Dry Powder Formulation and Usage

Abstract

To provide a dry powder for pulmonary delivery of NSAIDs, such as aspirin, and a drug delivery system for treating thrombosis.SOLUTION: A respirable dry powder comprises respirable dry particles that comprise acetylsalicylic acid, or a pharmaceutically acceptable salt thereof, wherein the dry powder comprises a mixture of: (i) dry particles having a volume median geometric diameter (VMGD) of about 5 μm or less; and (ii) dry particles having a volume median geometric diameter (VMGD) of about 15 μm or more.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61 / 817,435, filed April 30, 2013, which is incorporated by reference in its entirety.

[0002] The subject technology relates to pulmonary delivery of NSAIDs, such as aspirin. The subject technology also relates to devices and methods for delivery of substances, such as drugs, to the lungs using inhalation to treat disease. [Background technology]

[0003] Pulmonary delivery of therapeutic agents may offer several advantages over other delivery modes, including rapid onset of action, convenience of patient self-administration, reduced potential for drug side effects, ease of delivery by inhalation, no need for needles, etc. Inhalation therapy can provide a drug delivery system that is easy to use in an inpatient or outpatient setting, provides a very rapid onset of drug action, and minimizes the side effects that may result.

[0004] Metered dose inhalers (MDIs) are used to deliver therapeutic agents to the respiratory tract. MDIs are generally suitable for administering therapeutic agents that may be formulated as solid dry particles for inhalation in a pressurized volatile liquid. Opening the valve releases the suspension at a relatively high velocity. The liquid then evaporates, leaving behind a fast-moving aerosol of dry particles containing the therapeutic agent.

[0005] Liquid aerosol delivery is one of the oldest forms of pulmonary drug delivery. Typically, liquid aerosols are formed by air-jet nebulizers, which expel compressed air at high velocity from a small orifice, resulting in low pressure at the exit area due to the Bernoulli effect. See, for example, U.S. Pat. No. 5,511,726. The low pressure is used to draw the fluid to be aerosolized out of a second tube. The fluid breaks down into small droplets as it accelerates in the air stream. Disadvantages of this standard nebulizer design include a relatively large primary liquid aerosol droplet size, which often requires forcing the primary droplets over a baffle to produce secondary droplets of inhalable size, no uniformity in liquid aerosol droplet size, significant recirculation of most drug solutions, and a low density of small, inhalable liquid aerosol droplets in the inhaled air. Additionally, certain desired compounds may not be compatible with the solvents typically used in nebulizer delivery systems.

[0006] Ultrasonic nebulizers use a flat or concave piezoelectric disk immersed under a liquid reservoir to resonate the surface of the liquid reservoir, forming a liquid cone that releases aerosol particles from its surface (US Patent Publication 2006 / 0249144 and US Patent 5,551,416 (Patent Documents 2 and 3)). High aerosol concentrations can be achieved because no airflow is required for the aerosolization process. However, the piezoelectric components are relatively expensive to manufacture and inefficient at aerosolizing suspensions, which require the active agent to be dissolved in water or saline at low concentrations. Newer liquid aerosol technologies involve passing the liquid to be aerosolized through micron-sized holes to produce smaller, more uniform liquid-like dry particles for inhalation. See, for example, US Patents 6,131,570; 5,724,957 and 6,098,620 (Patent Documents 4-6). Disadvantages of this technique include relatively expensive piezoelectric and fine mesh components, and fouling of the pores with residual salts and solid suspensions.

[0007] Dry powder inhalers have historically relied on blending lactose, which allows for the administration of particles small enough for inhalation, but which are not sufficiently dispersible themselves. This method is known to be inefficient and not work for some drugs. Several groups have attempted to remedy these shortcomings by developing dry powder inhaler (DPI) formulations that are inhalable and dispersible, and therefore do not require blending lactose. Dry powder formulations for inhalation therapy have been described in U.S. Pat. No. 5,993,805 (Sutton et al.); U.S. Pat. No. 6,9216527 (Platz et al.); WO 0000176 (Robinson et al.); WO 9916419 (Tarara et al.); WO 0000215 (Bot et al); U.S. Pat. No. 5,855,913 (Hanes et al.); and U.S. Pat. Nos. 6,136,295 and 5,874,064 (Edwards et al.).

[0008] The widespread clinical use of dry powder inhalation delivery has been limited by the difficulty of developing a convenient portable device that produces dry powders of suitable particle size, particle density and dispersibility, maintains the stored dry powder in a dry state, and efficiently disperses the dry particles in the air to be inhaled. Furthermore, the particle size of dry powders for inhalation delivery is inherently limited by the fact that smaller dry particles for inhalation are difficult to disperse in the air. Dry powder formulations offer advantages over cumbersome liquid dosage forms and propellant-driven formulations, but are prone to aggregation and poor flowability. Aggregation and poor flowability significantly reduce the dispersibility and efficiency of dry powder-based inhalation therapy. For example, van der Waals interactions between particles and capillary concentration effects are known to cause the aggregation of dry particles. Hickey, A. et al, "Factors Influencing the Dispersion of Dry Powders as Aerosols", Pharmaceutical Technology, August, 1994 (Non-Patent Document 1).

[0009] To overcome interparticle adhesion forces, Batycky et al. teach in U.S. Pat. No. 7,182,961 the production of so-called "aerodynamically light inhalable particles." The particles have a volume median geometric diameter (VMGD) of greater than 5 microns (μm) as measured using a laser diffraction instrument, e.g., HELOS (manufactured by Sympatec, Princeton, NJ). See Batycky et al., column 7, lines 42-65. Another approach to improve the dispersibility of inhalable particles with a mean particle size of less than 10 μm includes the addition of water-soluble polypeptides or suitable excipients (e.g., amino acid excipients, e.g., leucine) in an amount of 50% to 99.9% of the total composition. Eljamal et al., U.S. Pat. No. 6,582,729, column 4, lines 12-19 and column 5, line 55 to column 6, line 31. However, this approach reduces the amount of active agent that can be delivered using a fixed amount of powder. Thus, an increased amount of dry powder is required to achieve the desired therapeutic outcome. For example, multiple inhalations and / or frequent administration may be required. Still other approaches include the use of devices that apply mechanical force, e.g., pressure from compressed gas, to small particles to disrupt interparticle adhesion during or immediately prior to administration. See, for example, U.S. Patent No. 7,601,336 (Lewis et al.), U.S. Patent No. 6,737,044 (Dickinson et al.), U.S. Patent No. 6,546,928 (Ashurst et al.) or U.S. Patent Publication No. 20090208582 (Johnston et al.) (Patent Documents 17-20).

[0010] A further limitation shared by each of the above methods is that the aerosol produced typically contains substantial amounts of inert carriers, solvents, emulsifiers, propellants and other non-medicinal materials.Generally, large amounts of non-medicinal materials are required to effectively formulate small enough inhalable dry particles (e.g., less than 5 μm and preferably less than 3 μm) for alveolar delivery.However, these amounts of non-medicinal materials also act to reduce the purity and amount of active drug substance that can be delivered.As a result, these methods remain virtually unable to accurately introduce many active drug doses into patients for systemic delivery.

[0011] Thromboembolism, such as myocardial infarction, deep vein thrombosis, pulmonary thrombosis, cerebral thrombosis, etc., may provide certain indications that allow the patient or clinician to provide initial treatment or treatment for the event. In some circumstances, 81 mg of low-dose or low-dose (baby) aspirin or regular aspirin (330 mg) may be administered orally to provide initial treatment for the patient.

[0012] There remains a need to provide new formulations of nonsteroidal anti-inflammatory drugs ("NSAIDs"), such as aspirin, that are suitable for pulmonary delivery. Summary of the Invention [Means for solving the problem]

[0013] The subject technology generally relates to a dry powder for inhalation having dry particles with an NSAID, such as acetylsalicylic acid, as an active ingredient. The dry particles for inhalation may be large or small, for example, having a mass median aerodynamic diameter (VMGD) between 0.5 μm and 30 μm. Alternatively or additionally, the dry powder for inhalation may have a mass median aerodynamic diameter (MMAD) of about 20 μm or less. Optionally, the MMAD of the particles may be between 0.5 and 10 μm, more preferably between 1 and 10 μm.

[0014] The dry powder may also contain a mixture of larger particles (e.g., 20-30 μm) and smaller particles (e.g., 5 μm or less), such that the smaller particles will reach the lower airways and the larger particles will be trapped in the upper airways.

[0015] The dry powder composition for inhalation may include a pharma- ceutically acceptable excipient, such as lecithin, sodium citrate, maltodextrin, or mannitol. The excipient may be present in an amount of about 5% to about 90% by weight. The inclusion of the excipient is optional.

[0016] In some embodiments, the NSAID, e.g., acetylsalicylic acid, is provided in a dry powder formulation having a mixture of particles of various sizes, e.g., (i) particles having a mean geometric diameter (VMGD) and / or mass median aerodynamic diameter (MMAD) of 5 μm or less, and (ii) particles having a mean geometric diameter (VMGD) and / or mass median aerodynamic diameter (MMAD) of 15 μm or more. In some embodiments, the composition may further comprise a pharma- ceutically acceptable excipient. In other embodiments, the composition is free or substantially free of excipients. In certain embodiments, the composition is free or substantially free of anti-agglomerating excipients.

[0017] The subject technology also relates to the inhalable dry powders or dry particles described herein for use in therapy (e.g., treatment, prevention, or diagnosis).The subject technology also relates to the treatment (e.g., prophylactic treatment, e.g., prevention or risk reduction) of cardiovascular diseases (e.g., thrombosis) described herein, and the use of the inhalable dry particles or dry powders described herein for use in the manufacture of a medicament for the treatment, prevention, or diagnosis of cardiovascular diseases (e.g., thrombosis) described herein.

[0018] The subject technology also provides a drug delivery system for the treatment (e.g., prophylactic treatment or risk reduction) of cardiovascular disease (e.g., thrombosis), comprising a therapeutically effective amount of a dry powdered NSAID (e.g., acetylsalicylic acid) and a dry powder inhaler, the dry powder inhaler comprising a mouthpiece, a reservoir for receiving a dose of the NSAID (e.g., acetylsalicylic acid), and a drive member for making the dose of acetylsalicylic acid available through the mouthpiece for inhalation by a patient. Preferably, the dose of the NSAID (e.g., acetylsalicylic acid) is about 40 mg or less, more preferably 30 mg or less.

[0019] Another aspect of at least one embodiment disclosed herein includes the recognition of a need for improved devices and methods for the delivery of agents to treat diseases that are effective in reducing the risk of thromboembolism in patients, that use smaller than traditional doses, and that are administered using a delivery mechanism that is more direct to the systemic blood flow.

[0020] Additional features and advantages of the subject technology will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the subject technology. The advantages of the subject technology will be realized and attained by the structures particularly pointed out in the written description and claims hereof as well as the appended drawings.

[0021] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the technology that is the subject of the claimed invention.

[0022] The accompanying drawings are intended to provide a further understanding of the subject technology, are incorporated in and constitute a part of this specification, illustrate aspects of the subject technology, and together with the description, serve to explain the principles of the subject technology. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram of a patient using a dry powder inhaler in accordance with some implementations of the methods and systems disclosed herein. [Diagram 2] 2A-F illustrate the use and configuration of a dry powder inhaler according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] In the following detailed description, numerous specific details are set forth to provide a thorough understanding of the subject technology. However, it will be understood by those skilled in the art that the subject technology may be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail in order not to obscure the subject technology.

[0025] 1. Introduction Thromboembolic signs and events Thromboembolism, such as myocardial infarction, deep vein thrombosis, pulmonary thrombosis, cerebral thrombosis, etc., may provide certain indications that allow the patient or clinician to provide initial treatment or treatment for the event. In some circumstances, 81 mg low dose or low dose (baby) aspirin or regular aspirin (330 mg) may be administered orally to provide initial treatment for the patient.

[0026] Based on some embodiments disclosed herein, it is recognized that the drug delivery system may not function as quickly as necessary to provide sufficient therapeutic effect, and therefore may not provide a favorable outcome. For this reason, some embodiments disclose drug delivery systems and related methods that provide accelerated and more effective routes and procedures to reduce the risk of thromboembolism and / or provide treatment for thromboembolism. For example, some embodiments provide systems and methods for administering nonsteroidal anti-inflammatory drugs ("NSAIDs") by inhalation, for example, by dry powder inhaler ("DPI") or metered dose inhaler ("MDI").

[0027] Delivery Mechanisms for Drugs Drugs can be administered orally in various ways, such as liquid, capsule, tablet or chewable tablet.In most cases, the oral route is used because it is the most convenient, safest and cheapest.However, oral drug delivery has limitations because it is the way that drugs typically travel through the digestive tract.

[0028] For example, when a drug is orally administered, it is absorbed in the mouth, stomach and small intestine. Before the drug can enter the bloodstream, it must pass through the intestinal wall and travel to the liver. While passing through the intestinal wall and liver, the drug is metabolized. This metabolism can reduce the amount of the drug that actually reaches the bloodstream. This metabolism reduces the bioavailability of the drug and is often referred to as the "first-pass effect". The percentage of drug lost through the first-pass effect is generally determined by absorption in the liver and gut wall, as well as enzymes in the gut lumen, gut wall, bacterial enzymes and hepatic (liver) enzymes.

[0029] Generally, the first-pass effect of aspirin significantly reduces the bioavailability of an administered dose. For example, due to the acidic conditions in the stomach, aspirin is absorbed in the stomach and upper small intestine. After absorption, aspirin is metabolized to acetic acid and salicylate. When taken orally, generally, only about one-third to two-thirds of an administered dose of aspirin is bioavailable due to the first-pass effect.

[0030] For example, Iwamoto K., GASTROINTESTINAL AND HEPATIC FIRST-PASS METABOLISM OF ASPIRIN IN RATS, J Pharm Pharmacol. 1982 Mar;34(3), pp.176-80, conducted a study of aspirin absorption in four male subjects after oral solution of 650 mg. The study report states that "the absorption process appeared to follow first-order kinetics, with half-lives ranging from 4.5 to 16.0 minutes among subjects. Comparison of areas under the aspirin plasma concentration-time curve after intravenous and oral routes indicated that only 68% of the administered dose reached the peripheral circulation intact."

[0031] Applicants have determined that even drugs administered by inhalation are subject to the first pass effect. For drug administration by inhalation, smaller particles pass via the nasal route, down the trachea (windpipe) and into the lungs. The size of the particles can be a determining factor in the overall efficacy of treatment. Once in the lungs, these particles are absorbed into the bloodstream.

[0032] Few drugs are administered by inhalation because the dose and timing of delivery of an inhaled drug can often be difficult to measure. Typically, this method is used to administer drugs that act specifically in the lungs, such as aerosolized antiasthmatic drugs in metered dose containers, and to administer gases used in general anesthesia.

[0033] Aspirin Pharmacokinetics Aspirin is an acetylated form of salicylic acid, and the active chemical in aspirin is called acetylsalicylic acid (ASA). Aspirin is used by many people to achieve the desired effects, with many people using low-dose aspirin, often daily. The principle action of aspirin is to impair the function of cyclooxygenase enzymes, specifically the COX1 and COX2 enzymes.

[0034] By inhibiting COX1, aspirin can irreversibly inhibit platelet aggregation and reduce the risk of blood clots. In addition, the disorder of COX2 enzyme can reduce inflammation, stiffness and pain in the body by inhibiting prostaglandins and thromboxanes. Therefore, individuals who are at high risk for heart attack, stroke, or have inflammation often take aspirin to treat the symptoms and effects of these conditions. As described, aspirin can effectively reduce the likelihood of such myocardial events, and can reduce pain and inflammation at a dose as low as low-dose aspirin. However, at least in part due to its inhibition of COX1, aspirin can increase the risk of bleeding and cause damage to organs, such as the stomach and intestines. The damage can be painful.

[0035] dry powder inhaler technology As mentioned above, oral delivery of aspirin may cause pain, risk of injury to the stomach wall resulting in indigestion, and high risk of bleeding. Furthermore, based on at least one aspect of the embodiments described herein, it is recognized that during emergency situations related to or that may result in thromboembolism, it is often difficult to administer the drug orally. For example, the patient may vomit or otherwise be unable to take the drug orally. Furthermore, oral administration of the drug may be undesirable because the drug does not immediately reach the systemic bloodstream, thus delaying the drug's important action. Even if the systemic bloodstream is reached, the amount of drug that reaches the systemic circulation is much less than the administered amount due to the first-pass effect in the liver and gastrointestinal tract. Therefore, based on the aspects of the various embodiments disclosed herein, it is recognized that alternative routes of administration may avoid these undesirable side effects.

[0036] Various embodiments disclosed herein reflect the new realization that delivery of drugs by inhalation at the early stage of an emergency provides a fast-acting and effective form of preliminary treatment for certain health conditions.For example, in some embodiments, upon complaint of severe thromboembolic symptoms, a patient can be administered a therapeutic amount of an NSAID via a DPI. The NSAID can address or provide treatment for the problem associated with the initial treatment of the health condition.

[0037] However, dry powder inhalation of drugs is generally limited to sub-milligram doses due to coughing. Current developments in particle technology, particularly the development of PulmoSphere™ technology, have enabled the delivery of large amounts of dry powder to the lungs in a single actuation. See David E. Geller, MD, et al., DEVELOPMENT OF AN INHALED DRY-POWDER FORMULATION OF TOBRAMYCIN USING PULMOSPHERE™ TECHNOLOGY, J Aerosol Med Pulm Drug Deliv. 2011 August; 24(4), pp. 175-82. In this publication, a dose of 112 mg of tobramycin (four capsules) was effectively delivered by PulmoSphere™.

[0038] According to some embodiments, it is recognized that the body contains various particle filters that limit the effectiveness of inhaled drugs. For example, the oropharynx tends to block the passage of particles with diameters larger than 5 μm. On the other hand, to reach the alveoli, particles must have a size of about 1 μm to about 5 μm. Thus, some embodiments herein disclose the preparation and use of inhalable aspirin using a technology similar to PulmoSphere™ to produce particles with a median geometric diameter of about 1 μm to about 5 μm, and in some embodiments, about 1.7 μm to about 2.7 μm.

[0039] There is no use of a single dose of aspirin via a dry powder inhaler to replace the traditional daily use of an NSAID (e.g., low-dose aspirin) or the emergency use of an NSAID as preventative care for thromboembolic symptoms. Accordingly, some embodiments disclosed herein provide methods for administering an NSAID via a dry powder inhaler in an amount less than a low-dose aspirin dose (e.g., less than 81 mg).

[0040] Thus, in some embodiments, a method for treating disease, for example, by reducing the risk of thromboembolism, may be provided. The method comprises administering an NSAID, for example, a salicylate, by DPI or MDI. For example, the method comprises administering an acetylsalicylate by DPI or MDI. The administered dose may be less than 25 mg of acetylsalicylic acid. Furthermore, the administered dose may be less than 20 mg of acetylsalicylic acid. The administered dose may be less than 15 mg of acetylsalicylic acid. The administered dose may also be less than 12 mg of acetylsalicylic acid. The administered dose may be less than 10 mg of acetylsalicylic acid. Furthermore, the administered dose may be less than 8 mg of acetylsalicylic acid. The administered dose may be less than 5 mg of acetylsalicylic acid. In some embodiments, the administered dose may be less than 2 mg of acetylsalicylic acid.

[0041] For example, in some embodiments, the dose may be about 2 mg to about 30 mg of acetylsalicylic acid. In some embodiments, the dose may be about 4 mg to about 25 mg of acetylsalicylic acid. The dose may be about 6 mg to about 20 mg of acetylsalicylic acid. Furthermore, in some embodiments, the dose may be about 8 mg to about 15 mg of acetylsalicylic acid. Furthermore, in some embodiments, the dose may be about 10 mg to about 13 mg of acetylsalicylic acid. For example, in some embodiments, the dose may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of acetylsalicylic acid.

[0042] Further, the dose of acetylsalicylic acid may be less than about 80 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 1 mg to about 75 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 2 mg to about 60 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 5 mg to about 40 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 10 mg to about 30 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 12 mg to about 25 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 15 mg to about 20 mg.

[0043] According to some embodiments, such doses may provide a bioequivalent dose when compared to typical doses of 81 mg to about 325 mg, with fewer negative side effects.

[0044] Thus, in some embodiments, an NSAID, such as aspirin, may be administered by a DPI or MDI in a single dose that is significantly smaller than traditional oral administration of aspirin, which dose tends to avoid the negative side effects associated with some NSAIDs, such as aspirin, but may provide bioequivalent treatment. Additionally, systems for administering such treatment are provided.

[0045] A DPI or MDI may have a mouthpiece and a drive member that makes the NSAID available for inhalation by the patient, reducing the risk of thromboembolism.

[0046] For example, according to some embodiments, a method of reducing a risk of thromboembolism is provided that may include administering a dose of a nonsteroidal anti-inflammatory drug by a dry powder inhaler, the dose being effective to reduce a risk of thromboembolism in a patient, the dry powder inhaler may have a mouthpiece and a drive member that makes available a dose of the nonsteroidal anti-inflammatory drug for inhalation by the patient to reduce the risk of thromboembolism.

[0047] According to some embodiments, a drug delivery system for treating a disease, for example by reducing the risk of thromboembolism, may also be provided. The system may have a dose of a nonsteroidal anti-inflammatory agent in powder form. The dose may be effective to reduce the risk of thromboembolism in a patient. The system may also have a dry powder inhaler. The dry powder inhaler may have a mouthpiece, a reservoir for receiving a dose of the nonsteroidal anti-inflammatory agent, and an actuation member for making the dose of the nonsteroidal anti-inflammatory agent available through the mouthpiece for inhalation by a patient.

[0048] In some embodiments, the thromboembolism comprises at least one of myocardial infarction, deep vein thrombosis, pulmonary thrombosis or cerebral thrombosis.The dose of the nonsteroidal anti-inflammatory agent can be administered as a preliminary treatment in response to the indication of thromboembolism.The nonsteroidal anti-inflammatory agent can comprise aspirin.Furthermore, the dose of the nonsteroidal anti-inflammatory agent can be administered in a single dose.

[0049] 2.Definition As used herein, the term "about" means a value of + / - 5%.

[0050] As used herein, the term "dry powder" refers to a composition comprising finely dispersed dry particles for inhalation that can be dispersed in an inhalation device and then inhaled by a subject. Such dry powders or particles may contain up to about 15% water or other solvents, or may be substantially free of water or other solvents, or may be anhydrous.

[0051] As used herein, the term "dry particles" refers to particles for inhalation that may contain up to about 15% water or other solvent, or may be substantially free of water or other solvent, or may be anhydrous.

[0052] As used herein, the term "inhalable" refers to dry particles or powders suitable for delivery to the respiratory tract (e.g., pulmonary delivery) in a subject by inhalation. Inhalable dry powders or particles have a mass median aerodynamic diameter (MMAD) of less than about 10 μm, preferably about 5 μm or less.

[0053] As used herein, the term "administration" or "administering" of the inhalable dry particles means introducing the inhalable dry particles into the respiratory tract of a subject.

[0054] The term "dispersibility" is a technical term that describes the characteristics of dry powders or dry particles dispersed in an inhalation aerosol. Dispersibility of dry powders or dry particles is expressed herein as an index of the volume median geometric diameter (VMGD) measured at a dispersion (i.e. regulator) pressure of 1 bar divided by the VMGD measured at a dispersion (i.e. regulator) pressure of 4 bar, or the VMGD at 0.5 bar divided by the VMGD at 4 bar measured by HELOS / RODOS. These indices are referred to herein as "1 / 4 bar" and "0.5 / 4 bar", respectively. Dispersibility is correlated with a low index. For example, 1 / 4 bar means the VMGD of the inhalable dry particles or powder discharged from the orifice of the RODOS dry powder dispenser (or equivalent technology) at about 1 bar, measured by HELOS or other laser diffraction system, divided by the VMGD of the same inhalable dry particles or powder measured by HELOS / RODOS at 4 bar. Thus, a highly dispersible dry powder or dry particle will have a ratio of 1 / 4 bar or 0.5 / 4 bar close to 1.0. Highly dispersible powders have a low tendency to agglomerate, aggregate or conglomerate together, and / or, if they do agglomerate, aggregate or conglomerate together, they are easily dispersed or deagglomerated when they are discharged from the inhaler and inhaled by the subject. Dispersibility can also be evaluated by measuring the size of the particles discharged from the inhaler as a function of flow rate.

[0055] As used herein, the term "emitted dose" or "ED" refers to a measure of the delivery of a pharmaceutical formulation from a suitable inhalation device after a firing or dispersion event. More specifically, for dry powder formulations, the ED is a measure of the proportion of powder that is drawn out of the unit dose package and exits the mouthpiece of the inhalation device. The ED is defined as the ratio of the dose delivered by the inhalation device to the apparent dose (i.e., the amount of powder per unit dose placed in the suitable inhalation device before firing). The ED is an experimentally measured parameter and can be determined using the method of USP Section 601 Aerosols, Metered-Dose Inhalers and Dry Powder Inhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose from Dry Powder Inhalers, United States Pharmacopeia Convention, Rockville, MD, 13th Revision, 222-225, 2007. This method uses an in vitro device set up that mimics patient dosing.

[0056] As used herein, the terms "FPF(<5.6)", "FPF(<5.6 μm)" and "fine particle fraction less than 5.6 μm" refer to the fraction of a sample of dry particles having an aerodynamic diameter less than 5.6 μm. For example, FPF(<5.6) may be determined by dividing the amount of dry powder for inhalation deposited on the collection filter of a stage 1 and 2-stage disintegrating Andersen Cascade Impactor (ACI) by the amount of dry powder for inhalation weighed into a capsule for delivery to the device. This parameter may also be specified as "FPF_TD(<5.6)". In this case, TD refers to the total dose. Similar measurements may be made using an 8-stage ACI. The 8-stage ACI cutoffs vary at a standard 60 L / min flow rate, but the FPF_TD(<5.6) may be estimated from the complete 8-stage data set. The 8-stage ACI results can also be calculated by the USP method using the dose recovered in the ACI instead of that which was in the capsule to determine the FPF.

[0057] As used herein, the terms "FPF(<3.4)", "FPF(<3.4 μm)" and "fine particle fraction less than 3.4 μm" refer to the fraction of the amount of inhalable dry particles with an aerodynamic diameter less than 3.4 μm. For example, FPF(<3.4) can be determined by dividing the amount of inhalable dry powder deposited on the collection filter of a 2-stage collapse ACI by the total amount of inhalable dry powder weighed into a capsule for delivery to a device. This parameter may also be specified as "FPF_TD(<3.4)". In this case, TD refers to the total dose. Similar measurements can be made using an 8-stage ACI. The results of the 8-stage ACI can also be calculated by the USP method using the dose collected in the ACI instead of that in the capsule to determine the FPF.

[0058] As used herein, the terms "FPF(<5.0)", "FPF(<5.0 μm)" and "fine particle fraction less than 5.0 μm" refer to the fraction of the inhalable dry particle dose that has an aerodynamic diameter less than 5.0 μm. For example, FPF(<5.0) can be determined by using an 8-stage ACI at a standard flow rate of 60 L / min and extrapolating from the complete data set of the 8-stage. This parameter may also be specified as "FPF_TD(<5.0)". In this case, TD refers to the total dose.

[0059] The term "nanoparticles" refers to particles having single crystal grains between about 1 nm and about 900 nm, preferably between about 5 nm and about 500 nm. Individual particles may be agglomerated into clusters / agglomerates.

[0060] The term "excipient" refers to a pharmacologically inactive substance that is formulated with an active pharmaceutical ingredient ("API").

[0061] The use of expressions such as "aspects" does not entail that such aspect is essential to the subject technology or that such aspect applies to all configurations of the subject technology. Disclosure of an aspect may apply to all configurations or one or more configurations. An aspect may provide one or more examples of the present disclosure. Expressions such as "an aspect" may mean one or more aspects, and vice versa. Expressions such as "embodiments" does not entail that such an embodiment is essential to the subject technology or that such an embodiment applies to all configurations of the subject technology. Disclosure of an embodiment may apply to all embodiments or one or more embodiments. An embodiment may provide one or more examples of the present disclosure. References to "an embodiment" and the like may mean one or more embodiments, and vice versa. References to "a configuration" and the like do not entail that such a configuration is essential to the subject technology or that such a configuration applies to all configurations of the subject technology. Disclosure of a configuration may apply to all configurations or to one or more configurations. A configuration may provide one or more examples of the present disclosure. References to "a configuration" and the like may mean one or more configurations, and vice versa.

[0062] 3. Nonsteroidal anti-inflammatory drugs (NSAIDs) NSAIDs, such as aspirin, provide various beneficial effects and contribute to reducing the risk of cardiovascular disease (e.g. thrombosis).However, the use of NSAIDs, such as aspirin, in clinical settings has traditionally been limited to oral administration.Oral administration of aspirin can result in the loss or inactivation of about 2 / 3 of the oral dose, for example, due to the first-pass effect in the gastrointestinal tract and liver.On the other hand, 1 / 3 of the dose reaches the systemic bloodstream to provide the desired effect, and the negative side effects caused by sufficient doses often prevent patients from using aspirin regularly or daily.

[0063] Furthermore, in many situations, for example, in emergency situations, oral administration of NSAIDs, for example, aspirin, may be inappropriate because it may take too long to become effective. Based on at least one aspect of some embodiments disclosed herein, it is recognized that alternative administration methods and systems can be implemented to use lower doses and provide a more direct delivery mechanism to the systemic bloodstream. Thus, some embodiments disclosed herein allow the beneficial effects of NSAIDs, for example, aspirin, to be achieved on a regular basis and in emergency situations while minimizing the previous disadvantages associated with the use of NSAIDs.

[0064] Various studies have determined that aspirin has a significant effect of reducing the risk of myocardial infarction. However, these studies have provided insufficient data in stroke, pulmonary thrombosis or deep vein thrombosis. In these studies, a dose of 325 mg of aspirin was used. However, these studies are based on their findings in oral administration of aspirin, and do not suggest DPI or MDI routes. Said routes are provided in some embodiments disclosed herein. Furthermore, administration of aspirin has negative side effects, such as significantly increasing major gastrointestinal and extracranial bleeding by more than 50%. This has led to some discussion that aspirin is of uncertain net value for preventive treatment.

[0065] Further studies have examined whether the benefits of aspirin can be obtained at low doses, such as low-dose aspirin (i.e., 81 mg). In the Swedish Aspirin Low-Dose Clinical Trial (SALT), low-dose (75 mg / day) aspirin was found to significantly reduce the risk of stroke or death in patients with cerebrovascular ischemic events. However, the study also reported gastrointestinal side effects, including a significant excess of bleeding episodes. A Danish study found that sufficient platelet inhibition was achieved at 50 mg / day in patients receiving aspirin as an antithrombotic agent, while the remaining patients required more than 50 mg / day. Furthermore, a Dutch TIA study concluded that aspirin at any dose above 30 mg daily prevented 13% of vascular events and that a need exists for more effective agents. However, no studies or teachings on aspirin administration by DPI or MDI at very low doses have been provided.

[0066] Dry powder formulations of aspirin for inhalation have been developed, but reports state that such formulations have not been clinically feasible because of the difficulty in meeting the high dose requirements of aspirin (approximately 80 mg / day for low-dose prevention of coronary events and stroke, and at least 300 mg / day for relief of pain or fever) with pulmonary delivery of the dry powder.

[0067] Furthermore, these reports recognize that the side effects of dry powder in the lungs, such as coughing, cannot be avoided unless the dose is less than tens of milligrams in one breath. Thus, previous teachings suggest that it may not be possible to meet the higher dose requirements of aspirin using DPIs. Finally, it has also been taught that the incidence of aspirin intolerance in asthmatics is higher when aspirin is delivered by inhalation other than orally.

[0068] In yet another study, the authors stated that the use of nanoparticle drugs for dry powder inhaler (DPI) delivery is not straightforward. Direct inhalation of nanoparticle drugs is not possible due to their small size. Due to their nanometer size, the nanoparticle drugs are mainly exhaled from the lungs without any deposition in the lungs. Furthermore, the severe aggregation problem caused by the small size makes their physical handling difficult for DPI delivery. Therefore, "large hollow carrier particles" of nanoparticle drugs have been developed for pulmonary delivery of some drugs. See Hadinoto et al., Drug Release Study Of Large Hollow Nanoparticulate Aggregates Carrier Particles For Pulmonary Delivery, International Journal of Pharmaceutics 341 (2007) 195-20.

[0069] In the Hadinoto study, the authors used aspirin as a model for a "poorly water-soluble" drug. The authors acknowledged that "for aspirin, due to the high dose requirement of aspirin (approximately 300 mg / day), nanoparticle polymer delivery is not the most suitable delivery method." Overall, the goal of the study was to identify important aspects of the formulation of the large hollow nanoparticle aggregates. See above.

[0070] In some embodiments of the invention disclosed herein, methods and systems are provided for treating disease (e.g., preventive treatment or risk reduction), e.g., treating cardiovascular disease (e.g., thrombosis) by administering a very small amount of an NSAID, e.g., low-dose aspirin, via a DPI. The dose can be much less than the dose of low-dose aspirin (e.g., less than 81 mg). The dosage can be less than 25 mg of acetylsalicylic acid. Additionally, the dosage can be less than 20 mg of acetylsalicylic acid. The dosage can be less than 15 mg of acetylsalicylic acid. The dosage can be less than 12 mg of acetylsalicylic acid. The dosage can be less than 10 mg of acetylsalicylic acid. Additionally, the dosage can be less than 8 mg of acetylsalicylic acid. The dosage can be less than 5 mg of acetylsalicylic acid. In some embodiments, the dosage can be less than 2 mg of acetylsalicylic acid.

[0071] For example, based on some embodiments, the dose may be about 2 mg to about 30 mg. In some embodiments, the dose may be about 4 mg to about 25 mg of acetylsalicylic acid. The dose may be about 6 mg to about 20 mg of acetylsalicylic acid. Furthermore, in some embodiments, the dose may be about 8 mg to about 15 mg of acetylsalicylic acid. Furthermore, in some embodiments, the dose may be about 10 mg to about 13 mg of acetylsalicylic acid. For example, in some embodiments, the dose may be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of acetylsalicylic acid.

[0072] Further, the dose of acetylsalicylic acid may be less than about 80 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 1 mg to about 75 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 2 mg to about 60 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 5 mg to about 40 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 10 mg to about 30 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 12 mg to about 25 mg. In some embodiments, the dose of acetylsalicylic acid may be from about 15 mg to about 20 mg.

[0073] Such doses may provide a bioequivalent dose with fewer negative side effects when compared to typical doses of 81 mg to about 325 mg.

[0074] In some embodiments, NSAIDs can be used in various methods and systems. In some embodiments, NSAIDs can include salicylates, i.e., salts and esters of salicylic acid. Salicylates have antiplatelet effects. In addition, NSAIDs can include one or more of the following:

[0075] [Table 1]

[0076] Other alternatives may be used in place of NSAIDs in some methods or systems disclosed herein. Such alternatives include Plavix (clopidogrel), COX-2 inhibitors, and other therapeutic agents, such as nattokinase (an enzyme extracted and purified from the Japanese food called natto (EC 3.4.21.62)). In addition, other agents that provide various beneficial effects, such as being effective in reducing the risk of cardiovascular disease (e.g., thrombosis) in patients, may also be used in some embodiments. Thus, the discussion of the methods and systems will generally apply to these various alternatives. However, for purposes of discussion, the present disclosure often refers to aspirin. It is believed that the methods, effects, pharmacokinetic data, and other considerations related to aspirin may be similarly applied to other NSAIDs, based on some embodiments.

[0077] 4. Dry Powders and Particles The subject technology relates to dry powders and dry particles for inhalation having, as the active ingredient, an NSAID, such as acetylsalicylic acid.

[0078] In one embodiment, the dry particles of the subject technology are small and preferably dispersible. The size of said dry particles can be expressed in various ways conventional in the art, such as fine particle fraction (FPF), volume median geometric diameter (VMGD) or mass median aerodynamic diameter (MMAD).

[0079] In certain embodiments, the dry particles of the subject technology are small and preferably dispersible. For example, the dry particles of the subject technology may have a VMGD of about 10 μm or less (e.g., about 0.1 μm to about 10 μm) when measured by HELOS / RODOS at 1.0 bar. Preferably, the dry particles of the subject technology have a VMGD of about 9 μm or less (e.g., about 0.1 μm to about 9 μm), about 8 μm or less (e.g., about 0.1 μm to about 8 μm), about 7 μm or less (e.g., about 0.1 μm to about 7 μm), about 6 μm or less (e.g., about 0.1 μm to about 6 μm), about 5 μm or less (e.g., less than 5 μm, about 0.1 μm to about 5 μm), about 4 μm or less (e.g., 0.1 μm to about 4 μm), about 3 μm or less (e.g., 0.1 μm to about 3 μm), about 2 μm or less (e.g., 0.1 μm to about 2 μm), about 1 μm or less (e.g., 0.1 μm to about 1 μm), about 0.5 μm to about 6 μm, about 0.5 μm to about 5 μm, about 0.5 μm to about 4 μm, about 0.5 μm to about 3 μm, or about 0.5 μm to about 2 μm. In an exemplary embodiment, the dry particles of the subject technology have a VMGD of about 1.3 to about 1.7 μm as measured by HELOS / RODOS at 1.0 bar. In another exemplary embodiment, the dry particles of the subject technology have a VMGD of about 0.5 μm to about 2 μm as measured by HELOS / RODOS at 1.0 bar.

[0080] In certain embodiments, the dry particles of the subject technology are large and preferably disperse.For example, the dry particles of the subject technology can have a VMGD of about 30 μm or less (about 5 μm to about 30 μm) when measured by HELOS / RODOS at 1.0 bar.Preferably, the dry particles of the subject technology can have a VMGD of about 25 μm or less (e.g., about 5 μm to about 25 μm), about 20 μm or less (e.g., about 5 μm to about 20 μm), about 15 μm or less (e.g., about 5 μm to about 15 μm), about 12 μm or less (e.g., about 5 μm to about 12 μm), about 10 μm or less (e.g., about 5 μm to about 10 μm) or about 8 μm or less (e.g., 6 μm to about 8 μm) when measured by HELOS / RODOS at 1.0 bar.

[0081] The dry powders described herein may include a mixture of larger and smaller particles.

[0082] Preferably, the dry particles of the subject technology, regardless of whether the particles are small or large, are dispersible and have a ¼ bar and / or 0.5 / 4 bar of about 2.2 or less (e.g., from about 1.0 to about 2.2) or about 2.0 or less (e.g., from about 1.0 to about 2.0). Preferably, the dry particles of the subject technology have a ¼ bar and / or 0.5 / 4 bar of about 1.9 or less (e.g., about 1.0 to about 1.9), about 1.8 or less (e.g., about 1.0 to about 1.8), about 1.7 or less (e.g., about 1.0 to about 1.7), about 1.6 or less (e.g., about 1.0 to about 1.6), about 1.5 or less (e.g., about 1.0 to about 1.5), about 1.4 or less (e.g., about 1.0 to about 1.4), about 1.3 or less (e.g., less than 1.3, about 1.0 to about 1.3), about 1.2 or less (e.g., 1.0 to about 1.2), about 1.1 or less (e.g., 1.0 to about 1.1 μm), or the dry particles of the subject technology have a ¼ bar of about 1.0.

[0083] Alternatively or additionally, the dry particles for inhalation of the subject technology may have an MMAD of about 10 μm or less, e.g., about 0.5 μm to about 10 μm. Preferably, the dry particles of the subject technology have an MMAD of about 5 μm or less (e.g., about 0.5 μm to about 5 μm, preferably about 1 μm to about 5 μm), about 4 μm or less (e.g., about 1 μm to about 4 μm), about 3.8 μm or less (e.g., about 1 μm to about 3.8 μm), about 3.5 μm or less (e.g., about 1 μm to about 3.5 μm), about 3.2 μm or less (e.g., about 1 μm to about 3.5 μm), about 4 μm or less (e.g., about 4 μm to about 4 μm), about 5 μm or less (e.g., about 5 μm to about 5 μm), about 6 μm or less (e.g., about 6 μm to about 6 μm), about 7 μm or less (e.g., about 7 μm to about 7 μm), about 8 μm or less (e.g., about 8 μm to about 8 μm), about 9 μm or less (e.g., about 9 μm to about 9 μm), about 10 μm or less (e.g., about 10 μm to about 10 μm). to about 3.2 μm), about 3 μm or less (e.g., about 1 μm to about 3.0 μm), about 2.8 μm or less (e.g., about 1 μm to about 2.8 μm), about 2.2 μm or less (e.g., about 1 μm to about 2.2 μm), about 2.0 μm or less (e.g., about 1 μm to about 2.0 μm), or about 1.8 μm or less (e.g., about 1 micron to about 1.8 μm).

[0084] Alternatively or in addition, the dry powders and dry particles of the subject technology have an FPF of less than 5.0 μm (FPF_TD<5.0 μm) of at least about 20%, at least about 30%, at least about 45%, preferably at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 65%, or at least about 70%. Alternatively or in addition, the dry powders and dry particles of the subject technology have an FPF of emitted amount less than 5.0 μm (FPF_ED<5.0 μm) of at least about 45%, preferably at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, or at least about 85%.

[0085] Alternatively or in addition, the inhalable dry powders and dry particles of the present invention may have an FPF of less than about 5.6 μm (FPF<5.6 μm) of at least about 20%, at least about 30%, at least about 40%, preferably at least 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65% or at least about 70%.

[0086] Alternatively or in addition, the dry powders and dry particles of the present invention may have an FPF of less than about 3.4 μm (FPF<3.4 μm) of at least about 20%, preferably at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least 45%, at least about 50% or at least about 55%.

[0087] Alternatively or additionally, the dry powders and dry particles for inhalation of the subject technology have a density of about 0.1 g / cm 3 to about 1.0 g / cm 3 For example, small, dispersible dry particles have a tap density of about 0.1 g / cm 3 to about 0.9 g / cm 3 , about 0.2g / cm 3 to about 0.9 g / cm 3 , about 0.2g / cm 3 to about 0.9 g / cm 3 , about 0.3g / cm 3 to about 0.9 g / cm 3 , about 0.4g / cm 3 to about 0.9 g / cm 3 , about 0.5g / cm 3 to about 0.9 g / cm 3 or about 0.5g / cm 3 to about 0.8 g / cm 3 , greater than about 0.4g / cc, greater than about 0.5g / cc, greater than about 0.6g / cc, greater than about 0.7g / cc, or about 0.1g / cm 3 to about 0.8 g / cm 3 , about 0.1g / cm 3 to about 0.7 g / cm 3 , about 0.1g / cm 3 to about 0.6 g / cm 3 , about 0.1g / cm 3 to about 0.5 g / cm 3 , about 0.1g / cm 3 to about 0.4 g / cm 3 , about 0.1g / cm 3 to about 0.3 g / cm 3 , 0.3g / cm 3In a preferred embodiment, the tap density is greater than about 0.4 g / cc. In another preferred embodiment, the tap density is greater than about 0.5 g / cc. Alternatively, the tap density is less than about 0.4 g / cc.

[0088] Alternatively or additionally, the dry powder and dry particles for inhalation of the subject technology can have a water or solvent content of less than about 15% by weight of said dry particles for inhalation.For example, the dry particles for inhalation of the subject technology can have a water or solvent content of less than about 15% by weight, less than about 13% by weight, less than about 11.5% by weight, less than about 10% by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6% by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or can be anhydrous.The dry particles for inhalation of the subject technology can have a water or solvent content of less than about 6% and more than about 1%, less than about 5.5% and more than about 1.5%, less than about 5% and more than about 2%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%.

[0089] Depending on the specific application of the dry powders described herein, the dry powders and particles may contain a low or high percentage of the active ingredient in the composition. For example, the dry particles may contain 3% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 50% or more, 60% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, or 95% or more (by weight) of the active ingredient (e.g., acetylsalicylic acid).

[0090] 5. Dry Powder Delivery Through some embodiments disclosed herein, applicants have overcome the problems recognized by conventional teachings. In particular, applicants have recognized that when a drug is inhaled into the lungs, the drug can be dispersed toward the alveoli. The alveoli function primarily to exchange carbon dioxide for oxygen, and also produce enzymes. Thus, inhaled substances, such as pathogens, drugs, or other chemicals, can be processed in the alveoli.

[0091] Alveoli have a network of elastic fibers and capillaries that resemble meshed spheres on their outer surface. The capillaries are responsible for transporting oxygen-depleted blood to the lungs and oxygen-rich blood from the lungs via the pulmonary arteries and veins. Inside each alveolus is a thin tissue known as the alveolar capsule or alveolar epithelium. The alveolar epithelium is composed of two distinct types of cells known as smooth type I and type II. Type I smooth cells cover most of the surface area of ​​the epithelium and are tightly packed, allowing only small molecules, such as oxygen and carbon dioxide, to pass between them. Type II alveolar cells help produce pulmonary surfactant, which is used in gas exchange. Additionally, the alveolar epithelium also contains macrophages, which help dispose of particulate foreign matter, such as dust, tar, and pathogens. Despite the small size of the alveoli (only about 250 μm), an adult human may have between 200 and 400 million alveoli, so that the alveolar breathing area may be about 1,400 or 1,600 square feet.

[0092] Based on some embodiments disclosed herein, the absorption of NSAIDs administered by DPI or MDI through pulmonary capillaries and epithelium can provide immediate and effective treatment to address thromboembolic symptoms.One novel realization in some embodiments is that the substantial first-pass effect caused by oral administration of NSAIDs, such as aspirin, can be avoided by administration by dry powder inhaler.Furthermore, there has been no teaching or suggestion in the past regarding the pharmacokinetics of dry powder delivery of NSAIDs, such as aspirin, and the possible metabolism or inactivation of said drug when it encounters the endothelial tissue of pulmonary capillaries.

[0093] The delivery of NSAIDs by DPI or MDI is a complex and unpredictable technical field that is not simply provided and that even those skilled in the art cannot predict the results.Therefore, there is no reason for those skilled in the art to believe that the combination of previous systems or treatment methods could present the embodiments disclosed herein.For example, in some embodiments herein, the unpredictable result is observed that when the drug passes through the endothelium of pulmonary artery and alveolus, the first-pass effect is minimized, resulting in a very low rate of activation of the drug compared to other drug delivery routes.

[0094] The endothelium of the pulmonary capillaries acts as a barrier by allowing materials to selectively enter and exit the bloodstream. It would be expected that aspirin would be inactivated in the pulmonary capillaries, which are lined with endothelial cells. The endothelial cells are extremely metabolically active. Thus, one skilled in the art would expect that aspirin would be inactivated by the endothelium of the pulmonary capillaries. However, based on some embodiments disclosed herein, it is believed that when a powdered drug encounters the endothelium, the endothelium may metabolize or activate a very small portion of the powdered drug, compared to the metabolism provided by the digestive tract and liver. For example, after being converted to salicylic acid in the stomach, as much as 80% of the salicylic acid is metabolized in the liver. Thus, only a small amount of salicylic acid is bioavailable to the systemic bloodstream.

[0095] However, it is believed that the majority of the salicylic acid metabolized from the inhaled aspirin powder will be bioavailable to the systemic bloodstream. Thus, doses much smaller than those of low-dose aspirin (e.g., less than 81 mg) can be provided by dry powder inhalers. This can provide a very small dose while still providing a bioequivalent dose.

[0096] Furthermore, based on aspects of some embodiments, it is believed that a similar first pass effect may be experienced at the endothelium of the pulmonary capillaries. Thus, with respect to providing an inhaled dose that is bioequivalent to orally administered low-dose aspirin, it should be accounted for that said inhaled dose will experience some first pass effect through the endothelium of the pulmonary capillaries.

[0097] According to some embodiments, the first pass effect through the endothelium of the pulmonary capillaries can be minimal and provide little overall impact on the inhaled dose.

[0098] However, in some embodiments, it is believed that the first pass effect through the pulmonary capillary endothelium can be entirely ignored, and therefore the inhaled dose does not need to be adjusted to compensate for the first pass effect through the pulmonary capillaries.

[0099] Thus, in some embodiments, the unpredictable result is that even extremely low doses of aspirin (and possibly other NSAIDs) can provide significant therapeutic effects while providing minimal or negligible side effects. For example, low doses of 1 mg, 2 mg, 3 mg, 4 mg or 5 mg of acetylsalicylic acid can be effective in reducing the risk of thromboembolism. Thus, in accordance with some embodiments, the net benefit is dramatically improved at significantly low doses. These results and outcomes are unpredictable due to the complex and unpredictable nature of drug interactions in the body, drug delivery pathways and ultra-small drug structures. Finally, there is no teaching or other prior reference that discloses a system or method for achieving therapeutically beneficial results while substantially avoiding any negative side effects using DPI or MDI drug delivery mechanisms that include ultra-small NSAIDs.

[0100] According to some embodiments, the dry powder administration of NSAIDs, for example, salicylates such as acetylsalicylic acid, can have particles with a median aerodynamic diameter of about 1 μm to about 5 μm, as described above.The particles can be highly porous, can exhibit sponge-like morphology, and can be a component of carrier particles.The particles can also exhibit spherical shape, whereby the shape and porous surface can serve to reduce the contact area between particles, thus resulting in little particle agglomeration and more effective distribution through the lungs.Dry powder technology, for example PulmoSphere™, can be implemented in the embodiments of the methods and systems disclosed herein.

[0101] Referring to FIG. 1, in dry powder inhalation techniques, a patient may use a dry powder inhaler 10 to inhale a powder formulation of a drug, such as an NSAID. The dose is effective to reduce the risk of thromboembolism in the patient. In some embodiments, it is recognized that the lungs are efficient filters and generally only allow particles with a size of less than 5 μm. For example, after the drug enters the main bronchial trunk 20, the drug will enter each lung 22, 24. The drug will then pass through the bronchial tree 26, 28 until it reaches the individual alveoli 30 in the lungs 22, 24. The alveoli are each long and numerous, as described below. Thus, the dry powder inhaler 10 may allow a patient to self-administer a dose of particles with a size of about 1 μm to about 5 μm. In some embodiments, the particle size may be about 2 μm to about 4 μm.

[0102] In accordance with some embodiments, various types of inhalers can be used to deliver the drug using a DPI or MDI delivery system. The dosage can be effective to reduce the risk of thromboembolism in the patient.

[0103] For example, the dry powder inhaler 10 may have a mouthpiece, a reservoir for receiving an NSAID, and a drive member for making the NSAID available through the mouthpiece for inhalation by a patient.

[0104] 2A-2F, for example, illustrate a DPI delivery device 100 having a mouthpiece 102 and a drug compartment 104. The drug compartment 104 can be inserted into an inhaler body cavity 110.

[0105] For example, as shown in Fig. 2B, the medicament compartment 104 may be inserted into the body cavity 110 in a storage position 120 for storage purposes. However, the medicament compartment 104 may also be moved to a first position 122, shown in Fig. 2C. In the first position 122, the first container 140 of the medicament compartment 104 is aligned with the airway 142 of the mouthpiece. In this first position 122, the medicament contained in the first container 140 may be delivered through the airway 142 of the mouthpiece and inhaled by the patient, as shown in Fig. 2D.

[0106] Further, as shown in Figure 2E, the medicament compartment 104 can be moved to a second position 124. In the second position 124, the second container 144 is aligned with the airway 142 of the mouthpiece. In such a position, the medicament contained in the second container 144 can be inhaled by the patient, as illustrated in Figure 2F.

[0107] During the process of breathing, the lungs are usually continuously exposed to various sizes of substances present in the environment. This can include pollen (20-90 μm), bacteria (0.2-200 μm) and smoke particles (0.01-1 μm). The deposition of a particular particle depends on a number of factors, such as the size and density of the particle and the flow rate of air into and out of the lungs and the residence time of the particle in the respiratory system. In addition, the human body has developed systems to protect against the harmful effects of some of these inhaled substances, such as processing them as phagocytosis. Thus, one factor to consider when designing systems and methods for delivering pharmaceutical compounds by inhalation is the effect that particle size has on the location in the airways where the drug particles will likely be deposited after inhalation.

[0108] Particles entering the lungs are deposited along the airway sequence by collision, settling and diffusion. In many cases, the behavior of particles in the airflow can be described by their aerodynamic diameter, as described in detail herein. Similar to the Reynolds number concept in aerodynamics, two particles with the same aerodynamic diameter will behave identically in the airflow, regardless of their actual geometric (i.e., physical) size.

[0109] It has been shown previously that particle size, or more precisely, aerodynamic diameter, significantly influences the location in the respiratory system where a particle will most likely be deposited after inspiration. For example, Heyder et al. (J. Aerosol. Sci. 17, 811-825, 1986) examined the deposition of particles in the size range of 5 nm to 15 μm in the respiratory tract. Their study showed that particles with an aerodynamic diameter larger than 5 μm are preferentially deposited by inertial impaction in the mouth and upper respiratory tract. Smaller particles (aerodynamic diameter in the range of 1-5 μm) are deposited deeper in the lungs by impaction and settling. On the other hand, very small particles (aerodynamic diameter <1 μm) remain mainly suspended in the airstream and are exhaled.

[0110] Others have found similar results for pulmonary drug delivery, with particles having a median aerodynamic diameter of about 2 μm likely to be efficiently deposited in the alveolar space, with a slight deposition of nearly 90% of the delivered particle dose (Byron, 1986, J. Pharm. Sci. 75(5), 433-438). In contrast, if the particles have a median aerodynamic diameter in the range of 5-10 μm, only about 10% of the delivered dose will be deposited in the alveoli, with about 40% deposition in the airways and the remainder in the oral cavity and pharynx. If the median aerodynamic diameter is 15 μm or greater, the particles will be preferentially deposited in the oral cavity and pharynx. Given the proximity of the alveolar epithelium to the systemic circulation and the known benefits of delivering drugs to the lungs to avoid loss of pharmaceutical agent through first-pass effect due to hydrolysis in the gastrointestinal tract or processing in the liver, there are advantages to be gained by designing powdered drug compositions that will be most efficiently delivered to and deposited in the airways, and in particular, the alveolar spaces.

[0111] Further advantages are obtained by deposition of drugs in the alveolar space. For example, the large available surface area and thin thickness of the alveolar epithelium provide for nearly instantaneous transfer of drugs to the circulatory system. Similarly, when blood leaves the alveolar capillaries and first returns to the heart via the pulmonary veins, significant levels of therapeutic molecules can be delivered near the heart almost instantly. This is a particular advantage in designing treatments for cardiovascular conditions such as those in the present case.

[0112] Therefore, antithrombotic agents such as NSAIDs can be delivered at higher plasma concentrations than would be possible with the same orally administered dose of said agent.These levels can be achieved more rapidly by pulmonary delivery compared to oral administration.Therefore, those skilled in the art will understand that it will be possible to achieve circulating plasma levels of NSAIDs in coronary circulation that are effective for reducing the risk of thromboembolism with lower doses than would be required if NSAIDs were taken orally according to current physician recommendations.

[0113] As described herein, one aspect of the subject technology provides an apparatus and method for providing a therapeutically effective amount of NSAID to reduce the risk of thromboembolism.As described above, the general approach is to deliver NSAID by inhaler in a pharma-ceutically acceptable powder form (e.g., acetylsalicylic acid and / or its "ASA" derivatives).However, there are many challenges in delivering a therapeutically effective amount of NSAID by dry powder inhalation system.

[0114] One challenge in designing such treatment systems is the limitation on the size of the dose that can be comfortably tolerated by the patient. For example, in some cases, it has been shown that about 40 to about 50 mg of powdered compound can be comfortably delivered in a single inhalation dose. At the same time, no currently available inhalation device is capable of delivering more than about 50 mg of powder per delivery. However, the recommended dose of ASA for treating suspicious symptoms consistent with preventing myocardial infarction is to chew two 81 mg tablets of ASA. Thus, the recommended dose for such treatment is about 160 mg. This suggests that to provide the same amount of ASA as recommended by oral administration, a patient may have to administer as many as four inhalation doses within the same period. Studies have shown that a patient can realistically administer five inhalation doses within one minute using currently available inhaler technology.

[0115] As mentioned above, there is a general tendency that particle deposition in the alveolar space increases when particle size decreases. Studies on nanoparticle distribution have shown that inhaled nanoparticles with a size of less than 100 nm are desirable for minimizing alveolar deposition and pulmonary phagocytosis (Hoet et al., 2004, J. Nanbiotechnol. 2, doi:10.1186 / 1477-3155-2-12). Nanoparticles offer additional advantages in terms of dispersion of active compounds and, ultimately, in uptake rate compared to coarser preparations. The most obvious of these is that smaller particles tend to disperse and dissolve faster than larger ones. However, nanometer-sized particles are not optimal for use in the delivery of powdered pharmaceuticals, since they tend not to deposit efficiently, remain suspended in the airstream, and are exhaled upon exhalation.

[0116] One way to overcome this problem is by the use of methods to produce particles with nanoparticle aggregates having an average aerodynamic size optimal for efficient alveolar deposition. For example, Hadinoto et al. (2004, Int. J. Pharma., doi:10.1016 / j.ijpharm.2007.03.035) show that large hollow shells with nanoparticles can be produced by spray drying methods. These particles have a large geometric diameter (10-15 μm), but they have a small aerodynamic diameter (1-3 μm) that is desirable for delivery of compounds to deeper regions of the lung. Furthermore, these large hollow shells rapidly deaggregate into component nanoparticles that provide rapid release of pharmaceutical agent. Furthermore, Hadinoto et al. show that this method can be employed to produce preparations of ASA for use in powder inhalation devices. Thus, these methods can be used in combination with the subject technology to achieve ASA particles of aerodynamic size for deposition in the alveolar space. In this case, more than 90% of the drug is released from the particles within 30 minutes.

[0117] However, despite the ability to produce optimally sized particles, there are further problems in the preparation of pharmaceutical compositions for use by inhalation. Typically, it has been observed that uniformly sized powders tend to aggregate and form larger aggregates due to a phenomenon known as bridging. If bridging occurs, the particles will behave aerodynamically as very large particles and will not tend to reach the alveolar space as described above. Delivery to said space is desirable to optimize the rapid delivery of the desired drug. To reduce the aggregation of pharmaceutical active agents, the drug is often blended with excipient particles, such as lactose, to prevent aggregation. Although the addition of excipients is an effective way to prevent aggregation, the addition reduces the amount of pharmaceutical active compound per measured inhalation dose. As a result, the patient will have to receive more doses to achieve the same intake of the pharmaceutical active compound. In emergency situations, this may be impractical. For example, if a preparation was prepared with 50% ASA component and 50% excipients, with a limit of 40 mg of powder per dose, a patient would have to inhale approximately 8 doses to receive the recommended 162 mg of ASA for treatment of symptoms suggestive of impending infarction. In such circumstances, dry powder inhalers may be of little practical use.

[0118] However, in the present case, the inventors have now found that cross-linking can be reduced by mixing particles of the same active ingredient (e.g., ASA) using batches of particles with different size distributions. For example, a composition with a relatively uniform particle size would aggregate, but by providing a blended composition with some particles having a median aerodynamic diameter in the range of about 1 μm to about 5 μm, other particles having a median aerodynamic diameter in the range of about 5 μm to about 15 μm, and still other particles having a median aerodynamic diameter larger than about 15 μm, aggregation will be prevented and the deposition properties of the preparation will be maintained. In fact, the pharma- ceutical active compound is used to replace the function of an excipient (e.g., lactose) in preventing aggregation during storage of a pharmaceutical. To the inventors' knowledge, it has never been considered to use the pharma- ceutical active ingredient as an excipient itself for the purpose of preventing aggregation.

[0119] Moreover, unlike many other drugs, NSAIDs and especially ASA can effectively enter circulation through routes other than alveolar epithelium.In particular, ASA can enter body by absorption through mucous layer of oral cavity and pharynx and certainly airway epithelium.Therefore, by providing an inhalable form of ASA regardless of particle size, the inhaled dose can be substantially absorbed into systemic circulation and can be effective in reducing the risk of thromboembolism.

[0120] Furthermore, by selecting the ratio of different particle sizes, it is possible to provide a faster or slower acting formulation based on the location where the drug is ultimately deposited.For example, in some embodiments, it may be desirable to provide a preparation with 80% ASA particles having a median aerodynamic diameter of about 1 μm to about 5 μm and about 20% particles having a median aerodynamic diameter of at least 15 μm.However, other combinations are possible, and those skilled in the art will easily understand that a faster acting preparation will have proportionally smaller particles, while a slower acting preparation will have proportionally larger particles.Thus, for example, by using the devices and methods described herein, a therapeutically effective amount of NSAID, such as ASA, can be provided through the airways at least as rapidly as can be achieved by oral administration.

[0121] If a slower acting dosage form is desired, the formulation may include increasing the fraction of particles having a median aerodynamic diameter in the range of about 5 μm to about 10 μm, or 15 μm or greater. These preparations will provide a more gradual increase in circulating levels of ASA and its metabolic derivatives, resulting in deposition in either the airways or the oral cavity and pharynx.

[0122] In either case, the subject technology provides formulations that can deliver ASA and its pharmacologically active metabolic by-products (e.g., salicylates) to the systemic circulation at least as fast, if not faster, than can be achieved by oral administration. Moreover, the formulations are effective to deliver ASA and its pharmacologically active metabolic by-products to the systemic circulation at levels at least equivalent to those observed following oral administration of the same amount of ASA.

[0123] For example, pharmacokinetic studies have shown that after oral administration of ASA, peak plasma levels are achieved after approximately 20 minutes and then decay rapidly due to its relatively short elimination half-life (15-20 minutes). In comparison, plasma levels of the main pharmacologically active metabolite, salicylate, are elevated for a period of approximately 45 minutes after administration of ASA and remain elevated for much longer due to its significantly longer elimination half-life (2-3 hours) (Dressman et al., 2012, Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Acetylsalicylic Acid, doi 10.1002 / jps.2312).

[0124] Notably, the pharmacokinetic behavior of ASA has been found to be linear over the dose range of 30-400 mg. Thus, extrapolating from these data, one would predict that peak circulating plasma levels of ASA and SA would be approximately 4 mcg / mL and 10 mcg / mL, respectively, and would have the same time kinetics, as noted above.

[0125] Thus, one aspect of the subject technology provides a dry powder having a mixture of particles of various sizes.

[0126] For example, the dry powder may have a ratio of larger size particles (e.g., VMGD≧15 μm, e.g., ≧20 μm or 20-30 μm) as measured by VMGD to smaller size particles (e.g., VMGD≦5 μm, e.g., 1-3 μm) as measured by VMGD at about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about The ratio (w / w) may be 1:8, about 1:10, about 1:15, about 1:20, about 1:25, about 1:30, about 1:40, about 1:50, about 1:100, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 40:1, about 50:1 or about 100:1, etc.

[0127] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% (by weight) of particles having a VMGD of about 10 μm or less, preferably about 5 μm or less. Generally, particles of 10 μm or less can reach the lungs, and generally, particles of 5 μm or less (e.g., 1-3 μm) can reach the alveoli.

[0128] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% (by weight) of particles having a VMGD between about 5 μm and about 20 μm, preferably between about 5 μm and about 15 μm or between about 5 μm and about 10 μm.

[0129] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% (by weight) of particles having a VMGD of about 15 μm or greater, preferably 20 μm or greater.

[0130] The above features may be combined, for example, the dry powder may have about 50% particles smaller than about 5 μm (VMGD), about 25% particles between about 5 and about 15 μm (VMGD), and about 25% particles larger than about 15 μm (VMGD).

[0131] The dry powder may also have a mixture of particles with different mass median aerodynamic diameters (MMAD). For example, the dry powder may have a mixture of larger sized particles (e.g., MMAD ≥ 15 μm, e.g., ≥ 20 μm or 20-30 μm) and smaller sized particles (e.g., MMAD ≤ 5 μm, e.g., 1-3 μm) in a ratio of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:10, about 1:1 The mixture may have a ratio (w / w) of about 1:5, about 1:20, about 1:25, about 1:30, about 1:40, about 1:50, about 1:100, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 40:1, about 50:1 or about 100:1, etc.

[0132] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% (by weight) of particles having an MMAD of about 10 μm or less, preferably about 5 μm or less. Generally, particles of 10 μm or less can reach the lungs, and generally, particles of 5 μm or less (e.g., 1-3 μm) can reach the alveoli.

[0133] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% (by weight) of particles having an MMAD between about 5 μm and about 20 μm, preferably between about 5 μm and about 15 μm or between about 5 μm and about 10 μm.

[0134] Alternatively or in addition, the dry powder may have about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99% (by weight) of particles having an MMAD of about 15 μm or greater, preferably 20 μm or greater.

[0135] The above features may be combined, for example, the dry powder may have about 50% particles less than about 5 μm (MMAD), about 25% particles between about 5 and about 15 μm (MMAD), and about 25% particles greater than about 15 μm (MMAD).

[0136] In some embodiments, the dry powder is free or substantially free of excipients, hi some embodiments, the dry powder is free or substantially free of anti-agglomeration (anti-crosslinking) excipients.

[0137] In certain embodiments, the dry powder has a mixture of particles of various sizes, which is effective in substantially preventing or reducing particle bridging.In certain embodiments, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85% or at least about 90% of the NSAID (e.g., acetylsalicylic acid) in the dry powder is delivered to the alveolar region of the lung.

[0138] 6. Methods for Preparing Dry Powders and Dry Particles Dry particles and dry powders for inhalation can be prepared using any suitable method. Many suitable methods for preparing dry powders and particles for inhalation are conventional in the art, including single and double emulsion solvent evaporation methods, spray drying, milling (e.g., jet milling), blending, solvent extraction, solvent evaporation, phase separation, single and complex coacervation, interfacial polymerization, supercritical carbon dioxide (CO2) and other suitable methods. Dry particles for inhalation can be prepared using methods for preparing microspheres or microcapsules known in the art. These methods can be used under conditions that result in the formation of dry particles for inhalation with desired aerodynamic properties (e.g., aerodynamic diameter and geometric diameter). If necessary, dry particles for inhalation with desired properties, such as size and density, can be selected using suitable methods, such as sieving.

[0139] The dry particles for inhalation can be spray-dried. Suitable spray-drying techniques are described, for example, in "Spray Drying Handbook" by K. Masters, John Wiley & Sons, New York (1984), which was developed by BUCHI Laboratory Equipment or GEA Niro drying technology. Typically, during spray-drying, heat from a hot gas, for example heated air or nitrogen, is used to evaporate the solvent from droplets formed by atomizing a continuous liquid supply. If necessary, the spray-drying or other equipment used to prepare the dry particles, for example jet milling equipment, can include an in-line geometric particle size analyzer that measures the geometric diameter of the dry particles for inhalation as they are produced, and / or an in-line aerodynamic particle size analyzer that measures the aerodynamic diameter of the dry particles for inhalation as they are produced.

[0140] For spray drying, a solution, emulsion or suspension containing the components of the dried particles to be produced in a suitable solvent (aqueous solvent, organic solvent, aqueous-organic mixture or emulsion) may be distributed to a drying vessel by an atomizing device. For example, a nozzle or a rotary atomizer may be used to distribute the solution or suspension to the drying vessel. For example, a rotary atomizer with 4 or 24 impellers may be used. Examples of suitable spray dryers that may be equipped with either a rotary atomizer or a nozzle include the Mobile Minor Spray Dryer or Model PSD-1, both manufactured by Niro, Inc. (Denmark). The actual spray drying conditions will vary to some extent depending on the composition of the spray drying solution or suspension and the material flow rate. Those skilled in the art will be able to determine the appropriate conditions based on the composition of the solution, emulsion or suspension to be spray dried, the desired particle properties and other factors. Generally, the inlet temperature to the spray dryer is about 100°C to about 300°C, and preferably about 220°C to about 285°C. The outlet temperature of the spray dryer will vary depending on factors such as the feed temperature and the properties of the material being dried. Typically, the outlet temperature is about 50° C. to about 150° C., preferably about 90° C. to about 120° C. or about 98° C. to about 108° C. If necessary, the dry particles for inhalation produced can be fractionated by volumetric size, for example using sieving, or by aerodynamic size, for example using a cyclone, and / or further separated based on density, using techniques known to those skilled in the art.

[0141] To prepare the dry particles for inhalation of the subject technology, generally, a solution, emulsion or suspension (i.e., feed material) containing the dry powder of the desired component is prepared and spray-dried under suitable conditions.Preferably, the dissolved or suspended solids concentration of the feed material is at least about 1 g / L, at least about 2 g / L, at least about 5 g / L, at least about 10 g / L, at least about 15 g / L, at least about 20 g / L, at least about 30 g / L, at least about 40 g / L, at least about 50 g / L, at least about 60 g / L, at least about 70 g / L, at least about 80 g / L, at least about 90 g / L or at least about 100 g / L.The feed material can be provided by preparing a single solution or suspension by dissolving or suspending the appropriate components (e.g., salts, excipients, other active ingredients) in a suitable solvent. The solution, emulsion or suspension can be prepared using any suitable method, such as bulk mixing of dry and / or liquid components, or static mixing of liquid components to form a combination. For example, a hydrophilic component (e.g., an aqueous solution) and a hydrophobic component (e.g., an organic solution) can be combined using a static mixer to form a combination. The combination can then be atomized to produce droplets. The droplets are dried to form dry particles for inhalation. Preferably, the atomization step is performed immediately after the components are combined in the static mixer.

[0142] In one example, dry particles for inhalation having acetylsalicylic acid and sodium citrate are prepared by spray drying.

[0143] The feedstock or components of the feedstock may be prepared using any suitable solvent, such as an organic solvent, an aqueous solvent, or a mixture thereof. Suitable organic solvents that may be used include, but are not limited to, alcohols, such as ethanol, methanol, propanol, isopropanol, butanol, and the like. Other organic solvents include, but are not limited to, perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether, and the like. Co-solvents that may be used include aqueous solvents and organic solvents, such as, but are not limited to, the organic solvents listed above. Aqueous solvents include water and buffer solutions (e.g., phosphate buffers).

[0144] The feedstock or components of the feedstock may have any desired pH, viscosity or other properties. If necessary, a pH buffer may be added to the solvent or co-solvent or to the resulting mixture. Generally, the pH of the mixture ranges from about 3 to about 8.

[0145] Inhalation particles can also be produced by jet milling. See, for example, the technology developed by Apex Process Technology or Jetpharma SA. Jet milling is a method that uses highly compressed air or other gases, usually in a vortex motion, to make fine particles collide with each other in a chamber. Jet mills can reduce the particle size of solids to the low micron to submicron range. The milling energy is generated by a gas stream from a horizontal milling air nozzle. The particles in the fluidized bed formed by the gas stream are accelerated toward the center of the mill and collide with slower moving particles. The gas stream and the particles carried by it create intense turbulence, and as the particles collide with each other, they are milled.

[0146] Wet grinding is a method that combines techniques to achieve small particle size (bottom-up techniques, e.g., controlled crystallization or nanocrystallization, or top-down techniques, e.g., high shear mixing or high pressure homogenization) with appropriate isolation techniques (e.g., spray drying or filtration with drying treatment). See, for example, the techniques developed by Hovione. These combinations can be used to adjust particle size and morphology to meet specific drug delivery needs. The method allows control of particle size distribution during the plugged period and in-process sampling, and maintains a crystalline state (with little or no amorphous inclusions).

[0147] The wet grinding technique may be repeated multiple times to achieve a grain size of about 500 nanometers or less.

[0148] The particles described herein can be encapsulated, for example, with a pharmaceutical excipient, such as lactose, a sugar, or a polymer.

[0149] The above techniques may be combined, for example after the wet grinding process the particles may be spray-dried (e.g. for the purposes of microencapsulation).

[0150] The inhalable dry particles and dry powders can be processed and then separated, for example, by cyclone filtration or centrifugation, to provide a particle sample with a preselected size distribution. For example, more than about 30%, more than about 40%, more than about 50%, more than about 60%, more than about 70%, more than about 80%, or more than about 90% of the inhalable dry particles in the sample can have a diameter within a selected range. The selected range within which a certain percentage of the inhalable dry particles fall can be, for example, any of the size ranges described herein, for example, the VMGD of about 0.1 to about 3 μm.

[0151] The diameter of the inhalable dry particles, for example its VMGD, can be measured using an electronic zone sensing instrument, for example, a Multisizer IIe (Coulter Electronic, Luton, Beds, UK) or a laser diffraction instrument, for example, a HELOS system (Sympatec, Princeton, NJ). Other instruments for measuring the geometric diameter of particles are well known in the art. The diameter of the inhalable dry particles in the sample will be in a range depending on factors such as particle composition and synthesis method. The size distribution of the inhalable dry particles in the sample can be selected to allow optimal deposition in the target site in the respiratory system.

[0152] Empirically, aerodynamic diameter can be measured using time-of-flight (TOF) measurements. For example, an instrument such as the Model 3225 Aerosizer DSP particle size analyzer (Amherst Process Instrument, Inc., Amherst, Massachusetts) can be used to measure aerodynamic diameter. The Aerosizer measures the time taken for individual inhalable dry particles to pass between two fixed laser beams.

[0153] Aerodynamic diameter can also be measured empirically directly using conventional gravity settling methods, which measure the time required for a sample of dry particles for inhalation to settle a specific distance. Indirect methods for measuring mass median aerodynamic diameter include the Andersen Cascade Impactor and the Multi-Stage Liquid Impinger (MSLI) method. Methods and instruments for measuring the aerodynamic diameter of particles are well known in the art.

[0154] Tap density is a measurement of the bulk mass density that characterizes a particle. The bulk mass density of a statistically isotropic particle is defined as the mass of said particle divided by the minimum spherical bulk volume that can be enclosed within it. Features that can contribute to lowering tap density include irregular surface texture and porous structure. Tap density can be measured by using equipment known to those skilled in the art, such as a dual platform microprocessor-controlled tap density tester (Vankel, NC), a GeoPyc™ instrument (Micrometrics Instrument Corp., Norcross, GA) or a SOTAX tap density tester model TD2 (SOTAX Corp., Horsham, PA). Tap density can be measured using the method of USP Bulk Density and Tapped Density, United States Pharmacopia convention, Rockville, MD, 10th Supplement, 4950-4951, 1999.

[0155] Fine particle fraction can be used as one way to characterize the aerosol performance of a dispersed powder. Fine particle fraction describes the size distribution of airborne inhalable dry particles. Gravimetric analysis using a cascade impactor is one way to measure the size distribution or fine particle fraction of airborne inhalable dry particles. The Andersen Cascade Impactor (ACI) is an 8-stage impactor that can separate the aerosol into 9 separate fractions based on aerodynamic size. The size cutoff of each stage is determined by the flow rate at which the ACI is operated. The ACI is built from a multi-stage consisting of a series of nozzles (i.e., jet plates) and impaction surfaces (i.e., impaction disks). At each stage, the aerosol stream passes through the nozzles and impacts on the surfaces. Inhalable dry particles in the aerosol stream with a large enough inertia will impact on the plate. Smaller inhalable dry particles that do not have enough inertia to impact on the plate will remain in the aerosol stream and be carried to the next stage. Each successive stage of the ACI has a higher aerosol velocity at the nozzle, so that smaller dry particles for inhalation can be collected at each successive stage.

[0156] If necessary, a 2-stage disintegration ACI can also be used to measure the fine particle fraction. The 2-stage disintegration ACI consists of only the top two stages of the 8-stage ACI, and allows the collection of two different powder fractions. Specifically, the 2-stage disintegration ACI is calibrated so that the fraction of powder collected on stage 1 is composed of inhalable dry particles with an aerodynamic diameter less than 5.6 μm and greater than 3.4 μm. Thus, the fraction of powder that passes through stage 1 and is deposited on the collection filter is composed of inhalable dry powder with an aerodynamic diameter less than 3.4 μm. The airflow in such a calibration is about 60 L / min.

[0157] The FPF (<5.6) has been shown to correlate with the fraction of the powder that is able to enter the patient's lungs, while the FPF (<3.4) has been shown to correlate with the fraction of the powder that reaches the patient's deep lungs. These correlations provide quantitative metrics that can be used for particle optimization.

[0158] ACI can be used to approximate the emitted dose. In this specification, the doses are referred to as weighted recovered dose and analytical recovered dose. "Weighted recovered dose" is defined as the ratio of powder weighed on all stage filters of the ACI to the apparent dose. "Analytical recovered dose" is defined as the ratio of powder recovered by cleaning all stages, all stage filters and intake ports of the ACI to the apparent dose. The FPF_TD(<5.0) is the ratio of the insertion amount of the deposited powder below 5.0 μm on the ACI to the apparent dose. The FPF_RD(<5.0) is the ratio of the insertion amount of the deposited powder below 5.0 μm on the ACI to either the weighted recovered dose or the analytical recovered dose.

[0159] Another way to approximate the emitted dose is to determine how much powder leaves the container, e.g., a trap or blister, upon actuation of a dry powder inhaler (DPI). This takes into account the rate that leaves the capsule, but does not take into account any powder that has accumulated on the DPI. The emitted dose is the ratio of the capsule weight, including the dose, before actuation of the inhaler to the capsule weight after actuation of the inhaler. This measurement may also be referred to as the capsule emitted powder mass (CEPM).

[0160] The Multi-Stage Liquid Impinger (MSLI) is another device that can be used to measure the fine particle fraction. The Multi-Stage Liquid Impinger operates on the same principle as the ACI, but instead of eight stages, the MSLI has five. Additionally, each MSLI stage consists of a glass frit wetted with ethanol instead of a solid plate. The wetted stages are used to prevent particle bouncing and re-entrainment, which can occur when using the ACI.

[0161] The subject technology also relates to dry powders or dry particles for inhalation produced using any of the methods described herein.

[0162] The dry particles for inhalation of the subject technology can also be characterized by the chemical stability of the salt or excipients that the dry particles for inhalation have. The chemical stability of the constituent salts can affect important characteristics of the particles for inhalation, such as shelf life, suitable storage conditions, acceptable environment for administration, biological compatibility and efficacy of the salts. Chemical stability can be evaluated using techniques well known in the art. One example of a technique that can be used to evaluate chemical stability is reversed-phase high performance liquid chromatography (RP-HPLC). The dry particles for inhalation of the subject technology contain salts that are generally stable over a long period of time.

[0163] If necessary, the inhalable dry particles and dry powders described herein can be further processed to improve stability. An important characteristic of pharmaceutical dry powders is whether they are stable under various temperature and humidity conditions. Unstable powders will absorb moisture from the environment and agglomerate, which will change the particle size distribution of the powder.

[0164] Excipients, such as maltodextrin, can be used to form more stable particles and powders. The maltodextrin can act as an amorphous phase stabilizer and prevent ingredients from changing from an amorphous to a crystalline state. Alternatively, a post-processing step can be used to help the particles overcome the crystallization process in a controlled manner (e.g., in a dust collector at high humidity), which involves further processing the resulting powder to restore its dispersibility if agglomerates form during the crystallization process, for example, by passing the particles through a cyclone to break up the agglomerates. Another possible approach is to optimize around the processing conditions that result in the production of more crystalline and therefore more stable particles. Another approach is to try to produce a more stable form of the salt using different excipients or different levels of the current excipients.

[0165] The inhalable dry particles and dry powders described herein are suitable for inhalation therapy.The inhalable dry particles can be manufactured with suitable material, surface roughness, diameter and tap density for localized delivery to selected areas of respiratory system, such as deep lung or upper or middle airways.For example, higher density or larger inhalable dry particles can be used for upper airways delivery, or the mixture of different sizes of inhalable dry particles in samples provided with the same or different formulations can be administered to target different areas of lungs in one dose.

[0166] To relate the dispersion of powder at various inhalation flow rates, volumes, and from inhalers of various resistances, the energy required to perform an inhalation maneuver can be calculated. Inhalation energy is calculated using the equation E=R 2 Q 2 V, where E is the inhaled energy in Joules and R is the inhaled energy in kPa. 1 / 2 where ρ is the inhaler resistance in L / LPM, Q is the constant flow rate in L / min, and V is the inspired air volume in L.

[0167] In a healthy adult population, peak inspiratory flow rates (PIFR) of 0.02 and 0.055 kPa were obtained using values ​​of peak inspiratory flow rate (PIFR) measured by Clarke et al. (Journal of Aerosol Med, 6(2), p.99-110, 1993). 1 / 2 For flow rates Q from two inhaler resistances of 100 / LPM, it is predicted that inhalation energies in the range of 2.9 to 22 Joules could be achieved with an inhalation volume of 2 L based on both FDA guidance documents for dry powder inhalers and a study by Tiddens et al. (Journal of Aerosol Med, 19, (4), p. 456-465, 2006), which found an average inhalation volume of 2.2 L for adults with various DPIs.

[0168] Dry powder particles can also be prepared using electrohydrodynamic spraying in a cone-jet mode, as described by Li et al., Chemical Engineering Science 61 (2006) 3091-3097. For example, an aspirin solution flowing through a needle can be subjected to an electric field to generate droplets. The method is said to produce a trail of droplets with a near monodisperse distribution, leading to the formation of aspirin particle crystals.

[0169] 7. Treatment Method In another aspect, the subject technology is a method for treating (e.g., prophylactically treating or reducing the risk of) cardiovascular disease (e.g., thrombosis) comprising administering to the airways of a subject in need thereof an effective amount of an inhalable dry particle or dry powder described herein.

[0170] Cardiovascular diseases include, for example, atherosclerosis, coronary artery disease (CAD), angina pectoris (commonly known as "angina"), thrombosis, ischemic heart disease, coronary insufficiency, peripheral vascular disease, myocardial infarction, cerebrovascular disease (e.g., stroke), transient ischemic attack, arteriolosclerosis, small vessel disease, elevated cholesterol, intermittent claudication or hypertension.

[0171] The dry particles and dry powders for inhalation can be administered to the airways of the subject in need thereof by any suitable method, for example, using pharyngeal injection techniques and / or inhalation devices, for example, dry powder inhalers (DPIs) or metered dose inhalers (MDIs). Numerous DPIs are available, for example, the inhalers disclosed in U.S. Pat. Nos. 4,995,385 and 4,069,819, Spinhaler® (Fisons, Loughborough, UK), Rotahalers®, Diskhaler® and Diskus® (GlaxoSmithKline, Research Triangle Technology Park, North Carolina), FlowCapss®, TwinCaps®, XCaps (Hovione, Loures, Portugal), Inhalators® (Boehringer-Ingelheim, Germany), Aerolizer® (Novartis, Switzerland) and others known to those skilled in the art.

[0172] In general, inhalation devices (e.g., DPIs) can deliver a maximum amount of dry powder or dry particles in a single inhalation. The maximum amount relates to the volume of a blister, capsule (e.g., having a volume of sizes 000, 00, 0E, 0, 1, 2, 3, and 4, 1.37 ml, 950 μl, 770 μl, 680 μl, 480 μl, 360 μl, 270 μl, and 200 μl), or other means of containing dry particles or dry powder in the inhaler. Thus, delivery of a desired or effective amount may require two or more inhalations. Preferably, each dose administered to a subject in need thereof contains an effective amount of dry particles or dry powder for inhalation and is administered using about four or less inhalations. For example, each dose of dry particles or dry powder for inhalation may be administered in one inhalation or two, three, or four inhalations. The dry particles and dry powder for inhalation are preferably administered in one breath-activated step using a breath-activated DPI. When this type of device is used, the subject's inhalation energy both disperses the inhalable dry particles and draws them into the airways.

[0173] Said inhalable dry particles or dry powders can be delivered by inhalation to the desired area in the airway as required.It is well known that particles with an aerodynamic diameter of about 1 micron to about 3 μm can be delivered to the deep lung.Particles with a larger aerodynamic diameter, for example, about 3 μm to about 5 μm, can be delivered to the middle and upper airway.

[0174] For dry powder inhalers, oral deposition is dominated by inertial impaction and is therefore characterized by the Stokes number of the aerosol (DeHaan et al. Journal of Aerosol Science, 35(3), 309-331, 2003). For comparable inhaler geometry, breathing pattern and oral geometry, the Stokes number or the oral deposition is primarily affected by the aerodynamic size of the inhaled powder. Thus, factors involved in oral deposition of powder include the size distribution of individual particles and the dispersibility of the powder. If the MMAD of individual particles is too large, e.g., greater than 5 μm, a high proportion of the powder will be deposited in the oral cavity. Similarly, poor powder dispersibility indicates that particles will exit the dry powder inhaler and enter the oral cavity as agglomerates. Agglomerated powder will behave aerodynamically similarly to individual particles of the same size as the agglomerates. Thus, even if the individual particles are small (e.g., MMAD of 5 μm or less), the size distribution of the inhaled powder may have an MMAD greater than 5 μm, resulting in increased oral deposition.

[0175] It is therefore desirable to have a powder in which the particles are small (e.g. 5 μm or less, e.g. MMAD between 1 and 5 μm) and very dispersible (e.g. ¼ bar less than 2.0, and preferably less than 1.5, or alternatively 0.5 / 4 bar). More preferably, the dry powder for inhalation has an MMAD between 1 and 4 μm or between 1 and 3 μm, and a ¼ bar less than 1.4 or less than 1.3, and more preferably less than 1.2.

[0176] The absolute geometric diameter of the particles, measured at 1 bar using a HELOS system, is not critical, provided that the bulk density of the particles is sufficient, such that the MMAD is in one of the ranges listed above, where MMAD is the square root of VMGD times bulk density (MMAD=VMGD * The bulk density is calculated by taking the square root of the bulk density (Bulk Density). Higher bulk density particles are desirable when it is desired to deliver a high unit dose of salt using a fixed volume dosing container. Higher bulk density allows more powder to be contained within the fixed volume dosing container. Preferred bulk densities are greater than 0.1 g / cc, greater than 0.25 g / cc, greater than 0.4 g / cc, greater than 0.5 g / cc, and greater than 0.6 g / cc.

[0177] The inhalable dry powders and particles of the subject technology can be used in compositions suitable for drug delivery via the respiratory system. For example, such compositions can include blends of the inhalable dry particles of the subject technology with one or more dry particles or powders, such as dry particles or powders that contain another active agent or that consist of or consist essentially of one or more pharma- ceutically acceptable excipients.

[0178] Dry powders and particles for inhalation suitable for use in the method of the subject technology can travel through the upper airways (i.e., oropharynx and pharynx) to the lower airways, which include the trachea, which then branches into bronchi and bronchioles, which then pass through the terminal bronchioles, which then divide into respiratory bronchioles, and then reach the terminal respiratory zone, alveoli, or deep lung. In one embodiment of the subject technology, the majority of the dry powder or particles for inhalation is deposited in the deep lung. In another embodiment of the subject technology, it is delivered primarily to the central airways. In another embodiment, it is delivered to the upper airways.

[0179] The inhalable dry particles or dry powders of the subject technology can be delivered by inhalation at various parts of the respiratory cycle (e.g., laminar flow during breathing). An advantage of the high dispersibility of the dry powders and dry particles of the subject technology is the ability to target deposition in the airways. For example, breath-controlled delivery of nebulized solutions is a recent development in liquid aerosol delivery (Dalby et al. in Inhalation Aerosols, edited by Hickey 2007, p. 437). In this example, nebulized droplets are released only during a specific part of the respiratory cycle. For deep lung delivery, the droplets are released at the beginning of the inhalation cycle. For mid-airway deposition, they are released later in the inhalation.

[0180] The dry powders of the subject technology also offer advantages in timing drug delivery in the respiratory cycle and targeting locations in a person's lungs: Because the dry powders for inhalation of the subject technology can be dispersed rapidly, e.g., within a fraction of a typical inhalation maneuver, the timing of powder dispersion can be controlled to deliver an aerosol at a specific time during the inhalation.

[0181] A highly dispersible powder allows the entire dose of the aerosol to be dispersed in the beginning of the inhalation. The patient's inhalation flow rate increases to the peak inhalation flow rate, but a highly dispersible powder will already begin to disperse at the beginning of the increase and can completely disperse the dose in the first part of the inhalation. Dispersing most of the aerosol within the first part of the inhalation is favorable for deep lung deposition, since the inhaled air at the beginning of the inhalation ventilates the deepest parts of the lung. Similarly, for central deposition, dispersing a high concentration of the aerosol in the air that will ventilate the central airways can be achieved by rapid deposition of the dose in the middle to end of the inhalation. This can be achieved by a number of mechanical and other means, such as a time, pressure or flow operated switch that adds the patient's inhaled air to the powder that is dispersed only after the switch condition is met.

[0182] Aerosol dosages, formulations and delivery systems may be selected for particular therapeutic applications, as described, for example, in Gonda, I. "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," Critical Reviews in Therapeutic Drug Carrier Systems, 6:273-313 (1990); and Moren, "Aerosol Dosage Forms and Formulations," in Aerosols in Medicine, Principles, Diagnosis and Therapy, Moren, et al., Eds., Esevier, Amsterdam (1985).

[0183] The appropriate interval between administrations that provides the desired therapeutic effect can be determined based on the severity of symptoms, the overall health condition of the subject and the tolerance of the subject to inhalable dry particles and dry powders and other considerations.Based on these and other considerations, clinicians can determine the appropriate interval between administrations.Generally, inhalable dry particles and dry powders are administered once, twice or three times a day as needed.

[0184] In some embodiments, the amount of NSAID delivered to the airways (e.g., lungs, respiratory tract) is from about 0.001 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.002 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.005 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.01 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.02 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.05 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.075 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.1 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.2 mg / kg body weight / dosage to about 2 mg / kg body weight / dosage, from about 0.5 mg / kg from about 2 mg / kg body weight / dose or from about 0.75 mg / kg body weight / dose to about 2 mg / kg body weight / dose.

[0185] In certain embodiments, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the administered acetylsalicylic acid reaches the subject's systemic circulation within about 60 minutes of administration, or within about 40 minutes of administration, or within about 30 minutes of administration, or within about 20 minutes of administration, or within about 15 minutes of administration.

[0186] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid and its pharmacologically active metabolic by-products to the systemic circulation at levels substantially the same or higher than those delivered by oral administration of about 30 mg of acetylsalicylic acid.

[0187] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid and its pharmacologically active metabolic by-products to the systemic circulation at levels substantially the same or higher than those delivered by oral administration of about 40 mg of acetylsalicylic acid.

[0188] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid and its pharmacologically active metabolic by-products to the systemic circulation at levels substantially the same or higher than those delivered by oral administration of about 50 mg of acetylsalicylic acid.

[0189] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid and its pharmacologically active metabolic by-products to the systemic circulation at levels substantially the same or higher than those delivered by oral administration of about 80 mg of acetylsalicylic acid.

[0190] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid and its pharmacologically active metabolic by-products to the systemic circulation at levels substantially the same or higher than those delivered by oral administration of about 162 mg of acetylsalicylic acid.

[0191] The dose of acetylsalicylic acid administered to achieve substantially the same or higher levels (or average levels in a patient population) compared to the levels delivered by oral administration of about 30 mg, about 40 mg, about 50 mg, about 80 mg or about 182 mg of acetylsalicylic acid can be determined by conventional methods. The doses, administration techniques and schedules are known in the art and are within the capabilities of a skilled physician. For example, the serum level in a subject of acetylsalicylic acid or its metabolites (or the average serum level in a subject population) can be measured by conventional pharmacokinetic or pharmacodynamic studies.

[0192] In certain embodiments, the methods and delivery devices described herein may deliver acetylsalicylic acid to the systemic circulation such that circulating plasma levels of acetylsalicylic acid are at least about 1 mcg / mL, at least about 2 mcg / mL, at least about 3 mcg / mL, at least about 4 mcg / mL, at least about 5 mcg / mL or at least about 6 mcg / mL within about 60 minutes of administration, or within about 40 minutes of administration, or within about 30 minutes of administration, or within about 20 minutes of administration, or within about 15 minutes of administration.

[0193] In certain embodiments, the methods and delivery devices described herein can deliver acetylsalicylic acid to the systemic circulation such that circulating plasma levels of salicylate are about 8 mcg / mL, about 9 mcg / mL, about 10 mcg / mL, about 11 mcg / mL, about 12 mcg / mL, about 15 mcg / mL within about 60 minutes of administration, or within about 40 minutes of administration, or within about 30 minutes of administration, or within about 20 minutes of administration, or within about 15 minutes of administration.

[0194] If necessary or indicated, the dry particles and dry powders for inhalation described herein may be administered together with one or more other therapeutic agents. The other therapeutic agents may be administered by any suitable route, for example, orally, parenterally (e.g., intravenous, intraarterial, intramuscular or subcutaneous injection), topically, by inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), rectally, vaginally, etc. The dry particles and dry powders for inhalation may be administered before, substantially simultaneously with, or after the administration of the other therapeutic agent. Preferably, the dry particles and dry powders for inhalation and the other therapeutic agent are administered to provide a substantial overlap in their pharmacological activities.

[0195] The foregoing description is provided to enable one skilled in the art to practice the various configurations described herein. While the subject technology has been specifically described with reference to various figures and configurations, it should be understood that these are for illustrative purposes only and should not be taken as limiting the scope of the subject technology.

[0196] There may be many other ways of implementing the subject technology. The various functions and components described herein may be separated from those shown without departing from the scope of the subject technology. Various modifications to these configurations will be readily apparent to those skilled in the art. The general principles defined herein may be applied to other configurations. Thus, many changes and modifications may be made to the subject technology by those skilled in the art without departing from the scope of the subject technology.

[0197] It is understood that the specific order or hierarchy of steps in the methods disclosed is an illustration of exemplary approaches. Based on design preferences, the specific order or hierarchy of steps in the methods may be rearranged. Some steps may occur simultaneously. The accompanying method claims present components of the various steps in a sample order, and are not meant to be limited to the specific order or hierarchy presented.

[0198] As used herein, "at least one" following a series of items with the term "and" or "or" separating any of the items modifies the list as a whole, and not each member (i.e., each item) of the list. The phrase "at least one" does not require the selection of at least one of each of the listed items; rather, the phrase can mean at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. By way of example, the phrase "at least one of A, B, and C" or "at least one of A, B, or C" means, respectively, only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0199] Additionally, to the extent that terms such as "include," "have," and the like are used in the detailed description or claims, such terms are intended to be inclusive in a manner similar to the term "comprise" when "comprise" is interpreted as used as a transitional term in the claims.

[0200] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

[0201] Reference to a singular component is not intended to mean "one and only one" unless otherwise specified, but rather "one or more." Masculine pronouns (e.g., he) include feminine and neuter genders (e.g., she and it), and vice versa. The term "some" means one or more. Underlined and / or italicized headings and subheadings are used for convenience only, do not limit the subject art, and are not to be referred to in connection with the interpretation of the subject art description. All structural and functional equivalents to the components of the various configurations described throughout this disclosure that are known or later become known to those skilled in the art are expressly incorporated herein by reference and are intended to be encompassed by the subject art. Furthermore, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is expressly recited in the detailed description above.

[0202] While the subject technology has been described in connection with the detailed description of the invention, it should be understood that the foregoing description is intended to be illustrative and not limiting of the scope of the subject technology. Other aspects, advantages and modifications of the subject technology are within the scope of the claims set forth below. The specification is most fully understood in light of the teachings of the references cited within the specification. The embodiments within the specification provide illustrations of embodiments of the invention and should not be construed as limiting the scope of the invention. Those skilled in the art will readily recognize that many other embodiments are encompassed by the invention. All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent that material incorporated by reference contradicts or is inconsistent with this specification, the specification will take precedence over any such material. The citation of any reference in this specification is not an admission that such reference is prior art to the present invention.

[0203] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the embodiments described below.

Claims

1. 1. A dry powder for inhalation comprising dry particles for inhalation, The dry particles for inhalation comprise acetylsalicylic acid or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient; The inhalable dry particles have a volume median geometric diameter (VMGD) of about 5.0 μm or less; A dry powder for inhalation, wherein more than 95% by weight of said dry particles is said acetylsalicylic acid or a pharma- ceutically acceptable salt thereof.

2. A drug delivery system comprising: The system comprises a dry powder for inhalation according to claim 1 .

3. 3. The drug delivery system of claim 2, wherein the acetylsalicylic acid or a pharma- ceutically acceptable salt thereof is present in a dose of less than 81 mg.

4. 4. A drug delivery system according to claim 2 or claim 3, comprising a mouthpiece, a reservoir for receiving a dose of the acetylsalicylic acid or a pharma- ceutically acceptable salt thereof, and a drive member for making the dose of the acetylsalicylic acid or a pharma- ceutically acceptable salt thereof available through the mouthpiece for inhalation by a patient.

Images