Rifapentine composition

Abstract

The present invention relates to a solid composition comprising nanoparticles of rifamycin, such as rifapentine, dispersed in a matrix comprising a first excipient and a second excipient. The invention also relates to microneedle arrays, implantable rods, aqueous dispersions and pharmaceutical compositions obtained from said solid compositions as well as their uses.

Description

[0001] This invention relates to chemical compositions. More specifically, but not exclusively, this invention relates to chemical compositions for the treatment and prevention of infections, and has a particular (but not exclusive) application in the treatment and prevention of bacterial infections such as tuberculosis.

[0002] background

[0003] Tuberculosis is an infectious disease that primarily affects the lungs and is usually caused by the bacterium Mycobacterium tuberculosis. Most cases are latent tuberculosis, and those with the infection are asymptomatic and non-infectious. A small number of cases, particularly prevalent in immunocompromised patients, continue to present with symptoms. Therefore, although latent infection itself poses a small risk, the fact that it can progress to active disease makes treatment necessary for affected individuals. Due to its thick capsule, Mycobacterium tuberculosis is resistant to degradation by macrophages, and the thick capsule helps it resist reactive oxygen species in phagocytosomnography. Furthermore, granuloma formation isolates the bacteria, causing them to become dormant, thus triggering latent infection.

[0004] Public health initiatives prioritize the use of vaccines to limit the risk and spread of tuberculosis. However, these vaccines are not entirely effective in the population, and their effectiveness diminishes over time. Therefore, numerous treatment regimens have been developed to address active and latent tuberculosis, generally involving the administration of antibiotics over extended periods. For example, treatment for latent tuberculosis (often referred to as "tuberculosis prevention") requires at least one month and typically three to nine months. Due to the length of these treatment regimens, the development of antibiotic resistance is not uncommon, and this problem is exacerbated by patient adherence issues, which may be more common in latent tuberculosis because patients do not experience the physical discomfort of the infection itself during treatment. Therefore, many regimens utilize combinations of antibiotics in addition to the extended treatment duration.

[0005] A family of antibiotics commonly used in the treatment of tuberculosis (latent and active) is the rifamycin class, which is also used to treat leprosy. This family includes rifamycin SV, rifampin, rifabutin, rifapentine, rifalacizumab, and rifaximin. The structure of rifapentine is reproduced as follows:

[0006]

[0007] To improve patient compliance and thus successfully treat infections, it is desirable to provide patients with formulations of these antibiotics that are more effective and / or less troublesome. For example, alternative dosage forms and / or reduced dosing frequencies. Invention Overview

[0009] A first aspect of the present invention relates to a solid composition comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a matrix comprising a first excipient and a second excipient, wherein said first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose, and wherein said second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80, and sorbitol monolaurate.

[0010] The first excipient and the second excipient may be selected from the following combinations:

[0011] -PVP and benzalkonium chloride

[0012] -PVP and AOT

[0013] -PVP and polysorbate 20

[0014] -PVP and polysorbate 80

[0015] - Lactose and AOT

[0016] - Lactose and poloxamer

[0017] - Sucrose and benzalkonium chloride

[0018] -Sugar and AOT

[0019] - Sucrose and dehydrated sorbitol monolaurate

[0020] -Sugar and poloxamer

[0021] - Poloxamer and polysorbate 20

[0022] -Polosham and AOT

[0023] -PEG and AOT

[0024] -PEG and poloxamer

[0025] The first excipient and the second excipient may be selected from the following combinations:

[0026] -PVP and AOT

[0027] - Lactose and AOT

[0028] The solid composition may contain:

[0029] 10 to 80% by weight of the aforementioned rifamycin, such as rifapentine;

[0030] 10 to 80% by weight of the first excipient; and

[0031] 1 to 25% by weight of the second excipient.

[0032] The solid composition may contain:

[0033] 30 to 60% by weight of the aforementioned rifamycin, such as rifapentine;

[0034] 30 to 60% by weight of the first excipient; and

[0035] 5 to 20% by weight of the second excipient.

[0036] The solid composition may contain:

[0037] 40 to 50% by weight of the aforementioned rifamycin, such as rifapentine;

[0038] 40 to 50% by weight of the first excipient; and

[0039] 5 to 15% by weight of the second excipient.

[0040] The solid composition may contain:

[0041] 30 to 50% by weight of the aforementioned rifamycin, such as rifapentine;

[0042] 40 to 60% by weight of the first excipient; and

[0043] 1 to 10% by weight of the second excipient,

[0044] The solid composition may contain:

[0045] 35 to 45% by weight of the aforementioned rifamycin, such as rifapentine;

[0046] 50 to 60% by weight of the first excipient; and

[0047] 1 to 5% by weight of the second excipient.

[0048] Nanoparticles may have a particle size in the range of 10 to 2500 nm, preferably in the range of 20 nm to 2000 nm, more preferably in the range of 50 nm to 1500 nm, further preferably in the range of 100 nm to 1000 nm, and most preferably in the range of 200 to 800 nm.

[0049] The nanoparticles may have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.5.

[0050] A second aspect of the present invention relates to a method for preparing a solid composition according to a first aspect of the present invention, the method comprising:

[0051] (a) Preparing an oil-in-water emulsion, the oil-in-water emulsion comprising:

[0052] - An oil phase containing the rifamycin, such as rifapentine; and

[0053] - An aqueous phase comprising a first excipient and a second excipient, each as defined in the first aspect of the invention; and

[0054] (b) Remove oil and water from the oil-in-water emulsion to form the solid composition.

[0055] A third aspect of the present invention relates to a method for preparing a solid composition according to a first aspect of the present invention, the method comprising:

[0056] (a) Providing an active solution of the rifamycin, such as rifapentine, contained in a water-miscible solvent;

[0057] (b) Providing a carrier substance solution comprising a first excipient and a second excipient, each as defined in the first aspect of the invention;

[0058] (c) Mix the solutions prepared in steps (a) and (b); and

[0059] (d) Remove the mixed solvent to prepare the solid composition.

[0060] Alternatively, the method may include:

[0061] (a) Providing an active solution containing the rifamycin, such as rifapentine, and the second excipient in a water-miscible solvent;

[0062] (b) Providing a carrier substance solution comprising a first excipient as defined in any one of claims 1 to 6;

[0063] (c) Mix the solutions prepared in steps (a) and (b); and

[0064] (d) Remove the mixed solvent to prepare the solid composition.

[0065] The method of the second aspect of the present invention, wherein the step of removing oil and water from the oil-in-water emulsion, or the method of the third aspect of the present invention, wherein the step of removing the mixed solvent includes spray drying or freeze drying.

[0066] A fourth aspect of the present invention relates to an aqueous dispersion comprising a plurality of rifamycin, such as rifapentine, nanoparticles, said nanoparticles being dispersed in an aqueous medium and stabilized by a mixture of a first excipient and a second excipient; wherein said first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose, and wherein said second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80, and sorbitol monolaurate.

[0067] The aqueous dispersion may include rifamycin nanoparticles, such as rifapentine, as defined in any one of claims 2 to 8, a first excipient, and a second excipient in an aqueous medium.

[0068] Rifamycin, such as rifapentine, can be present in an aqueous dispersion at a concentration of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0069] The fifth aspect of the present invention relates to a method for preparing an aqueous dispersion according to the fourth aspect of the present invention, the method comprising dispersing a solid composition according to the first aspect of the present invention in an aqueous medium.

[0070] The sixth aspect of the present invention relates to a pharmaceutical composition comprising the solid composition described in the first aspect of the present invention or the aqueous dispersion described in the fourth aspect of the present invention, and optionally one or more other pharmaceutically acceptable excipients.

[0071] The seventh aspect of the present invention relates to an injectable formulation comprising the solid composition of the first aspect of the present invention, the aqueous dispersion of the fourth aspect of the present invention, or the pharmaceutical composition of the sixth aspect of the present invention.

[0072] The injectable formulation may be a subcutaneous or intramuscular injectable formulation, and optionally the injectable formulation is suitable for provision in the form of a reservoir.

[0073] The eighth aspect of the present invention relates to a method for preparing an implantable rod, the method comprising the steps of compressing a solid composition according to the first aspect of the present invention and heating the compressed solid composition for a period of time.

[0074] The solid composition can be compressed in a mold, optionally in the form of a cylinder.

[0075] The solid composition can be heated to 60 to 160°C, preferably 80 to 140°C, more preferably 100 to 120°C, and most preferably about 105°C.

[0076] Compression can be performed under reduced pressure atmosphere.

[0077] The heating process can last from 1 minute to 40 minutes, preferably 5 minutes to 30 minutes, more preferably 10 minutes to 25 minutes, and most preferably about 20 minutes.

[0078] The method described in the eighth aspect of the present invention may further include the step of cooling the rod, optionally under a reduced pressure atmosphere.

[0079] The ninth aspect of the present invention relates to an implantable rod prepared by the method described in the eighth aspect of the present invention.

[0080] The tenth aspect of the present invention relates to an implantable rod comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a monolithic material comprising a first excipient and a second excipient, wherein said first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose, and wherein said second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80, and sorbitol monolaurate.

[0081] The rifamycin nanoparticles, such as rifapentine, the first excipient, and / or the second excipient may be as defined in the first aspect of the invention.

[0082] The eleventh aspect of this invention relates to a method for preparing a microneedle array, the microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition, the method comprising the following steps:

[0083] (a) Dispersing the solid composition according to any one of claims 1 to 8 and at least one structural polymer in a solvent to form a microneedle precursor dispersion;

[0084] (b) Place the microneedle precursor dispersion into a mold;

[0085] (c) The microneedle precursor dispersion is compressed in the mold and then dried to form microneedles containing the first composition;

[0086] (d) Add the substrate precursor solution to the mold;

[0087] (e) Compress the substrate precursor solution and then dry it to form a substrate of the second composition; and

[0088] (f) Remove the microneedle array from the mold.

[0089] Steps b) and c) can be repeated before steps d) to f).

[0090] The solvent may be an aqueous solvent, such as water.

[0091] The at least one structural polymer may be selected from PVA, PVP, and combinations thereof.

[0092] The substrate precursor solution may contain a base polymer dispersed in an aqueous solvent such as water and optionally one or more additives such as glycerol, wherein the base polymer is selected from PVP.

[0093] The twelfth aspect of the present invention relates to a microneedle array prepared by the method described in the eleventh aspect of the present invention.

[0094] The thirteenth aspect of the present invention relates to a microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition, wherein the first composition comprises nanoparticles of rifamycin, such as rifapentine, dispersed in a bulk material comprising a first excipient, a second excipient, and at least one structural polymer.

[0095] The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0096] The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0097] The rifamycin nanoparticles, such as rifapentine, the first excipient, and / or the second excipient may be as defined in the first aspect of the invention.

[0098] The at least one structural polymer may be selected from PVA, PVP, and combinations thereof.

[0099] The second composition may contain a base polymer, such as PVP, and optionally one or more additives, such as glycerin.

[0100] The fourteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to the ninth or tenth aspect of the present invention, or a microneedle array according to the twelfth or thirteenth aspect of the present invention, which are used as a drug.

[0101] The fifteenth aspect of the present invention relates to a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to the ninth or tenth aspect of the present invention, or a microneedle array according to the twelfth or thirteenth aspect of the present invention, for the treatment and / or prevention of tuberculosis, such as latent tuberculosis.

[0102] The aqueous dispersion, pharmaceutical composition, or injectable formulation for use according to the fourteenth or fifteenth aspect of the invention, wherein the concentration of rifapentine may be 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0103] An implantable rod for use according to the fourteenth or fifteenth aspect of the invention, wherein rifamycin, such as rifapentine, is present in the implantable rod at a concentration in the range of 30 to 80% by weight, preferably 40 to 70% by weight, and most preferably about 50% by weight.

[0104] The microneedle array according to the fourteenth or fifteenth aspect of the invention, wherein the microneedle array may contain rifamycin, such as rifapentine, in the range of 0.1 to 20 mg, preferably between 0.5 and 10 mg, more preferably between 1 and 5 mg, and most preferably between 1 and 2 mg.

[0105] The sixteenth aspect of the present invention relates to a method for treating and / or preventing tuberculosis, the method comprising administering to a patient suffering from tuberculosis or at risk of tuberculosis a therapeutically effective amount of a solid composition according to the first aspect of the present invention, an aqueous dispersion according to the fourth aspect of the present invention, a pharmaceutical composition according to the sixth aspect of the present invention, an injectable formulation according to the seventh aspect of the present invention, an implantable rod according to the ninth or tenth aspect of the present invention, or a microneedle array according to the twelfth or thirteenth aspect of the present invention.

[0106] In the method described in the sixteenth aspect of the present invention, the concentration of rifamycin, such as rifapentine, in the aqueous dispersion, the pharmaceutical composition, or the injectable formulation may be 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0107] In the method described in the sixteenth aspect of the invention, the concentration of rifamycin, such as rifapentine, in the implantable rod can be in the range of 40 to 80% by weight, preferably 50 to 70% by weight, and most preferably about 60% by weight.

[0108] In the method described in the sixteenth aspect of the present invention, the microneedle array may contain rifamycin, such as rifapentine, in the range of 1 to 20 mg, preferably between 2 and 10 mg, more preferably about 5 mg of rifamycin, such as rifapentine.

[0109] In the method described in the sixteenth aspect of the invention, the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod can form a reservoir in the patient's body, optionally wherein the reservoir maintains a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient's body for a period of at least two weeks, preferably at least one week more, more preferably at least two months, further more preferably at least three months, and most preferably at least four months.

[0110] In the method described in the sixteenth aspect of the invention, the microneedle array can gradually release rifamycin, such as rifapentine, optionally wherein the microneedle array maintains a therapeutically effective concentration of rifamycin in the patient's body for a period of at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.

[0111] In the method described in the sixteenth aspect of the invention, the patient may require administration of the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod up to three times, preferably up to two times, and most preferably only once, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, throughout the duration of treatment.

[0112] In the method described in the sixteenth aspect of the invention, the patient may need to use the microneedle array for administration up to six times a day, preferably up to four times a day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient's body for the duration of treatment. Brief description of the attached diagram

[0114] Figure 1The graph shows the change in rifapentine concentration over time in plasma obtained from male Sprague Dawley rats after intramuscular injection of an aqueous dispersion containing rifapentine nanoparticles according to the invention, as described in Example 6.

[0115] Figure 2 A graph showing the change in rifapentine concentration over time in plasma obtained from male Sprague Dawley rats after implantation of an implant containing rifapentine nanoparticles according to the invention, as described in Example 8. For clarity, the curves of animals provided with two 15 mm implants showed the highest rifapentine concentrations at the end of the experiment, the curves of animals provided with one 15 mm implant showed lower rifapentine concentrations, and the curves of animals provided with two 8 mm implants terminated at approximately 500 hours.

[0116] Figure 3 This demonstrates the effect achieved by microneedles containing rifapentine nanoparticles according to the invention. The needle penetration percentage of the continuous layer of M, as described in Example 10.

[0117] Figure 4 The diagram shows rifapentine permeation into the Franz diffusion cell (in μg) achieved by microneedles containing rifapentine nanoparticles according to the invention, as described in Example 11. The higher lines correspond to microneedle arrays cast twice, showing a greater amount of rifapentine permeation; however, the lower lines correspond to microneedle arrays cast only once, showing a lesser amount of rifapentine permeation.

[0118] Figure 5 The left side shows the amount of rifapentine delivered by the microneedles containing rifapentine nanoparticles according to the invention via drug penetration (blue, lower column) and skin deposition (pink, higher column); the right side shows the percentage of rifapentine delivered by the microneedles containing rifapentine nanoparticles according to the invention via drug penetration (blue, lower column) and skin deposition (pink, higher column), as described in Example 11.

[0119] Figure 6 A graph showing the change in rifapentine concentration over time in plasma obtained from female Sprague Dawley rats after administration of a microneedle array containing rifapentine nanoparticles according to the invention, as described in Example 12.

[0120] Figure 7 The graph shows the change in rifapentine concentration over time in plasma obtained from male Sprague Dawley rats after intramuscular injection of rifapentine nanoparticles according to the invention at a dose of 150 mg / kg, as described in Example 14.

[0121] Figure 8 The graph shows the change in rifapentine concentration over time in plasma obtained from male Sprague Dawley rats after intramuscular injection of rifapentine nanoparticles according to the invention at a dose of 300 mg / kg, as described in Example 14.

[0122] definition

[0123] Unless otherwise stated, the term "particle size" as used in this application refers to the Z-mean hydrodynamic diameter. Particle size and polydispersity can be evaluated using any suitable technique known in the art, such as laser diffraction, laser scattering, or electron microscopy. In embodiments of the invention, particle size and polydispersity (i.e., Z-mean hydrodynamic diameter) are evaluated by dispersing the solid composition at a concentration of 1 mg / mL in an aqueous medium and determining the particle size using dynamic light scattering (e.g., using a Malvern Panalytical Limited Zetasizer Ultra).

[0124] In the context of this invention, the term nanoparticles can be broadly interpreted to include particles having a particle size of less than 5 μm, preferably less than 3 μm, or most preferably less than 1 μm. In embodiments, the particle size is in the range of 100 to 800 nm.

[0125] The term "rifamycin" refers to antibiotics belonging to the rifamycin family, as well as their pharmaceutically acceptable salts, solvates, derivatives, prodrugs, and any polymorphic or amorphous forms. Specific rifamycin drugs include rifamycin SV, rifampin, rifabutin, rifapentine (the structure of which is shown in the background section), rifalac, and rifaximin. These drugs are generally poorly soluble in water.

[0126] Unless otherwise stated, the term "patient" includes both human and animal patients.

[0127] The term "SDN" is an abbreviation for "solid pharmaceutical nanoparticles," and in this application, this abbreviation is used to refer to the solid composition of the present invention.

[0128] The term "other drugs" as used in this application refers to the following (non-exhaustive) list of other drugs that can be used in combination with the rifamycin drugs described in this application and formulated in combination therapies for prophylaxis and / or treatment according to the present invention: ethambutol, isoniazid, pyrazinamide, streptomycin, aminoglycosides (e.g., amikacin, kanamycin), polypeptides (e.g., capreomycin, purpuricin, envelopromycin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin), thioamides (e.g., ethionamide, prothionamide), cycloserine, terizone, macrolides (e.g., clarithromycin), linezolid, thiourea, thioridazine, arginine, vitamin D, bedaquiline, and their pharmaceutically acceptable salts, solvates, and derivatives, their prodrugs, and any polymorphic or amorphous forms thereof.

[0129] It will be understood that references to “preventing” or “prevention” refer to preventive treatment and include preventing or delaying the onset of clinical symptoms of a developing condition, symptom, or disease in a patient who may have or be susceptible to the condition, symptom, or disease but has not yet experienced or exhibited clinical or subclinical symptoms of the condition, symptom, or disease.

[0130] It should be understood that references to “treatment” or “treating” of a state, symptom or disease include: (1) suppressing a state, symptom or disease, i.e. preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or the development of at least one of its clinical or subclinical symptoms; or (2) alleviating or reducing a disease, i.e. causing the disappearance of a state, symptom or disease or at least one of its clinical or subclinical symptoms.

[0131] In the context of this invention, the terms "preventing" or "prevention" should not be considered to refer only to drugs that are completely effective in treating a particular condition, symptom, or disease, but should also cover drugs that are partially effective.

[0132] Furthermore, when considered from the perspective of the patient population to be treated, the terms "preventing" and "prevention" should be considered to cover drugs that help reduce the incidence of a target condition or disease (such as tuberculosis) in the target population, as well as drugs that help completely eradicate a target condition, condition, or disease from the target population.

[0133] "Therapeutic effective amount" refers to the amount of a compound that is sufficient to treat and / or prevent a disease when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the patient's age, weight, etc.

[0134] As used in this application, the term "consistently of..." means that the given product or method consists only of the specified substance or step and optional other substances or steps that do not materially affect the features of the claimed invention. Suitably, a product consisting substantially of one or more specified substances contains greater than or equal to 85% of the specified substance, more preferably greater than or equal to 90%, more preferably greater than or equal to 95%, and most preferably greater than or equal to 98% of the specified substance.

[0135] Unless otherwise stated, the weight percentage (“wt%”) discussed in this application refers to the weight percentage of a specific component as a proportion of the total weight of the composition.

[0136] The reference in this application to a component that is “(substantially) immiscible” with another component means that a mixture containing the two components cannot form a single phase.

[0137] Injectability is a measure of whether a solution, dispersion, or suspension is suitable for administration by injection. A composition is considered injectable if it can be manually passed through a 25G needle. It will be understood that the combination of the composition and the 25G needle is purely for the purpose of determining that the given composition is injectable and that the composition can be used in practice with needles of lower gauges. As is known in the art, 25G refers to a 25 gauge needle (i.e., a needle with an inner diameter of 0.26 mm and an outer diameter of 0.514 mm).

[0138] solid composition

[0139] A first aspect of the present invention provides a solid composition comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a mixture of solid excipients comprising a first excipient and a second excipient.

[0140] The rifamycins that make up the nanoparticles, such as rifapentine, can be amorphous (i.e., substantially non-crystalline in nature).

[0141] The solid excipient mixture is in matrix form. In one embodiment, the matrix is ​​highly porous and dissolves rapidly upon contact with an aqueous solution. In an alternative embodiment, the matrix is ​​relatively compact but still readily dissolves upon contact with an aqueous solution.

[0142] The solid compositions of the present invention can be administered to a patient as is, or further formulated to provide pharmaceutical compositions, in the form of, for example, tablets, capsules, lozenges, or dispersible powders or granules. In one embodiment, they can be formulated into implantable rods.

[0143] The nanoparticles of the present invention have an average particle size of less than 5 micrometers (μm). In specific embodiments, the nanoparticles have an average particle size of 10 nm to 2500 nm, preferably 20 nm to 2000 nm, more preferably 50 nm to 1500 nm, further preferably 100 nm to 1000 nm, and most preferably 100 nm to 500 nm. In embodiments, the nanoparticles have a particle size in the range of 1 to 1000 nm. It will be understood that references to particle size refer to the Z-mean hydrodynamic diameter of the nanoparticles.

[0144] The nanoparticles may have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.5.

[0145] The particle size and polydispersity of nanoparticles can be evaluated using any suitable technique known in the art (e.g., laser diffraction, laser scattering, electron microscopy). In embodiments of the invention, the solid composition is dispersed in an aqueous medium at a concentration of 1 mg / mL and dynamic light scattering (e.g., using...) is employed.

[0146] The Malvern Panalytical Limited Zetasizer Ultra measures particle size to assess particle size and polydispersity (i.e., Z-mean hydrodynamic diameter).

[0147] The solid composition may comprise particles or granules of a relatively large size, for example, 5 to 30 micrometers (μm), but each particle or granule may comprise multiple nanoparticles of rifamycin, such as rifapentine, dispersed in a mixture of a first excipient and a second excipient. Alternatively, the solid composition may comprise larger, monolithic materials of any suitable shape or size. Furthermore, when the solid composition is mixed with an aqueous medium, these monolithic materials, larger particles or granules, disperse to form discrete rifamycin nanoparticles.

[0148] In one embodiment, the solid composition comprises a first excipient and a second excipient. In an alternative embodiment, the solid composition comprises an additional excipient selected from those listed herein as suitable first and / or second excipients.

[0149] In one embodiment, the solid composition comprises essentially a rifamycin, such as rifapentine, a first excipient, and a second excipient. In another embodiment, the solid composition comprises a rifamycin, such as rifapentine, a first excipient, and a second excipient.

[0150] First excipient

[0151] The first excipient is a hydrophilic polymer or a sugar. In principle, any hydrophilic polymer or sugar suitable for use in pharmaceutical formulations can be used in this invention.

[0152] Particularly suitable polymers include: polyvinylpyrrolidone (including PVP k30 (such as Kollidon)). TM 30 obtained), PVP k17 (such as can be used as Kollidon) TM 17PF obtained), PVP k15 (e.g., can be used as Plasdone) TM C-15 obtained) and PVP k12 (such as can be used as Kollidon) TM 12PF (obtained); polyethylene glycols (such as PEG 400, PEG 1000 and PEG 4000); and nonionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) and two laterally connected hydrophilic chains of polyethylene oxide (poly(ethylene oxide)), also known as poloxamers (such as those available in Synperionics). TM Pluronic TM and Kolliphor TM Those obtained within the scope, including Pluronic TM F68 and Pluronic TM F127).

[0153] It will be understood that any weight-average molecular weight (Mw) or number-average molecular weight (Mn) values ​​referenced in this application can be determined by any method known in the art suitable for a particular polymer.

[0154] In one embodiment, polyvinylpyrrolidone has a weight average molecular weight of 1,000 to 1,000,000 g / mol. In a specific embodiment, polyvinylpyrrolidone has a weight average molecular weight of 1,000 to 40,000 g / mol, preferably 2,000 to 20,000 g / mol. In another embodiment, polyvinylpyrrolidone has a K value of 5 to 30, preferably 10 to 20, and most preferably 12 to 17. Alternatively, the K value may be about 12, about 15, or about 17. As is known in the art, the K value is obtained from relative viscosity measurements and calculated according to Fickentscher's equation.

[0155] Poloxamer is a nonionic triblock copolymer comprising a central hydrophobic chain of polypropylene and a hydrophilic chain of polyethylene oxide on either side of that central hydrophobic chain. Poloxamers are typically named with the letter "P" followed by three numbers (e.g., P407), where the first two numbers multiplied by 100 give the approximate molecular weight of the polypropylene chain, and the third number multiplied by 10 provides the percentage of polyethylene oxide content in the poloxamer. For example, P407 is a poloxamer with approximately 4,000 g / mol polypropylene molecular weight and approximately 70% polyethylene oxide content, while P188 is a poloxamer with approximately 1,800 g / mol polypropylene molecular weight and approximately 80% polyethylene oxide content. Poloxamer is also known as... And several other trade names. Suitably, the poloxamer is a pharmaceutically acceptable poloxamer. In a specific embodiment, the poloxamer is P407 or P188.

[0156] Polyethylene glycol (PEG) is a polyether containing repeating ethylene oxide units. PEG can exist in linear, branched, comb-shaped, or star-shaped forms. Preferably, the PEG is linear PEG.

[0157] PEG can have a number average molecular weight of 100 to 20,000 g / mol, preferably 500 to 10,000 g / mol, more preferably 1,000 to 8,000 g / mol, and most preferably about 4,000 g / mol.

[0158] Generally, monosaccharides, disaccharides, and oligosaccharides can be suitable for use in the solid compositions of this invention. A disaccharide is defined as a carbohydrate consisting of two monosaccharide residues. In this application, an oligosaccharide is defined as a carbohydrate consisting of 3 to 10 monosaccharide residues.

[0159] The monosaccharide may be selected from ribose, arabinose, xylose, lysolose, ribulose, xylulose, allose, azoose, glucose, mannose, gulose, idose, galactose, taloose, allulose, fructose, sorbose, and tagatose. Either D- or L-isomers may be used, with naturally occurring isomers preferred.

[0160] The disaccharide can be selected from any binary combination of the monosaccharides mentioned above. Preferred disaccharides are lactose and sucrose.

[0161] Oligosaccharides can be selected from any combination of the above monosaccharides.

[0162] In this invention, the first excipient is selected from hydrophilic polymers and sugars that, together with the second excipient as defined in this application, can stabilize rifamycin nanoparticles, such as rifapentine, in an aqueous dispersion and are also suitable for pharmaceutical use (e.g., those listed on the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (FDA CDER) list of inactive ingredients, particularly those designated as suitable for intramuscular injection).

[0163] Second excipient

[0164] The second excipient is a surfactant. In principle, any surfactant suitable for use in pharmaceutical formulations can be used in this invention. Examples of such surfactants include:

[0165] (a) Nonionic surfactants (e.g., ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitol alkyl esters; ethylated sorbitol alkyl esters; alkyl ethoxylates; Pluronics) TM Alkyl polyglucoside; stearyl alcohol ethoxylate; alkyl polyglucoside; sucrose fatty acid ester (anionic, cationic, amphoteric or zwitterionic);

[0166] (b) Anionic surfactants (e.g., alkyl ether sulfates; alkyl ether carboxylates; alkylbenzene sulfonates; alkyl ether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; alkane sulfonates; secondary n-alkane sulfonates; α-olefin sulfonates; hydroxyethyl sulfonate sulfonates; alginates);

[0167] (c) Cationic surfactants (e.g., fatty amine salts; fatty diamine salts; quaternary ammonium compounds); Surfactants; matte surfactants; sulfonium oxide surfactants); or

[0168] (d) Amphoteric surfactants (e.g., N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; amide betaine).

[0169] The surfactants particularly suitable for use in this invention can be selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0170] In this invention, the surfactant is selected from those surfactants that, together with the first excipient defined in this application, can stabilize rifamycin, such as rifapentine, nanoparticles in an aqueous dispersion and are also suitable for pharmaceutical use (e.g., those listed in the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (FDA CDER) as inactive ingredients, particularly those designated as suitable for intramuscular injection).

[0171] The specific combination of the first excipient and the second excipient

[0172] The first excipient and the second excipient may be selected from any of those outlined above. Specifically, the first excipient and the second excipient may be selected from combinations thereof:

[0173] PVP and benzalkonium chloride; PVP and AOT; PVP and poloxamer; PVP and polysorbate 20; PVP and polysorbate 80; PVP and sorbitol monolaurate;

[0174] PEG and benzalkonium chloride; PEG and AOT; PEG and poloxamer; PEG and polysorbate 20; PEG and polysorbate 80; PEG and sorbitol monolaurate;

[0175] Poloxamer and benzalkonium chloride; Poloxamer and AOT; Both are poloxamer; Poloxamer and polysorbate 20; Poloxamer and polysorbate 80; Poloxamer and sorbitol monolaurate;

[0176] Sucrose and benzalkonium chloride; sucrose and AOT; sucrose and poloxamer; sucrose and polysorbate 20; sucrose and polysorbate 80; sucrose and sorbitol monolaurate;

[0177] Lactose and benzalkonium chloride; lactose and AOT; lactose and poloxamer; lactose and polysorbate 20; lactose and polysorbate 80; lactose and sorbitol monolaurate.

[0178] The first excipient and the second excipient may be the same. It will be understood that in embodiments where both the first excipient and the second excipient are the same (e.g., in the case of poloxamer, listed as both the first excipient and the second excipient), the amounts of the first excipient and the second excipient should be combined to achieve the desired amount of excipient.

[0179] The combination of a first excipient and a second excipient is particularly suitable for use in solid compositions containing nanoparticles of rifamycin (such as rifapentine):

[0180] -PVP and benzalkonium chloride

[0181] -PVP and AOT

[0182] -PVP and polysorbate 20

[0183] -PVP and polysorbate 80

[0184] - Lactose and AOT

[0185] - Lactose and poloxamer

[0186] - Sucrose and benzalkonium chloride

[0187] -Sugar and AOT

[0188] - Sucrose and dehydrated sorbitol monolaurate

[0189] -Sugar and poloxamer

[0190] - Poloxamer and polysorbate 20

[0191] -Polosham and AOT

[0192] -PEG and AOT

[0193] -PEG and poloxamer

[0194] In the embodiments, the combination of the first excipient and the second excipient, particularly suitable for use in solid compositions containing nanoparticles of rifamycin (such as rifapentine), can be selected from:

[0195] -PVP and benzalkonium chloride

[0196] -PVP and AOT

[0197] -PVP and polysorbate 20

[0198] -PVP and polysorbate 80

[0199] - Lactose and AOT

[0200] - Lactose and poloxamer

[0201] - Sucrose and benzalkonium chloride

[0202] -Sugar and AOT

[0203] - Sucrose and dehydrated sorbitol monolaurate

[0204] - Poloxamer and polysorbate 20

[0205] In the embodiments, the combination of the first excipient and the second excipient, particularly suitable for use in solid compositions containing nanoparticles of rifamycin (such as rifapentine), can be selected from:

[0206] -PVP and AOT

[0207] - Lactose and AOT

[0208] -Sugar and AOT

[0209] -Sugar and poloxamer

[0210] -Polosham and AOT

[0211] -PEG and AOT

[0212] -PEG and poloxamer

[0213] A particularly preferred combination of a first excipient and a second excipient used in solid compositions containing nanoparticles of rifamycin (such as rifapentine) is:

[0214] -PVP and AOT

[0215] - Lactose and AOT

[0216] The most preferred combination of the first excipient and the second excipient used in solid compositions containing nanoparticles of rifamycin (e.g., rifapentine) is PVP and AOT.

[0217] Formulation of solid compositions

[0218] In a specific embodiment, the solid composition described herein may contain 10 to 95% by weight of rifamycin, such as rifapentine. Preferably, or in another embodiment, the solid composition may contain 20 to 90% by weight of rifamycin, such as rifapentine. More preferably, or in another embodiment, the solid composition may contain 30 to 80% by weight of rifamycin, such as rifapentine; 40 to 70% by weight of rifamycin, such as rifapentine; or 45 to 60% by weight of rifamycin, such as rifapentine.

[0219] The solid composition comprises a total of 5 to 90% by weight of the first excipient and the second excipient. In another embodiment, the solid composition comprises a total of 10 to 80% by weight of the first excipient and the second excipient. In yet another embodiment, the solid composition comprises a total of 20 to 70% by weight of the first excipient and the second excipient, a total of 30 to 60% by weight of the first excipient and the second excipient, or a total of 40 to 55% by weight of the first excipient and the second excipient.

[0220] The first excipient and the second excipient may be present in a mass ratio ranging from 1:1 to 8:1; preferably from about 2:1 to 6:1; more preferably from about 4:1 to 5:1.

[0221] The solid composition may contain 10 to 80% by weight of the first excipient; preferably 20 to 70% by weight of the first excipient; more preferably 30 to 60% by weight of the first excipient; and most preferably 40 to 50% by weight of the first excipient.

[0222] The solid composition may contain 1 to 25% by weight of the second excipient; preferably 3 to 20% by weight; more preferably 5 to 15% by weight. In another embodiment, the solid composition contains about 10% by weight of the second excipient.

[0223] In a specific embodiment, the solid composition comprises: 10 to 80 wt% rifamycin, such as rifapentine; 10 to 80 wt% of the first excipient; and 1 to 25 wt% of the second excipient. Preferably, the solid composition comprises: 30 to 60 wt% rifamycin, such as rifapentine; 30 to 60 wt% of the first excipient; and 5 to 20 wt% of the second excipient. More preferably, the solid composition comprises: 40 to 50 wt% rifamycin, such as rifapentine; 40 to 50 wt% of the first excipient; and 5 to 15 wt% of the second excipient. Alternatively, the solid composition comprises: 20 to 60 wt% rifapentine, such as rifamycin; 30 to 70 wt% of the first excipient; and 1 to 10 wt% of the second excipient. Preferably, the solid composition comprises: 30 to 50 wt% rifapentine, such as rifamycin; 50 to 60 wt% of the first excipient; and 2 to 5 wt% of the second excipient. More preferably, the solid composition comprises: about 40 wt% rifapentine, such as rifamycin; about 57 wt% of the first excipient; and about 3 wt% of the second excipient.

[0224] Unless otherwise stated, the above weight percentages refer to the weight percentage of a specific component as a proportion of the total weight of the solid composition.

[0225] The solid composition may contain additional excipients, for example, to further promote the dispersion or stability of the nanoparticle dispersion in aqueous media, pharmaceutically acceptable diluents, or in vivo.

[0226] Method for preparing solid compositions

[0227] The solid compositions of the present invention can be prepared by a number of methods well known in the art, including top-down physical methods such as nano (or bead) milling and high-pressure homogenization. Other suitable techniques for forming the compositions are described in general terms in Horn and Reiger, Angew. Chem. Int. Ed., 2001, 40, 4330-4361.

[0228] In a preferred method, the solid composition of the present invention is prepared by an oil-in-water emulsion technique, by which rifamycin, such as rifapentine, is dissolved in an oil phase and a first excipient and a second excipient are present in an aqueous phase. The oil and aqueous solvent are then removed by freeze-drying, spray drying, or spray granulation to provide the solid composition according to the present invention.

[0229] Therefore, according to one aspect of the invention, a general method for preparing a solid composition comprising nanoparticles of rifamycin, such as rifapentine, as defined in this application, the method comprising:

[0230] (a) Preparing an oil-in-water emulsion, the oil-in-water emulsion comprising:

[0231] - An oil phase containing the rifamycin, such as rifapentine; and

[0232] - An aqueous phase comprising a first excipient and a second excipient, each as defined in this application; and

[0233] (b) Remove oil and water from the oil-in-water emulsion to form the solid composition.

[0234] The advantage of the method of the present invention is that the emulsion formed in the initial step is sufficiently homogeneous and stable, thereby enabling efficient and uniform drying during the removal of oil and water. Furthermore, the formed nanoparticles are substantially uniform in their physical form (size, shape, etc.).

[0235] The oil-in-water emulsion formation step can be performed using methods well known in the art. Therefore, any method suitable for forming an oil-in-water emulsion can be used. Specifically, the oil and aqueous phases can be mixed using methods well known in the art to form the oil-in-water emulsion. For example, the mixing can involve stirring, ultrasonic treatment, homogenization, or a combination thereof. In a specific embodiment, the mixing is facilitated by ultrasonic treatment and / or homogenization.

[0236] The water-in-oil formation step can be carried out, for example, by using the method described in WO 2004 / 011537 A1 (COOPER et al.), which is hereby formally incorporated in this application by reference.

[0237] In a specific implementation plan, the formation of an oil-in-water emulsion includes:

[0238] (i) Providing an oil phase containing the rifamycin, such as rifapentine;

[0239] (ii) Providing an aqueous phase comprising the first excipient and the second excipient; and

[0240] (iii) Mix the oil phase and the aqueous phase to prepare an oil-in-water emulsion.

[0241] Suitablely, the oil phase is provided by dissolving rifamycin, such as rifapentine, in a suitable organic solvent.

[0242] Suitablely, the aqueous phase is provided by dissolving the first and second excipients in an aqueous medium, preferably water. Alternatively, the aqueous phase can be provided by mixing aqueous solutions of the first and second excipients, prepared separately.

[0243] In a specific implementation, an additional aqueous medium (e.g., water) or organic solvent is added before or during the mixing step (iii).

[0244] Suitablely, rifamycin, such as rifapentine, is concentrated in the oil-in-water emulsion as much as possible to facilitate efficient scale-up of the method. For example, suitablely, rifamycin, such as rifapentine, is concentrated in the oil phase at a concentration of 20 mg / ml or higher, more preferably 30 mg / ml or higher, even more preferably 40 mg / ml or higher, and most preferably greater than 50 mg / ml.

[0245] Suitablely, the concentration of the first excipient in the aqueous phase is 1 to 50 mg / mL, more preferably 2 to 30 mg / mL, or even more preferably 5 to 20 mg / mL.

[0246] Suitablely, the concentration of the second excipient in the aqueous phase is 0.1 to 25 mg / mL, more preferably 0.2 to 10 mg / mL, or even more preferably 0.5 to 5 mg / mL.

[0247] In the aqueous phase, the mass ratio of the first excipient to the second excipient can be in the range of 9:1 to 1:1; preferably in the range of 7:1 to 2:1, and more preferably in the range of 6:1 to 3:1.

[0248] The organic solvent forming the oil phase is (substantially) immiscible with water. Suitably, the organic solvent is proton-phobic. Suitably, the organic solvent has a boiling point of less than 120°C, suitably less than 100°C, and suitably less than 90°C.

[0249] In a specific implementation, the organic solvent is selected from Class 2 or Class 3 solvents listed in the International Council for Harmonisation of Technical Requirements for Human Use (ICH) guidelines regarding residual solvents.

[0250] In a specific embodiment, the organic solvent is selected from chloroform, dichloromethane, dichloroethane, tetrachloroethane, cyclohexane, hexane, isooctane, dodecane, decane, methyl butyl ketone (MBK), methylcyclohexane, tetrahydrofuran, toluene, xylene, butyl acetate, mineral oil, tert-butyl methyl ether, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, methyl ethyl ketone, ethyl acetate, diethyl ether, pentane, and propyl acetate, or any suitable combination thereof.

[0251] In a specific implementation, the organic solvent is chloroform.

[0252] The organic solvent may include a co-solvent. The co-solvent may be selected from C1 to C4 alcohols (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and isobutanol) and C5 to C7 alkanes (such as pentane, hexane, and heptane).

[0253] The oil phase can comprise 1 to 40% of the oil-in-water emulsion by volume. Preferably, the oil phase comprises 10 to 35% of the oil-in-water emulsion by volume, and most preferably 15 to 35% by volume. In an embodiment, the oil phase comprises approximately 25% of the oil-in-water emulsion by volume.

[0254] Suitably, the mixing step (iii) prepares a substantially homogeneous oil-in-water emulsion. As previously described, mixing can be performed using methods well known in the art. Suitably, the mixing step (iii) involves stirring, sonication, homogenization, or a combination thereof. In a specific embodiment, the mixing step (iii) involves sonication and / or homogenization.

[0255] Oil and water can be removed using methods well known in the art. Suitable methods for oil and water removal include freeze drying, spray drying, or spray granulation.

[0256] Oil and water can be removed using the method described in WO 2004 / 011537 A1 (COOPER et al.), the entire contents of which are incorporated herein by reference.

[0257] In a specific implementation, the removal of oil and water involves freeze-drying the oil-in-water emulsion. Therefore, the removal of oil and water may suitably include freezing the oil-in-water emulsion and then removing the solvent under vacuum.

[0258] Preferably, the oil-in-water emulsion can be frozen by external cooling. For example, the container holding the oil-in-water emulsion can be externally cooled, for instance, by submerging the container in a cooling medium, such as liquid nitrogen. Alternatively, the container holding the oil-in-water emulsion may be provided with an external "jacket" through which coolant circulates to freeze the oil-in-water emulsion. Alternatively, the container may include internal components through which coolant circulates to freeze the oil-in-water emulsion.

[0259] In another alternative, the oil-in-water emulsion is frozen by direct contact with a cooling medium at an effective freezing temperature. In this case, the cooling medium (e.g., liquid nitrogen) can be added to the oil-in-water emulsion, or the oil-in-water emulsion can be added to the cooling medium. In a specific embodiment, the oil-in-water emulsion is suitably added dropwise to a fluid medium (e.g., liquid nitrogen). This order of addition provides higher purity of the final product. Thus, frozen droplets of the oil-in-water emulsion can be suitably formed. These frozen droplets can be suitably separated (e.g., under vacuum to remove the fluid medium / liquid nitrogen). The solvent is then suitably removed from the frozen droplets under vacuum. The resulting solid composition is then separated.

[0260] Oil and water are preferably removed by spray drying because this method eliminates the need for frozen oil-in-water emulsions and preserves the nanoparticle properties of the solid composition through the rapid nature of solvent evaporation.

[0261] In another preferred method, the solid composition of the present invention is prepared by nanoprecipitation technology, by which rifamycin, such as rifapentine, is dissolved in a water-miscible solvent and a first excipient and a second excipient are dissolved in water. The two solutions are combined to precipitate rifamycin, such as rifapentine, in the form of nanoparticles. The general procedure for this type of preparation of solid compositions is as follows:

[0262] (a) Providing an active solution of the rifamycin, such as rifapentine, contained in a water-miscible solvent;

[0263] (b) Providing a carrier substance solution comprising a first excipient and a second excipient;

[0264] (c) Mix the solutions prepared in steps (a) and (b); and

[0265] (d) Remove the mixed solvent to prepare the solid composition.

[0266] The solution is typically provided by dissolving rifamycin, such as rifapentine, in a water-miscible solvent and dissolving a first excipient and a second excipient in an aqueous solvent. The rifamycin, such as rifapentine, and the first and second excipients are selected from those described for solid compositions.

[0267] The alternative procedures for preparing solid compositions are as follows:

[0268] (a) Providing an active solution containing the rifamycin, such as rifapentine, and a second excipient in a water-miscible solvent;

[0269] (b) Provide a carrier substance solution containing the first excipient;

[0270] (c) Mix the solutions prepared in steps (a) and (b); and

[0271] (d) Remove the mixed solvent to prepare the solid composition.

[0272] The solution is typically provided by dissolving rifamycin (such as rifapentine) and a second excipient in a water-miscible solvent and dissolving a first excipient in an aqueous solvent, wherein the rifamycin (such as rifapentine), the first excipient (such as PVP), and the second excipient (such as AOT) are selected from those described for solid compositions.

[0273] Rifamycin, such as rifapentine, can be treated with any water-miscible solvent capable of dissolving it at the desired concentration. Suitable water-miscible solvents include acetone, methyl ethyl ketone (MEK), butanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), ethanol, methanol, propanol, and mixtures thereof. Particularly suitable solvents are methanol, acetone / ethanol mixtures, acetone / methanol mixtures, and MEK / ethanol mixtures. Acetone / ethanol mixtures can be prepared in any suitable proportion. Preferred volume ratios are in the range of 90 / 10 to 10 / 90, 70 / 30 to 30 / 70, or 50 / 50. (The last two sentences are repetitive and can be omitted.) The preferred volume ratio is in the range of 90 / 10 to 10 / 90, in the range of 70 / 30 to 30 / 70, or in the range of 50 / 50. Rifamycin, such as rifapentine, may be present at a concentration of at least 20 mg / mL, preferably at least 30 mg / mL, more preferably at least 40 mg / mL, and most preferably at least 50 mg / mL.

[0274] The aqueous solvent is typically deionized water. The first excipient may be present in the carrier material solution at a concentration of 1 to 40 mg / mL, preferably 5 to 30 mg / mL, and more preferably 10 to 20 mg / mL. The second excipient may be present in the carrier material solution at a concentration of 0.5 to 20 mg / mL, preferably 1 to 10 mg / mL, and more preferably 2 to 5 mg / mL.

[0275] A solution of rifamycin, such as rifapentine, and a solution of the first and second excipients are mixed in a volume ratio ranging from 1:15 to 1:1, preferably from 1:9 to 3:4. The volume ratio is preferably in the range of 1:6 to 1:2, such as about 1:4.

[0276] After mixing, the total solids content (i.e., the sum of rifamycin, such as rifapentine, the first excipient, and the second excipient in the mixed solvent) can be in the range of 1 to 40 mg / mL, preferably 2 to 30 mg / mL, more preferably 5 to 25 mg / mL, and most preferably 10 to 20 mg / mL. Alternatively, the total solids content can be about 15 mg / mL.

[0277] The solution can be mixed by any suitable method. Typically, a rotary stirring system, such as a magnetic or overhead stirrer, is used. The pharmaceutically active compound has reduced solubility in the mixed solvent system, resulting in a supersaturated solution. The pharmaceutically active compound thus precipitates from the solution, producing nanoparticles stabilized by a carrier substance. Mixing can be instantaneous or it can be carried out over a period of time. The latter can be achieved using a pump, such as a peristaltic pump, at a rate of 1 to 120 mL / min, preferably 20 to 100 mL / min, more preferably 40 to 80 mL / min, and most preferably about 60 mL / min.

[0278] Homogenizing the mixed solution is beneficial to reduce aggregation and promote uniformity in particle size. Any suitable homogenizer, such as a rotary homogenizer or micronizer, can be used. Similarly, ultrasonic treatment of the mixed solution is beneficial. Any suitable ultrasonic instrument, such as a probe ultrasonicator, can be used.

[0279] In some embodiments, the active solution is heated to increase the solubility of the pharmaceutically active compound therein, thereby enabling the use of higher concentrations and increasing the degree of supersaturation when mixed with the carrier substance solution, especially when the carrier substance solution is maintained at ambient temperature (about 25°C). Any suitable temperature can be used, such as 30 to 90°C, 40 to 80°C, 50 to 70°C, or about 60°C.

[0280] Any suitable method for removing the mixed solvent can be used, provided it does not provide an opportunity for the nanoparticles to aggregate. This can be achieved by extremely rapid solvent removal or by rapidly solidifying the dispersion and sublimating the solid solvent (e.g., freeze-drying). The former method is preferred, using spray drying or spray granulation techniques due to their high throughput and acceptability in pharmaceutical applications. It will be understood that parameters of spray drying and spray granulation methods, such as flow rate and temperature, can be varied to achieve efficient drying and obtain the desired powdered and granular products. If necessary, the resulting solids can be subjected to further drying procedures, such as drying under vacuum, to remove any residual solvent.

[0281] The present invention also provides solid compositions that are obtainable, acquired, or directly obtained by any of the methods described in this application.

[0282] Aqueous dispersions

[0283] This application also provides aqueous dispersions that can be obtained, acquired, or directly obtained by dispersing the solid composition defined in this application in an aqueous medium.

[0284] When the solid composition is dispersed in an aqueous medium, the first and second excipients dissolve in the aqueous medium to release rifamycin, such as rifapentine, nanoparticles in a dispersed form. The rifamycin, such as rifapentine, nanoparticles previously dispersed in the solid mixture of the first and second excipients then become dispersed in the aqueous medium and stabilized by the first and second excipients, thus preventing premature coagulation and aggregation.

[0285] In a specific embodiment, the aqueous medium comprises 20 to 99.5% by weight of the total aqueous dispersion. In a specific embodiment, the aqueous medium comprises 50 to 98% by weight of the total aqueous dispersion. In a specific embodiment, the aqueous medium comprises 70 to 95% by weight of the total aqueous dispersion. Suitably, the remaining proportion of the aqueous dispersion consists substantially of rifamycin, such as rifapentine, a first excipient, and a second excipient, the proportions of which in the total aqueous dispersion are calculated accordingly (and scaled proportionally) with reference to the proportions listed in the solid composition.

[0286] For aqueous dispersions of rifamycin nanoparticles, such as rifapentine, the concentration of rifamycin can be at least 100 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 500 mg / mL. Alternatively, the concentration of rifamycin can be from 100 to 1000 mg / mL, preferably 150 to 800 mg / mL, more preferably 200 to 600 mg / mL, even more preferably 250 to 500 mg / mL, and most preferably 300 to 400 mg / mL.

[0287] In a specific embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional pharmaceutically acceptable diluents or excipients. In a specific embodiment, the aqueous medium comprises saline or phosphate-buffered saline (PBS).

[0288] The nanoparticles may have an average particle size of less than 5 micrometers (μm). In specific embodiments, the nanoparticles have an average particle size of 10 nm to 2500 nm, preferably 20 nm to 2000 nm, more preferably 50 nm to 1500 nm, further preferably 100 nm to 1000 nm, and most preferably 100 nm to 500 nm. In other embodiments, the nanoparticles have a particle size in the range of 1 to 1000 nm. It will be understood that references to particle size refer to the Z-mean hydrodynamic diameter of the nanoparticles.

[0289] The nanoparticles may have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.5.

[0290] The particle size and polydispersity of nanoparticles can be evaluated using any suitable technique known in the art (e.g., laser diffraction, laser scattering, electron microscopy). In embodiments of the invention, the solid composition is dispersed in an aqueous medium at a concentration of 1 mg / mL and dynamic light scattering (e.g., using...) is employed.

[0291] The Malvern Panalytical Limited Zetasizer Ultra measures particle size to assess particle size and polydispersity (i.e., Z-mean hydrodynamic diameter).

[0292] The aqueous dispersion can be used in microneedle arrays, for example, in formulations of microneedle arrays described later in this document.

[0293] Methods for preparing aqueous dispersions

[0294] The present invention provides a method for preparing an aqueous dispersion, the method comprising dispersing a solid composition in an aqueous medium as defined in this application.

[0295] In a specific embodiment, the aqueous medium is water. In an alternative embodiment, the aqueous medium comprises water and one or more additional excipients. In a specific embodiment, the aqueous medium comprises saline or phosphate-buffered saline (PBS).

[0296] Dispersing a solid composition in an aqueous medium may include adding the solid composition to the aqueous medium (or vice versa) and suitably agitating the resulting mixture (e.g., by shaking, homogenization, sonication, stirring, etc.).

[0297] Pharmaceutical Composition

[0298] This invention provides pharmaceutical compositions comprising solid compositions or aqueous dispersions as defined in this application. The pharmaceutical compositions of this invention may further comprise one or more additional pharmaceutically acceptable excipients.

[0299] The solid compositions of the present invention can be formulated into forms suitable for oral use (e.g., tablets, lozenges, hard or soft capsules, or dispersible powders or granules) using techniques known in the art. Therefore, in this process, the solid compositions of the present invention can be mixed with one or more additional pharmaceutical excipients, such as anti-adhesives, binders, coatings, enteric materials, disintegrants, fillers, diluents, flavoring agents, colorants, lubricants, flow aids, preservatives, adsorbents, and sweeteners.

[0300] In a specific embodiment, the pharmaceutical composition is a tablet or capsule comprising a solid composition.

[0301] The aqueous dispersions of the present invention can be applied as is or further formulated with one or more additional excipients to provide dispersions, elixirs or syrups suitable for oral administration or dispersions suitable for parenteral administration (sterile aqueous dispersions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration).

[0302] In a specific embodiment, the pharmaceutical composition is an aqueous dispersion as described in this application. This dispersion can be used to accurately measure smaller doses, such as those suitable for administration to children.

[0303] In a specific embodiment, the pharmaceutical composition is in a form suitable for parenteral delivery, whether via subcutaneous or intramuscular delivery.

[0304] It will be understood that the different pharmaceutical compositions of the present invention can be obtained by conventional procedures well known in the art, using pharmaceutical excipients well known in the art.

[0305] The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of rifamycin, such as rifapentine. Those skilled in the art will know how to determine and select a suitable therapeutically effective amount of rifamycin, such as rifapentine, to be included in the pharmaceutical compositions of the present invention.

[0306] Injectable formulations

[0307] This invention provides an injectable formulation comprising the solid composition described herein, the aqueous dispersion described herein, or the pharmaceutical composition described herein. In one embodiment, the injectable formulation is intramuscularly injectable. In other embodiments, the injectable formulation is subcutaneously injectable.

[0308] The formulation may be in solid (or substantially solid, such as a paste) or liquid or semi-solid form, wherein rifamycin, such as rifapentine, is present in the form of nanoparticles. The nanoparticles of rifamycin, such as rifapentine, may be dispersed in one or more carrier substances. When in liquid form, each nanoparticle of rifamycin, such as rifapentine, is stabilized by a first excipient and a second excipient.

[0309] Long-acting injectable formulations

[0310] This invention provides a long-acting injectable formulation comprising an aqueous dispersion or a pharmaceutical composition as described in this application. The long-acting injectable formulation may be intramuscularly injectable or subcutaneously injectable. In addition to rifamycin nanoparticles such as rifapentine and an aqueous medium, the long-acting injectable formulation may further comprise one or more additional pharmaceutically acceptable excipients, such as thickeners, preservatives, and stabilizers.

[0311] Injectable formulations of rifamycin, such as rifapentine, in nanoparticle form can be long-acting injectable formulations. These formulations are advantageously designed for intramuscular or subcutaneous injection, forming a reservoir at the injection site. Long-acting injectable formulations improve adherence to prevention and / or treatment, particularly for viral diseases requiring extended treatment duration, such as tuberculosis, and improve subsequent outcomes. Furthermore, reservoir injection is beneficial because it is easier to administer than conventional formulations, thus enabling simpler follow-up / continuous care.

[0312] The long-acting injectable formulation of this invention allows for the formation of reservoirs of rifamycin nanoparticles, such as rifapentine, because these drugs are poorly soluble in aqueous media, preventing them from rapidly leaving the reservoir and entering the patient's bloodstream. Typically, long-acting injectable formulations are administered intramuscularly or subcutaneously to specific sites, such as the deltoid, dorsogluteal, ventrogluteal, vastus lateralis, and rectus femoris muscles. Each site has a limit on the maximum volume that can be injected without causing excessive discomfort or loss of effectiveness in the patient. This maximum volume, even for larger sites, is typically only up to 3 mL. Administration takes longer than standard injections, typically requiring 10 seconds to administer 1 mL.

[0313] This limitation on the number of suitable sites and the permissible volume in each method means that it is important for long-acting injectable formulations to contain high concentrations of rifamycin, such as rifapentine, in order to minimize the volume required to provide a reservoir capable of releasing a therapeutically effective amount of rifamycin (and thus minimize the number of injections and duration).

[0314] Furthermore, unwilling to be bound by any theory, rifamycins, such as rifapentine, are considered to be released from the reservoir at a rate defined by their physicochemical properties (e.g., solubility controlling the rate at which each rifamycin dissolves from the nanoparticle surface) and the local physiological environment. Therefore, a minimum concentration of rifamycin must be present in the reservoir to ensure that when rifamycin is released at the rate defined by its physicochemical properties and the local physiological environment (which itself can be further influenced by the reservoir, such as by the formation of granulomas around the reservoir), the amount released is a therapeutically effective amount (i.e., the concentration of rifamycin in the formulation must be sufficient to produce a therapeutically effective concentration of rifamycin in vivo). Moreover, the therapeutically effective amount of rifamycin must be maintained throughout the duration of treatment, meaning that the reservoir must contain all the rifamycin required for the duration of treatment.

[0315] For long-acting injectable formulations of rifamycin nanoparticles, such as rifapentine, the concentration of rifamycin can be at least 150 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 500 mg / mL. Alternatively, the concentration of rifamycin, such as rifapentine, can be from 100 to 1000 mg / mL, preferably from 200 to 900 mg / mL, more preferably from 300 to 800 mg / mL, and most preferably from 500 to 700 mg / mL.

[0316] Preferably, rifamycin, such as rifapentine, is released from a reservoir of rifamycin nanoparticles into the patient's bloodstream at a controlled rate, thereby achieving a therapeutically effective dose of rifamycin for at least about two weeks from the date of administration. More preferably, the therapeutically effective dose of rifamycin is sustained for at least about three weeks from the date of injection administration, more preferably at least about one month, and most preferably at least about two months from the date of administration.

[0317] Implantable rod

[0318] The present invention provides an implantable rod comprising nanoparticles of rifamycin, such as rifapentine, wherein the nanoparticles are dispersed in a bulk material of a first excipient and a second excipient.

[0319] The rifamycins that make up the nanoparticles, such as rifapentine, can be amorphous (i.e., substantially non-crystalline in nature).

[0320] The nanoparticles of the present invention have an average particle size of less than 5 micrometers (μm). In a specific embodiment, the nanoparticles have an average particle size of 10 nm to 2500 nm, preferably 20 nm to 2000 nm, more preferably 50 nm to 1500 nm, further preferably 100 nm to 1000 nm, and most preferably 100 nm to 500 nm. In an embodiment, the nanoparticles have a particle size in the range of 1 to 1000 nm. It will be understood that references to particle size refer to the Z-mean hydrodynamic diameter of the nanoparticles.

[0321] The nanoparticles of the present invention may have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.5.

[0322] The particle size and polydispersity of nanoparticles can be evaluated using any suitable technique known in the art (e.g., laser diffraction, laser scattering, electron microscopy). In embodiments of the invention, the solid composition is dispersed in an aqueous medium at a concentration of 1 mg / mL and dynamic light scattering (e.g., using...) is employed.

[0323] The Malvern Panalytical Limited Zetasizer Ultra measures particle size to assess particle size and polydispersity (i.e., Z-mean hydrodynamic diameter).

[0324] The bulk material containing the first and second excipients is non-porous in nature.

[0325] The first excipient may be as described with respect to the solid compositions of the present invention. In embodiments, the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0326] The second excipient may be as described with respect to the solid compositions of the present invention. In embodiments, the second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80, and sorbitol monolaurate.

[0327] The first excipient and the second excipient may be used in any combination as described with respect to the solid compositions of the present invention.

[0328] The relative amounts of rifapentine, such as rifapentine, the first excipient, and the second excipient can be used in any combination as described in this application with respect to the solid compositions of the present invention.

[0329] The implantable rod is suitable for implantation into a patient's body (e.g., subcutaneously). The rod can have any suitable shape or size for implantation. In one embodiment, the rod is cylindrical. The length of the rod can be between 1 and 100 mm, preferably between 1 and 80 mm, more preferably between 2 and 50 mm, further more preferably between 5 and 40 mm, and most preferably between 10 and 20 mm. The diameter of the rod can be between 0.1 and 5 mm, preferably between 0.5 and 2.5 mm, more preferably between 1 and 2 mm.

[0330] Method for preparing implantable rods

[0331] Implantable rods can be prepared by any suitable method for converting fine thermoplastic solids into a bonded, monolithic material, such as injection molding, extrusion molding, and other methods known to those skilled in the art. A suitable method involves heating while compressing the solid composition described in the first aspect of the invention, causing the porous matrix of the first and second excipients to collapse and bind the discrete particles to form a monolithic material. Removing porosity increases the density of the composition, making it more manageable and allowing it to be inserted into the composition as an implant. This also extends the time required to dissolve the composition. Without being bound by any theory, the inventors' experience is that the nanoparticle properties of active compounds, such as rifamycins like rifapentine, are retained in the implantable rods after conversion. Preparing implants using the solid compositions of the present invention results in higher concentrations of rifamycin while retaining the highly dispersed properties of the nanoparticle formulation.

[0332] Compressive force can be applied under reduced pressure (e.g., vacuum). This helps remove any remaining volatile substances, such as solvents, and reduces the rate of bubble formation by removing any gases entrained in the solid composition. Certain devices can also use pressure differentials to apply compressive force to the solid composition.

[0333] Heating and compressing a solid composition requires raising its temperature so that the discrete volumes of the first and second excipients bind together under the pressure of the compression step. However, this temperature must be below the temperature at which rifamycin, such as rifapentine, deteriorates. The compressed solid composition can be heated to 60 to 160°C, preferably 80 to 140°C, more preferably 100 to 120°C, and most preferably approximately [temperature missing].

[0334] A temperature of 105°C. The elevated temperature is maintained for a period of 1 to 40 minutes, preferably 5 to 30 minutes, more preferably 10 to 25 minutes, and most preferably about 20 minutes. Preferably, compression and / or vacuum are maintained during the heating step. Heat can be provided for the heating step using any suitable method. For example, an electric heater such as a hot plate.

[0335] Alternatively, the rod can be cooled after the heating step. For example, by contacting it with a cold surface.

[0336] microneedle array

[0337] This invention provides a microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition, wherein the first composition comprises nanoparticles of rifamycin, such as rifapentine, dispersed in a bulk material comprising a first excipient, a second excipient, and at least one structural polymer. By using nanoparticles of rifamycin, such as rifapentine, particularly those present in the solid compositions of this invention, higher loadings of water-insoluble drugs can be obtained while retaining their highly dispersed properties.

[0338] The rifamycins that make up the nanoparticles, such as rifapentine, can be amorphous (i.e., substantially non-crystalline in nature).

[0339] The nanoparticles of the present invention have an average particle size of less than 5 micrometers (μm). In a specific embodiment, the nanoparticles have an average particle size of 10 nm to 2500 nm, preferably 20 nm to 2000 nm, more preferably 50 nm to 1500 nm, further preferably 100 nm to 1000 nm, and most preferably 100 nm to 500 nm. In an embodiment, the nanoparticles have a particle size in the range of 1 to 1000 nm. It will be understood that references to particle size refer to the Z-mean hydrodynamic diameter of the nanoparticles.

[0340] The nanoparticles of the present invention may have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.5.

[0341] The particle size and polydispersity of nanoparticles can be evaluated using any suitable technique known in the art (e.g., laser diffraction, laser scattering, electron microscopy). In embodiments of the invention, the solid composition is dispersed in an aqueous medium at a concentration of 1 mg / mL and dynamic light scattering (e.g., using...) is employed.

[0342] The Malvern Panalytical Limited Zetasizer Ultra measures particle size to assess particle size and polydispersity (i.e., Z-mean hydrodynamic diameter).

[0343] The bulk material containing the first and second excipients is non-porous in nature.

[0344] The first excipient may be as described with respect to the solid compositions of the present invention. In embodiments, the first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0345] The second excipient may be as described with respect to the solid compositions of the present invention. In embodiments, the second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80, and sorbitol monolaurate.

[0346] In principle, any hydrophilic polymer suitable for use in pharmaceutical formulations can be used as the structural polymer, such as a polymer suitable as a first excipient. In embodiments, the structural polymer is chosen to be the same as the first excipient, as this helps ensure compatibility. In embodiments, the structural polymer is selected from PVA, PVP, and combinations thereof. Polymers with a MW less than 60 kDa are preferred (e.g., PVA with a MW of 9-10 and PVP with a MW of 58 kDa), as they are known to be rapidly eliminated from the human body via renal excretion. The purpose of the structural polymer is to provide microneedles with sufficient mechanical strength to allow for insertion into the skin and subsequent delivery of rifamycins, such as rifapentine.

[0347] The relative amounts of rifamycin, such as rifapentine, the first excipient, and the second excipient can be as described in this application regarding the solid compositions of the present invention. The ratio of rifamycin, the first excipient, and the second excipient relative to the structural polymer can range from 10 to 80 wt% rifamycin, such as rifapentine; 10 to 80 wt% the first excipient; and 1 to 25 wt% the second excipient. Preferably, the solid composition comprises 30 to 60 wt% rifamycin, such as rifapentine; 30 to 60 wt% the first excipient; and 5 to 20 wt% the second excipient. More preferably, the solid composition comprises 40 to 50 wt% rifamycin, such as rifapentine; 40 to 50 wt% the first excipient; and 5 to 15 wt% the second excipient.

[0348] The substrate comprises a base polymer. In principle, any hydrophilic polymer suitable for use in pharmaceutical formulations can be used as the base polymer, such as a polymer suitable as a first excipient. In embodiments, the base polymer is selected to be the same as the first excipient and / or structural polymer.

[0349] In this embodiment, the base polymer is PVP. Typically, the base polymer comprises a high molecular weight polymer, such as PVP with a MW of 360 kDa, to impart a degree of rigidity to the substrate. The substrate may further comprise one or more additives to enhance its properties; for example, low molecular weight polyols, such as glycerol, can reduce the substrate's brittleness. If additives are present, the additives and base polymer are used in a mass ratio of 1:40 to 1:10, preferably 1:30 to 1:15, and more preferably about 1:20.

[0350] The relative amounts of the first composition and the second composition are determined by the physical dimensions of the microneedles relative to the substrate, with the majority of the microneedle volume containing the first composition and the remaining microneedle volume and substrate volume containing the second composition. In an embodiment, at least 50% of the microneedle volume contains the first composition, preferably at least 60%, more preferably at least 80%, more preferably at least 90%, and most preferably substantially all of the microneedle volume contains the first composition.

[0351] By controlling the loading of rifamycin, such as rifapentine, and the size of the microneedle array, the microneedle array can be designed to contain virtually any suitable amount of rifamycin, such as rifapentine. In an embodiment, the microneedle array contains 0.1 to 20 mg, preferably 0.5 to 10 mg, more preferably 1 to 5 mg, and most preferably 1 to 2 mg of rifamycin, such as rifapentine.

[0352] The dimensions of the microneedles and microneedle arrays are determined by the mold used in their fabrication, and the microneedles and microneedle arrays can have substantially suitable dimensions. The height of the microneedles can range from 50 to 1000 μm, preferably from 500 to 900 μm. The base width of the microneedles can range from 50 to 500 μm, preferably from 100 to 300 μm. The spacing between the microneedles can range from 50 to 200 μm, preferably about 100 μm. The area of ​​the microneedle array can range from 0.1 to 100 cm². 2 Within the range of 0.5 to 30 cm, it is preferred. 2 Within a certain range. Microneedle arrays can contain 2 to 2000 microneedles. Typically, the microneedles are arranged in a grid, but virtually any arrangement can be used.

[0353] The needles of a microneedle array can have any suitable geometry. For example, they can be conical, truncated conical, cylindrical, cubic, truncated conical, pyramidal with a square base, pyramidal with a pentagonal base, arrow-shaped, etc.

[0354] Methods for preparing microneedle arrays

[0355] Microneedle arrays can be prepared by any suitable method known to those skilled in the art. A suitable method includes the following steps: a) dispersing the solid composition according to the invention and at least one structural polymer in a solvent to form a microneedle precursor dispersion; b) placing the microneedle precursor dispersion into a mold; c) compressing the microneedle precursor dispersion in the mold and then drying it to form microneedles; d) adding a substrate precursor solution to the mold; e) compressing the substrate precursor solution and then drying it to form the substrate; and f) removing the microneedle array from the mold. While not wishing to be bound by any theory, the inventors' experience is that the nanoparticle properties of active compounds such as rifamycin, such as rifapentine, are retained in the microneedles. Using the solid composition of the invention to prepare microneedle arrays enables higher loadings of water-insoluble drugs while maintaining their water-dispersible nanoparticle form. For the avoidance of doubt, the microneedles formed in steps b) and c) are retained in the mold, and a substrate precursor solution is added on top of them to form a microneedle array. Steps b) and c) can be repeated to increase the volume of microneedles formed from the first composition. It will be understood that this repetition is performed before the deposition of the substrate.

[0356] The step of dispersing the solid composition and at least one structural polymer according to the invention may include the following individual steps: dispersing the solid composition in a first amount of solvent, dissolving the at least one structural polymer in a second amount of solvent, and then mixing. The microneedle precursor dispersion may contain 10 to 50% by weight, preferably 20 to 40% by weight, more preferably 25 to 35% by weight, and most preferably about 30% by weight of the solid composition. The microneedle precursor dispersion may contain 1 to 20% by weight, preferably 5 to 15% by weight, and more preferably about 10% by weight of the least one structural polymer.

[0357] The mold contains microcavities corresponding to the shape of the microneedles. The steps of placing the microneedle precursor dispersion into the mold, compressing, and drying to form the microneedles do not fill the mold cavities. Therefore, these steps can be repeated to increase the volume of the filled cavities.

[0358] The substrate precursor solution comprises a base polymer, a solvent, and optionally one or more additives. The solution may contain between 10 and 50% by weight of the base polymer, preferably between 20 and 40% by weight, more preferably about 30% by weight. If additives are present, the substrate precursor solution contains between 0.1 and 5% by weight, preferably between 0.5 and 3% by weight, more preferably about 1.5% by weight.

[0359] The solvent is typically water. Besides rifamycins such as rifapentine, the components forming the microneedle array are water-soluble and also have other advantages (e.g., non-toxic, non-flammable, readily available), as do the rifamycins.

[0360] The compression of the solution can be performed using any suitable method known in the art, such as a pressure chamber or centrifugation. The compression of the microneedle precursor dispersion is preferably performed in a pressure chamber. Centrifugation is also preferred for compressing the substrate precursor solution.

[0361] The drying step can be performed using any suitable method known in the art. Typically, the drying step is carried out under ambient conditions (i.e., simply allowing the solvent to evaporate). However, it will be understood that the drying rate can be increased by applying elevated temperatures, increasing the airflow above the sample, or applying reduced pressure.

[0362] After drying, the microneedle array may retain residual water. The residual water should not exceed 15% by weight of the microneedle array. The residual water content can be 1 to 15% by weight of the microneedle array, typically 5 to 10% by weight.

[0363] Uses of solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, and microneedle arrays.

[0364] This invention provides solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods or microneedle arrays as defined in this application, which are used as pharmaceuticals.

[0365] This invention provides solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods or microneedle arrays as defined in this application for the treatment and / or prevention of tuberculosis, such as latent tuberculosis.

[0366] In the embodiments, the concentration of rifamycin, such as rifapentine, in the aqueous dispersion, pharmaceutical composition, or injectable formulation used for the treatment and / or prevention of tuberculosis is in the range of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL. Alternatively, the concentration of rifamycin, such as rifapentine, is at least 150 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 500 mg / mL.

[0367] In the embodiments, the implantable rod for the treatment and / or prevention of tuberculosis contains rifamycin, such as rifamycin, in a concentration of 20 to 80% by weight, preferably 30 to 70% by weight, more preferably 40 to 60% by weight, and most preferably about 50% by weight.

[0368] In the implementation scheme, the microneedle array for the treatment and / or prevention of tuberculosis comprises rifamycin in the range of 1 to 20 mg, preferably in the range of 2 to 10 mg, and more preferably about 5 mg, such as rifapentine. It will be understood that the dose of rifamycin provided to the patient can be varied by using larger and / or multiple microneedle arrays.

[0369] The present invention provides a method for treating and / or preventing tuberculosis, such as latent tuberculosis, comprising administering to a patient who has tuberculosis or is at risk of developing tuberculosis a therapeutically effective amount of a solid composition, an aqueous dispersion, a pharmaceutical composition, an injectable formulation, an implantable rod, or a microneedle array as defined in this application.

[0370] In the embodiments, the concentration of rifamycin, such as rifapentine, contained in the aqueous dispersion, pharmaceutical composition, or injectable formulation is in the range of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL. Alternatively, the concentration of rifamycin is at least 150 mg / mL, preferably at least 200 mg / mL, more preferably at least 300 mg / mL, and most preferably at least 500 mg / mL.

[0371] Aqueous dispersions, pharmaceutical compositions, injectable formulations, or implantable rods can form reservoirs in the patient's body (e.g., in muscles or subcutaneously), optionally wherein the reservoirs maintain therapeutically effective concentrations of rifamycin, such as rifapentine, in the patient's body for at least two weeks, preferably at least one month, more preferably at least two months, further more preferably at least three months, and most preferably at least two weeks.

[0372] Once attached to the skin, the microneedle array or array gradually releases rifamycin, such as rifapentine, and optionally maintains a therapeutically effective concentration of rifamycin in the patient's body for at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours. At the end of the time period, the microneedle array or array is removed from the patient's skin, and if treatment continues, it is replaced with a new microneedle array or array.

[0373] In the implementation scheme, the method requires administering an aqueous dispersion, pharmaceutical composition, injectable formulation, or implantable rod up to three times, preferably up to two times, and most preferably only once, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient throughout the duration of treatment.

[0374] In the implementation scheme, the method requires administering the microneedle array up to six times a day, preferably up to four times a day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient throughout the duration of treatment.

[0375] In any or all of the uses and methods described above, the administration form of rifamycin, such as rifapentine, in nanoparticle form, preferably provides a controlled-release bolus formulation of rifamycin that, when administered to a patient, releases rifamycin into the patient's bloodstream over a period of at least about two weeks from the date of administration. More preferably, the release period is at least about one month from the date of injection, insertion, or patch application; more preferably, at least about two months; even more preferably, at least about three months; and most preferably, at least about four months.

[0376] Treatment definition

[0377] As used in this application, "treatment" includes both curative and preventative treatment. As used in this application, "patient" means an animal in need of treatment, preferably a mammal, and more preferably a human.

[0378] The amount of rifamycin, such as rifapentine, applied should be the therapeutically effective amount for the treatment of a disease or ailment and the preventive effective amount for the prevention of a disease or ailment.

[0379] The term "therapeutic effective amount" as used in this application refers to the amount of rifamycin, such as rifapentine, required to treat or improve tuberculosis. The term "prophylactic effective amount" as used in this application refers to the amount of rifamycin required to prevent tuberculosis. The exact dosage usually depends on the patient's condition at the time of administration. Factors that may be considered when determining the dosage include the severity of the patient's disease condition, the patient's overall health, age, weight, sex, diet, time, frequency and route of administration, drug combination, sensitivity to response, and the patient's tolerance or response to the therapy. The precise amount can be determined through routine experiments, but ultimately rests with the clinician's judgment. In some cases, the effective dosage may be from 0.01 mg / kg / day (mass of the drug relative to the patient's mass) to 1000 mg / kg / day, for example, from 1 mg / kg / day to 100 mg / kg / day. The composition may be administered to the patient alone or in combination with other agents, drugs, or hormones. For long-acting injectable formulations, an amount of composition sufficient to release rifamycin, such as rifapentine, at the rates described above may be administered. Alternatively, long-acting injectable formulations may be administered in amounts of 0.1 mL to 10 mL, 0.2 mL to 6 mL, 0.5 mL to 5 mL, or 1 mL to 3 mL.

[0380] Application route

[0381] The solid compositions, aqueous dispersions, pharmaceutical compositions, injectable formulations, implantable rods, or microneedle arrays of the present invention can be administered to patients via any convenient route of administration. More than one route of administration can be used in combination in the defined treatment and / or prophylactic regimens, particularly for combination therapies, where one component of the combination can be administered via one route while another component can be administered via a different route. All such combinations are therefore considered.

[0382] Routes of administration include, but are not limited to: oral (e.g., by ingestion); buccal administration; sublingual administration; transdermal administration (including microneedle arrays, such as via patches, plasters, etc.); transmucosal administration (including, such as via patches, plasters, etc.); intranasal administration (e.g., via nasal sprays); ocular administration (e.g., via eye drops); pulmonary administration (e.g., by using aerosols, such as inhalation or blowing therapy via the mouth or nose); rectal administration (e.g., via suppositories or enemas); vaginal administration (e.g., via pessaries); parenteral administration, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intracardiac, intraarterial, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; or by implantation of a reservoir, storage facility, or implantable rod, such as subcutaneously or intramuscularly.

[0383] Most preferably, the administration route is via injection into a reservoir (e.g., intramuscular or subcutaneous injection) or implantation of an implantable rod. Alternatively, the administration route is percutaneous delivery via a microneedle array.

[0384] Preferably, the injectable formulation of the present invention is a reservoir formulation, which, upon administration, provides controlled release in the patient for a period of at least about two weeks from the date of administration. More preferably, the release period is at least about one month from the date of injection, more preferably at least about two months, more preferably at least about three months, and most preferably at least about four months.

[0385] The implantable rod of the present invention is a reservoir formulation that, upon administration, provides controlled release into the patient over a period of at least about two weeks from the date of administration. More preferably, the release period is at least about one month from the date of rod implantation, more preferably at least about two months, further more preferably at least about three months, and most preferably at least about four months. Without being bound by any theory, it is considered that the implant gradually dissolves to form a liquid reservoir and that rifamycin, such as rifapentine, is gradually released from the implant and subsequently the liquid reservoir.

[0386] The microneedle array of the present invention is a transdermal release formulation that, upon administration, provides controlled release in the patient for at least about 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.

[0387] Partial Reagent Kit

[0388] The present invention provides a component kit containing a solid composition or pharmaceutical composition as defined in this application, the pharmaceutical composition comprising a solid composition as defined in this application and a pharmaceutically acceptable aqueous diluent.

[0389] The solid composition or pharmaceutical composition comprising the solid composition as defined in this application can be dispersed in a diluent to provide an aqueous dispersion as defined in this application. The entire dispersion can then be administered, or a portion thereof can be metered and then administered (thus providing different dosages to individual patients). Example

[0390] Example 1: Rifapentin SDN formed by emulsion-templating freeze-drying

[0391] Rifapentine was dissolved in chloroform at a concentration of 100 mg / mL, and the first and second excipients were each dissolved in water at a concentration of 22.5 mg / mL to provide three stock solutions. 50 μL of the rifapentine solution, 178 μL of the first excipient solution, and 44 μL of the second excipient solution were combined. The mixture was then emulsified using a Covaris S220x. The resulting emulsion was then immediately frozen with liquid nitrogen and freeze-dried using VirTis Benchtop Pro for approximately 48 hours. The resulting solid product was in the form of a monolithic material comprising 50 wt% rifapentine, 40 wt% of the first excipient, and 10 wt% of the second excipient.

[0392] The first excipients tested were Plasdone C15, Kollidon 12PF, lactose, sucrose, Prologinic F68, and PEG 4000. The second excipients tested were benzalkonium chloride, AOT, Prologinic F68, Tween 20, Tween 80, and Span 20.

[0393] Screening Analysis

[0394] The sample was dispersed in water at a concentration of 1 mg / mL rifapentine. The particle size of the nanoparticle dispersion was then measured using dynamic light scattering (DLS) on a Malvern Zetasizer Nano ZS. Data analysis was performed using three measurements (optimized using automated measurement, Malvern Zetasizer software version 7.11). Particles were considered seed products if they met the following criteria.

[0395] Nanodispersion quality assessment standards

[0396] If a particle meets the following criteria, it is identified as a potential product:

[0397] (i) The sample is completely dispersed and does not contain visible large particles;

[0398] (ii) Particle Z-mean value < 1000 nm;

[0399] (iii) Polydispersity Index (PDI) < 0.4;

[0400] (iv) The standard deviation of the three scans relative to the mean Z-mean is <5%; and

[0401] (v) At least two out of three DLS scans pass the “Dimensional Quality Report”.

[0402] The “Size Quality Report” includes twelve tests for the reliability of the recorded data, which are automatically applied to each measurement using MalvernZetasizer software. These tests ensure that the sample is within the appropriate size range for DLS, has a PDI of less than 1, is within the correct concentration range, and ensures good cumulative and distribution fit (i.e., data error less than 0.005). Ten combinations passed the screening criteria.

[0403]

[0404] Example 2: Rifapentin SDN formed by nanoprecipitation and freeze-drying

[0405] Rifapentine was dissolved in methanol at a concentration of 100 mg / mL, and the first and second excipients were each dissolved in water at a concentration of 22.5 mg / mL to provide three stock solutions. 50 μL of the rifapentine solution, 178 μL of the first excipient solution, and 44 μL of the second excipient solution were combined and shaken by hand to induce nanoprecipitation. The resulting suspension was then immediately frozen with liquid nitrogen and freeze-dried using VirTis Benchtop Pro for approximately 48 hours. The resulting solid product was in the form of a monolithic material comprising 50 wt% rifapentine, 40 wt% of the first excipient, and 10 wt% of the second excipient.

[0406] The first and second excipients, as well as the screening process and criteria, are as described in Example 1. Eight combinations passed the screening criteria.

[0407]

[0408] Example 3: Plasdone rifapentine formed by nanoprecipitation and freeze-drying C15 / AOT SDN

[0409] Rifapentine was dissolved in methanol at a concentration of 50 mg / mL, Plasdone C15 in water at a concentration of 20 mg / mL, and AOT in water at a concentration of 5 mg / mL. Six mL of the Plasdone C15 stock solution and six mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 digital homogenizer set to 14,000 rpm. Immediately afterwards, 3 mL of the rifapentine stock solution was added via a peristaltic pump at a flow rate of 60 mL / min. Mixing was continued for approximately 15–20 seconds after the addition was complete. Half of the resulting suspension was immediately frozen in liquid nitrogen, and the remaining half was homogenized five times at 20,000 psi using an LV1 microjets. The sample was freeze-dried for ~48 hours using a VirTis Benchtop Pro condenser set to -100°C and a pressure of <40 μBar to obtain a rifapentine composition containing 50 wt% rifapentine, 40 wt% Plasdone C15, and 10 wt% AOT. The sample was dispersed in water at 1 mg / mL for the active ingredient and screened as described in Example 1.

[0410]

[0411]

[0412] Example 4: Plasdone risoferment formed by nanoprecipitation and spray drying C15 / AOT SDN

[0413] Rifampin was dissolved in methanol at a concentration of 50 mg / mL, Plasdone C15 in water at a concentration of 20 mg / mL, and AOT in water at a concentration of 5 mg / mL. Eight mL of the Plasdone C15 stock solution and eight mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 digital homogenizer set to 14,000 rpm. Immediately afterward, 4 mL of the rifapentin stock solution was added via a peristaltic pump at a flow rate of 60 mL / min. Mixing was continued for approximately 15–20 seconds after the addition was complete. Half of the resulting suspension was immediately spray-dried, and the remaining half was homogenized five times at 20,000 psi using an LV1 microjets high-pressure homogenizer before spray drying. The spray dryer conditions were as follows: flow rate 5 mL / min, using a Buchi B-290mini spray dryer (100% suction, nitrogen at 5 bar pressure, Q-Flow specification 45, outlet temperature 65°C). The resulting composition contained 50% by weight rifapentine, 40% by weight Plasdone C15, and 10% by weight AOT. The sample was dispersed in water at 1 mg / mL for the active ingredient and screened as described in Example 1.

[0414]

[0415] The injectability of each composition was tested at elevated rifapentine concentrations. Dispersions were prepared by vortexing the solid composition in water at the desired concentration for 30 seconds. The dispersions were then manually passed through a 25G needle. Those that passed easily, without clogging, and were repeated after one hour were considered successful. The compositions were found to be injectable at all test concentrations up to 250 mg / mL (for rifapentine).

[0416] Example 5: Plasdone risoferment formed by nanoprecipitation and spray drying C15 / AOT SDN

[0417] Rifapentine was dissolved in methanol at a concentration of 40 mg / mL, Plasdone C15 was dissolved in water at a concentration of 25 mg / mL, and AOT was dissolved in water at a concentration of 5 mg / mL. Eight mL of the Plasdone C15 stock solution and eight mL of the AOT stock solution were combined and mixed using an Ultra-Turrax T25 digital homogenizer set to 14,000 rpm. The rifapentine stock solution (4 mL) was then immediately added via a peristaltic pump at a flow rate of 60 mL / min. After the addition was complete, mixing continued for approximately 15–20 seconds. The suspension was spray-dried as described in Example 4 to prepare a composition containing 40 wt% RFP, 50 wt% Plasdone C15, and 10 wt% AOT. The sample was dispersed in water at a concentration of 1 mg / mL for rifapentine and screened as described in Example 1.

[0418] Formulation duplication Dz(nm) PdI 1 226 0.070 2 238 0.040 3 239 0.070

[0419] The injectability of the composition was tested as described in Example 4. The composition was found to be injectable at all tested concentrations (in terms of rifapentine) up to 300 mg / mL.

[0420] The procedure was repeated for alternative rifapentine stock solutions using different solvent solutions:

[0421]

[0422]

[0423] The process was also repeated for alternative first excipients:

[0424]

[0425] Example 6: Long-lasting in vivo effect of rifapentine after intramuscular injection

[0426] A rifapentine formulation in water (rifapentine) was prepared. 40 / Plasdone C15 50 / AOT 10 The aqueous dispersion of the drug has a total drug concentration of 300 mg / mL.

[0427] Male Sprague Dawley rats (250–300 g – Charles River) were intramuscularly injected with different volumes (150 μl per thigh) of an aqueous dispersion in both thighs, with four animals in each group. Plasma was collected periodically from the tail vein over a 28-day period, and the concentration of rifapentine was quantified using LC / MS-MS. Data are presented in... Figure 1 The graph was plotted and showed that the concentration of rifapentine gradually decreased during the 28-day experimental period, confirming that the relevant concentration of rifapentine was maintained during the said duration.

[0428] Example 7: Formulation of an implantable rod

[0429] An implantable rod was prepared using the MeltPrep VCM Essentials instrumentation via vacuum compression molding (VCM) method. The instrumentation consists of a hot plate, a nitrogen-assisted cooling plate, a vacuum pump, a substrate, a VCM sample chamber, a VCM body, a PTFE sample tube with a 2 mm inner diameter, a PTFE-coated separation foil with a 2 mm diameter, a 15 mm piston, and a low-pressure cap.

[0430] Before sample separation, the hot plate is heated to 105°C and maintained at a vacuum pressure of -1 bar for about 20 minutes.

[0431] Insert the sample tube into the VCM sample chamber and then mount it onto the substrate. Next, insert and place the separation foil at the bottom of the tube, then add the powdered formulation (~30 mg) using a funnel, compacting it as much as possible using a needle. Then, place a second separation foil on top of the sample, and then insert a 15 mm piston into the sample tube. Next, place the VCM body on top of this assembly and attach the low-pressure cap. Apply a vacuum of -1 bar to the sample chamber and then place it on a hot plate. Heat the sample to 105°C for four minutes, then transfer the sample to a cooling plate and cool for 2 minutes. Obtain an opaque black rod weighing ~30 mg with a length of 8 mm and a diameter of 2 mm.

[0432] Example 8: Long-lasting in vivo effect of rifapentine after implantation

[0433] This experiment was conducted on male Sprague Dawley rats (250–300g – Charles River). Two rods were implanted subcutaneously into each scapular region in each rat. The rods contained the following rifapentine formulation: rifapentine. 40 / Plasdone C15 50 / AOT 10 Four research groups varied the size and / or number of implants to control the rifapentine dosage:

[0434] 1- Two 15mm implants per animal (approximately 46mg rifapentine dose per animal);

[0435] 2 – One 15mm implant per animal (approximately 23mg rifapentine per animal);

[0436] 3 – Two 8mm implants per animal (26mg rifapentine dose); and

[0437] 4 – Two excipient-only implants per animal (0 mg rifapentine dose).

[0438] Plasma was collected periodically from the tail vein over a 35-day period, and the concentration of rifapentine in it was quantified using LC / MS-MS. This data is in... Figure 2 The data were plotted and showed that the concentration of rifapentine gradually decreased during the 35-day experimental period, confirming that the relevant concentration of rifapentine was maintained during the said duration.

[0439] Example 9: Formulation of microneedles

[0440] A PVA (Sigma Aldrich, nominal MW 9-10 kDa) containing 20% ​​by weight / weight PVA (M) was prepared in deionized water. w A polymer stock solution containing 9-10 kDa and 20% by weight Plasdone K29 / 32. This was achieved using a Speedmixer. TM The polymer stock solution of 27.8% by weight was mixed with 27.8% by weight rifapentine formulation (rifapentine) at 3500 rpm. 40 / Plasdone C15 50 / AOT 10 The needle-layer composition was prepared by mixing 30% by weight of PVP (Sigma Aldrich, nominal MW 360 kDa, M) with 44.4% by weight of deionized water for 5 minutes. The mixture was further purified by mixing with 44.4% by weight of deionized water for 5 minutes before ultrasonication and centrifugation. nA substrate composition was prepared by mixing 360 kDa (K value 80-100), 1.5% wt / wt glycerol, and the balance deionized water.

[0441] The needle-layer composition was cast into a shape arranged at 0.49 cm. 2 A 16x16 array of microneedles is formed over the region, each with a height of 850 μm (600 μm for the pyramidal tip and 250 μm for the base pillar) and a pillar width of 300 μm, with a spacing of 100 μm between needles. The array is placed in a pressure chamber and treated with 5 bar pressure for 3 minutes. In some embodiments, a second layer of needles is cast and the array is placed in the pressure chamber and further treated with 5 bar pressure for 5 minutes. The microneedles are then allowed to dry overnight.

[0442] 650 μl of the substrate composition was cast onto the prepared needles and centrifuged at 5000 rpm for 15 minutes, followed by drying under ambient conditions for 48 hours. The assembled microneedle arrays were then removed from the mold, and excess substrate material was removed. A single-cast microneedle array was found to have a rifapentine loading of 1.37 ± 0.095 mg, while a two-cast microneedle array was found to have a rifapentine loading of 1.72 ± 0.15 mg.

[0443] Example 10: Insertion efficiency of microneedle array

[0444] The microneedle array was applied to the layer by using a force of 32N (equivalent to the force of a human thumb). Using an in vitro skin model with a thickness of approximately 252 μm per layer (M), the insertion efficiency of the microneedle array was determined. The following equation was used... The percentage of insertion for each layer is calculated based on the number of holes punched in each layer of M.

[0445]

[0446] exist Figure 3 An instance is shown in The puncture marks are generated in the four consecutive layers of M. It can be seen that the microneedle array completely penetrates... The first two layers of M maintain some penetration through to The fourth layer of M.

[0447] Example 11: In vitro evaluation of microneedles

[0448] Ex vivo skin deposition experiments were performed using a modified Franz diffusion cell. Full-thickness skin was collected and excised within 24 hours of birth. On the day of the experiment, the skin was first pre-equilibrated in PBS at pH 7.4 for 30 minutes until completely thawed, and then carefully shaved. The skin was then glued to the donor chamber of the Franz diffusion cell using cyanoacrylate to ensure adhesion to the device during microneedle insertion and throughout the experiment. The microneedle array was applied to the skin for 30 seconds using firm thumb pressure. A stainless steel cylinder (11 mm in diameter, 11.5 g in weight) was placed on top of each microneedle array to maintain its position throughout the experiment.

[0449] Fill the receiving chamber with PBS (pH 7.4) containing 12 mL of 1% SLS (by weight / volume) and 0.1% ascorbic acid (by weight / volume). Clamp the donor chamber onto the top of the receiving chamber and use... M-coated containers prevent solvent evaporation. At predetermined time points (1, 2, 3, 4, 6, 10, and 24 hours), 200 μL samples were collected from the receiving chamber and replaced with fresh release medium. At 24 hours, the Franz cell was disassembled, the skin surface was blistered to remove surface drug, and rifapentine was extracted from the skin. The cumulative amount of rifapentine delivered from each formulation to the skin and receiving chamber was also determined. To extract the drug from the skin, skin samples collected at 24 hours were cut into small pieces, and 0.5 mL of water was added to each sample. These were then homogenized for 15 minutes using Tissue Lyser LT. 1 mL of methanol was then added, and the sample was homogenized again for another 15 minutes. The samples were then transferred to tubes, followed by the addition of 3.5 mL of methanol. After 30 min of sonication, 100 μL of the sample was diluted to 1 mL using PBS buffer (containing 1% W / v SLS and 0.1% W / v ascorbic acid). The samples were vortexed and centrifuged, and then analyzed by HPLC.

[0450] Data Overview Figure 4 and Figure 5Within 24 hours, for a single-cast microneedle array, 114.6 ± 20.8 μg of rifapentine was delivered to the receiving chamber of the Franz diffusion cell and 729.6 ± 85.4 μg of rifapentine was delivered to the skin. For a two-cast microneedle array, 138.7 ± 25.7 μg of rifapentine was delivered to the receiving chamber of the Franz diffusion cell and 817.7 ± 174.7 μg of rifapentine was delivered to the skin within 24 hours. This resulted in a total delivery of 842.2 ± 79.5 μg of rifapentine to the skin and receiving chamber within 24 hours, or 61.4% of the rifapentine initially present in the single-cast microneedle array. For a two-cast microneedle array, the total delivery of 956.4 ± 158.0 μg of rifapentine to the skin and receiving chamber within 24 hours, or 55.6% of the rifapentine initially present. Most of the delivered rifapentine remains in the skin, which is believed to be due to the high hydrophobicity of these compounds.

[0451] Example 12: Long-lasting in vivo effect of rifapentine after application of microneedle array

[0452] Female Sprague-Dawley rats (total n=64) aged 11–12 weeks with an average body weight of 271.5 ± 22.3 g were acclimatized to the environment for seven days prior to the experiment. Four microneedle arrays (each loaded with 1.4 mg rifapentine to a total dose of 5.6 mg per rat) were applied to the rats.

[0453] To minimize interference from hair during microneedle array application, dorsal hair was removed from rats in cohort 1 (rats 1-6) prior to the experiment. Most of the hair was shaved using a power clipper, and any remaining hair residue was removed with depilatory cream. Rats were then left in a 24-hour period to allow skin recovery and ensure full restoration of skin barrier function before microneedle array fixation. The following day, rats were sedated with a gaseous anesthetic gas (oxygen containing 2-4% volume / volume isoflurane), and the microneedle array was fixed to the compressed portion of the dorsal skin of cohort 1 rats using firm thumb pressure. Subsequently, Tegaderm... TM The film is placed on top of the microneedle array and motion tape is applied to keep them in place.

[0454] Plasma was collected periodically from the tail vein over a 24-hour period, and the concentration of rifapentine in it was quantified using LC / MS-MS. This data was obtained in... Figure 6 The data were plotted and displayed as a consistent concentration of rifapentine during the 24-hour experimental period, confirming that the relevant concentration of rifapentine was maintained during the said duration.

[0455] Example 13 - Plasdone Plasdone formed by nanoprecipitation and spray drying C15 / AOT SDN

[0456] Rifampin was dissolved in methanol at a concentration of 50 mg / mL, Plasdone C15 was dissolved in water at a concentration of 14.25 mg / mL, and AOT was dissolved in water at a concentration of 15 mg / mL. 0.8 mL of AOT stock solution was added to 3.2 mL of rifampin stock solution and mixed using a vortex mixer for 30 seconds. The resulting mixture was immediately added to 16 mL of Plasdone C15 stock solution using a peristaltic pump at a flow rate of 5 mL / min, while stirring with a stir bar. The sample was stirred for at least 5 minutes prior to spray drying. The sample was then spray-dried using a Buchi B-290 mini spray dryer (100% suction, nitrogen at 5 bar pressure, Q-Flow specification 45, outlet temperature 65°C) at a flow rate of 5 mL / min (while stirring with a stir bar to prevent any possible sedimentation) to give a rifampin composition containing approximately 40 wt% RFP, 57 wt% Plasdone C15, and 3 wt% AOT. The method was repeated on a larger scale, with 5 mL of LAOT stock solution and 20 mL of rifapentine stock solution added to 100 mL of Plasdone C15 stock solution at a flow rate of 5 mL / min. The sample was dispersed in water at 1 mg / mL for the active ingredient and screened as described in Example 1.

[0457] scale Dz(nm) PdI small-scale 198.7 0.14 large-scale 237.2 0.27

[0458] Example 14: In vivo long-acting effect of rifapentine after administration of long-acting injectable formulations containing different concentrations of excipient AOT efficacy

[0459] Male Sprague-Dawley rats (total n = 68) aged 11–12 weeks with an average body weight of 315.6 ± 15.3 g were acclimatized to the environment for seven days prior to the experiment. The rats were divided into cohorts and administered the following via intramuscular injection:

[0460] 1. Rifapentine 40 / Plasdone C15 57 / AOT3 SDNs, administered at a dose of 300 mg / kg rifapentine, via two injections of 150 μL each time;

[0461] 2. Rifapentine 40 / Plasdone C15 50 / AOT 10 SDNs, administered at a dose of 300 mg / kg rifapentine, via two injections of 150 μL each time;

[0462] 3. Plasdone C15 reconstructed from spray-dried powder 57 / AOT3 (control), administered via two injections of 150 μL each time;

[0463] 4. Plasdone C15 reconstructed from spray-dried powder 50 / AOT 10 (Control) Two injections of 150 μL each time;

[0464] 5. Water (control), administered via two injections of 150 μL each time;

[0465] 6. Rifapentine 40 / Plasdone C15 57 / AOT3 SDN, at a dose of 150 mg / kg rifapentine, was administered via two 75 μL injections; and

[0466] 7. Rifapentine 40 / Plasdone C15 50 / AOT 10 SDN, at a dose of 150 mg / kg rifapentine, was administered via two injections of 75 μL each.

[0467] Before injection, the formulation was dispersed in water for injection. Buprenorphine was administered subcutaneously to all rats to relieve pain prior to intramuscular injection.

[0468] Cohorts 1 through 5 each consisted of three cages, with four mice in each cage. Cohorts 6 and 7 each consisted of only one cage, with four rats in each cage.

[0469] Plasma was collected periodically from the caudal vein over a 56-day period, and the concentration of rifapentine in it was quantified using LC / MS-MS. This data is in... Figure 7 (150 mg / kg cohort) and Figure 8 The graphs (300 mg / kg cohort) show no significant difference in rifapentine plasma concentrations between the stated formulations.

[0470] Invention Clause:

[0471] Clause 1. A solid composition comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a matrix comprising a first excipient and a second excipient.

[0472] The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0473] The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0474] Clause 2. The solid composition of Clause 1, wherein the first excipient and the second excipient are selected from the combination of:

[0475] -PVP and benzalkonium chloride

[0476] -PVP and AOT

[0477] -PVP and polysorbate 20

[0478] -PVP and polysorbate 80

[0479] - Lactose and AOT

[0480] - Lactose and poloxamer

[0481] - Sucrose and benzalkonium chloride

[0482] -Sugar and AOT

[0483] - Sucrose and dehydrated sorbitol monolaurate

[0484] -Sugar and poloxamer

[0485] - Poloxamer and polysorbate 20

[0486] -Polosham and AOT

[0487] -PEG and AOT

[0488] -PEG and poloxamer.

[0489] Clause 3. The solid composition described in Clause 2, wherein the first excipient and the second excipient are selected from the combination of:

[0490] -PVP and AOT

[0491] - Lactose and AOT.

[0492] Clause 4. Any of the solid compositions described in the preceding clauses, wherein the composition comprises:

[0493] 10 to 80% by weight of the aforementioned rifamycin, such as rifapentine;

[0494] 10 to 80% by weight of the first excipient; and

[0495] 1 to 25% by weight of the second excipient,

[0496] Clause 5. The solid composition described in Clause 4, wherein the composition comprises:

[0497] 30 to 60% by weight of the aforementioned rifamycin, such as rifapentine;

[0498] 30 to 60% by weight of the first excipient; and

[0499] 1 to 20% by weight of the second excipient.

[0500] Clause 6. The solid composition described in Clause 5, wherein the composition comprises:

[0501] 40 to 50% by weight of the aforementioned rifamycin, such as rifapentine;

[0502] 40 to 50% by weight of the first excipient; and

[0503] 5 to 15% by weight of the second excipient.

[0504] Clause 7. The solid composition described in Clause 5, wherein the composition comprises:

[0505] 30 to 50% by weight of the aforementioned rifamycin, such as rifapentine;

[0506] 40 to 60% by weight of the first excipient; and

[0507] 1 to 10% by weight of the second excipient.

[0508] Clause 8. The solid composition described in Clause 7, wherein the composition comprises:

[0509] 35 to 45% by weight of the aforementioned rifamycin, such as rifapentine;

[0510] 50 to 60% by weight of the first excipient; and

[0511] 1 to 5% by weight of the second excipient.

[0512] Clause 9. The solid composition described in any of the preceding clauses, wherein the nanoparticles have a particle size in the range of 10 to 2500 nm, preferably in the range of 20 nm to 2000 nm, more preferably in the range of 50 nm to 1500 nm, further preferably in the range of 100 nm to 1000 nm, and most preferably in the range of 200 to 800 nm.

[0513] Clause 10. The solid composition described in any of the preceding clauses, wherein the nanoparticles have a polydispersity of less than or equal to 0.8, preferably less than or equal to 0.6, more preferably less than or equal to 0.5.

[0514] Clause 11. A method for preparing a solid composition according to any one of Clauses 1 to 10, the method comprising:

[0515] (a) Preparing an oil-in-water emulsion, the oil-in-water emulsion comprising:

[0516] - An oil phase containing the rifamycin, such as rifapentine; and

[0517] - An aqueous phase comprising the first and second excipients as defined in any one of Clauses 1 to 10; and

[0518] (b) Remove oil and water from the oil-in-water emulsion to form the solid composition.

[0519] Clause 12. A method for preparing a solid composition according to any one of Clauses 1 to 10, the method comprising:

[0520] (a) Providing an active solution of the rifamycin, such as rifapentine, contained in a water-miscible solvent;

[0521] (b) Provide a carrier substance solution containing a first excipient and a second excipient as defined in any one of Clauses 1 to 10;

[0522] (c) Mix the solutions prepared in steps (a) and (b); and

[0523] (d) Remove the mixed solvent to prepare the solid composition.

[0524] Alternatively, the method may include:

[0525] (a) Providing an active solution containing the rifamycin, such as rifapentine, and the second excipient in a water-miscible solvent;

[0526] (b) Provide a carrier substance solution containing a first excipient as defined in any one of Clauses 1 to 10;

[0527] (c) Mix the solutions prepared in steps (a) and (b); and

[0528] (d) Remove the mixed solvent to prepare the solid composition.

[0529] Clause 13. The method of Clause 11, wherein the step of removing oil and water from the oil-in-water emulsion, or the method of Clause 12, wherein the step of removing the mixed solvent includes spray drying or freeze drying.

[0530] Clause 14. An aqueous dispersion comprising a plurality of rifamycin nanoparticles, such as rifapentine, said nanoparticles being dispersed in an aqueous medium and stabilized by a mixture of a first excipient and a second excipient;

[0531] The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0532] The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0533] Clause 15. The aqueous dispersion described in Clause 14, wherein the aqueous dispersion comprises nanoparticles of rifamycin, such as rifapentine, as defined in any one of Clauses 2 to 10, a first excipient, and a second excipient in the aqueous medium.

[0534] Clause 16. The aqueous dispersion described in Clause 14 or Clause 15, wherein rifamycin, such as rifapentine, is present in the aqueous dispersion at a concentration of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0535] Clause 17. A method for preparing an aqueous dispersion according to any one of Clauses 14 to 16, the method comprising dispersing a solid composition according to any one of Clauses 1 to 10 in an aqueous medium.

[0536] Clause 18. A pharmaceutical composition comprising a solid composition as described in any one of Clauses 1 to 8 or an aqueous dispersion as described in any one of Clauses 14 to 16 and optionally one or more other pharmaceutically acceptable excipients.

[0537] Clause 19. An injectable formulation comprising any one of the solid compositions described in Clauses 1 to 10, any one of the aqueous dispersions described in Clauses 14 to 16, or the pharmaceutical composition described in Clause 18.

[0538] The injectable formulations described in Clause 20 and Clause 19, wherein the injectable formulation is a subcutaneous or intramuscular injectable formulation, and optionally the injectable formulation is suitable for provision in a reservoir form.

[0539] Clause 21. A method for preparing an implantable rod, the method comprising the steps of compressing a solid composition according to any one of Clauses 1 to 10 and heating the compressed solid composition for a period of time.

[0540] Clause 22. The method of Clause 21, wherein the solid composition is compressed in a mold, optionally the mold being cylindrical.

[0541] Clause 23. The method of Clause 21 or Clause 22, wherein the solid composition is heated to a temperature of 60 to 160°C, preferably 80 to 140°C, more preferably 100 to 120°C, and most preferably about 105°C.

[0542] Clause 24. The method of any one of Clauses 21 to 23, wherein the compression is performed under a reduced pressure atmosphere.

[0543] Clause 25. The method of any one of Clauses 21 to 24, wherein the heating step is performed for 1 minute to 40 minutes, preferably 5 minutes to 30 minutes, more preferably 10 minutes to 25 minutes, and most preferably for a period of about 20 minutes.

[0544] Clause 26. The method of any one of Clauses 21 to 25, further comprising the step of cooling the rod, optionally under reduced pressure.

[0545] Clause 27. An implantable rod prepared by any one of Clauses 21 to 25.

[0546] Clause 28. An implantable rod comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles dispersed in a monolithic material comprising a first excipient and a second excipient.

[0547] The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0548] The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0549] Clause 29. The implantable rod described in Clause 28, wherein the rifamycin, such as rifapentine nanoparticles, the first excipient, and / or the second excipient are as defined in any one of Clauses 2 to 10.

[0550] Clause 30. A method for preparing a microneedle array, said microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition, said method comprising the steps of:

[0551] (a) Dispersing a solid composition according to any one of clauses 1 to 10 and at least one structural polymer in a solvent to form a microneedle precursor dispersion;

[0552] (b) Place the microneedle precursor dispersion into the mold;

[0553] (c) The microneedle precursor dispersion is compressed in a mold and then dried to form microneedles containing the first composition;

[0554] (d) Add the substrate precursor solution to the mold;

[0555] (e) Compress the substrate precursor solution and then dry it to form a substrate of the second composition; and

[0556] (f) Remove the microneedle array from the mold.

[0557] Clause 31. The method described in Clause 30, wherein steps b) and c) are repeated before steps d) to f).

[0558] Clause 32. The method described in Clause 30 or Clause 31, wherein the solvent is an aqueous solvent, such as water.

[0559] Clause 33. The method of any one of Clauses 30 to 32, wherein the at least one structural polymer is selected from PVA, PVP and combinations thereof.

[0560] Clause 34. The method of any one of Clauses 31 to 33, wherein the substrate precursor solution comprises a base polymer selected from PVP dispersed in an aqueous solvent such as water and optionally one or more additives such as glycerol.

[0561] Clause 35. A microneedle array prepared by any one of Clauses 31 to 34.

[0562] Clause 36. A microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition.

[0563] The first composition comprises rifamycin nanoparticles, such as rifapentine, dispersed in a bulk material comprising a first excipient, a second excipient, and at least one structural polymer.

[0564] The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose.

[0565] The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

[0566] Clause 37. The microneedle array described in Clause 36, wherein the rifamycin, such as rifapentine, nanoparticles, the first excipient, and / or the second excipient are as defined in any one of Clauses 2 to 10.

[0567] The microneedle array described in Clause 38, Clause 36, or Clause 37, wherein the at least one structural polymer is selected from PVA, PVP, and combinations thereof.

[0568] Clause 39. Microneedle arrays of any one of Clauses 36 to 38, wherein the second composition comprises a base polymer such as PVP and optionally one or more additives such as glycerin.

[0569] Clause 40. A solid composition according to any one of Clauses 1 to 10, an aqueous dispersion according to any one of Clauses 14 to 16, a pharmaceutical composition according to Clause 18, an injectable formulation according to Clause 19 or Clause 20, an implantable rod according to any one of Clauses 27 to 29, or a microneedle array according to any one of Clauses 35 to 39, used as a medicament.

[0570] Clause 41. A solid composition according to any one of Clauses 1 to 10, an aqueous dispersion according to any one of Clauses 14 to 16, a pharmaceutical composition according to Clause 18, an injectable formulation according to Clause 19 or Clause 20, an implantable rod according to any one of Clauses 27 to 29, or a microneedle array according to any one of Clauses 35 to 39, for the treatment and / or prevention of tuberculosis, such as latent tuberculosis.

[0571] Clause 42. An aqueous dispersion, pharmaceutical composition or injectable formulation for use according to Clause 40 or Clause 41, wherein the concentration of rifapentine is 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0572] Clause 43. An implantable rod for use according to Clause 40 or Clause 41, wherein rifamycin, such as rifapentine, is present in the implantable rod at a concentration in the range of 30 to 80% by weight, preferably 40 to 70% by weight, and most preferably about 50% by weight.

[0573] Clause 44. A microneedle array for use according to Clause 40 or Clause 41, wherein the microneedle array comprises rifamycin, such as rifapentine, in the range of 0.1 to 20 mg, preferably 0.5 to 10 mg, more preferably 1 to 5 mg, and most preferably 1 to 2 mg.

[0574] Clause 45. A method for treating and / or preventing tuberculosis, comprising administering to a patient suffering from tuberculosis or at risk of tuberculosis a therapeutically effective amount of any of the solid compositions described in any of Clauses 1 to 10, an aqueous dispersion described in any of Clauses 14 to 16, a pharmaceutical composition described in Clause 18, an injectable formulation described in Clause 19 or Clause 20, an implantable rod described in any of Clauses 27 to 29, or a microneedle array described in any of Clauses 35 to 39.

[0575] Clause 46. The method described in Clause 45, wherein rifamycin, such as rifapentine, is in the aqueous dispersion, the pharmaceutical composition, or the injectable formulation at a concentration of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0576] Clause 47. The method of Clause 45, wherein rifamycin, such as rifapentine, is in the implantable rod at a concentration in the range of 40 to 80% by weight, preferably in the range of 50 to 70% by weight, and most preferably about 60% by weight.

[0577] The method described in Clause 48. Clause 45, wherein the microneedle array comprises rifapentine in the range of 1 to 20 mg, preferably in the range of 2 to 10 mg, more preferably about 5 mg of rifamycin, such as rifapentine.

[0578] The method of any one of Clauses 45 to 47, wherein the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod forms a reservoir in the patient's body, optionally wherein the reservoir maintains a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient's body for a period of at least two weeks, preferably at least one week more, more preferably at least two months, further more preferably at least three months, and most preferably at least four months.

[0579] The method described in any one of Clauses 50, 45 to 48, wherein the microneedle array gradually releases rifamycin, such as rifapentine, optionally wherein the microneedle array maintains a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient's body for at least 4 hours, preferably at least 6 hours, more preferably at least 12 hours, and most preferably at least 24 hours.

[0580] Clause 51. The method of any one of Clauses 45 to 47 and 49, wherein the patient is required to be administered the aqueous dispersion, the pharmaceutical composition, the injectable formulation, or the implantable rod up to three times, preferably up to two times, and most preferably only once, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, for the duration of treatment.

[0581] The method of any one of Clauses 52, 45, 48, and 50, wherein the patient is required to receive the microneedle array up to six times a day, preferably up to four times a day, more preferably twice a day, and most preferably once a day, to maintain a therapeutically effective concentration of rifamycin, such as rifapentine, in the patient for the duration of treatment.

[0582] Clause 53. Use of a solid composition according to any one of Clauses 1 to 10, an aqueous dispersion according to any one of Clauses 14 to 16, a pharmaceutical composition according to Clause 18, an injectable formulation according to Clause 19 or Clause 20, an implantable rod according to any one of Clauses 27 to 29, or a microneedle array according to any one of Clauses 35 to 39 for the manufacture of a medicament for the treatment and / or prevention of tuberculosis, such as latent tuberculosis.

[0583] Clause 54. Use of the aqueous dispersion, pharmaceutical composition or injectable formulation as described in Clause 53, wherein the concentration of rifapentine is 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

[0584] Clause 55. Use of the implantable rod as described in Clause 53, wherein rifamycin, such as rifapentine, is present in the implantable rod at a concentration in the range of 30 to 80% by weight, preferably in the range of 40 to 70% by weight, and most preferably about 50% by weight.

[0585] Clause 56. Use of the microneedle array as described in Clause 53, wherein the microneedle array comprises rifamycin, such as rifapentine, in the range of 0.1 to 20 mg, preferably 0.5 to 10 mg, more preferably 1 to 5 mg, and most preferably 1 to 2 mg.

Claims

1. A solid composition comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a matrix comprising a first excipient and a second excipient. The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose. The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

2. The solid composition of claim 1, wherein the first excipient and the second excipient are selected from the combination of: -PVP and benzalkonium chloride -PVP and AOT -PVP and polysorbate 20 -PVP and polysorbate 80 - Lactose and AOT - Lactose and poloxamer - Sucrose and benzalkonium chloride -Sugar and AOT - Sucrose and dehydrated sorbitol monolaurate -Sugar and poloxamer - Poloxamer and polysorbate 20 -Polosham and AOT -PEG and AOT -PEG and poloxamer Preferably, the first excipient and the second excipient are selected from the following combinations: -PVP and AOT - Lactose and AOT.

3. The solid composition according to any one of the preceding claims, wherein the composition comprises: 10 to 80% by weight of the aforementioned rifamycin, such as rifapentine; 10 to 80% by weight of the first excipient; and 1 to 25% by weight of the second excipient, Preferably, the composition comprises: 30 to 60% by weight of the aforementioned rifamycin, such as rifapentine; 30 to 60% by weight of the first excipient; and 5 to 20% by weight of the second excipient.

4. The solid composition of claim 3, wherein the composition comprises: 40 to 50% by weight of the aforementioned rifamycin, such as rifapentine; 40 to 50% by weight of the first excipient; and 5 to 15% by weight of the second excipient.

5. The solid composition of claim 3, wherein the composition comprises: 30 to 50% by weight of the aforementioned rifamycin, such as rifapentine; 40 to 60% by weight of the first excipient; and 1 to 10% by weight of the second excipient, Preferably, the composition comprises: 35 to 45% by weight of the aforementioned rifamycin, such as rifapentine; 50 to 60% by weight of the first excipient; and 1 to 5% by weight of the second excipient.

6. The solid composition of any one of the preceding claims, wherein the nanoparticles have: (i) a particle size in the range of 10 to 2500 nm, preferably 20 nm to 2000 nm, more preferably 50 nm to 1500 nm, further preferably 100 nm to 1000 nm, and most preferably in the range of 200 to 800 nm; and / or (ii) Polydispersity less than or equal to 0.8, preferably less than or equal to 0.6, and more preferably less than or equal to 0.

5.

7. A method for preparing a solid composition according to any one of claims 1 to 6, the method comprising: (a) Preparing an oil-in-water emulsion, the oil-in-water emulsion comprising: - An oil phase containing the rifamycin, such as rifapentine; and - An aqueous phase comprising the first excipient and the second excipient as defined in any one of claims 1 to 6; and (b) Remove oil and water from the oil-in-water emulsion to form the solid composition.

8. A method for preparing a solid composition according to any one of claims 1 to 6, the method comprising: (a) Providing an active solution of the rifamycin, such as rifapentine, contained in a water-miscible solvent; (b) Providing a carrier substance solution comprising a first excipient and a second excipient as defined in any one of claims 1 to 6; (c) Mix the solutions prepared in steps (a) and (b); and (d) Remove the mixed solvent to prepare the solid composition; Alternatively, the method may include: (a) Providing an active solution containing the rifamycin, such as rifapentine, and the second excipient in a water-miscible solvent; (b) Providing a carrier substance solution comprising a first excipient as defined in any one of claims 1 to 6; (c) Mix the solutions prepared in steps (a) and (b); and (d) Remove the mixed solvent to prepare the solid composition.

9. The method of claim 7, wherein the step of removing oil and water from the oil-in-water emulsion, or the method of claim 8, wherein the step of removing the mixed solvent includes spray drying or freeze drying.

10. An aqueous dispersion comprising a plurality of nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in an aqueous medium and stabilized by a mixture of a first excipient and a second excipient; The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose. The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

11. The aqueous dispersion of claim 10, wherein: (i) the aqueous dispersion comprises, in the aqueous medium, nanoparticles of rifamycin, such as rifapentine, as defined in any one of claims 2 to 6, a first excipient, and a second excipient; and / or (ii) Rifamycin, such as rifapentine, is present in the aqueous dispersion at a concentration of 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

12. A method for preparing an aqueous dispersion according to claim 10 or claim 11, the method comprising dispersing the solid composition according to any one of claims 1 to 6 in an aqueous medium.

13. A pharmaceutical composition comprising the solid composition of any one of claims 1 to 6 or the aqueous dispersion of claim 10 or 11 and optionally one or more other pharmaceutically acceptable excipients.

14. An injectable formulation comprising the solid composition of any one of claims 1 to 6, the aqueous dispersion of claim 10 or 11, or the pharmaceutical composition of claim 13, optionally wherein the injectable formulation is a subcutaneous or intramuscular injectable formulation, and further optionally wherein the injectable formulation is suitable for delivery in a reservoir form.

15. A method for preparing an implantable rod, the method comprising the steps of compressing a solid composition according to any one of claims 1 to 6 and heating the compressed solid composition for a period of time.

16. The method of claim 15, wherein the solid composition: (i) compressed in a mold, optionally the mold being cylindrical; and / or (ii) Heated to a temperature of 60 to 160°C, preferably 80 to 140°C, more preferably 100 to 120°C, and most preferably about 105°C.

17. The method of any one of claims 15 to 16, wherein the compression is performed under a reduced pressure atmosphere.

18. The method of any one of claims 15 to 17, wherein the heating step is performed for 1 minute to 40 minutes, preferably 5 minutes to 30 minutes, more preferably 10 minutes to 25 minutes, and most preferably for a period of about 20 minutes.

19. The method of any one of claims 15 to 18, further comprising the step of cooling the rod, optionally performing the cooling under a reduced pressure atmosphere.

20. An implantable rod prepared by any one of claims 15 to 19.

21. An implantable rod comprising nanoparticles of rifamycin, such as rifapentine, said nanoparticles being dispersed in a bulk material comprising a first excipient and a second excipient. The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose. The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

22. The implantable rod of claim 21, wherein the rifamycin, such as rifapentine, nanoparticles, the first excipient, and / or the second excipient are as defined in any one of claims 2 to 6.

23. A method for preparing a microneedle array, the microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition, the method comprising the following steps: (a) Dispersing the solid composition according to any one of claims 1 to 6 and at least one structural polymer in a solvent to form a microneedle precursor dispersion; (b) Place the microneedle precursor dispersion into a mold; (c) The microneedle precursor dispersion is compressed in a mold and then dried to form microneedles containing the first composition; (d) Add the substrate precursor solution to the mold; (e) Compress the substrate precursor solution and then dry it to form a substrate of the second composition; and (f) Remove the microneedle array from the mold.

24. The method of claim 23, wherein: (i) Repeat steps b) and c) before steps d) to f); and / or (ii) The solvent is an aqueous solvent, such as water; and / or (iii) The at least one structural polymer is selected from PVA, PVP, and combinations thereof; and / or (iv) The substrate precursor solution comprises a base polymer dispersed in an aqueous solvent such as water and optionally one or more additives, such as glycerol, wherein the base polymer is selected from PVP.

25. A microneedle array prepared by the method of claim 23 or claim 24.

26. A microneedle array comprising microneedles of a first composition arranged on one side of a substrate of a second composition. The first composition comprises rifamycin nanoparticles, such as rifapentine, dispersed in a bulk material comprising a first excipient, a second excipient, and at least one structural polymer. The first excipient is selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene-polyoxypropylene block copolymer (poloxam), lactose, and sucrose. The second excipient is selected from benzalkonium chloride, sodium dioctyl succinate sulfonate (AOT), polyoxyethylene-polyoxypropylene block copolymer (poloxam), polysorbate 20, polysorbate 80 and dehydrated sorbitol monolaurate.

27. The microneedle array of claim 26, wherein: (i) the nanoparticles of the rifamycin, such as rifapentine, the first excipient, and / or the second excipient as defined in any one of claims 2 to 6; and / or (ii) The at least one structural polymer is selected from PVA, PVP, and combinations thereof; and / or (iii) The second composition comprises a base polymer, such as PVP, and optionally one or more additives, such as glycerin.

28. The solid composition according to any one of claims 1 to 6, the aqueous dispersion according to claim 10 or 11, the pharmaceutical composition according to claim 13, the injectable formulation according to claim 14, the implantable rod according to any one of claims 20 to 22, or the microneedle array according to any one of claims 25 to 27, used as a drug.

29. A solid composition according to any one of claims 1 to 6, an aqueous dispersion according to claim 10 or 11, a pharmaceutical composition according to claim 13, an injectable formulation according to claim 14, an implantable rod according to any one of claims 20 to 22, or a microneedle array according to any one of claims 25 to 27, for the treatment and / or prevention of tuberculosis, such as latent tuberculosis.

30. An aqueous dispersion, pharmaceutical composition or injectable formulation for use according to claim 28 or claim 29, wherein the concentration of rifapentine is 100 to 1000 mg / mL, preferably 200 to 900 mg / mL, more preferably 300 to 800 mg / mL, and most preferably 500 to 700 mg / mL.

31. An implantable rod for use according to claim 28 or claim 29, wherein rifamycin, such as rifapentine, is present in the implantable rod at a concentration of 30 to 80% by weight, preferably 40 to 70% by weight, and most preferably about 50% by weight.

32. A microneedle array for use according to claim 28 or claim 29, wherein the microneedle array comprises rifapentine, preferably 0.5 to 10 mg, more preferably 1 to 5 mg, and most preferably rifamycin, such as rifapentine, in the range of 1 to 2 mg.

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