formulation from which the agglomerated particles are formed. Lyophilised particles that contain the API can, for example, be mixed with additional particles that comprise excipient(s), but no API. The additional particles that comprise excipient(s), but no API, can be formed by an alternative process, such as spray drying. In one example, lyophilised solid particles that comprises the API (and optionally one or more excipients), can be mixed with (additional) excipient(s) and the binder to form a solid formulation that is then agglomerated into particles so that all or most of the agglomerated particles contain the API. Alternatively, agglomerated secondary particles containing the API, in which primary particles that contain API are bound to each other by binder, can be mixed with additional particles that comprise additional excipient(s) but no API, to form a dry powder formulation that comprises the agglomerated secondary particles that contain the API and other particles that contain no API.

[0192] In the method of the first aspect of the disclosure, the method comprises the step of agglomerating a solid formulation. The constituents of the solid formulation prior to agglomeration may be in the form of a spray dried powder, a freeze-dried powder, a dry powder formulation obtained without spray drying and without freeze drying, or a combination thereof. For example, the solid formulation can comprise a powder comprising the API that is a lyophilized powder and a further powder comprising one or more excipients that has not been freeze dried.

[0193] The dry powder formulation can have a Dv50 of at least 10 pm, such as in a range of 15 to 500 pm, especially 20 to 300 pm. The dry powder formulation can have a Dv50 in a range of 25 to 100 pm. The dry powder formulation can have a Dv10 above about 10 pm, for example in the range of from 10 to 50 pm, such as from 15 to 40 pm. The dry powder formulation can have a Dv90 below about 500 pm, such as below about 250 pm.

[0194] It will be understood that, as is usual in particle size measurement, the term “Dv50” can refer to the particle size corresponding to a median volume distribution. Similarly, “Dv10” can refer to the particle size corresponding to the 10thpercentile of the cumulative volume distribution; “Dv90” can refer to the particle size corresponding to the 90thpercentile of the cumulative volume distribution. Particle size distributions may be measured using a laser diffraction particle size analyser, such as a Malvern Mastersizer 3000 available from Malvern Panalytical of Malvern, UK. Unless otherwise stated, particle sizes quoted herein are measured on a dry dispersion obtained using Venturi system operating at a dispersive pressure of 2 bar. A Mie processing method is typically used. These may also be measured by scanning electron microscopy (SEM).

[0195] Advantageously, for the dry powder formulation, no more than 10 % of the particles by volume in the dry powder formulation have a diameter of less than 10 pm. Preferably, no more than 10 % of the particles by volume in the dry powder formulation have a diameter of less than 10 pm.

[0196] The bulk density of the dry powder formulation is advantageously in the range of from 0.1 to 1 g / cm3, such as from 0.2 to 0.6 g / cm3. It has been found that lyophilised formulations, especially lyophilised formulations containing peptide APIs, are of a bulk density that is too low to be suitable for use as powders for nasal delivery. The method of the first aspect of the disclosure has been found to be effective in increasing the density of a lyophilised powder to within the range required for nasal delivery, for example to within the ranges specified above.

[0197] Preferred formulations

[0198] The dry powder formulation can comprise:

[0199] (a) bulking agent comprising one or both of (i) a filler, especially a sugar alcohol such as mannitol, and (ii) a permeability enhancer, especially a permeability enhancer which consists of or comprises one or more of a cyclodextrin, dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC), and salcaprozate (SNAC), especially DPC;

[0200] (b) a peptide API; and

[0201] (c) a binder, especially, a polymeric binder formed from N-vinylpyrrolidone monomer and cellulose binders, such as povidone and HPMC; and optionally

[0202] (d) an optional amino acid component, especially an a-amino acid with non-polar, aliphatic side groups, most especially leucine; wherein the dry powder formulation has a water content of less than 10 weight percent, advantageously less than 4 weight percent, and contains from 1 to 12 weight percent, advantageously from 1 to 5 weight percent, of the binder based on the total weight of the formulation.

[0203] The dry powder formulation can comprise:

[0204] (a) bulking agent comprising one or both of (i) a filler, especially a sugar alcohol such as mannitol, and (ii) a permeability enhancer comprising cyclodextrin as a major component (i.e. at least 70% (w / w) of the permeation enhancers present optionally in combination with further permeability enhancers as a minor component (i.e. 30% (w / w) or less of the permeation enhancers present) which can consists of or comprises one or more of dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC) and salcaprozate (SNAC), especially DPC;

[0205] (b) a peptide API; and

[0206] (c) a polymeric binder formed from N-vinylpyrrolidone monomer and cellulose binders, such as povidone and HPMC; and optionally

[0207] (d) an optional amino acid component, especially an a-amino acid with non-polar, aliphatic side groups, most especially leucine; wherein the dry powder formulation has a water content of less than 4 weight percent and contains from 1 to 5 percent by weight of the binder based on the total weight of the formulation.

[0208] In the formulations described above, the filler can constitute from 25 to 50 % of the formulation by weight and the permeability enhancer may constitute from 30 to 65 % of the formulation by weight. For example, the formulation can comprise from 25 to 50 % (w / w) of sugar alcohol, especially mannitol, and 30 to 60 % (w / w) of cyclodextrin. The formulation can include less than 10 % (w / w) of further permeability enhancers in addition to the cyclodextrin, such as less than 10 % in total of one or more of dodecylphosphocholine (DPC), lauroyl-L-carnitine (LLC), and salcaprozate (SNAC).

[0209] When the one or more excipients other than a binder is or includes one or more cyclodextrin permeability enhancers, the one or more cyclodextrins can have 5 to 10 glucose units, and / or be selected from p-cyclodextrin (IUPAC name: cyclomaltoheptaose, also known as “Betadex”) and / or 2-hydroxypropyl-p-cyclodextrin (also known as “HP-Betadex”).

[0210] EXPERIMENTAL

[0211] The following experimental section shows how to provide a dry powder formulation that: is well suited to collection (e.g. in terms of static charge, aggregation, flowability, adhesion to vessel); has a low moisture (especially, low water) content (ideally less than 5% w / w; e.g. analysed by Karl Fischer colorimetry); is formed of appropriately sized particles; has a good yield (when formed by spray drying from a solution in purified water of the powder components; ideally, the yield is more than 50%); and / or has an appropriate glass transition temperature (e.g. analysed by modulated differential scanning calorimetry, mDSC).

[0212] Aformulation preferably meets at least some, ideally all, of the above criteria.

[0213] Thus, the quality target product profile for the dry powder formulations is listed in Table 1.

[0214] Table 1: Quality target product profile

[0215] Excipients as shown in Table 2 were used to form excipient packages as dry powder formulations. Table 2: Materials

[0216] Example excipient packages 1 to 12 were prepared by freeze drying from a solution of their components in purified water. The constituents of the excipient packages are shown in Table 3, which provides % w / w of components based on the total weight of the excipient package (not on the total weight of the final powder, which can further comprise water).

[0217] Table 3: Formulations

[0218] Particle agglomeration - excipient mixtures Example excipient mixtures 1 to 12 were prepared by combining a total of 2.5 g of the constituents in the proportions shown in Table 3 in an appropriate container, such as, for example, 16 ounce (475 ml) glass jars, and subjecting the mixtures to fluidization using RAM at an acceleration of 95 G for a duration of 1 minute. A LabRAM II, Resodyn accoustic mixer obtained from Resodyn, Butte, Montana, USA. MADG was carried out in the LabRAM II, Resodyn acoustic mixer operating at an acceleration of 35 G for a duration of 3 minutes with 2% water (50 pl) added using an NS130K SONOZAP atomizer obtained from Sonaer of Melville, New York, USA, operating at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz and a power output and 2.4 watts to provide a plume of fine water droplets.

[0219] Moisture Content

[0220] The moisture content can be analysed by a colorimetric Karl Fischer test. Suitable powders tend to have a moisture content of less than 5 % w / w, based on the total weight of the powder formulation.

[0221] The parameters described below may used to determine the moisture content:

[0222] Particle Size Distribution (PSD)

[0223] The particle size distribution of the prepared formulations can be analysed using a Malven Mastersizer 3000, obtainable from Malvern Panalytical of Malvern, U.K or a Symaptec instrument. The formulation was dispersed as a dry dispersion via a Venturi system at a pressure of 2 bar at room temperature and PSD was determined by laser diffraction using an Mie processing method.

[0224] The dry powder formulation suitably has a Dv50 in a range of 25 to120 pm. The dry powder formulation suitably has a Dv10 of at least about 10 pm and a Dv90 below about 250 pm. Suitably, no more than 15% of the volume of the dry powder formulation is made up of particles have a diameter of less than 10 pm.

[0225] The particle size distribution of the formulations 1 to 12 of Table 3 above following the agglomeration process described above are shown in Tables 4 and 5 below:

[0226] Table 4: Formulations properties following RAM

[0227] The initial RAM process was found to substantially increased the density of the excipient mixtures, with a four-fold increase in density being typical. However, the particle size distribution remained unsuitable for nasal delivery with a substantial proportion of fine particles remaining. Typically, more than 10% by volume of the formulations after RAM processing were made up of particles having a diameter of less than 10 pm.

[0228] Table 5: Formulation properties following MADG

[0229] The MADG step further increased the density of the particles, but to a lower degree than the initial RAM step. However, the MADG step led to a substantial reduction in the proportion of particles that have a particle size of less than 10 pm. The final column of

[0230] Table 5 shows the percentage reduction in the volume of the formulation made up of particles that have a particle size of less than 10 pm. The water content of each of formulations 1 to 12 was 2%. Example formulations 13 to 24 were prepared by combining the excipients as supplied by the manufacturer and lyophilized leuprolide API or lyophilized semaglutide API as solid powders. The % w / w of components based on the total weight of the excipient package (not on the total weight of the final powder, which can further comprise water) are shown in Table 6 below.

[0231] Table 6: Formulations comprising API

[0232] Example mixtures 13 to 27 were prepared by combining a total of 35 g of the constituents in the proportions shown in Table 6 in 16 ounce (475 mL) glass jars and subjecting the mixtures to fluidization using RAM in a LabRAM II, Resodyn accoustic mixer for 45 minutes. The mixtures of examples 28 to 32 were additionally mixed in a ball mill prior to fluidization using RAM.

[0233] MADG for formulations 13 to 24 was carried out with the acoustic mixer operating at an acceleration of 35 G for a duration of 3 minutes with 2% added water (50 pl) at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz at a power output of 2.4 watts.

[0234] MADG for formulation 25 was carried out in the acoustic mixer operating at an acceleration of 35 G for a duration of 3 minutes with 4% added water (100 pl) at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz at a power output of 2.4 watts. MADG for formulations 26 to 32 were carried out in the acoustic mixer operating at an acceleration of 35 G for a duration of 3 minutes with the amount of added water listed in Table 7 below at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz at 2.4 watts. The particle size distribution of the formulations 13 to 32 of Table 6 above following the agglomeration process described above are shown in Table 7 below:

[0235] Table 7: Formulation properties following RAM and MADG

[0236] The results in table 7 demonstrate that when a formulation is prepared in accordance with the process of the invention, it is possible to produce dry powder formulations that are suitable for nasal delivery.

[0237] The improved results obtained with formulations 17 to 25 compared to those of formulations 13 to 16 indicate that the inclusion of a filler having an average particle size of 50 to 100 pm may be advantageous compared to the use of a filler with a smaller particle size. The inclusion of a permeation enhancer also appearto improve the particle size distribution of the formulation, with a DPC having a greater positive impact on the particle size distribution that LLC. Example formulation 25 demonstrates that the methods of the invention can be used to prepare particles with an acceptable particle size distribution for nasal delivery using formulations with a high portion of lyophilised API. However, when the amount of leuprolide API exceeded 50% in formulations 26 and 27 it was necessary to include a high amount of waterto achieve an acceptable particle size distribution.

[0238] Example formulations 28 to 32 demonstrate that the invention is appliable to other APIs, the results obtained with leuprolide being reproducible with the alternative peptide API, semaglutide.

[0239] Table 8: Formulations comprising semaglutide

[0240] Example mixtures 33 to 35 were prepared by combining a total of 35 g of the constituents in the proportions shown in Table 8 in 16 ounce (475 mL) glass jars and subjecting the mixtures to fluidization in a LabRAM II, Resodyn accoustic mixer for 45 minutes.

[0241] MADG for formulations 33 to 35 was carried out with the acoustic mixer operating at an acceleration of 35 G for a duration of 3 minutes with the amount of added water shown in Table 9 below at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz at 2.4 watts.

[0242] The particle size distribution of the formulations 33 to 35 of Table 8 above following the agglomeration process described above are shown in Table 9 below:

[0243] Table 9: Formulation properties following RAM and MADG

[0244] The addition of 3.3 wt% water to formulation 33 also provided a viable formulation, whereas significant granulation was observed when 6.6 wt% water was added and the addition of 13.7 wt% water led to over granulation with improper fluidization of the solid formulation during MADG. The addition of 10 wt% water to formulations 34 and 35 led to over granulation with improper fluidization of the solid formulation during MADG.

[0245] Example mixtures 36 and 37 comprising riboflavin (B2) were prepared to confirm the applicability of the method of the invention to additional classes of API. Table 10: Formulations comprising riboflavin

[0246] Example mixtures 36 and 37 were prepared by combining 1.75 g of riboflavin (B2) and 0.75g of HPMC and subjecting the mixtures to fluidization using RAM in a LabRAM II, Resodyn acoustic mixer operating at 45G for 5 minutes. MADG for on formulations 36 and 37 was carried out with the acoustic mixer operating at an acceleration of 35 G for a duration of 3 minuteswith the amount of added water shown in Table 11 below at a flow rate of 150 pl / min with the ultrasonic nozzle operated at 130 Hz at 2.4 watts.

[0247] Table 11: Formulation properties following RAM and MADG The applicability of the method of the invention to a hydrophobic API was confirmed by preparing the formulations shown in Table 12 below. RAM mixing of the constituents was carried out in a LabRAM II, Resodyn acoustic mixer operating at an acceleration of 45G for 5 minutes and then granulation was performed at 35G for 4 minutes with water being added at 150 pl / min with the ultrasonic nozzle operated at 130 Hz at 2.4 watts. Table 12: Formulations comprising loxapine and properties following RAM and MADG The formulations were vacuum dried after MADG processing at 32 °C for 48 hours and then particle size distribution was determined using a Malvern Mastersizer 3000 at 2.0 bar dispersive pressure. Where in the foregoing description, features or limitations are mentioned which have equivalents that are known, evident or foreseeable to those skilled in the art in the light of the present disclosure, then such equivalents are incorporated herein as if particularly set forth. Reference should be made primarily to the claims for determining the scope of the subject-matter of the present disclosure. The scope of protection sought by the present application further encompasses any such equivalents. It will also be appreciated by those skilled in the art that features or limitations of the disclosed subject-matter that are described as preferable, suitable, advantageous, convenient or the like may be optional and may not limit the scope of the independent claim(s) or the protection sought unless explicitly stated otherwise. Moreover, it is to be understood that such optional features or limitations, while of potential benefit in some implementations of the disclosed subject-matter, may be undesirable, and may therefore be absent or omitted in other implementations.

Claims

CLAIMS1. A method of forming a dry powder formulation of particles suitable for nasal delivery using moisture activated dry granulation (MADG), the dry powder formulation comprising an API and one or more excipients, wherein the one or more excipients comprise or consist of at least one binder, the method comprising the steps of:(a) fluidizing a dry composition comprisingthe API;(b) adding water to the fluidized dry composition as a mist of droplets to form a solid formulation; and(c) agglomerating the solid formulation to form agglomerated particles comprising the API, wherein the one or more binders are advantageously: included in the dry composition prior to fluidization; added during fluidization of the dry composition; added separately to or simultaneously with the addition of the water; or added after the water either during or prior to the agglomeration step.

2. The method according to claim 1 , wherein at least one binder is present in the solid formulation in a total amount of from 1 to 10 percent by weight, based on the total weight of the solid formulation and / or water is present in the solid formulation in an amount of up to 10 percent by weight based on the total weight of the solid formulation.

3. The method according to claim 1 , wherein at least one binder is present in the solid formulation in a total amount of from 1 to 6 percent by weight based on the total weight of the solid formulation, and wherein water is present in the solid formulation in an amount of up to 6 percent by weight based on the total weight of the solid formulation.

4. The method of any one of claims 1 to 3, comprising adding a mist of liquid from an ultrasonic nozzle.

5. The method of any preceding claim, wherein the dry composition is fluidized using resonant acoustic mixing (RAM) prior to addition of the water.

6. The method of any preceding claim, wherein the density of the solid formulation increases by at least 3-fold, especially at least 5-fold over steps (a) to (c).

7. The method of any preceding claim, wherein the water is added to the solid formulation as a mist of droplets having a median volume droplet size (Dv50) of less than 100 pm.

8. The method of any preceding claim, wherein the binder is present in the dry composition or is added to the fluidized dry composition with the water, e.g. as an aqueous solution.

9. The method of any preceding claim, wherein the API is a peptide, especially a GLP- 1 receptor agonist.

10. The method of any preceding claim, wherein the binder is water-activated binder.11 . The method of any preceding claim, wherein the one or more excipients includes a filler.

12. The method of any preceding claim, wherein the one or more excipients includes a permeability enhancer.

13. A dry powder formulation of particles suitable for nasal delivery, which is obtainable using the method of any one of claims 1 to 12, the dry powder formulation comprising: an active pharmaceutical ingredient (API) and one or more excipients that comprise or consist of at least one binder, wherein the particles include agglomerated secondary particles that include constituent primary particles comprising the API bound to each other with the at least one binder.

14. The dry powder formulation of claim 13, wherein the particles have a Dv50 in the range of 10 to 500 pm and less than 10% by volume of particles having a diameter of less than 10 pm.

15. The dry powder formulation of claim 13, wherein the total amount of binder(s) present is from 1 to 6 percent by weight based on the total weight of the dry powder formulation, and no more than 6 percent by weight of water, based on the total weight of the dry powder formulation, is present in the dry powder formulation.

16. The dry powder formulation of any one of claims 13 to 15, wherein the agglomerated particles include first primary particles that contain the API, and second primary particles that lack the API, wherein the first and second primary particles are bound together with the at least one binder.

17. The dry powder formulation of any one of claims 13 to 16, wherein the density of the formulation is from 0.2 to 0.6 g / cm3.

18. The dry powder formulation of any one of claims 13 to 17, wherein the solid particulate powder has a Dv10 of above 10 pm, especially a Dv10 of above 15 pm, and a Dv90 of below 500 pm, especially a Dv90 of below 250 pm.

19. The dry powder formulation as defined in any one of claims 13 to 18, wherein the solid particulate powder having a Dv50 in a range of 20-200 pm, especially in the range of from 25-120 pm.

20. A dosage form for nasal delivery or inhalation, comprising the dry powder formulation as defined in any one of claims 13 to 19.

Images