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    • 专利摘要:
    crystalline diketopiperazine composition, methods of producing diketopiperazine particles, making a composition and treating and using a crystalline diketopiperazine composition. the present document discloses dkp microcrystals produced by an improved method in which they are not irreversibly self-assembled into microparticles. microcrystals can be dispersed by atomization and re-formed by spray drying to particles having spherical shell morphology. the active agents and excipients can be incorporated into the particles by spray drying a solution containing the components to be incorporated into the microcrystalline diketopiperazine particles. in particular, microcrystalline particle compositions are suitable for pulmonary drug delivery of one or more peptides, proteins, nucleic acids and/or small organic molecules.
    公开号:BR112015023168B1
    申请号:R112015023168-3
    申请日:2014-03-14
    公开日:2021-08-10
    发明作者:Bryan R. Wilson；Joseph J. Guarneri；Marshall L. Grant
    申请人:Mannkind Corporation；
    IPC主号:
    专利说明:

    FIELD OF TECHNIQUE
    [001] The present invention relates to microcrystalline diketopiperazine (DKP) particles, compositions and methods for producing the particles and method for using the particles. In particular, the particles can be used as a delivery system for drugs or active agents in the treatment of disease or disorders, for example, of endocrine origin, including diabetes and obesity. BACKGROUND
    [002] The release of drugs has been a major problem for years, particularly when the compound to be released is unstable under conditions found in the gastrointestinal tract when administered orally to an individual, before reaching the site where it is. directed. For example, it is preferable in many cases to administer drugs orally, especially in terms of ease of administration, patient compliance and reduced cost. However, many compounds are ineffective or exhibit low or variable potency when given orally. This is supposedly due to the fact that drugs are unstable to conditions in the digestive tract or because they are inefficiently absorbed.
    [003] Due to the problems associated with the oral application of drugs, the application of drugs in the lungs has been explored. For example, typically, drugs released into the lungs are designed to have an effect on lung tissue, for example, vasodilators, surfactants, chemotherapeutic agents, or vaccines for flu or other respiratory illnesses. Other drugs, including nucleotide drugs, have been released into the lungs due to the fact that they represent a particularly suitable tissue for treatment, for example, of cystic fibrosis gene therapy, in which retroviral vectors expressing a defective adenosine deaminase are administered to the lungs .
    [004] The release of drugs to the lungs can also be performed by agents that have systemic effects. Advantages to the lungs from the release of systemic agents include the large surface area and ease of absorption through the mucosal surface of the lung. Lung drug delivery systems present many difficulties, for example, the use of propellants, and aerosolization of biological agents such as proteins and peptides can lead to denaturation, and excessive loss of the agent to be delivered. Another problem associated with all of these forms of lung drug release is the difficulty in releasing drugs into the lungs due to problems in getting the drug through all natural barriers, such as the inner lining of the tracheal cilia, and into try to administer a uniform volume and weight of drug.
    [005] Consequently there is room for improvement in pulmonary drug delivery. SUMMARY DESCRIPTION
    [006] The present disclosure provides improved microcrystalline particles, compositions, methods for making the particles and methods that allow for improved delivery of drugs to the lungs to treat diseases and disorders in an individual. The embodiments disclosed herein achieve improved release by providing crystalline diketopiperazine compositions comprising microcrystalline diketopiperazine particles that have high drug adsorption capacity yielding powders that have high drug content of one or more active agents. Powders made with the present microcrystalline particles can release increased drug content in smaller amounts than the powder dose, which can facilitate drug delivery to a patient. Powders can be made by various methods, including methods that use surfactant-free solutions or solutions that comprise surfactants depending on the starting materials.
    [007] Certain embodiments described herein may comprise powders comprising a plurality of substantially formless microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell that may be porous and comprise non-self-assembled diketopiperazine crystallites .
    [008] Certain embodiments described herein comprise powders comprising a plurality of substantially shapeless microcrystalline particles, wherein the particles have a substantially hollow spherical structure and comprise a shell that may be porous and comprise crystallites of a diketopiperazine that are not self-assembled and the particles have a volume median geometric diameter less than 5 µm.
    [009] In a particular embodiment herein, up to about 92% of the microcrystalline particles have a volume median geometric diameter of < 5.8 µm. In one embodiment, the particle shell is constructed from interlocking diketopiperazine crystals that have one or more drugs adsorbed on their surfaces. In some embodiments, the particles can capture drug in their interior void volume and/or combinations of drug adsorbed to the surface of the crystallites and drug trapped in the interior void volume of the spheres.
    [010] In certain embodiments, a diketopiperazine composition comprising a plurality of substantially uniformly formed microcrystalline particles is provided, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that are not self-assembled ; wherein the particles are formed by a method comprising the step of combining diketopiperazine which has a trans isomer content in the range of about 45% to 65% in a solution and an acetic acid solution without the presence of a surfactant and homogenizing concomitantly in a high shear mixer at high pressures up to 13.79 MPa (2000 psi) to form a precipitate; washing the suspended precipitate with deionized water; concentrate the suspension and dry the suspension in a spray drying apparatus.
    [011] The method may further comprise the steps of adding with mixing a solution comprising an active agent or an active ingredient such as a drug or bioactive agent before the spray drying step so that the active agent or active ingredient is adsorbed and/or trapped in or within the particles. Particles made by this process can be in the submicron size range prior to spray drying.
    [012] In certain embodiments, a diketopiperazine composition comprising a plurality of substantially uniformly formed microcrystalline particles is provided, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that are not self-assembled and the particles have a volume mean geometric diameter less than or equal to 5 µm; in which the particles are formed by a method comprising the step of combining diketopiperazine in a solution and an acetic acid solution without the presence of a surfactant and homogenizing concomitantly in a high shear mixer at high pressures of up to 13.79 MPa ( 2000 psi) to form a precipitate; washing the suspended precipitate with deionized water; concentrate the suspension and dry the suspension in a spray drying apparatus.
    [013] The method may further comprise the steps of adding with mixing a solution comprising an active agent or an active ingredient such as a drug or bioactive agent before the spray drying step so that the active agent or active ingredient is adsorbed and/or trapped in or within the particles. Particles made by this process can be in the submicron size range prior to spray drying.
    [014] In certain embodiments, a diketopiperazine composition comprising a plurality of substantially uniformly formed microcrystalline particles is provided, wherein the particles have a substantially hollow spherical structure and comprise a shell comprising crystallites of a diketopiperazine that are not self-assembled and the particles have a volume mean geometric diameter less than or equal to 5 µm; in which the particles are formed by a method comprising the step of combining diketopiperazine in a solution and an acetic acid solution without the presence of a surfactant and without the presence of an active agent and homogenizing concomitantly in a high shear pressure mixer highs of up to 13.79 MPa (2,000 psi) to form a precipitate; washing the suspended precipitate with deionized water; concentrate the suspension and dry the suspension in a spray drying apparatus.
    [015] The method may further comprise the steps of adding with mixing a solution comprising an active agent or an active ingredient such as a drug or bioactive agent before the spray drying step so that the active agent or active ingredient is adsorbed and/or trapped in or within the particles. Particles made by this process can be in the submicron size range prior to spray drying.
    [016] In one embodiment, the composition may comprise microcrystalline particles that comprise one or more active ingredients; wherein the active ingredients are peptides, proteins, nucleic acid molecules, small organic molecules or combinations thereof. In those embodiments where the active ingredient is a peptide, oligopeptide, polypeptide or protein, the peptide, oligopeptide, polypeptide or protein may be an endocrine hormone, a neurotransmitter, a vasoactive peptide, a receptor peptide, a receptor agonist or antagonist, and the like . In some embodiments, the endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, peptide YY, leptin, or an analog of said endocrine hormone. In embodiments, excipients can be incorporated into the particles by the addition of one, another or all of the raw materials used in the spray drying step.
    [017] In an embodiment where the composition comprises insulin as the active ingredient, the compositions may contain insulin in amounts of up to, for example, 9 units or 10 units per milligram of powder to be delivered to a patient. In this embodiment, insulin can be delivered to a patient in amounts of up to, for example, 100 units in a single inhalation using a dry powder inhaler. The compositions can be administered to a patient in need of insulin to treat diabetes and/or hyperglycemia.
    [018] In an exemplary embodiment, the crystalline diketopiperazine composition comprises a diketopiperazine of the formula 2,5-diketo-3,6-bis(NX-4-aminoalkyl)piperazine, wherein alkyl denotes an alkyl containing 3 to 20 atoms of carbon, including propyl, butyl, pentyl, hexyl, heptyl and the like; and the formula is, for example, 2,5-diketo-3,6-bis(NX-4-aminobutyl)piperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, malonyl and glutaryl or a salt thereof. In a particular embodiment, the diketopiperazine is (bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketo-diketopiperazine which has the formula:

    [019] In various embodiments, a method for forming dry powders comprising microcrystalline particles suitable for pulmonary administration is provided; wherein the method can be performed using surfactant-free solutions or solutions comprising a surfactant. In one aspect, the diketopiperazine comprises a trans isomer content in the range of about 45% to 65%.
    [020] Certain embodiments described herein include methods for producing dry powders comprising crystalline diketopiperazine microparticles from starting materials comprising free acid diketopiperazines.
    [021] Certain embodiments described herein include methods for producing dry powders comprising crystalline diketopiperazine microparticles from starting materials comprising salts of diketopiperazine.
    [022] In one embodiment, the method comprises: dissolving a diketopiperazine in aqueous ammonia to form a first solution; feeding the first solution and a second solution comprising about 10.5% acetic acid concurrently to a high shear mixer at an approximate pH of less than 6.0 under high pressure; homogenize the first solution and the second solution to form a suspension comprising diketopiperazine crystallites in the suspension, wherein the suspension has a bimodal distribution of crystallites having particle sizes in the range of about 0.05 µm to about 10 µm in diameter; atomizing the suspension under a stream of air or gas; and reforming the particles by spray drying into a dry powder comprising the microcrystalline particles having substantially hollow spheres.
    [023] In another embodiment, the method comprises: dissolving a diketopiperazine in aqueous sodium hydroxide and optionally a surfactant to form a first solution; feeding the first solution and a second solution comprising about 10.5% acetic acid and, optionally, a surfactant concurrently with a high-shear mixer at an approximate pH of less than 6.0 under high pressure; homogenize the first solution and the second solution to form a suspension comprising diketopiperazine crystallites in the suspension, wherein the suspension has a bimodal distribution of crystallites having particle sizes in the range of about 0.05 µm to about 10 µm in diameter and comprising a trans isomer content in the range of 45% to 65%; atomize the suspension under a air or gas stream; and reforming the particles by spray drying into a dry powder comprising the microcrystalline particles having substantially hollow spheres.
    [024] In one embodiment, the method comprises: dissolving a diketopiperazine in aqueous ammonia to form a first solution; feeding the first solution and a second solution comprising about 10.5% acetic acid concurrently with a high shear mixer to an approximate pH of less than 6.0 under high pressure to form a suspension comprising crystallites of the diketopiperazine in the suspension, wherein the suspension has a bimodal distribution of crystallites having particle sizes in the range of about 0.05 µm to about 10 μm in diameter; atomize the suspension under a stream of air or gas; and reforming the particles by spray drying into a dry powder comprising the microcrystalline particles having substantially hollow spheres.
    [025] The method may further comprise the step of adding a third solution to the diketopiperazine crystallite suspension before atomizing the suspension; wherein the solution contains a drug or a pharmaceutically active ingredient and the atomization step can be carried out using a 2-fluid external mixing nozzle in a spray dryer fitted with a high-efficiency cyclone separator under air or gas , including nitrogen gas.
    [026] In certain embodiments, suspended particles have a particle size distribution as a bimodal curve as measured by laser diffraction; wherein a first particle peak has an average particle size from about 0.2 µm to about 0.4 µm and a second particle peak which has an average particle size from about 2.1 µm to about 2, 4 µm in diameter.
    [027] In some embodiments, the suspension atomizing step uses a nitrogen stream of about 700 liters of nitrogen per hour as the process gas and the nozzle temperature can be maintained at about 25 °C.
    [028] The microcrystalline particles formed by the above method are not self-assembled when suspended in a solution such as water or other aqueous-based solvent. In a particular embodiment, the method comprises a diketopiperazine of the formula 2,5-diketo-3,6-bis(NX-4-aminobutyl)piperazine, wherein X is selected from the group consisting of fumaryl, succinyl, maleyl, malonyl and glutaryl. In a specific embodiment, the method comprises homogenizing in a high-shear mixer a solution of diketopiperazine, wherein the diketopiperazine is (bis-3,6-(N-fumaryl-4-aminobutyl)-2,5-diketo-diketopiperazine, or a salt thereof, including, disodium, dipotassium, magnesium, calcium and dilithium salts.
    [029] In one embodiment, a crystalline diketopiperazine composition comprising a plurality of microcrystalline particles substantially uniform in size is obtained as a product of the spray drying step.
    [030] In one embodiment, a crystalline diketopiperazine composition comprising a plurality of microcrystalline particles with a bimodal size distribution is obtained as a product of the crystallite formation step.
    [031] When a rupture step is used, the larger species of the bimodal distribution can be changed to smaller sizes.
    [032] Certain embodiments comprise a method for forming microcrystalline particles of a diketopiperazine acid to form dry powders carrying high drug content comprising using a salt of a diketopiperazine as a starting material, including 2,5-diketo-salt 3,6-bis(N-fumaryl-4-aminobutyl)piperazine disodium, the method comprising: dissolving a salt of diketopiperazine in water comprising a surfactant in an amount of from about 0.2% to about 6% ( in w/w) to form a first solution; combine the first solution with a second solution comprising from about 8% to about 12% (w/w) acetic acid concomitantly in a high shear mixer at a pH approximate less than 6.0 under high pressure; homogenize the first solution and the second solution to form a suspension comprising diketopiperazine crystallites in the suspension, wherein the suspension has a bimodal distribution of crystallites having particle sizes. ula in the range of about 0.05 µm to about 10 µm in diameter; atomize the suspension under a stream of air or gas; and reforming the particles by spray drying to a dry powder comprising microcrystalline diketopiperazine acid particles having substantially hollow spheres.
    [033] In a specific embodiment, microcrystalline particles can be made by a process comprising preparing a first solution comprising a diketopiperazine in water, for example, salt of 2,5-diketo-3,6-(N-fumaryl- 4-aminobutyl)piperazine disodium and a surfactant such as polysorbate 80; preparing a second solution comprising acetic acid at a concentration of about 10.5% (w/w) and a surfactant at a concentration of about 0.5% (w/w); mixing the first solution and the second solution in a high-shear mixer to form a suspension; optionally testing the suspension to determine the particle size distribution so that the suspension comprises a bimodal particle size distribution, with particles in the size range of about 0.2 µm to about 10 µm in diameter, where a first particle peak has an average diameter of about 0.4 µm and a second particle peak has an average diameter of about 2.4 µm and spray-dry the suspension to obtain a dry powder.
    [034] Certain embodiments may comprise a disruption step to reduce the size of the larger size population in the bimodal distribution, for example, using sonication, agitation or homogenization. In embodiments, the rupture step can be performed before atomizing the suspension.
    [035] In the embodiments herein, the method for producing the microcrystalline diketopiperazine particles may additionally include a washing step with the use of deionized water. In one embodiment, the atomization step can be carried out, for example, with the use of a 2-fluid external mixing nozzle in a spray dryer fitted with a separate high-efficiency cyclone.
    [036] The method may further comprise the step of adding a solution comprising one or more active agents to the suspension prior to dispersion and/or spray drying, wherein the active agent is a peptide, an oligopeptide, a polypeptide, a protein , a nucleic acid molecule or a small organic molecule. Peptides can be endocrine hormones, including insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, peptide YY, leptin or an analogue of said endocrine hormone, and the like. The method may optionally comprise the step of adding a solution comprising a surfactant and/or a pharmaceutically acceptable carrier, including amino acids such as leucine, isoleucine and/or monosaccharides, disaccharides or oligosaccharides such as lactose, trehalose and the like or sugar alcohols including mannitol, sorbitol and the like.
    [037] In another embodiment, a composition comprising more than one active agent can be made using the present method. The method of producing such a composition comprises the steps of producing microcrystalline diketopiperazine particles comprising more than one active agent wherein each agent/active ingredient is processed separately into a solution and added to separate suspensions of diketopiperazine particles and the conditions of solution are altered to promote adsorption of the active agent onto the crystallite surfaces, then the two or more separate suspensions comprising the active agents are mixed before dispersing and spray drying the particles. In a variant procedure, the blend includes a suspension containing diketopiperazine particles without active agent, for example, in order to achieve a lower overall content of active agent. In an alternative embodiment, the one or more independent solutions containing a single active agent can be combined with a single suspension comprising the diketopiperazine particles before dispersing and spray drying the particles. The resulting dry powder comprises a composition comprising two or more active ingredients. In such embodiments, the amount of each ingredient in the composition can be controlled depending on the need of the patient population to be treated.
    [038] In another embodiment, the dry powder comprises a composition comprising 2,5-diketo-3,6-bis(NX-4-aminobutyl)piperazine, wherein X is fumaryl and the composition comprises substantially homogeneous microcrystalline particles comprising a drug; wherein the particles are substantially spherical in shape having a substantially hollow core and the crystallites form a shell of the sphere. In another embodiment, the dry powders comprise a diketopiperazine of the formula 2,5-diketo-3,6-bis(NX-4-aminobutyl)piperazine and a drug, wherein the drug is a peptide, wherein the peptide may be a peptide. various peptide lengths, molecular sizes or masses, including; insulin, glucagon-like peptide-1, glucagon, exendin, parathyroid hormone, calcitonin, oxyntomodulin, and the like.
    [039] Additional embodiments include drug delivery systems comprising an inhaler with or without a cartridge, wherein the cartridge is a unit dose dry powder medicament container, e.g., a cartridge and a powder comprising the particles disclosed herein and an active agent. In one embodiment, the delivery system for use with dry powders includes an inhalation system comprising a high-resistance inhaler that has air ducts that provide a high resistance to air flow through the ducts to deagglomerate and dispense the powder. . In one embodiment, the inhalation system has a resistance value of, for example, approximately 0.065 to about 0.200 (VkPa)/liter per minute. In certain embodiments, dry powders can be effectively delivered by inhalation with an inhalation system where the peak inhalation pressure differential can be in the range of about 2 to about 20 kPa, which can produce flow rates of about 2 to about 20 kPa. peak resulting from about between 7 and 70 liters per minute. In certain embodiments, the inhalation system is configured to deliver a single dose by discharging powder from the inhaler as a continuous stream or as one or more pulses of powder delivered to a patient. In some embodiments disclosed herein, the dry powder inhaler system comprises a predetermined mass flow balance within the inhaler, wherein the inhaler conduits are designed to have varying flow distribution during inhalation. For example, a flow balance of approximately 10% to 70% of the total flow from the inhaler to the patient is released through one or more dispensing ports, such air flow passes through an air duct designed with an area for contain the powder formulation and where approximately 30% to 90% of airflow is generated from other inhaler ducts during an inhalation maneuver. In addition, the bypass flow or flow that does not enter and exit the powder containment area such as through a cartridge can be recombined with the flow exiting the powder dispensing port within the inhaler to dilute, accelerate, and most importantly , deagglomerate fluidized powder before leaving the nozzle. In one embodiment, flow rates in the range of about 7 to 70 liters per minute result in greater than 75% of container or cartridge contents being dispensed in bulk masses between 1 and 50 mg. In certain embodiments, an inhalation system as described above can emit a respirable charge/fraction of a powder dose at percentages greater than 40% in a single inhalation, greater than 50%, greater than 60%, or greater than 70%.
    [040] In certain embodiments, drug delivery systems comprising inhalers may comprise inhalers particularly suitable for use with the morphology of the particles comprising the dry powder, such as, for example, a crystalline or amorphous morphology.
    [041] In particular embodiments, an inhalation system is provided which comprises a dry powder inhaler, a dry powder formulation comprising microcrystalline particles of fumaryl diketopiperazine having a trans FDKP isomer content between 45% and 65% and a or more than one active agent. In some aspects of this embodiment of the inhalation system, the dry powder formulation is provided in a unit dose cartridge. Alternatively, the dry powder formulation can be pre-loaded into the inhaler. In this embodiment, the configuration of the inhalation system allows the deagglomeration mechanism of the inhaler to produce respirable fractions greater than 50%; that is, more than half of the powder contained in the inhaler (cartridge) is emitted as particles smaller than 5.8 µm. Inhalers can discharge more than 85% of a powdered medicine contained within the container during dosing. In certain embodiments, inhalers can discharge greater than 85% of a powdered medicine contained in a single inhalation. In one embodiment, inhalers can discharge more than 90% of cartridge contents or container contents in less than 3 seconds at pressure differentials between 2 and 5 kPa with charge masses in the range of up to 30 mg.
    [042] The embodiments disclosed in this document also include methods. In one embodiment, a method of treating a disease or disorder related to the endocrine system which comprises administering to a person in need thereof a dry powder formulation comprising microcrystalline FDKP particles comprising a FDKP which may have a trans isomer content of about 45 to about 65% and a drug suitable for treating said disease or disorder in which microparticles are produced by the present methods. One embodiment includes a method of treating an insulin-related disorder which comprises administering a dry powder comprising the microcrystalline FDKP particles described above to a person in need thereof. The method comprises administering to a subject a dry powder formulation comprising microcrystalline particles of fumaryl diketopiperazine which have a trans isomer content in the range of about 45% to 65%, such particles are hollow spheres and do not contain any surfactant. In various embodiments, an insulin-related disorder may specifically include or exclude any or all prediabetes, type 1 diabetes mellitus (honeymoon stage, post honeymoon stage, or both), type 2 diabetes mellitus, gestational diabetes, hypoglycemia , hyperglycemia, insulin resistance, secretory dysfunction, impaired early-phase insulin release, loss of pancreatic β-cell function, loss of pancreatic β-cells, and metabolic disturbance. In one embodiment, the dry powder comprises insulin. In other embodiments, the dry powder comprises oxyntomodulin, peptide YY, leptin, oxytocin, glucagon, an exendin, GLP-1 analogs thereof, or combinations thereof.
    [043] Another embodiment disclosed herein includes a method for releasing a peptide including GLP-1, oxyntomodulin, peptide YY, oxytocin, insulin to a patient in need thereof which comprises administering a dry powder comprising microcrystalline diketopiperazine particles disclosed in present document to the deep lung by inhalation of the dry powder by the patient. In aspects of this embodiment, the particular features of an inhaler system are specified. BRIEF DESCRIPTION OF THE FIGURES
    [044] The following drawings form part of this descriptive report and are included to further demonstrate certain aspects of the examples disclosed in this document. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed realization of the specific embodiments presented herein.
    [045] Figures 1A and 1B are scanning electron micrographs (SEM) of diketopiperazine fumaryl particles comprising insulin and showing the solid compositions of the lyophilized particles at low (1A) and high (1B) magnification.
    [046] Figure 2 depicts a graphical representation of the particle size distribution of the particles depicted in Figures 1A and 1B as measured by the probability density function scale (pdf, left geometric y axis) and cumulative distribution function (cdf, right y axis).
    [047] Figure 3 depicts a graphical representation of the particle size distribution of particles obtained from an embodiment prepared from a suspension in which microcrystalline particles are formed without surfactant in any of the solutions used. The graph shows a typical bimodal distribution of microcrystalline particles as measured by the probability density function scale (pdf, left geometric y axis) and cumulative distribution function scale (cdf, right geometric y axis).
    [048] Figure 4 depicts an SEM at low magnification (2500X) of FDKP particles recovered from an embodiment herein in which a surfactant-free particle suspension is lyophilized.
    [049] Figure 5 depicts a graphical representation of the freeze-dried particle size distribution in the suspension as depicted in Figure 4 formed without surfactant and showing an increase in particle size as measured by the probability density function scale (pdf, axis left y geometry) and cumulative distribution function scale (cdf, right y geometry axis).
    [050] Figure 6 depicts an SEM (at 2,500X) of a claimed embodiment showing microcrystalline particles made from free surfactant solutions that are spray dried.
    [051] Figure 7 depicts a graphical representation of the particle size distribution of spray dried free surfactant particles dispersed in water.
    [052] Figure 8 depicts a graphical representation of the particle size distribution of spray-dried free surfactant particles dispersed in 0.1 M HCl (pH 2).
    [053] Figure 9 depicts a graphical representation of the bimodal particle size distribution of a suspension formed by crystallizing Na2FDKP with acetic acid in the presence of surfactant.
    [054] Figures 10A and 10B depict two scanning electron micrographs of particles prepared by spray drying the suspension of crystals prepared from Na2FDKP at magnifications of 2,500X (10A) and 10,000X (10B).
    [055] Figures 11A and 11B are scanning electron micrographs of spray-dried surfactant-free FDKP particles with approximately 10% by weight insulin at magnifications of 2,500X (11A) and 5,000X (11B).
    [056] Figures 12A and 12B are two scanning electron micrographs of particles prepared by spray drying the suspension of crystals prepared from Na2DKP at magnifications of 2,500X (12A) and 10,000X (12B).
    [057] Figure 13 depicts a graphical representation of the particle size distribution formed by spray drying a suspension of FDKP crystallized from a solution of Na2FDKP and polysorbate 80. The particles were dispersed in water for measurement.
    [058] Figure 14 depicts a graphical representation of the particle size distributions of a spray-dried combination powder and crystallite suspension with the individual active agents. Number 1 represents the particle size distribution of the combined microcrystalline powder composition comprising two different active agents; in the separate active agent-diketopiperazine particle suspension, wherein one composition contained FDKP-GLP-1 particles and the other contained FDKP-insulin (3) in suspensions which were combined before being spray dried. DETAILED DESCRIPTION
    [059] As reported, drug delivery to the lungs offers many advantages. It is difficult to release drugs into the lungs, however, due to problems in transporting drugs beyond natural physical barriers in a uniform volume and weight of drug. Disclosed herein are crystalline diketopiperazine compositions, dry powders and methods for making the particles. The crystalline composition and dry powder thereof comprise microcrystalline particles of diketopiperazines, which are substantially uniformly defined spheres comprising a shell comprising diketopiperazine crystallites and a core. In certain embodiments, the core can be hollow. In one embodiment, the diketopiperazine has a defined trans isomer content that may be beneficial to the particles such as drug release agents, methods for making the particles, and methods of treatment using the particles. The particles disclosed herein have a greater ability to load and deliver drug content to the patient at lower doses than standard prior art particles.
    [060] As used herein, an "analog" includes compounds that have similarity to another compound. Thus, compounds that have structural similarity to another (a parent compound) that mimics the biological or chemical activity of the parent compound are analogous. There are no minimum or maximum numbers of elemental or functional group substitutions required to qualify a compound as an analogue provided that the analogue has the ability to mimic, in some relevant way, or identically, complementary or competitively, the biological or chemical properties of the compound parent. In some instances, an analog comprises a fragment of the parent compound either in isolation or linked to another molecule and may contain other alterations as well. Analogs of the compounds disclosed herein may have equal, lesser or greater activity than their parent compounds.
    [061] As used herein, the term "microparticle" refers to a particle with a diameter of about 0.5 to about 1000 µm, regardless of the precise exterior or interior structure. Microparticles that are about 0.5 to about 10 microns in diameter can reach the lungs, successfully passing through most natural barriers. A diameter of less than about 10 microns is needed to cross the curve of the throat and a diameter of about 0.5 microns or more is needed to avoid being exhaled. To reach the deep lung (or alveolar region) where the most effective absorption is believed to occur, it is preferable to maximize the proportion of particles contained in the "breathable fraction" (RF), generally accepted to be those particles with an aerodynamic diameter of about 0.5 to about 5.7 microns, although some references use different ranges in some way as measured using standard techniques, for example with an Andersen Cascade Impactor. Other impactors can be used to measure aerodynamic particle size such as the IMPACTOR NEXT GENERATION™ (NGI™, MSP Corporation), for which the respirable fraction is defined by similar aerodynamic size, eg < 6.4 µm. In some embodiments, a laser diffraction apparatus is used to determine particle size, for example, the laser diffraction apparatus disclosed in US Patent Application Serial No. 12/727,179, filed March 18, 2010 , which is incorporated herein in its entirety for its relevant teachings, wherein the volume median geometric diameter (VMGD) of the particles is measured to evaluate the performance of the inhalation system. For example, in various embodiments, cartridge emptying of >80%, 85% or 90% and a VMGD of emitted particles of <12.5 μm, < 7.0 μm, < 5.8 μm or < 4.8 µm may indicate progressively better aerodynamic performance. The embodiments disclosed herein show that FDKP particles with a trans-isomer content of between about 45% to about 65% exhibit beneficial drug delivery characteristics to the lungs such as improved aerodynamic performance.
    [062] The respirable fraction in charge (RF/charge) represents the % of powder in a dose that is emitted from an inhaler upon discharging the filled powder content for use as the dose and that is suitable for breathing , that is, the percentage of particles in the filled dose that are emitted with sizes suitable for pulmonary delivery, which is a measure of particle aerodynamic performance. As described in this document, an RF/load value of 40% or greater than 40% reflects acceptable aerodynamic performance characteristics. In certain embodiments described herein, the respirable fraction under load may be greater than 50%. In an exemplary embodiment, a respirable fraction under charge may be up to about 80%, where about 80% of the charge is emitted with particle sizes < 5.8 µm as measured using standard techniques.
    [063] As used herein, the term "dry powder" refers to a fine particulate composition that is not suspended or dissolved in a propellant, carrier or other liquid. It is not necessarily intended to imply a complete absence of all water molecules.
    [064] Specific RF/charge values may depend on the inhaler used to deliver the powder. Powders generally tend to agglomerate and certain crystalline DKP particles form particularly cohesive powders. One of the functions of a dry powder inhaler is to deagglomerate the powder so that the resulting particles comprise a respirable fraction suitable for delivering a dose by inhalation. However, deagglomeration of cohesive powders is typically incomplete so that the particle size distribution seen when measuring the respirable fraction as released by an inhaler will not match the size distribution of the primary particles, i.e. the profile will be skewed towards to large particles. Inhaler designs vary in their de-agglomeration effectiveness and thus the absolute RF/charge value observed using different designs will also vary. However, the ideal RF/load as a function of isomeric content will be the same from inhaler to inhaler.
    [065] As used herein, the term "about" is used to indicate that a value includes the standard deviation of the measurement for the device or method that is employed to determine the value.
    [066] As used herein, the term "surfactant free" is used to indicate that no surfactant was present in any of the reagents, including solutions and/or suspensions used in the process to produce the microcrystalline particles.
    [067] As used herein, the term "crystallite" is used to refer to the integral crystal units of a diketopiperazine particle, which can have variable sizes.
    [068] As used herein, "microcrystalline particles" comprise crystallites of a diketopiperazine and have a particle size distribution of 0.05 µm to about 100 µm as measured by laser diffraction having particle sizes smaller than 50 μm, smaller than 20 μm or smaller than 10 μm in diameter. In one embodiment, crystallites can be in the 0.01 to 1 µm size range. DICETOPIPERAZINS
    [069] A class of drug-releasing agents that have been used to overcome problems in pharmaceutical techniques, such as drug instability and/or insufficient absorption, are the 2,5-diketopiperazines. The 2,5-diketopiperazines are represented by the compound of the general Formula 1 as shown below wherein E1 and E2 are independently N or more particularly NH. In other embodiments, E1 and/or E2 are independently an oxygen or a nitrogen so that in either of the substituents for E1 and E2 is an oxygen and the other is a nitrogen, the formula yields the substitution analog diketomorpholine or, when both E1 and E2 are oxygen, the formula yields a diketodioxane substitution analogue.

    [070] Such 2,5-diketopiperazines have been shown to be useful in drug delivery, specifically those bearing acidic R1 and R2 groups as described, for example, in US Patents 5,352,461 entitled "Self Assembling Diketopiperazine Drug Delivery System", 5,503 .852 titled "Method For Making Self-Assembling Diketopiperazine Drug Delivery System", 6,071,497 titled "Microparticles For Lung Delivery Comprising Diketopiperazine", and 6,331,318 titled "Carbon-Substituted Diketopiperazine Delivery System", each of which is incorporated into the This document is a reference in its entirety due to all the teachings related to diketopiperazine and diketopiperazine-mediated drug release. Diketopiperazines can be formed into microparticles that incorporate a drug or microparticles onto which a drug can be adsorbed. The combination of a drug and a diketopiperazine can impart improved drug stability and/or absorption characteristics. These microparticles can be administered by various routes of administration. As dry powders, microparticles can be released through inhalation to specific areas of the respiratory system, including the lungs.
    [071] Such prior art microparticles are typically obtained by pH-based precipitation of the free acid (or base) resulting in self-assembled microparticles comprising aggregated crystal slabs with a pinkish morphology. Particle stability can be improved by small amounts of a surfactant, such as polysorbate-80, in the DKP solution from which the particles are precipitated (see, for example, US Patent No. 7,799,344 entitled "Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents" which is incorporated herein by reference in its entirety due to all teachings relating to the formation and loading of DKP microparticles and dry powders thereof) . Finally, the solvent can be removed to obtain a dry powder. Solvent removal methods include lyophilization and spray drying (see, for example, US Patent No. 8,039,431 entitled "A method for improving the pharmaceutical properties of microparticles comprising diketopiperazine and an active agent" and US Patent No. 6,444,226 entitled "Purification and Stabilization of Peptide and Protein Pharmaceutical Agents", each of which is incorporated herein by reference in its entirety due to all teachings relating to the formation and loading of DKP microparticles and dry powders thereof). The particles disclosed herein are distinct from prior art particles in that they are physically and morphologically distinct entities and are produced by an improved method. The present disclosure refers to FDKP to be understood as the free acid or dissolved anion.
    [072] Other prior art particles are obtained by spray drying DKP solutions to obtain particles of amorphous DKP salts typically having a collapsed spherical morphology such as those disclosed in US Patent Nos. 7,820,676 and 8,278,308, entitled “Diketopiperazine salts for drug delivery and related methods”.
    [073] Methods for synthesizing diketopiperazines are described in, for example, Katchalski, et al., J. Amer. Chem. Soc. 68, 879 to 880 (1946) and Kopple, et al., J. Org. Chem. 33(2), 862 to 864 (1968), the teachings of which are incorporated herein by reference in their entirety. 2,5-diketo-3,6-di(aminobutyl)piperazine (Katchalski et al. refers to the same as lysine anhydride) can also be prepared by cyclodimerizing N-ε-PL-lysine in molten phenol , similar to the Kopple method, followed by removal of the blocking (P) groups with an appropriate reagent and conditions. For example, CBz protecting groups can be removed using 4.3M HBr in acetic acid. This route uses a commercially available material, it involves reaction conditions that are reported to have preserved the stereochemistry of the starting materials in the product, and all steps can easily be scaled up to manufacture. Methods for synthesizing diketopiperazines are also described in U.S. Patent No. 7,709,639 entitled "Catalysis of Diketopiperazine Synthesis", which is also incorporated by reference herein for its teachings thereon.
    [074] Fumaryl diketopiperazine (bis—3,6-(N-fumaryl-4-aminobutyl)-2,5-diketo-diketopiperazine; FDKP) is a preferred diketopiperazine for pulmonary applications:

    [075] FDKP provides a beneficial microparticle matrix due to its low solubility in acid, however, it is readily soluble at neutral or basic pH. These properties allow FDKP to crystallize and the crystals to self-assemble into microparticles under acidic conditions. Particles dissolve readily under physiological conditions where the pH is neutral. As noted, microparticles that are about 0.5 to about 10 microns in diameter can reach the lungs, successfully passing through most natural barriers. Particles in this size range can readily be prepared from FDKP.
    [076] FDKP has two asymmetric centers in the deketopiperazine ring. FDKP is manufactured as a mixture of geometric isomers that are identified as “cis-FDKP” and “trans-FDKP” according to the arrangement of the side chains in relation to the central “ring” of the diketopiperazine. The R,R and S,S enantiometers have "side arms" of propenyl(amidobutyl) that protrude from the same flat side of the diketopiperazine ring (A and B below) and are thus referred to as the cis isomers as the R,S compound has "side arms" that protrude from opposite flat sides of the diketopiperazine ring (C below) and is referred to as the trans isomer.

    [077] FDKP microparticle powders with acceptable aerodynamic performance as measured by RF/load with moderately effective inhalers such as the MEDTONE® inhaler disclosed in US Patent No. 7,464,706 entitled "Unit Dose Cartridge and Dry Powder Inhaler", which is incorporated by reference herein for its teachings thereon, were produced from FDKP having a trans isomer content in the range of about 45 to about 65%. Particles with isomer content in this range also work well with high-efficiency inhalers such as those disclosed in US Patent No. 8,499,757 entitled, "A Dry Powder Inhaler and System for Drug Delivery", filed June 12, 2009, US Patent No. 8,424,518 entitled "pDry Powder Inhaler and System for Drug Delivery", filed June 12, 2009, US Patent Application No. 13/941,365 entitled "Dry Powder Drug Delivery System and Methods", filed 12 of July 2013 and US Patent Application No. 12/717,884 entitled "Improved Dry Powder Drug Delivery System", filed March 4, 2010, such disclosures are incorporated herein by reference for their teachings regarding to them. Powders comprising microparticles containing more than 65% trans-FDKP tend to have lower and more variable RF/charge. FDKP trans-isomer enriched microparticles altered the morphology and also led to viscous suspensions that are difficult to process.
    [078] FDKP microparticle formulations having a trans isomer content of from about 45% to about 65% have provided powders with acceptable aerodynamic properties as disclosed in US Patent No. 8,227,409, the disclosures of which are incorporated herein by way of reference to his teachings in relation to them. FDKP particle formulations having a defined specific surface area of less than 67 m 2 /g also provide dry powders for inhalation with acceptable aerodynamic properties as disclosed in US Patent No. 8,551,528 entitled "Diketopiperazine Microparticles with Defined Specific Surface Areas” filed June 11, 2010, the disclosure of which is incorporated herein by reference to its teachings thereon. These FDKP powders, however, tend to be cohesive and the inhaler is designed to overcome this characteristic.
    [079] It is, therefore, desirable to produce diketopiperazine powders that have a particle composition that is less cohesive, which would allow for more effective drug delivery and fewer inhaler designs overall. The present disclosure certifies that the present method for producing microcrystalline diketopiperazine particles as exemplified by FDKP and FDKP disodium salt provides microcrystalline dry powders with acceptable aerodynamic performance, such powders are less cohesive, differ in density, have an alternative physical structure that it is not self-assembled in suspension and provides increased capacity for drug content, including the release of one or more active agents, which was not anticipated.
    [080] It was determined that improved consistency in particle homogeneity could be achieved with a different process to produce diketopiperazine microparticles. The present methods for making the compositions and compositions comprising the present microcrystalline diketopiperazine particles provide dry powders for pulmonary inhalation with beneficial physical and morphological aerodynamic characteristics. SELECTION AND INCORPORATION OF ACTIVE AGENTS
    [081] In the exemplary embodiments comprising FDKP, at least as long as the microcrystalline particles described herein retain the above isomer content, they may adopt other additional features for lung release and/or drug adsorption. U.S. Patent No. 6,428,771 entitled "Method for Drug Delivery to the Pulmonary System" describes DKP particle delivery to the lung and is incorporated by reference herein for its teachings thereon. U.S. Patent No. 6,444,226 entitled "Purification and Stabilization of Peptide and Protein Pharmaceutical Agents" describes beneficial methods for adsorbing drugs onto microparticle surfaces and is also incorporated by reference herein for its teachings thereon. Microparticle surface properties can be manipulated to achieve desired characteristics as described in US Patent No. 7,799,344 entitled "Method of Drug Formulation based on Increasing the Affinity of Crystalline Microparticle Surfaces for Active Agents", which is incorporated by way of reference in this document to its teachings in relation to them. U.S. Patent No. 7,803,404 entitled "Method of Drug Formation based on Increasing the Affinity of Active Agents for Crystalline Microparticle Surfaces" describes methods for promoting adsorption of active agents onto microparticles. U.S. Patent No. 7,803,404 is also incorporated by reference herein for its teachings thereon. These teachings can be applied to the adsorption of active agent to suspended crystallites, for example, prior to spray drying.
    [082] The microcrystalline particles described in this document may comprise one or more active agents. As used herein, "active agent", used interchangeably with "drug", refers to pharmaceutical substances, including small molecule pharmaceuticals, biologicals and bioactive agents. Active agents can be of natural, recombinant or synthetic origin, including proteins, polypeptides, peptides, nucleic acids, organic macromolecules, synthetic organic compounds, polysaccharides and other sugars, fatty acids and lipids, and antibodies and fragments thereof, including, however, without limitation, humanized or chimeric antibodies, F(ab), F(ab)2, a single-chain antibody or fused to other polypeptides or monoclonal antibodies therapeutic or diagnostic to cancer antigens. Active agents can be included in a variety of biological classes and activities, such as vasoactive agents, neuroactive agents including opioid agonists and antagonists, hormones, anticoagulants, immunomodulating agents, cytotoxic agents, antibiotics, antiviral agents, antigens, infectious agents, mediators inflammatory, hormones, cell surface receptor agonists and antagonists, and cell surface antigens. More particularly, active agents may include, in a non-limiting manner, cytokines, lipokines, enkephalins, alkynes, cyclosporins, anti-IL-8 antibodies, IL-8 antagonists including ABX-IL-8; prostaglandins including PG-I2, LTB receptor blockers including LY29311, BIIL 284 and CP105696; triptans such as sumatriptan and palmitoleate, insulin and analogues thereof, growth hormone and analogues thereof, parathyroid hormone (PTH) and analogues thereof, parathyroid hormone-related peptide (PTHrP), ghrelin, obestatin, enterostatin, stimulating factor of granulocyte macrophage colony (GM-CSF), amylin, amylin analogues, glucagon-like peptide 1 (GLP-1), clopidogrel, PPACK (D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone), oxyntomodulin ( OXM), peptide YY(3-36) (PYY), adiponectin, cholecystokinin (CCK), secretin, gastrin, glucagon, motilin, somatostatin, brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), IGF-1, factor releasing hormone (GHRF), beta-4 integrin precursor (ITB4) receptor antagonist, analgesics, nociceptin, nocistatin, orphanin FQ2, calcitonin, CGRP, angiotensin, substance P, neurokinin A, pancreatic polypeptide, neuropeptide Y, sleep-inducing peptide of lta and vasoactive intestinal peptide; and analogues of active agents.
    [083] The drug content to be released in microcrystalline particles formed from FDKP or FDKP disodium salt can typically be greater than 0.01% (w/w). In one embodiment, the drug content to be delivered with the microcrystalline particles can be from about 0.01% (w/w) to about 75% (w/w); from about 1% to about 50% (w/w), from about 10% (w/w) to about 30% (w/w) or from about 10% to about 20% (in w/w). In one embodiment, for example, if the drug is insulin, the present microparticles typically comprise approximately 10% to 45% (w/w) or from about 10% to about 20% (w/w) of insulin. In certain embodiments, the drug content of the particles can vary depending on the shape and size of the drug to be delivered. In an embodiment where GLP-1 is used as an active agent, the GLP-1 content can be up to 40% (w/w) of the powder content.
    [084] In one embodiment, a composition comprising more than one active agent can be produced using the present method by adsorption, for example, binding the active agent to crystallites before forming the dry powder.
    [085] In one embodiment, a composition comprising more than one active agent can be produced using the present method by capturing the active agent between and among crystallites, for example, by spray drying the material, without first adsorb the active agent to the crystallites.
    [086] The method for producing such a composition may comprise the steps to produce microcrystalline diketopiperazine particles comprising more than one active agent wherein each agent/active ingredient is processed separately into a solution and added to separate suspensions of diketopiperazine particles Then the two or more separate suspensions comprising the active agents are mixed before dispersing and spray drying the particles.
    [087] In certain embodiments, crystallites can be mixed with a solution comprising one or more active agents.
    [088] In certain embodiments, crystallites can be mixed with a solution comprising one or more active agents in which the solution conditions are changed to promote adsorption of the active agent to the crystallite surface.
    [089] Each of multiple active agents can be adsorbed to a separate aliquot or species of crystallites. The aliquot adsorbed crystallites can then be mixed together and spray dried. Alternatively, an aliquot may contain no active agent in order to adjust the overall content of active agent in the dry powder without changing the conditions used to adsorb the active agent to crystallites.
    [090] In an alternative embodiment, the one or more independent solutions containing a single active agent can be combined with a suspension comprising the diketopiperazine particles prior to dispersion and spray drying to reform the particles. The resulting dry powder composition comprises two or more active ingredients. In that embodiment, the amount of each ingredient can be controlled in the composition depending on the need of the patient population to be treated.
    [091] As is evident from the above disclosure, the microparticles of the embodiments disclosed herein can take many different forms and incorporate many different drugs or active agents. EXAMPLES
    [092] The following examples are included to demonstrate the realizations of the disclosed microcrystalline diketopiperazine particles. It should be appreciated by those skilled in the art that the techniques disclosed in the examples which follow represent techniques developed by the inventors to function well in the practice of the present disclosure and, thus, can be considered to constitute the preferred modes for its practice. However, those of ordinary skill in the art should, in light of the present disclosure, appreciate that many changes can be made to the specific embodiments that are disclosed and still obtain a similar or similar result without departing from the scope of the invention. EXAMPLE 1
    [093] Fabrication of Standard FDKP Microparticles - A prior art manufacturing process has been used to produce FDKP microparticles for comparison purposes with the standard particles as disclosed in US Patent Nos. 7,799,344; 7,803,404 and 8,227,409, the disclosures of which are incorporated herein by reference because of their teachings on the relevant subject matter. In summary, in the typical FDKP particle formation process, FDKP and acetic acid feed solutions, each containing 0.05% (w/w) of polysorbate 80 (PS80), are combined in a high mixer shear. Table 1 below shows the components for the FDKP and insulin stock solutions.TABLE 1. - 10.5% ACETIC ACID SOLUTION FILTERED THROUGH A 0.2 µM MEMBRANE
    TABLE 2. - 2.5% FDKP SOLUTION FILTERED THROUGH A 0.2 μM MEMBRANE

    [094] A concentrated insulin stock solution can be prepared with 1 part insulin and 9 parts of about 2% acetic acid by weight. Insulin stock can be added gravimetrically to the suspension to achieve a loading of about 11.4% by weight. The insulin-containing suspension can be mixed for at least about 15 minutes and then titrated with about 14 to about 15% by weight aqueous ammonia at a pH of about 4.5 from an initial pH of about 3.5. The suspension can be quickly frozen in liquid nitrogen to form pellets with the use of a cryogranulator, for example, as disclosed in US Patent No. 8,590,320, such disclosure is incorporated herein by reference in its entirety and lyophilized for render the FDKP microparticles loaded with insulin in bulk, which form small crystals or clusters that are self-assembled into FDKP particles with an open structure as seen in Figures 1A and 1B.
    [095] The samples of the formed particles were studied to measure the size distribution of these particles in the suspension and the results are shown in Figure 2. The data in Figure 2 show a graphical representation of the particle size distribution measurements that are plotted in logarithmic scale as the probability density function (pdf, left geometric y axis) and the cumulative distribution function (cdf, right geometric y axis). The data show that the suspended particles have a single peak size distribution that is in the range of about 1.0 to about 10 µm in diameter centered at or about 2 µm.
    [096] Fabrication of Microcrystalline FDKP Particles - a 2.5% FDKP (w/w) was dissolved in a basic aqueous ammonia solution (1.6% ammonia). A 10.5% (w/w) acetic acid stock solution was added in a high-shear mixer (Sonolator) at an approximate pH of 2.0 under high pressure to produce the particles. The formed particles were washed in deionized water. It was revealed that diketopiperazine microparticles are not stable without the presence of a surfactant in the solutions, however, no surfactant was added to any of the solutions or reagents in producing the particles.
    [097] In these experiments, with the use of a double feed high shear mixer, equal masses of about 10.5% by weight of acetic acid and about 2.5% by weight of FDKP solutions at about 16 °C ± about 2 °C were fed at 13.79 MPa (2,000 psi) through a 0.65 mm2 (0.001 in2 ) orifice to form a precipitate by homogenization. The precipitate was collected in a deionized water (DI) reservoir of almost equal mass and temperature. The precipitate was concentrated and washed by tangential flow filtration with deionized water. The suspension can finally be concentrated to about less than 5% solids, for example, from about 2 to 3.5% based on the initial mass of FDKP. The concentrated suspension can be evaluated for solids content by an oven drying method. For samples containing the active ingredients, ie insulin and/or GLP-1, an FDKP suspension of the above was used which an insulin stock solution (insulin dissolved in 2% acetic acid) was added to the suspension during the mixture, then, the pH of suspension was titrated with ammonium hydroxide to pH 4.5 ± 0.3. Similarly, a GLP-1 dissolved in a 2% acetic acid stock solution was added gravimetrically with stirring to an FDKP suspension. The GLP-1 FDKP suspension was titrated to pH 4.5 ± 0.1. Each of the insulin-FDKP suspension and the GLP-1-FDKP suspension was independently dispersed using a 2-fluid external mixing nozzle in a Niro SD-Micro™ Spray Dryer fitted with a high-efficiency cyclone . Nitrogen was used as the process gas (25 kg/h) and the atomizing fluid (2.8 kg/h). The samples were processed using two spray dryer processing conditions that are listed in Table 3.

    [098] For control samples, crude microcrystalline FDKP particles were fabricated identically minus the insulin or GLP-1 loading step.
    [099] Figure 3 shows the data from the above experiment in which the feed solutions were free of surfactant. Figure 3 is a graph illustrating the particle size distribution of an FDKP particle suspension that exhibits a typical bimodal particle size distribution. The particle sizes herein are in the range of about 0.1 to about 10 µm in diameter with one population of particles being centered at 0.2 µm in diameter and another population of particles centered at 2.1 µm in diameter .
    [100] Sample suspensions were lyophilized and not spray dried. Figure 4 is an SEM at 2,500x magnification of lyophilized particles. As seen in Figure 4, upon freeze-drying a similar suspension, large flake-like particles were formed and generated a much larger average size when resuspended in water as seen in Figure 5. Figure 5 shows the suspended particle size distribution of a sample that has been freeze-dried from particles produced without the use of a surfactant. In that study, the particle size diameter of the resuspended particles increased from about 1 to about 90 µm or more.
    [101] Figure 6 shows a typical 2500x magnification of a scanning electron micrograph of the powder sample of a surfactant-free preparation of microcrystalline FDKP particles that was formed using the present method and spray dried as described above . As seen in Figure 6, the particles are homogeneously spherical in structure that comprise a shell of crystallites. When the surfactant-free suspension was spray dried, particles with a physical diameter of approximately 4 µm were formed as shown in Figure 6. Unlike standard FDKP particles, these particles dissociated into particles of 0.2 µm in diameter. when dispersed in water as shown in Figure 7. Therefore, surfactants are shown to play a role in particle integrity. Dispersing the particles in 0.01 M hydrochloric acid inhibited particle dissociation as shown in Figure 8. It is possible that dissolved FDKP precipitates during spray drying and may be deposited along the boundaries between the primary particles and may act as cement. The FDKP "cement" dissolves in water and the particles dissociate into the 0.2 µm primary particles; the lower solubility of FDKP in acid prevents dissolution and preserves particle integrity. EXAMPLE 2
    [102] Fabrication of Microcrystalline FDKP Particles by Alternative Process Using a Diketopiperazine Salt - Alternatively, FDKP crystallites can be formed from feed solutions containing surfactant. An FDKP feed solution was prepared by dissolving FDKP disodium salt (Na2FDKP) in water containing polysorbate 80 (PS80) as a surfactant without using ammonium as a reagent. A feed solution containing acetic acid (10.5% w/w) and PS80 (0.5% w/w) was also prepared. Mixing the two feed solutions in a DUAL FEED SONOLATOR crystallized the FDKP and yielded the bimodal particle size distribution illustrated in Figure 9. As shown in Figure 9, approximately 26% of the prime crystals formed were about 0.4 µm in diameter and about 74% of the coarse particles have a diameter of about 2.4 µm. This suspension was processed and spray dried to obtain particles and observed under SEM. SEM micrographs were taken at magnifications of 2,500x and 10,000x and shown in Figures 10A and 10B. Figures 10A and 10B show that the particles are similar and spherical in shape, but smaller than those shown in Figure 6 of Example 1, such particles were produced using FDKP as the free acid. Table 4 below shows some of the physical characteristics measured for a powder produced by freeze drying and a powder produced by spray drying (SD) using FDKP disodium salt.

    [103] The data show that powder produced from spray dried particles exhibited a higher respirable fraction (62.8 vs. 28%), higher cartridge emptying (% EC, 88.2% vs. 83.8%), and bulk (0.159 g/ml) and tap (0.234 g/ml) densities greater than lyophilized powder (0.019 and 0.03 g/ml, respectively). EXAMPLE 3
    [104] Fabrication of Microcrystalline FDKP Particles Containing an Active Agent - An active pharmaceutical ingredient (active agent) was incorporated into the particles by adding an active agent solution to a suspension of surfactant-free FDKP crystallites and then drying by spraying the mixture to remove the solvent as described in Example 1. Control particles (FDKP-insulin) were also produced by the standard self-assembly method using PS-80 in the solutions to produce a powder for pulmonary inhalation. In that study, insulin was dissolved in dilute acetic acid and added to a suspension of FDKP surfactant free crystallites (Samples 1 and 2 Table 5) prepared as in Example 1. The suspension was spray dried to obtain a dry powder containing approximately 10% by weight of insulin. Powder samples were taken for various analyzes including release via a high-resistance inhaler and scanning electron microscopy and the results are shown in Table 5. The particles were approximately the same size as the non-insulin particles (Example 1) and the morphology of the particles (Figure 11) was the same as those in Figure 6. In addition, both Samples 1 and 2 were a less dense powder than the standard particles and Sample 1 particles have a higher specific surface area ( SSA) than control. The distribution of insulin is not known, there is no obvious deposit of insulin on the particle surface to suggest that insulin is either inside the particle or embedded in the particle wall.

    [105] The data presented in Table 5, however, show that surfactant-free powders behave differently from standard particles at the same insulin content. For example, at the same insulin content, the surfactant-free powder was released more effectively (96.4%) from the inhaler than from the standard particle (85%). The increase in cartridge empty percentage (% EC) indicates that the powder has increased fluidity. The respirable fraction (% RF in Charge) was higher for the control particles as the inhaler used to test the powders was designed for the control powders. EXAMPLE 4
    [106] Fabrication of Microcrystalline FDKP Particles by Alternative Process Using a Diketopiperazine Salt - In this study, FDKP disodium salt was used to produce a FDKP salt particle suspension as described in Example 2. An insulin solution was added to a suspension of FDKP surfactant free microcrystals prepared as in Example 2. The suspension was spray dried to obtain a dry powder containing approximately 10% by weight of insulin. The morphology of the formed particles is shown in SEM in Figures 12A and 12B at magnifications of 2,500x and 10,000x (respectively). As seen in Figures 12A and 12B, the morphology was the same as the particles without insulin, showing a spherical shaped structure that has an average particle diameter of 2.6 µm as shown in Figure 13 and illustrated by particles also in the diameter range of about 1.0 µm to about 10 µm. EXAMPLE 5
    [107] Fabrication of Microcrystalline FDKP Particles Containing More Than One Active Agent - In another embodiment, a composition comprising more than one active agent can be produced using the present method. The method for producing such a composition comprises the steps as disclosed above for each individual active agent to form an active agent-FDKP suspension of each of the active agents to be incorporated into the composition. The suspensions are then combined and blended to form a blend. Then, the blended mixture is dispersed and spray dried as described to produce microcrystalline diketopiperazine particles that comprise more than one active agent. In an exemplary study, insulin-GLP-1 combination powder was produced.
    [108] FDKP crystallite suspensions prepared as in Example 1 were mixed with solutions of various active agents (eg, ghrelin, low molecular weight heparin, oxyntomodulin) and spray dried to obtain particles similar in properties to those in Example 3. EXAMPLE 6
    [109] Fabrication of Microcrystalline FDKP Particles Containing Two Active Agents - A combination powder with two active agents (GLP-1 and insulin) was produced by first preparing a suspension of FDKP crystallites with insulin and a second suspension of crystallites with GLP -1. The two suspensions were then mixed and the combined suspension was spray dried to obtain a dry powder containing both active agents. Crystallite suspensions were prepared as in Example 1; after the active agents were added, the suspension was adjusted to pH 4.5 to promote adsorption onto the crystallites. Figure 14 is a plot of data illustrating the particle size distribution of the spray-dried combination powder (1) and crystallite suspension with the individual active agents, FDKP-insulin (2) and FDKP-GLP-1.
    [110] As seen in Figure 14, the particle size distribution of the blend powder was centered between those of the two suspensions and was significantly narrower. The blending powder comprised particles having a diameter of about 1 µm to about 10 µm. The insulin-containing crystallites were smaller (from about 0.25 µm to about 10 µm) than the GLP-1 containing crystallites which have a diameter in the range of about 0.5 µm to about 50 µm. The atomization step in spray drying likely dissociates the original suspended crystallite clusters and reforms the particles with a size distribution that depends on the conditions in suspension and spray drying. EXAMPLE 7
    [111] Administration of a Dry Powder Composition Comprising Crystalline Diketopiperazine Particles to a Subject - Dry powder formulations comprising microcrystalline diketopiperazine microparticles produced with the disodium salt of FDKP (Na2FDKP) were produced as described in Example 1 above for contain 9 U of insulin per milligram of composition. High-resistance inhalers containing a cartridge (DreamboatTM inhaler, MannKind Corporation) were prepared containing 1 mg to 10 mg per dose and were prepared to administer to individuals diagnosed with diabetes. An inhaler containing a dose of insulin is provided to the patient to be treated and the patient inhales the dose of insulin in a single inhalation at the start, during a meal, or after a meal.
    [112] Unless otherwise indicated, all numbers expressing amounts of ingredients, properties such as molecular weight, reaction conditions, and so on used in this specification and claims shall be understood to be modified in all instances by the term "about". Consequently, except where otherwise indicated, the numerical parameters presented in the specification and claims attached below are approximations which may vary depending on the desired properties sought to be achieved by the present invention. At the very least, and not as an attempt to limit the application of the equivalents doctrine to the scope of the claims, each numerical parameter should be interpreted at least in light of the number of significant figures reported and through the application of common rounding techniques. Although the numerical ranges and parameters which establish the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as accurately as possible. Any numerical value, however, inherently contains certain errors that necessarily result from the standard deviation found in their respective test measurements.
    [113] The terms "a" and "an", "the" and "a" and similar referents used in the context of making the invention (especially in the context of the following claims) are to be interpreted as covering both the singular and the plural , unless otherwise indicated in this document or clearly contradicted by the context. The citation of ranges of values in this document is only intended to serve as a shorthand method for referring individually to each separate value covered by the range. Unless otherwise indicated in this document, each individual value is incorporated in the descriptive report as if it had been individually cited in this document. All methods described in this document may be performed in any other suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (eg, "as") provided herein is only intended to further illuminate the invention and does not propose a limitation on the scope of the otherwise claimed invention. No language in the descriptive report should be interpreted as indicating any unclaimed element essential to the practice of the invention.
    [114] The use of the term "or" in the claims is used to mean "and/or" unless explicitly stated as referring to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition referring to alternatives only and "and/or".
    [115] Groupings of elements or alternative embodiments of the invention disclosed herein are not to be considered as limitations. Each group member may be referred to and claimed individually or in any combination with other group members or other elements found herein. It is anticipated that one or more members of a group may be included or may have been excluded from a group for reasons of convenience and/or patentability. When any inclusion or exclusion occurs, it is considered, in this document, that the descriptive report contains the group, as modified, thus satisfying the written realization of all Markush groups used in the attached claims.
    [116] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Certainly, variations in those preferred embodiments will become apparent to those of skill in the art upon reading the previous embodiment. The inventor expects those skilled in the art to employ such variations as appropriate and the inventors intend that the invention be practiced other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, any combination of the elements described above in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted otherwise by the context.
    [117] The specific embodiments disclosed herein may be further limited in the claims with the use of language consisting of or consisting essentially of. When used in the claims, or as filed or amended by amendment, the transitional term “consisting of” excludes any element, step or ingredient not specified in the claims. The transition term "consisting essentially of" limits the scope of a claim to the materials or steps specified and those that do not materially affect the basic and innovative feature(s). The embodiments of the invention so claimed are inherently or expressly described and permitted herein.
    [118] In addition, numerous references have been made to patents for printed publications throughout this specification. Each of the above-cited references and printed publications are individually incorporated herein by reference in their entirety.
    [119] Furthermore, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the present invention. Other modifications that may be employed are within the scope of the invention. Thus, by way of example, but not limitation, alternative embodiments of the present invention may be used in accordance with the teachings herein. Consequently, the present invention is not limited thereto precisely as shown and described.
    权利要求:
    Claims (7)
    [0001]
    1. COMPOSITION OF CRYSTALLINE 3,6-BIS(N-FUMARYL-4-AMINOBUTYL)-2,5-DICETOPIPERAZINE, characterized by comprising a plurality of microcrystalline particles uniform in size having a hollow spherical structure and comprising an envelope comprising non-self-assembly diketopiperazine fumaryl crystallites, wherein the particles have a volume median geometric diameter of less than 5 µm, wherein the particles are formed without the presence of a surfactant by a method comprising the step of combining 3,6-bis (N-fumaryl-4-aminobutyl)-2,5-diketopiperazine dissolved in an aqueous ammonia solution and an acetic acid solution and homogenize concurrently in a high shear mixer at high pressures up to 13.79 MPa (2000 psi) to form a precipitate; washing the suspended precipitate with deionized water; concentrate the suspension, and dry the suspension in a spray drying apparatus.
    [0002]
    2. COMPOSITION, according to claim 1, characterized in that microcrystalline particles additionally comprise one or more active ingredients selected from insulin or an analogue thereof, glucagon-like peptide 1 (GLP-1), ghrelin, low weight heparin molecular, oxyntomodulin, or a mixture thereof.
    [0003]
    3. METHOD OF PRODUCTION OF 3,6-BIS(N-FUMARIL-4-AMINOBUTYL)-2,5-DICETOPIPERAZINE MICROCRYSTALLINE PARTICLES, suitable for pulmonary administration as a dry powder, characterized by comprising: (a) forming diketopiperazine particles, as defined in claim 1, in a suspension having a bimodal distribution in particle sizes ranging from 0.05 µm to 10 µm; (b) atomizing the suspension using a spray dryer under a stream of air or gas; and (c) reforming the particles by spray drying to a dry powder comprising the microcrystalline diketopiperazine particles having hollow spheres.
    [0004]
    4. METHOD according to claim 3, characterized in that it further comprises the step of adding a solution comprising one or more active agents to the suspension in step (a).
    [0005]
    5. COMPOSITION, according to claim 2, characterized by being used in the treatment of a disease or disorder related to the endocrine system in a patient who needs it.
    [0006]
    6. COMPOSITION, according to claim 2, characterized by being used in the treatment of hyperglycemia and/or diabetes in a patient who needs it.
    [0007]
    7. USE OF A CRYSTALLINE DICETOPIPERAZINE COMPOSITION as defined in any one of claims 1, 2, 5 and 6 comprising a plurality of microcrystalline particles substantially uniform in size having a substantially hollow spherical structure and comprising a shell comprising crystallites of diketopiperazine that are not self-assembled, in which the particles have a volume median geometric diameter of less than 5 µm, in which the microcrystalline particles additionally comprise one or more active ingredients, characterized in that it is for the manufacture of a drug to treat a disease or disorder .
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    同族专利:
    公开号 | 公开日
    US20200339520A1|2020-10-29|
    IL241490A|2019-12-31|
    US10745359B2|2020-08-18|
    AU2018253545A1|2018-11-22|
    KR102246914B1|2021-04-30|
    SG10201708090TA|2017-11-29|
    KR20150128984A|2015-11-18|
    MX369136B|2019-10-30|
    EP2970149A1|2016-01-20|
    AU2021203201A1|2021-06-24|
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    EP2970149B1|2019-08-21|
    KR20210048586A|2021-05-03|
    EP3587404A1|2020-01-01|
    AU2014228415B2|2018-08-09|
    AU2020200744B2|2021-05-27|
    US20190359576A1|2019-11-28|
    AU2020200744A1|2020-03-19|
    BR112015023168A2|2017-07-18|
    CN108578372B|2021-07-06|
    JP2019112450A|2019-07-11|
    CN108578372A|2018-09-28|
    ES2754388T3|2020-04-17|
    US11192862B2|2021-12-07|
    AU2014228415A1|2015-10-01|
    SG11201507564PA|2015-10-29|
    MX2019012752A|2019-12-16|
    JP2016515522A|2016-05-30|
    CN105102436B|2018-06-12|
    IL241490D0|2015-11-30|
    WO2014144895A1|2014-09-18|
    US20160031833A1|2016-02-04|
    CA2906817C|2022-01-18|
    US10421729B2|2019-09-24|
    AU2018253545B2|2019-11-14|
    JP6523247B2|2019-05-29|
    BR112015023168A8|2019-12-03|
    MX2015013017A|2016-07-20|
    HK1219097A1|2017-03-24|
    CA2906817A1|2014-09-18|
    JP2021054850A|2021-04-08|
    US20220048868A1|2022-02-17|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2019-05-21| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-09-10| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-02-02| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-06-29| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-08-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 14/03/2014, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201361800520P| true| 2013-03-15|2013-03-15|
    US61/800,520|2013-03-15|
    PCT/US2014/029491|WO2014144895A1|2013-03-15|2014-03-14|Microcrystalline diketopiperazine compositions and methods|
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