Drug delivery via the nasal cavity and lungs

Abstract

The present invention relates to a device (20) for delivering a drug (30) to a user via a nasal or pulmonary route. The device may be a pressurized metered-dose inhaler (200), an active dry powder inhaler (300 / 400), a soft mist inhaler (500), or a nebulizer (600). The device (20) includes a propellant energy source (40) for delivering the drug (30), the propellant energy source (40) being or containing an airborne gas (41), the airborne gas (41) being stored in a separate canister (45) at a pressure of at least 2 bar, adsorbed onto an adsorbent (42), and the airborne gas (41) being released from the adsorbent (42) to administer the drug (30). The device includes a gas delivery mechanism (50) having a metering chamber (52) having a larger capacity than a conventional pressurized metered-dose inhaler filled with propellant. The airborne gas (41) is released from the chamber during operation and travels along the conduit (25) to push the drug (30) out of the administration chamber (80), thereby aerosolizing it, and then leaves the device via the second conduit (27) and exits from the outlet (28) as a jet (60).

Description

[Technical Field]

[0001] This invention relates to nasal and pulmonary drug delivery. More particularly, this invention relates to novel drug delivery devices and methods for delivering drugs via nasal and oral-pulmonary pathways. This invention also relates to a power source comprising a canister of up to 50 ml, more preferably up to 35 ml, typically 10 to 22 ml, with a gas volume metering valve designed to carry 0.1 ml to 5 ml, more preferably 0.2 to 2.5 ml of propellant gas at a pressure of 2 to 10 bar. The term “drug” includes both prescription pharmaceuticals (including biologics) and other functional actives delivered to the user, encompassing both their pure forms and salts, as well as formulations. In contrast, the term “approved drug” is limited to drugs approved by regulatory authorities (including biological products), such as the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), or another national government agency. [Background technology]

[0002] The novel "Novel Platforms for Drug Delivery Application," Woodhead Publishing Series in Biomaterials, 2023, pages 568-606, https: / / www.sciencedirect.com / science / article / pii / B9780323913768000197, teaches that nasal and pulmonary drug delivery is an increasingly attractive route for the administration of many drugs for topical and systemic treatment, as well as for vaccine-mediated prophylaxis. This systemic treatment is particularly interesting for drugs with poor bioavailability because gastrointestinal transit and first-pass effects in the liver can be avoided.

[0003] As outlined in the recent review article, Frontiers in Drug Delivery, 13 April 2022, Respiratory Drug Delivery, Vol 2, 2022, Frontiers | Half a Century of Technological Advances in Pulmonary Drug Delivery: A Personal Perspective (frontiersin.org), inhalation therapy has been around for over 2000 years.

[0004] The basic lung delivery technology that has developed over the past half-century is best described as small personal portable aerosol generators. In fact, the lung respiratory market was worth $53 billion in 2021 (DataBridge Market Research).

[0005] Those are, ·Pressurised Metered Dose Inhalers (pMDI's); ·Powder Dose Inhalers (PDI's); • Soft mist inhalers (SMIs); and, Nebulizer They can be classified into four main types.

[0006] Those are, ·Powder; • Suspensions, dispersions, or emulsions; and, ·solution The drugs are delivered in this manner.

[0007] These technologies • Different operating characteristics; • Patient interface / user requirements; and • Dosage restrictions It holds.

[0008] These devices, drug forms, and technologies are shown in Figure 1 (quoted from the review article). [Overview of the project] [Problems that the invention aims to solve]

[0009] The devices (empty) and combination products (devices containing drugs) according to the present invention differ in many ways from conventional nasal and pulmonary inhalers, and Figures 2 to 6 show some prior art devices to highlight the main differences. However, these prior art devices are briefly described below.

[0010] Pressurized metered-dose inhalers (pMDIs)

[0011] A simple pressurized metered-dose inhaler of the present art is shown in Figure 2 and comprises a liquid (and gas headspace) mixed with a drug in the form of a suspension or solution as a propellant power source. A metered dose is administered upon actuation, and the device may be equipped with a mouthpiece or a nasal adapter. The aerosol is generated by the expansion of the liquid propellant.

[0012] The recognized advantages of pMDI-based inhalation systems are their portability and ease of operation.

[0013] A major patient-related issue with these devices is the need to synchronize inhalation with the actuation maneuver. pMDIs are active devices that deliver a single dose of a high-velocity jet (approximately 100 m / s at the point of origin) over several microseconds. pMDIs generate a high-velocity jet from the expansion of evaporating propellant at the actuator orifice. The speed and timing of the patient's coordination of inhalation with the device's actuation are known challenges. With pMDIs, patients need to coordinate the high-velocity spray actuation with their steady, slow inhalation. If patients inhale before or after actuation, a large portion of the medication is likely to hit the throat and be swallowed. A recent review revealed that 87% of patients with pMDIs exhibited such poor technique (J Allergy Clin Immunol Pract. 2022 Jul;10(7):1813-1824).

[0014] To overcome these problems, two approaches have been taken: spacers and breath-actuated pMDIs. Both approaches attempting to overcome these problems have their own complexities and drawbacks.

[0015] pMDI devices deliver smaller doses compared to DPIs and nebulizers, which limits the range of available therapeutic doses. It has been reported that patients dislike the cooling effect caused by rapid evaporation of propellant, namely the "Freon effect". It has been reported that when propellants were changed from CFCs to HFAs, and further new different HFAs were introduced, patients experienced changes in taste and sensation, associated these changes with inhaler malfunction, and thus reduced the frequency of use.

[0016] In addition, during use, pMDIs have the problem that insufficient liquid filling from the metering valve may occur. This metering valve relies on a constant liquid volume filling measured by gravimetry. If the device is not shaken properly and not held vertically, the amount of liquid filled into the valve will decrease, which may result in failure to administer the correct dose. For suspension formulations, to ensure that the suspension is resuspended in a uniform state and that the required dose is delivered, the user must shake the canister sufficiently and reproducibly.

[0017] HFA propellants, which exist as liquids in a compressed state, can act as solvents within the canister, and a major concern for all such materials is the potential for extraction and elution of chemicals from polymeric valve materials. Since the propellant contacts all internal canister and valve components, and also contacts the drug substance and excipients, it is necessary to prove that all of these do not cause adhesion, generation of contaminants and decomposition products, and expansion of gaskets.

[0018] All of these problems are irrelevant or less relevant to the present invention, in which the drug is metered outside the canister and the propellant is gaseous rather than liquid.

[0019] A major driving force for technology in this field has been legislation and regulation. In the mid-1990s, chlorofluorocarbon (CFC) propellants were banned on the grounds of their potential to deplete the ozone layer (Federal Register, 1994). The recognition that pMDIs, which were and still remain the mainstay of inhalation therapy, might no longer be available prompted enormous efforts to search for alternatives, which is reflected in the patent applications filed during that period. Between 1990 and 2010, nearly 1,000 patents describing inhalation technology were filed, compared with fewer than 100 in the preceding 20 years (Stein and Theil, J Aerosol Med Pulm Drug Delivery 2017 Feb;30(1):20-41.doi:10.1089 / jamp.2016.1297). However, initiatives for new technologies ended prematurely; alternative propellants were developed through enormous effort and investment, and pMDIs have remained the mainstream of inhalation therapy to this day.

[0020] However, Hydro Fluorocarbon Alkanes (HFAs), which are alternatives to CFCs, have a global warming potential (GWP) up to 3,350 times that of carbon dioxide (CO₂), and continue to be a major causative substance of global warming (On Drug Delivery, April 24 th 2023, Issue 145, page 13). It is known that a single pMDI releases an amount of CO₂ equivalent to 25 kg of CO₂ from one canister.

[0021] In fact, England's National Health Service (NHS) has identified metered-dose inhalers as accounting for 3% of its total emissions and 13% of its primary care emissions, and pharmaceutical company GSK estimates that metered-dose inhalers account for 45% of its carbon emissions (see, for example, The Climate is Changing for Metered-Dose Inhalers and Action is Needed, J. Pritchard, Drug Design, Development and Therapy 2020:14 3043-3055).

[0022] Therefore, there remains a clear and urgent need for more sustainable pMDI technologies.

[0023] In light of the global warming concerns associated with HFA propellants, the industry has developed alternative HFA propellants. For example, HFA152a is an alternative HFA propellant with a GWP 138 times that of CO2. However, a problem with such alternative propellants is that re-evaluation is extremely time-consuming and expensive. Such re-evaluation must be carried out for each of the wide range of medicinal compounds that need to be re-prescribed. Therefore, this overall re-prescription approach presents significant challenges in terms of toxicity testing, stability, extracts and elutes, propellant flammability, and how they cause changes in drug deposition in the lungs (On Drug Delivery, April 24). th 2923, Issue 145, pages 13-17).

[0024] As a category, there are multiple issues with both currently used and two newly proposed HFA propellants, namely HFA-152a and HFA-1234ze(E), and they have been reported to have pharmacological and toxic effects (Sellers, Allergy Asthma Clin Immunol (2017) 13:30, DOI 10.1186 / s13223-017-0202-0). Current propellants (HFAs) for pressurized metered-dose inhalers (pMDIs) are not pharmacologically inactive, and the compound family has smooth muscle relaxant and anesthetic effects. The new propellant HFA152a has been linked to cases of death resulting from the intentional inhalation of this gas from consumer aerosols (The Climate is Changing for Metered-Dose Inhalers and Action is Needed, J. Pritchard, Drug Design, Development and Therapy 2020:14 3043-3055).

[0025] The new HFAs are very different in their physicochemical properties; they are more flammable and chemically very stable. Therefore, they are polyfluoroalkyl substances (PFAS), "forever" chemicals, and they are also associated with significant environmental impact issues and, when decomposed by heat, produce hazardous products, such as hydrogen fluoride (HF).

[0026] The Organization for Economic Cooperation and Development (OECD) defines PFAS as medical-grade fluorinated gases that can be used as propellants. Germany, the Netherlands, Denmark, Norway, and Sweden have proposed regulations on PFAS in Europe, and these proposed regulations are likely to have stricter deadlines for banning the use of PFAS (A. Lee, “Developing the Next Generation of Inhalers” Technology Networks July 2023).

[0027] pMDIs are cheaper to manufacture than current DPIs, and therefore there are concerns about the cost burden when switching patients to DPIs. However, due to the reduction in usage caused by regulations on medical HFA propellants, their cost will increase by at least six times, making them more expensive (J. Pritchard, Drug Design, Development and Therapy 2020:14 3043-3055; Wilkinson and Woodcock, Br J Clin Pharmacol. 2022;88:3016-3022).

[0028] In contrast, the applicant has a proprietary power source containing an airborne gas adsorbed onto an adsorbent in a canister. This airborne propellant gas can aerosolize a unit dose of powder or liquid contained separately from the power source. The airborne propellant gas has zero GWP. Since the airborne propellant is simply used to entrain the drug into the airborne gas stream, there are no prior art problems associated with reformulation into alternative HFA propellants.

[0029] Dry Powder Inhalers (DPIs)

[0030] Dry powder inhalers come in multiple forms.

[0031] Passive devices (all currently available DPI devices) rely on the patient's inhalation effort to inhale, disperse, and deliver powder into the airway.

[0032] Active devices, in addition to patient inhalation, use mechanical or electrical technology to aspirate, disperse, and deliver powder into the airways.

[0033] The devices are further classified into "carrier"-based systems (which allow for delivery in single or multiple doses from a reservoir) and "agglomerate"-based systems.

[0034] Single-dose devices are capsule-based formulations, such as Aerolizer. 登録商標 (Novartis) and Handihaler 登録商標 (Boehringer Ingelheim), and also include multi-dose devices. These multi-dose devices include devices with multiple unit doses, such as Diskhaler 登録商標 and Diskus 登録商標 (Glaxo Smith Kline) and reservoir-type devices, such as Turbohaler (Astra Zeneca) and Pulvinal 登録商標 (Cheisi), includes.

[0035] Naturally, the design varies depending on the type, but the common basic features are as follows: • An inlet where air is drawn in; • A measuring-type dispensing chamber in which powdered medication is stored before operation; and, • The outlet through which the dosage is supplied to the user.

[0036] International Publication WO2024033662 discusses several challenges associated with current dry powder inhalers. Passive devices (all current devices) utilize a portion of the available energy from the patient's inhalation to act on the powder formulation, breaking down and resuspending the powdered drug, further de-aggregating the particles, and generating a fine, inhalable aerosol.

[0037] Many major commercially available DPIs achieve only 20-30% fine particle fraction (FPF) with aerodynamic diameters less than 5 μm. The remaining drug aggregates or adheres to larger carrier particles. In fact, International Publication No. WO2024033662 states that "A huge challenge for all current DPIs is that, because they are solely reliant upon harnessing energy from the patient's inspiratory maneuver, it is very difficult to achieve consistent drug delivery when the available energy varies considerably from patient to patient." He states that.

[0038] Active DPIs are still under development and have been developed before, but none are commercially available at present. The appeal of active DPIs lies in their ability to overcome significant user variability by having an internal energy source to generate inhalable aerosols; they are user-independent, and more specifically, independent of the user's inhalation method.

[0039] In fact, International Publication No. WO2024033662 is, "There are probably no active DPIs available because they are so complicated to design, optimize, and produce. The ideal DPI system, comprising a deagglomeration engine or apparatus, is a system that consistently produces a high fine particle fraction, regardless of the user's inhalation method, and is simple and cost-effective to manufacture." He states that.

[0040] The power source used by the applicant addresses these challenges and eliminates the complexity and cost requirements that have limited the successful commercialization of devices, such as the device disclosed by Nektar in U.S. Patent No. 6,257,233.

[0041] One such conventional design is shown in Figure 3, which illustrates a passive device for multiple doses. As previously mentioned, a major problem with such conventional passive dry powder inhalers is that the user's inspiratory flow rate varies greatly from user to user. This results in a significant decrease in dose reproducibility. Furthermore, in elderly and pediatric patients, such users typically cannot exert sufficient inspiratory effort and coordinated action to facilitate inhalation and deagglutination of the powder in order to deliver the intended aerosolized dose and form. In fact, this point is recognized in clinical practice guidelines, and in certain patient groups, only pMDIs are prescribed.

[0042] In the case of active devices • Auxiliary energy source It is also equipped with.

[0043] Most active devices rely on air pressure generated by a manually operated pump, which is primed with compressed air immediately before inhalation and released when a sensor built into the device detects the patient's airflow. Alternatively, the air pressure source may also be activated simultaneously with the user's inhalation.

[0044] One such conventional design is shown in Figure 4. The design shown is a single-dose device. This design uses a manual piston pump to supply the inhalation airflow. The problem with such a device is that considerable force is required to pressurize a small amount of air, and patients may not have sufficient dexterity or muscle strength to prime the pump. Also, because the pump mechanism is complex in order to minimize the effort required, the physical size of the device is large and the manufacturing cost is high.

[0045] In contrast, the present applicant has a power source that uses gas adsorbed on an adsorbent within a canister. This canister provides a substantially constant pressure source and flow rate of inhaled gas over a predetermined period of use of the canister. For this purpose, it can be used to provide a simple active DPI without the complexity and reproducibility problems of the prior art. The size and complexity of the device can be minimized, and the drug can be delivered to the lungs with minimal operation and inhalation effort by the user.

[0046] The gas is contained within the canister at a pressure of at least 2 bar and adsorbed onto an adsorbent, which is then released from the adsorbent to release the drug. A filter or frit ensures that the adsorbent is retained within the canister and not discharged with the gas.

[0047] Soft mist inhalers (SMIs)

[0048] The conventional soft mist inhaler shown in Figure 5 aerosolizes the drug solution by pushing the drug through a "uniblock" with an extremely small orifice. A compressed spring provides the force. The administration period is longer than 0.5 seconds for pMDIs, typically 1.2 seconds. One of the main problems with such devices is that they can only deliver small amounts of liquid, e.g., typically 15 μl (compared to, for example, 25-100 μl for pMDIs and over 10 mg for DPIs). Often, it is desirable to deliver much more drug than can be dissolved in such a small amount of liquid.

[0049] In contrast, the present applicant has a power source that uses gas adsorbed on an adsorbent within the canister. This allows the drug to be delivered from the capsule in powder form, which may contain at least an order of magnitude more of the drug than is possible with SMI (e.g., up to 50 mg of powder).

[0050] Each of the three types of devices described above can be used in combination with a valved holding chamber (VHC) or a spacer device that holds the aerosol until inhalation.

[0051] Nebulizer

[0052] The conventional nebulizer shown in Figure 6 uses a compressor to continuously aerosolize a drug-containing liquid solution or suspension in a reservoir for delivery to the user. Handheld nebulizers, which use a vibrating mesh to aerosolize liquids, are also used. Such devices are typically battery- or electrically powered and require expensive control electronics. Nebulizers do not deliver the drug in a single breath, but require several minutes to deliver the required dose, posing significant challenges to patient respiratory regulation and adherence to medication.

[0053] In contrast, the present applicant has a non-electric and portable power source, which is a gas adsorbed on an adsorbent in a canister, thereby enabling desired aerosolization by, for example, pulsed injection.

[0054] Prior art identified but deemed irrelevant includes U.S. Patent Application Publication US2014 / 0048566 and U.S. Patent Application Publication US2006 / 0049215, both of which incorporate a secondary container filled with activated carbon into a liquid-filled canister, and automatically repressurize the headspace above the liquid. [Means for solving the problem]

[0055] A device for delivering a drug to a user via a nasal or pulmonary route is provided, the device comprising a propellant energy source for delivering the drug, the propellant energy source being or comprising an aerial gas, the aerial gas being contained in a separate canister at a pressure of at least 2 bar, adsorbed onto an adsorbent, the aerial gas being released from the adsorbent for administering the drug, the device not comprising a bag-on valve.

[0056] In one embodiment, the propellant energy source, separate from the drug, is located upstream of the drug in the device, so that when the canister is activated, a unit dose of the drug is aerosolized from the device in a controlled manner.

[0057] Bag-on-valve technology and improved versions thereof are disclosed in International Publication No. WO2020021473, which is incorporated herein by reference.

[0058] Preferably, the pressure is 2 to 16 bar at 25°C, more preferably 2 to 10 bar, and most preferably 4 to 8 bar.

[0059] Preferably, the adsorbent is activated carbon or functionalized activated carbon.

[0060] The activated carbon can be prepared from a variety of carbon sources, including, in particular, natural carbon sources (e.g., peat, wood, coal, nut shells (e.g., coconut), petroleum coke, bone, bamboo shoots, drupe seeds and various other seeds), and synthetic sources (e.g., polyacrylonitrile or phenol-formaldehyde resin). The carbon is activated to develop a complex pore network and surface area sufficient for adsorption. These pores have a variety of sizes, ranging from microporous to sub-microporous dimensions of molecular-sized entities. Larger transport pores provide access to smaller pores where the majority of adsorption of propellants, such as gaseous substances, takes place. Carbon activation is carried out by gaseous activation at elevated temperatures using vapor, carbon dioxide, or other gases, or by chemical activation using, for example, zinc chloride or phosphoric acid. Other activation processes result in extensive physical adsorption properties and high volume adsorption porosity. It can be used to achieve a pore structure and surface area that provides adsorbing porosity.

[0061] In embodiments of the present invention, the activated carbon is prepared to contain a relatively high proportion of micropores and have a low adsorption enthalpy. This enables substantially maximum gas delivery. The size of the micropores is in the range of about 0.5 nm to about 2.5 nm. In one embodiment, the micropores are about 1.0 to about 2.0 nm. The adsorption enthalpy is less than about 25 kJ (per mole of adsorbate). In other words, activated carbon with high capacity uptake for compressed gas and low retention (or heel) at discharge provides maximum gas volume delivery. For high uptake, the activated carbon has a high concentration of micropores. For low retention, carbons with low adsorption enthalpy (for a particular gas) are selected. This is because there is a relatively good correlation between these two variables. Unlike conventional dispensing systems that rely on adsorbed permanent gases, the application of activated carbon in embodiments of the present invention makes it possible to condense or immobilize propellant / gas, resulting in increased gas storage and delivery capacity. Typically, gas storage is achieved by increasing the pressure in a container of a certain volume, and the amount of gas in the container basically follows the law of ideal gases under non-extreme conditions. Embodiments of the present invention can deliver more gas physically than non-carbon-filled containers, despite the volume reduction due to the carbon skeleton.

[0062] The activated carbon can be in various forms, most commonly in the form of powder, granules, or pellets.

[0063] Preferably, the gas in the atmosphere is air, oxygen, nitrogen, or carbon dioxide.

[0064] More preferably, the gas in the atmosphere is carbon dioxide, or air or oxygen rich in carbon dioxide. By using carbon dioxide, the volume of gas in the container increases, and therefore greater energy is provided.

[0065] Preferably, the device is a combination product comprising the device and a regulatory-approved drug, as is recognized in the pharmaceutical industry.

[0066] Combination products are defined by the FDA in 21 CFR 3.2(e) as follows: • Two or more regulated components (i.e., including drugs / devices, biologics / devices, or drugs / devices / biologics), which are combined or mixed by physical, chemical, or other means and manufactured as a single entity; • Two or more separate products packaged in a single package or as a unit, which include drug and device products, device and biological product products, or biological product and drug products; • Individually packaged drugs, devices, or biologics products intended for use only with specific approved drugs, devices, or biologics products, in accordance with the investigational plan or proposed labelling, where both are necessary to achieve the intended use, indication, or effect, and where the labeling of the approved product needs to be changed in accordance with the approval of the proposed product (for example, to reflect a significant change in intended use, dosage form, concentration (strength), route of administration, or dose); or • In accordance with the proposed labeling, separately packaged drugs, devices, or biological products are intended for use only with another individual identified drug, device, or biological product, where both are necessary to achieve the intended use, indication, or effect. The above includes both pre-filled drug / delivery systems and pre-filled biological product delivery / device systems (including metered-dose inhalers, dry powder inhalers, and nasal sprays).

[0067] Preferably, the device includes a gas delivery mechanism for releasing a sufficient volume of gas propellant at a speed that delivers / aerosolizes a unit dose of the drug.

[0068] One such gas delivery mechanism includes a metering valve, a gas metering chamber, a valve stem, and an actuator.

[0069] The measuring chamber preferably has a volumetric capacity of at least 0.1 ml, preferably 0.1 to 5 ml, which is an order of magnitude larger than the capacity required when measuring liquid propellant from a canister of up to 50 ml, and more particularly 10 to 22 ml.

[0070] The gas delivery mechanism further includes a gas inlet orifice and a gas outlet orifice, thereby facilitating the filling and emptying of the gas metering chamber.

[0071] Preferably, the device also includes a drug dosing mechanism for releasing a unit dose of a drug from the chamber, and the drug is delivered from the drug dosing mechanism.

[0072] One such drug administration mechanism comprises a chamber upstream of a gas propellant that holds a unit dose of the drug, and a piercing mechanism for releasing a pre-measured unit dose of powder, for example, from a capsule or blister pack.

[0073] Alternatively, the drug mechanism delivers a unit dose of powder or liquid from a bulk chamber, which is then mechanically extracted from the bulk chamber or reservoir as a metered dose for forward delivery by a gas propellant.

[0074] The drug in question is, a) Dry powder; b) A multiphase dispersion of a solid in a liquid or a liquid in a liquid; or, c) Monophase solution It is one of the following:

[0075] In the first embodiment, the device is a pressurized metered-dose inhaler driven by the propellant energy source.

[0076] The inhaler may be equipped with either a mouthpiece adapter or a nasal adapter, depending on whether it is intended to deliver the drug via the pulmonary or nasal route.

[0077] In the second embodiment, the drug is a) Dry powder and, The device is an activated dry powder inhaler driven by the propellant energy source.

[0078] In both the first and second embodiments, the drug may be supplied in a bulk chamber or in sealed unit dose form, such as a blister pack or capsule, in which case the device comprises a drug release mechanism for releasing the drug, such as a puncture mechanism in the case of a capsule or blister pack, or a carousel or other mechanism for transferring a unit dose from the bulk chamber to a unit dose chamber.

[0079] The device of the present invention can be used to deliver a wide range of drugs due to the advantages provided by the power source and the fact that it is not limited by the liquid nature of the propellant or the passive nature of the metered-dose inhaler (see Figure 1).

[0080] According to a particular preferred embodiment, the drug is delivered to treat respiratory diseases.

[0081] The drug may be delivered for local / topical or systemic treatment.

[0082] It is particularly effective for treating respiratory diseases, which may be selected from a group consisting of asthma, chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), or lung cancer (Inhaled drug delivery for the targeted treatment of asthma, Advanced Drug Delivery Reviews 198 (2023) 114858 and Pharmaceutical Technology, 26 August 2024 - (MSD snags European approval for pulmonary arterial hypertension therapy)).

[0083] According to several embodiments, the dried powder formulation may include a pharmaceutical product delivered to a subject to treat infections in the lungs of the subject, including bacterial infections, viral infections such as SARS-CoV-2 (COVID-19), influenza, RSV, and fungal infections.

[0084] Known antiinfective agents suitable for delivery include antibiotics, such as tobramycin; antiviral agents, such as remdesivir; and antifungal agents, such as voriconazole.

[0085] According to some embodiments, the agent may include a drug that is delivered directly to the throat and / or esophagus of the target.

[0086] According to several embodiments, the agent may include a drug that is delivered directly into the target nasal cavity.

[0087] Nasal delivery can be performed to any nasal cavity region, including the paranasal sinuses, but more specifically to one of the following two main target regions.

[0088] The primary target region is the lower part of the nasal airways, encompassing the anterior portions of the inferior and middle turbinates. This region, like all nasal mucosal regions posterior to the nasal vestibule, is richly vascularized. It is a region commonly used for both topical and systemic drug delivery (Kublik, H., & Vidgren, MT (1998). Nasal delivery systems and their effect on deposition and absorption. Advanced Drug Delivery Reviews, 29, 157-177). Drugs from the latter systemic delivery are rapidly absorbed into the bloodstream from this region. Systemic and topical therapies for chronic rhinosinusitis (CRS) include antihistamines and corticosteroids (Ehrick, JD, Shah, SA, Shaw, C., Kulkarni, VS, Coowanitwong, I., De, S., & Suman, JD (2013). Considerations for the development of nasal dosage forms. Sterile Product Development: Formulation, Process, Quality and Regulatory Considerations, (pp. 99-144)). This nasal airway region is typically targeted by aqueous nasal spray pumps.

[0089] The second target region is the olfactory region. Previous research has suggested that nasal drug delivery may allow for bypassing the blood-brain barrier (BBB), thereby enabling direct delivery of drugs to the central nervous system (Maaz, A., & De Bank, PA (2021). In Vitro Evaluation of Nasal Aerosol Depositions: An Insight for Direct Nose to Brain Drug Delivery. Pharmaceutics, 13, 1079). Two cranial nerves, the trigeminal nerve and the olfactory nerve, pass through the nasal cavity. The latter, the olfactory nerve, is attracting attention primarily for the development of intranasal drugs targeting drug delivery from the nasal cavity to the brain. Consequently, the olfactory epithelium in the posterior superior nasal cavity proved to be a target for intranasal therapeutics that bypass the blood-brain barrier (BBB) ​​(Rigaut, C., Deruyver, L., Goole, J., Haut, B., & Lambert, P. (2022). Instillation of a dry powder in nasal casts: Parameters influencing the olfactory deposition with uni- and bi-directional devices. Frontiers in Medical Technology, 4).

[0090] According to several embodiments, the drug or combination of drugs may be selected from the group consisting of the following: i. Long-acting muscarinic antagonists (LAMA), ii. Long-acting beta agonists (LABAs), iii. Short-acting beta-2 agonists (SABAs), and iv. Corticosteroids. The example is, i) Long-acting muscarinic antagonists (LAMAs) such as fluticasone, budesonide, mometasone, ciclesonide, beclomethasone or other corticosteroids, umeclidinium bromide, thiotopium, ipratropium and glycopyrronium, ii) Albuterol, salbutamol, or other short-acting β-agonists (SABAs), iii) Salmeterol, formoterol, indacaterol, vilanterol, or other long-acting β-agonists (LABAs); iv) Mucolytic agents, and, v) Phosphodiesterase-4 (PDE-4) inhibitors, such as tanimilast, siromilast, roflumilast, tetomimilast, ogremilast, apremilast, and picramiralast Includes.

[0091] Other drugs of particular interest for delivery using the device of the present invention include vaccines (both protein-based and RNA-based vaccines).

[0092] The drug is formulated based on the target.

[0093] For a formulation to reach the deep lungs or bloodstream via inhalation, the active ingredient in the formulation must be in the form of very fine particles, such as particles with a mass median aerodynamic diameter (MMAD) of less than 10 μm. It is well known that particles with an MMAD greater than 10 μm are likely to collide with the throat wall and generally do not reach the lungs. Particles with an MMAD in the range of 5-2 μm are generally deposited in the respiratory bronchioles, while particles with an MMAD in the range of 3-0.05 μm are more likely to be deposited in the alveoli and absorbed into the bloodstream.

[0094] Preferably, for delivery to the lower respiratory tract or deep lungs, the MMAD of the active particles is 10 μm or less, preferably 5 μm or less, more preferably 3 μm or less, and may be less than 2 μm, less than 1.5 μm, or less than 1 μm. In particular, for delivery to the deep lungs or the whole body, the size of the active particles may be 0.1 to 3 μm or 0.1 to 2 μm.

[0095] Ideally, at least 90% of the weight of the active particles in the dry powder formulation should have an aerodynamic diameter of 10 μm or less, preferably 5 μm or less, more preferably 3 μm or less, 2.5 μm or less, 2.0 μm or less, 1.5 μm or less, or 1.0 μm or less. Effective delivery also depends on patient education. Patients may be instructed to perform slow, long inhalations, including holding their breath for 3 seconds or more, to minimize (smaller) particles in their exhaled breath.

[0096] Particulate matter, i.e., particulate matter with an MMAD of less than 10 μm, tends to be highly aggregated, resulting in a stronger tendency for particles to aggregate. In inhalers, the aggregation of particulate matter and its adhesion to the walls of the inhaler are problematic, resulting in particulate matter being discharged from the inhaler as large, stable aggregates, remaining attached to the inside of the inhaler, or even clogging or blocking the inhaler.

[0097] Poor dose reproducibility results from the varying degree of stable particle aggregate formation between each inhaler use and between different inhalers and particle batches. Furthermore, the formation of large, stable aggregates means that the MMAD of the active particles is too large to reach the necessary areas in the lungs.

[0098] To improve this situation and provide desirable, consistent FPF and FPD, dry powder formulations often contain additive materials. These additive materials are intended to control the aggregation of particles in the dry powder formulation and, through interaction with the gas jet of the present invention as described herein, optimize the deaggregation of active particles back into individual microparticles during operation.

[0099] Preferably, the additive is an anti-adherent material, which tends to reduce the cohesive forces between particles and also minimize the adhesion of fine particles to the inner surface of the inhaler device. The additive is often referred to as a force control agent (FCA), and they typically result in better dose reproducibility and a higher particulate fraction. Known additives are usually composed of physiologically acceptable materials.

[0100] Preferred additives for use in dry powder formulations include amino acids, peptides, polypeptides having molecular weights of 0.25 to 1000 kDa, and their derivatives. Preferably, the FCA is substantially composed of amino acids, more preferably leucine, and advantageously L-leucine. D- and DL-forms may also be used. The FCA may contain or consist of metal stearates, such as magnesium stearate. In some embodiments, multiple different FCAs may be used.

[0101] Dry powder formulations often contain coarse carrier particulate additives mixed with particulate active material. In some formulations, a fine-sized fraction is also included because it has been shown to enhance the aerosolization efficiency of the drug. In such compositions, the fine active particles tend to adhere to the surfaces of the coarse and fine carrier particles rather than to each other in the inhaler; however, the interaction between the operation of the spraying device and the gas ejection causes the particles to separate and disperse, becoming individual particles that are inhaled into the respiratory system.

[0102] Incorporating carrier particles is also very appealing when the amount of activator is very small. Precisely and reproducibly administering very small amounts of fine powder is extremely difficult, and when the powder is mainly composed of activator particles, even slight variations in dose mean large variations in the amount of activator. Therefore, adding diluents in the form of larger additive particles and aggregates improves the reproducibility and precision of administration.

[0103] The carrier particles may contain or be composed of any acceptable additive material or combination of materials, preferably one or more of which are inert and physiologically acceptable. Advantageously, the carrier particles are polyols. In particular, the carrier particles may be particles of crystalline sugars, such as mannitol, dextrose, or lactose. Preferably, the carrier particles are lactose monohydrate.

[0104] Several formulations suitable for use in the devices of the present invention are already known, and these formulations are described, for example, in International Publication No. WO2001 / 78696, International Publication No. WO2006 / 056812, and International Publication No. WO2008053253.

[0105] In a third embodiment, the device is a soft mist inhaler powered by the propellant energy source.

[0106] In a fourth embodiment, the device is a nebulizer driven by the propellant energy source.

[0107] Any of the devices in the first to third embodiments may further include a valved holding chamber (VHC) or a spacer.

[0108] The device of the first to third embodiments may also require one or more metering devices for measuring the propellant energy source and / or the drug.

[0109] This invention is based on the fact that gas can be absorbed onto an adsorbent, such as activated carbon, under pressure, and that an available power source is generated as the volume of the stored gas increases.

[0110] While all gases in the air can be adsorbed, the high compressibility of carbon dioxide (for example, approximately 10 times when adsorbed on activated carbon at 10 bar) makes its use particularly attractive.

[0111] For example, 25cm 3 A canister filled with activated carbon and then filled with carbon dioxide, reaching a pressure of approximately 10 bar g, adsorbs approximately 2.3 g of carbon dioxide (about 1.3 liters of gas). Filling a carbon-containing canister with carbon dioxide can be achieved either by using compressed gas (or by adding a calculated weight of solid carbon dioxide to achieve the required pressure). The filled container released a total gaseous volume of 1.05 liters before the container pressure reached atmospheric pressure. This is in comparison to the release of only 0.13 liters of gas when a non-carbon container of the same size was filled with 10 bar g of carbon dioxide.

[0112] However, depending on the application, other airborne gases, such as oxygen and nitrogen (approximately three times the amount when adsorbed on activated carbon at 10 bar), may be used, or airborne gases rich in carbon dioxide may be used. In this regard, by filling the canister with more airborne gas (by adsorption), an energy source can be created that can be used in new designs of inhalers and nebulizers, as shown in the detailed explanation with reference to pMDI (Figures 7A, 7C, and 7D).

[0113] This technology is particularly well-suited to what is known in the pharmaceutical industry as a "combination product," that is, a combination of a device and a drug (including biological products) (typically in FDA-approved forms).

[0114] The term "drug" is defined as a pharmaceutically active component or other medically functional ingredient (e.g., saline solution or vaccine).

[0115] The combined product further includes a mechanism for releasing a sufficient volume of propellant at a rate that delivers / aerosolizes a unit dose of the drug.

[0116] The combination product may also include a drug release mechanism for releasing a unit dose of the formulated drug into a dose metering chamber from which the drug is released.

[0117] The key feature of each device type is the use of airborne gas adsorbed onto the adsorbent inside the canister as a power source.

[0118] By using such a power source, 〇Compact design; Ease of use by patients; A simpler and lower-cost design; ○Improvement of discharge stability; and, 〇 Ability to deliver high doses that could not be achieved using conventional devices. The advantages of this can be achieved.

[0119] A further aspect of the present invention is provided, a method for delivering a drug to a user via a nasal or pulmonary route, the method comprising delivering the drug by administering it from a device using a propellant energy source, the propellant energy source being or containing an airborne gas stored at a pressure of at least 2 bar in a canister separate from the drug, adsorbed onto an adsorbent, the airborne gas being released from the adsorbent for administration of the drug, and the device not having a bag-on valve.

[0120] A propellant energy source is provided, comprising a 10-50 ml canister filled with an airborne gas at a pressure of at least 2 bar, wherein the airborne gas is adsorbed onto an adsorbent, the airborne gas is released from the adsorbent for drug administration, and the canister comprises a gas delivery mechanism having a measuring chamber with a capacity of 0.2-5 ml.

[0121] Preferably, the delivery mechanism further comprises a metering valve, a valve stem, and an actuator.

[0122] Preferably, the delivery mechanism further includes a gas inlet orifice and a gas outlet orifice, which facilitates filling and emptying the gas metering chamber.

[0123] As shown in Figures 2 and 7A to 7D, the valve is typically actuated by the interaction of a canister and an actuator via a valve stem. The gas flow rate can be controlled by known means, such as the size of the orifice and conduit, and the use of reducers, thereby changing the flow rate from the chamber.

[0124] Embodiments of the present invention are further described below with reference to the accompanying drawings, which are shown below. [Brief explanation of the drawing]

[0125] [Figure 1] Figure 1 is a schematic diagram of a conventional inhaler, the drugs typically used, the limitations of the dose range, and the dosage forms (powder, suspension, solution). [Figure 2] Figure 2 is a schematic diagram of a conventional pressurized metered-dose inhaler, its metering valve, and an adapter for delivery to the nasal cavity or lungs. [Figure 3] Figure 3 is a schematic diagram of a conventional passive powder inhaler device equipped with a reservoir that delivers multiple doses via a metering mechanism. [Figure 4] Figure 4 is a schematic diagram of a conventional active powder inhaler device, which includes a pump and a mechanism for puncturing blister packs. [Figure 5] Figure 5 is a schematic diagram of a conventional soft mist inhaler device and its "uniblock" component. [Figure 6] Figure 6 is a schematic diagram of a conventional nebulizer. [Figure 7A] Figure 7A is a schematic diagram of an exemplary pressurized metered-dose inhaler according to the present invention. [Figure 7B] Figure 7B is a schematic diagram of a pMDI showing a typical metering mechanism (equipped with a metering valve, metering chamber, actuator valve stem, and actuator outlet orifice). [Figure 7C] Figure 7C is a schematic diagram of one embodiment of the weighing mechanism of the present invention, showing an enlarged weighing chamber in a closed / stationary position. [Figure 7D] Figure 7D shows the weighing mechanism of Figure 7C in the open / operating position. [Figure 8A] Figure 8A shows the equilibrium adsorption isotherms for oxygen, nitrogen, and carbon dioxide for various adsorbents, including granular activated carbon (and its functionalized variants). [Figure 8B] Figure 8B shows the equilibrium adsorption isotherms for oxygen, nitrogen, and carbon dioxide for various adsorbents, including granular activated carbon (and its functionalized variants). [Figure 8C] Figure 8C shows the equilibrium adsorption isotherms for oxygen, nitrogen, and carbon dioxide for various adsorbents, including granular activated carbon (and its functionalized variants). [Figure 9] Figure 9 is a graph showing the difference in gas pressure per unit gas mass between a canister filled only with carbon dioxide and a canister in which carbon dioxide is adsorbed onto activated carbon. [Figure 10] Figure 10 shows a powder dispensing test rig used to test powder delivery. [Figure 11] Figure 11 shows the capsule filling, perforation, and powder dispensing arrangement used in the test rig. [Figure 12]Figure 12 is a graph showing the capsule emptying performance (emitted dose) when a single 200ms air injection is performed through the test apparatus. [Figure 13] Figure 13 is a photograph illustrating the effective aerosolization of an exemplary powder for nasal delivery. [Modes for carrying out the invention]

[0126] An example combination product (10) or device (20) is shown in Figure 7A.

[0127] The figure shows a pressurized metered-dose inhaler (200), which illustrates the principle of utilizing a propellant energy source (40) to deliver the drug (30), the propellant energy source (40) being or containing an airborne gas (41), the airborne gas (41) being stored in a canister (45) at a pressure of at least 2 bar, adsorbed onto an adsorbent (42), the airborne gas (41) being released from the adsorbent (42) to dispense the drug (30), and the device (20) does not have a bag-on valve. If the adsorbent (42) is particulate, a filter or frit (not shown) may be used to ensure that any particulate matter generated by the adsorbent is not discharged from the canister with the gas flow.

[0128] The canister (45) is housed at the proximal (21) end of the device (20), the proximal (21) end being separated from the distal (22) end, which is the end of the device (20) from which the aerosol jet (60) is discharged when the device is in operation.

[0129] The device (20) comprises a canister retaining wall (23) and an end face (24) through which the valve stem (43) of the canister (45) passes. When the canister is operating, pushing the bottom (46) of the canister in the direction of the arrow releases gas from the canister and dispenses a unit dose (U) of the formulated drug (30).

[0130] The gas can be discharged in a “metered” fashion at a volume (V) of, for example, 0.1–5 ml, more particularly 0.2–2.5 ml, at a pressure (P) of, for example, 2–10 bar, and it has been demonstrated that it can effectively aerosolize high doses (up to 50 mg) of exemplary powder (Example 2) (Example 1).

[0131] In Figure 7A, the gas release mechanism (50) comprises a chamber (52) that is operationally in communication with the canister (45) and the device (20) (see Figure 7B as applicable to the claimed invention), and when the device is operated (by pushing the canister, the valve stem is pushed down and the valve opens - compare, for example, with Figures 7C and 7D), it releases a known amount of gas at a predetermined pressure, and the airborne gas (21) is desorbed from the adsorbent (42), so that the chamber (52) is filled with the airborne gas (21). Accordingly, when the metering valve (51) is activated, a metered amount of airborne gas (41) is released and directed from the valve stem (53) along the first conduit (25) to a drug administration chamber (80) holding a unit (U) dose of drug (30) in the illustrated example, the drug (30) is picked up by the administration chamber (80) as the gas passes from upstream of the drug (30) through the administration chamber (80), and the drug is carried through the second conduit (27) to the outlet orifice (28), where the drug is discharged from the device as a jet (60).

[0132] In this embodiment, the drug release mechanism (70) releases the drug (30) from the capsule by means of the piercing mechanism (72), and when the released drug (30) passes from the first conduit (25) through the administration chamber (80) and is discharged via the second conduit (27) and the exit orifice (28), the drug is aerosolized by the gas.

[0133] Although FIG. 7A shows a single unit dose, the drug release mechanism (70) can be distributed in multiple administrations by using a carousel as disclosed, for example, in International Publication No. WO2001 / 17595 (ML Labs), or alternatively by using the method described in the patient instructions for Relenza Rotadisc (Diskhaler available at https: / / www.medicines.org.uk / emc / files / pil.3809.pdf), or Clickhaler 登録商標 it will be appreciated that it can be a chamber refilled from a hopper, such as for dry powder inhalation (as shown as a detailed view of the metering cone of a Clickhaler in “Focussed in vitro proof of principle evaluation of a new chemical entity for asthma”, International Journal of Pharmaceutics 239 (2002) 149-156, FIG. 1).

[0134] It will also be appreciated that the drug to be delivered is not in powder form, but can be delivered as a liquid by filling the administration chamber (80) with a unit dose of liquid, for example, Respimat 登録商標 device (Development of Respimat 登録商標 Soft Mist 商標Inhaler and its clinical utility in respiratory disorders, Medical Devices: Evidence and Research 2011:4 145-155 (shown in Figure 8 of the paper).

[0135] Figure 7B shows a standard pMDI metering mechanism (50) also applicable to the present invention, comprising a metering valve (51) and an actuator device (20) mounted on a canister (45). It comprises a metering chamber (52) and a valve stem (53) connected to an outlet orifice (28).

[0136] Figures 7C and 7D show an exemplary and improved metering mechanism (50) having a metering chamber (52) with a larger capacity than existing pMDIs. The metering mechanism (50) also comprises a metering valve (51) and a valve stem (53), the metering valve having a gas inlet orifice (54) (Figure 7C) that allows gas to be filled into the chamber from the canister (45) when stationary, and a gas outlet orifice (55) (Figure 7D) that allows the gas to be discharged from the chamber (51) when the device (20) is activated.

[0137] To explain, a typical pMDI canister has a capacity of 10–22 ml, and the metering mechanism (50) discharges liquid rather than gas (21). Because the liquid expands approximately 200 times upon discharge, the metering chamber only needs to have a capacity of 20–100 μl to deliver a unit dose of the drug (30) dissolved or dispersed in the propellant. In contrast, mechanisms (50) used to deliver a quantitative dose of pressurized gas as needed are several orders of magnitude larger, ranging from 0.1 ml to 5 ml, more typically 0.5 ml to 2.5 ml. This is because the expansion of the gas depends entirely on the pressure at which it was stored. Thus, at a pressure of 10 bar, it expands 10 times when released to atmospheric pressure.

[0138] As shown in Figures 7C and 7D, the gas metering mechanism (50) comprises a metering valve (51), a gas chamber (52), a valve stem (53), a gas inlet orifice (54) that is open in the stationary position (7C), and a gas outlet orifice (55) that is closed in the stationary position.

[0139] When activated, the gas inlet orifice (54) is closed, and the gas is discharged through the valve stem (53) and then through the gas orifice (55).

[0140] This principle applies to each of the following: • Pressurized metered-dose inhaler (200); ·Dry powder inhaler (300 / 400); • Soft mist inhaler (500), and • Nebulizer (600) All of these "general-purpose" devices are shown in Figure 1, along with the following information: • Typical types of drugs administered by a given device; • The maximum lung dose that can be delivered under the current limitations of such devices; • Drug form 〇Solution (34), 〇Suspensions (32), dispersions or emulsions, 〇Powder(31) User limitations.

[0141] The basis for the present invention is further shown in Figures 8A to 8C and Figure 9.

[0142] Figures 8A to 8C (quoted from ASC Omega 2022, 7, 18409-18428) compare the equilibrium adsorption isotherms of various adsorbents, including granulated activated carbon (GAC) - pure (and functionalized) - at 25°C and pressures of 1 to 10 bar, respectively: ·oxygen, • Nitrogen; and, ·carbon dioxide. This indicates that considerable adsorption is achievable for each of these gases, with the greatest adsorption being for carbon dioxide. It is a fact that these airborne gases can be adsorbed from the canister under pressure that can be used as a propellant energy source (40), and then released. Such an energy source maintains a relatively constant pressure throughout the life of the canister, as shown in Figure 9. Various gases can be used individually or in combination.

[0143] Figure 9 from International Publication No. WO2008064293 compares the amount of carbon dioxide released from the canister when adsorbed carbon dioxide is released, with the amount of carbon dioxide released from the canister when carbon dioxide is released as compressed gas. This figure shows that adsorbed gas makes it easier to manage a "controlled" dose.

[0144] In one embodiment, as shown in Figures 7A to 7D, the canister may have the same dimensions as in the prior art (10 to 50 ml, typically 10 to 22 ml). Preferably, the canister is filled to at least 60%, 70%, 80% to 90%, or more of its volume.

[0145] Therefore, an exemplary drug for use in the improved pMDI inhaler of the present invention is salbutamol. Salbutamol is a drug used for the treatment of asthma. Accordingly, a device of the prior art may contain the drug and propellant in a canister having an internal volume of 20 ml, which is sufficient to administer a quantitative dose for up to 100 to 200 doses of drug therapy.

[0146] Surprisingly, the applicant has found that canisters of similar dimensions, using activated carbon absorbents and compressing CO2 as a propellant gas to approximately 2–10 bar, can also be used to dispense a large amount of powder from a perforated capsule. Thus, the dimensions, familiar shape, and portability of existing asthma inhalers can potentially be carried over to similar designs using zero global warming potential (zero GWP) propellants.

[0147] While a standard metering valve is shown in the embodiment in Figure 7B, it should be noted that such a metering valve is not necessarily required in the applicant's invention. In this embodiment, it is necessary to pass a minimum volume of gas to dispense a repeatable dose of a drug, for example, salbutamol from a perforated capsule, but such a minimum gas volume does not need to be precisely measured. The minimum gas volume varies depending on the mass of powder in the exemplary capsule. For capsules containing 10–50 mg of powder, the applicant found that such a minimum gas volume is in the range of 1–10 ml of gas (under atmospheric pressure).

[0148] Furthermore, the applicant has found that several alternative airborne gases can be used, as shown by the data in Figure 8.

[0149] Furthermore, in the case of a canister containing only compressed gas, as noted in Figure 9 (black rectangle), the canister must be compressed to a very high initial pressure of 16 bar in order to have a sufficient final operating pressure of 8 bar at the end of its product life. This pressure is too high for existing low-cost aluminum deep-drawn canisters used in inhalers. As a result, a much more expensive and bulky thick-walled CO2 cartridge would be required to store 16 bar. Such cartridges are too expensive and heavy for portable and disposable inhalers. However, in the case of an activated carbon canister (black diamond), an initial pressure of up to 10 bar, which is suitable for low-cost aluminum deep-drawn canisters, can be used.

[0150] In addition, as noted in Figure 9, in the case of compressed gas alone, the pressure drops by half from the beginning to the end of the canister's life. This causes significant fluctuations in the entrainment air flow, affecting the reproducibility of the dose throughout the canister's life. This problem is solved by an activated carbon canister, in which the pressure drop over the canister's operating life is only 20%.

[0151] As a result, the embodiments shown in Figures 7A to 7D solve many of the problems associated with each of the various conventional inhalers, particularly the pressing issue of high carbon footprint.

[0152] Figures 2 through 6 are included to illustrate how the present invention (and further supported by Figures 8 and 9), shown with reference to Figures 7A through 7D, may be applied to modify these conventional alternative devices, while many of the features of these devices may remain unchanged.

[0153] Referring to Figure 2, the conventional pressurized metered-dose inhaler (200) is a combination product (210) comprising a device (220), a drug (230), and a power source (240) or propellant (241). The drug (230) and propellant (241) (liquid, typically hydrofluoroalkane (HFA)) are held together in a sealed canister (245) under pressurization (P). The device (220) has an actuator body (222), a first opening (224) for receiving the canister (245), and a second opening (226) from which the aerosolized (260) drug (230) is discharged from the device (220). The device (220) has a measuring mechanism (250) for measuring a quantity, and comprises a measuring valve (252), an actuator (254), an actuator seat (256), and an actuator nozzle (258).

[0154] The device's operation results in the delivery of a metered dose, causing the liquid propellant to expand and aerosolize the drug, thereby expelling it through a suitable adapter (90) (nasal cavity (92) or mouthpiece (94)).

[0155] In contrast to conventional devices, as shown in Figures 7A to 7D, the device is driven by the release of airborne gas from an adsorbent contained separately in a container, rather than by a liquid propellant, thereby releasing a unit dose of the drug.

[0156] By controlling the volume (V) and flow rate (Q) of gas release, a unit dose of the drug is delivered.

[0157] The drug may be in the form of a powder, suspension, dispersion, emulsion, or solution.

[0158] Similarly, referring to Figure 3, a prior art dry powder inhaler (300) is a combination product (310) comprising a device (320), a drug (330), and a power source (340), such as a mechanical spring (342). The drug (330) is stored in a bulk chamber (380) and delivered to a metering chamber (382). The device (320) has a body (322). An overcap (324) at one end houses the power source (340), and the drug (330) is supplied from the bulk chamber (380) into the metering chamber (382) of a drug metering mechanism (350). A channel (326) in the device draws air into the entire device when the user inhales, and the aerosolized (360) drug (330) is discharged from the device (320).

[0159] Such a device can be modified according to the present invention, as shown in Figures 7A to 7D, so that a unit dose of powdered drug (330) is actively (not passively) released from the chamber using airborne gas discharged from a power source (40).

[0160] Similarly, referring to Figure 4, a prior art active dry powder inhaler (400) is a combination product (410) comprising a device (420), a drug (435), and a power source (440) in the form of a pump (442) and an integrated air storage unit (444). The drug (435) is stored in a chamber (480) in unit dose form, for example, in a blister (434), and released from the chamber by a blister puncture mechanism (470). The device (420) has a body (422), a first opening (424) for receiving the pump (442), and a second opening (426) from which the aerosolized (460) drug (435) is discharged from the device (420).

[0161] Such a device can be modified by the present invention, as shown in Figures 7A to 7D, to use airborne gas discharged from a power source (440) that replaces the pump and integrated air reservoir, to actively (rather than passively) release a unit dose of powdered drug (435) from the chamber.

[0162] Similarly, referring to Figure 5, the prior art active soft mist inhaler (500) is a combination product (510) comprising a device (520), a drug (530), and a power source (540) in the form of a spring (542) that thereby delivers a unit dose of the drug (530) from a chamber (580) in which the drug is aerosolized (560) through a uniblock (528).

[0163] The device (520) has a body (522), a first end (524) housing a spring (542), and a second opening (526) from which an aerosolized (560) drug (530) is discharged from the device (520), where the dose is held in a chamber (580) located midway between the ends, and a uniblock (528) is located behind the administration chamber.

[0164] The UniBloc (528) comprises a nozzle outlet (5281), a filter structure (5282), a silicon wafer (5283), and glass (5284).

[0165] Such a device can be modified according to the present invention, as shown in Figures 7A to 7D, to use airborne gas discharged from a power source (40) instead of a spring (542) to actively release a unit dose of powdered drug (530) from its chamber.

[0166] It may become possible to replace the integrally molded uniblock with a less expensive nozzle. This is because a longer dosing time (t) (equivalent to this delivery method) can be achieved by controlling the release time of the airborne gas from the dispenser. This also may result in a lower pressure required through the nozzle to produce a soft mist.

[0167] Finally, referring to Figure 6, a typical prior art neubuliser (600) comprises a device (620), a drug (630), and a power source (640) (pressurized gas from an electric compressor). The drug (630) is stored in a reservoir (680) and aerosolized. The device (620) has a body (622). The device (620) has a body (622), an air inlet (624), and an air outlet (628) or mouthpiece from which the aerosolized (660) drug (630) is discharged from the device (620). The device further comprises a baffle arrangement (626) for promoting aerosolization and pulverization.

[0168] During use, pressurized gas (air) aerosolizes the liquid medication in the reservoir, and as ambient air is drawn through the device into the mouthpiece, the aerosolized particles are taken in and delivered to the user. Some medication loss occurs through the inhalation port.

[0169] Such a device can be modified according to the present invention, as shown in Figures 7A to 7D, so that the drug (630) is aerosolized using airborne gas discharged from a power source (40) rather than air electrically driven through a compressor. Therefore, a main power supply or battery is not required for operation.

[0170] Example 1.

[0171] Powdered formulation

[0172] Based on the methodology of Suhaidi et al (2023) - Bulk Flow Optimisation of Amorphous Solid Dispersion Excipient Powders through Surface Modification. Pharmaceuticals,15, powder particles containing a fluorescein formulation suitable for nasal delivery were prepared.

[0173] The particles, dissolved in artificial mucus, fluoresce brightly under external light irradiation in a transparent nasal cast. Because the particles were intended for nasal delivery, they were formulated to have a particle size distribution with the majority of particles in the 10 μm to 40 μm range.

[0174] By blending 90% maltodextrin, 5% L-leucine, and 5% fluorescein, a powder with a particle size range suitable for nasal delivery and good fluidity was produced. The powder exhibited a vivid green color under UV light.

[0175] The resulting optimized fluorescent powder mixture's particle size distribution was measured three times using a Microtrac Camsizer X2 particle size and shape analyzer. The particle size ranges were Dv10 = 15.1 μm; Dv50 = 23.7 μm; Dv90 = 35.8 μm. These particle sizes measured by the Camsizer are geometric median diameters. Since the particles were spherical and had a bulk density of approximately 1, these can be considered to be approximately the same as the aerodynamic diameter.

[0176] Example 2.

[0177] Aerosolization of powder

[0178] To demonstrate that the power source can aerosolize particles, larger and heavier nasal particles (size range 10–40 μm) were used for delivery to the nasal cavity or lungs, in contrast to lighter and smaller lung particles (size range 2–10 μm), placed in capsules, and inserted into a powder dispensing test rig, as shown in Figure 10, which will be described later. The rig (700) comprises an air inlet (710), an adjustable regulator (720), and a solenoid valve (730) connected to an Arduino controller (750) linked to a computer (760) via a relay (740). A perforated capsule (30) is placed inside a chamber (770) (see also Figure 11), and a controlled air pulse is released to deliver the drug (30) from a spray nozzle (780) onto a plate in a conical funnel (790) as a jet (60), which can be visualized under UV light.

[0179] Nasal powder dispensing device

[0180] Dry powder inhalers (DPIs) for pulmonary inhalation therapy are similar to nasal powder delivery devices, both of which release dry powder particles from a reservoir as an aerosol jet for delivery to the patient. However, the particle size characteristics differ for pulmonary inhalation, with particles between 2 μm and 5 μm considered optimal for topical respiratory delivery (Islam, N., & Gladki, E. (2008). Dry powder inhalers (dpis) - a review of device reliability and innovation. International Journal of Pharmaceutics, 360, 1-11).

[0181] DPIs are i) Capsule; ii) Multi-dose strips, or iii) Bulk powder reservoirs It is known that powdered drugs are released from one of these.

[0182] There are several commercially available capsule-based DPIs (Deep Packet Injections), which offer several advantages over powder reservoir devices because the capsule and blister packaging protect the powder contents from moisture. Furthermore, capsule filling lines are widely used and deployed in the pharmaceutical industry.

[0183] Capsule-based DPIs also exhibit good dose-to-dose consistency (Islam & Gladki, 2008). Well-known capsule-based DPIs that have been on the market for many years include Breezhaler 登録商標 (Novartis,Basel,Switzerland);HandiHaler 登録商標 (Boeringer Ingelheim,Germany);Twister 登録商標 (Aptar, IL, USA); and Rotahaler 登録商標 (Cipla, Mumbai, India) is included. Consequently, the applicant selected a nasal powder delivery device that uses fluorescein-stained particles filled in capsules for testing.

[0184] Plastiape RS01 is another example of a commercially available capsule-based DPI (hereinafter referred to as cDPI). Like almost all DPIs, it is a passive device, which requires the user to activate the device by oral inhalation in order to allow the released drug particles to be inhaled (Elkins, MR, Anderson, SD, Perry, CP, Daviskas, E., & Charlton, B. (2014) Inspiratory flows and volumes in subjects with non-cf bronchiectasis using a new dry powder inhaler device. Open Respir Med J, 8, 8-13). The capsule filling, piercing and powder dispensing device (70) features two hollow stainless steel piercing spikes (72) that penetrate each of the opposite dome-shaped ends of a size 3 gelatin capsule (Figure 11). The penetrating spikes create a 1.15 mm diameter hole in the capsule (Martinelli, F., Balducci, AG, Rossi, A., Sonvico, F., Colombo, P., & Buttini, F. (2015). “pierce and inhale” design in capsule based dry powder inhalers: Effect of capsule piercing and motion on aerodynamic performance of drugs. International Journal of Pharmaceutics, 487, 197-204). The user deploys these cavity spikes by pressing two spring-loaded buttons located in opposite directions. While passive oral inhalation methods for inducing powder delivery are not suitable for nasal delivery devices, the RS01 device has a capsule piercing arrangement suitable for emptying capsules.A similar method for puncturing capsules is described in Farkas, D., Hindle, M., & Longest, PW (2017). Development of an inline dry powder inhaler that requires low air volume. Journal of Aerosol Medicine and Pulmonary Drug Delivery, 31, 255-265. In this latter study, the authors describe the use of a "straight-through" airflow design in which pulses of air push the powder contents inside the capsule longitudinally.

[0185] Measurement of the dose released from the capsule

[0186] For the simplicity of the approach described by Farkas et al. (2017), the applicant used a “straight-through” capsule puncture approach in a custom-designed nasal powder delivery device. A manual “squeeze bulb” powder insufflator was obtained (Sheehy House Insufflator, Grace Medical, Memphis, USA). As part of the test apparatus described earlier with reference to Figure 10, the manual “squeeze bulb” was replaced with a programmable air pulse source. To test capsule emptying performance, capsules were filled with 10, 20, 30, 40, and 50 mg of fluorescent powder mixtures. Five repeated tests were performed for each mass in 10 mg increments. Thus, a total of 25 capsules were tested. Each capsule had its domed end punctured using the RS01 device shown in Figure 11, which has a dosing chamber (70) with a puncture mechanism (72) in which the capsule is placed. First, each empty capsule was weighed on an analytical balance before filling to determine its mass m1. Next, the capsule was weighed after filling to determine its mass m2. Then, the mass mp of the powder inside the capsule was calculated as (m2-m1). After a single 200ms air burst at a pressure of 1 bar g was released through the capsule from the test apparatus, the empty capsule was weighed again on an analytical balance to determine its mass m3. The mass md of the powder released from the capsule was calculated as follows. Md = mp - (m3 - m1) Finally, the emitted dose (ED) was calculated as a percentage as follows: ED = 100 (md / mp)

[0187] result

[0188] Capsule emptying performance.

[0189] Figure 12 plots the performance (dose released) of emptying a capsule using a single 200 ms burst of air applied through the test apparatus. This chart demonstrates the effective performance of emptying the capsule for each mass increase. Of the 25 capsules tested, one capsule (powder mass 40 mg) had a relatively low (Poor) emptying rate (60%), resulting in a lower percentage.

[0190] A photograph of the discharged jet (60) is shown in Figure 13.

Claims

1. A device (20) for delivering a drug (30) to a user via a nasal or pulmonary route, wherein the device (20) includes a propellant energy source (40) for delivering the drug (30), the propellant energy source (40) being or containing an air gas (41), the air gas (41) being contained in a separate canister (45) at a pressure of at least 2 bar, adsorbed onto an adsorbent (42), the air gas (41) being released from the adsorbent (42) to administer the drug (30), and the device (20) not having a bag-on valve.

2. The device according to claim 1, wherein the gas in the air is air, oxygen, nitrogen, or carbon dioxide.

3. The device according to claim 2, wherein the gas in the air is carbon dioxide or rich in carbon dioxide.

4. The device according to any one of claims 1 to 3, which is a combination product (10) comprising the device (20) and the drug (30).

5. The device according to claim 4, further comprising a gas metering mechanism (50) for releasing a sufficient volume (V) of the airborne gas (41) at a flow rate (Q) that delivers / aerosolizes (60) a unit dose (U) of the drug (30).

6. The device according to claim 5, wherein the gas metering mechanism (50) comprises a metering valve (51), a metering chamber (52), a valve stem (53), and an actuator.

7. The device according to claim 6, wherein the gas metering mechanism (50) further comprises a gas inlet orifice (54) and a gas outlet orifice (55), thereby enabling the metering chamber (52) to be filled from the canister (45) and discharged to the device (20).

8. The device according to any one of claims 1 to 7, further comprising a drug release mechanism (70) for releasing a unit dose (U) of the drug (30) from a unit dose drug chamber (80), from which the unit dose (U) of the drug (30) is delivered to a target.

9. The device according to claim 8, wherein the drug release mechanism (70) includes a capsule puncture mechanism (72).

10. The device according to claim 8, wherein the drug release mechanism (70) comprises a carousel for releasing a unit dose of drug from a bulk drug chamber (382) to a unit dose drug chamber (80).

11. The device is classified as a combination product (10), the drug comprises a biological product, is an approved pharmaceutical product, and a) Dry powder (31); b) A multiphase dispersion of a solid in a liquid (32) or a liquid in a liquid (33); or, c) Single-phase solution (34) One of the following is present in the device: The device according to any one of claims 1 to 10.

12. The device according to claim 11, wherein the device (20) is a pressurized metered-dose inhaler (200) driven by the propellant energy source (40).

13. The aforementioned drug (30) a) Dry powder (31) And, The device (20) is an activated dry powder inhaler (300) driven by the propellant energy source (40). The device according to claim 11.

14. The device according to claim 11, which is a soft mist inhaler (400) driven by the propellant energy source (40).

15. The device according to any one of claims 1 to 14, further comprising a mouthpiece adapter (92) or a nasal adapter (94).

16. The device according to any one of claims 12 to 15, wherein the drug (30) is provided in a bulk chamber (382).

17. The device according to any one of claims 12 to 15, as dependent on claim 8, wherein the drug (30) is provided in a sealed unit dose form (35), and the drug release mechanism (70) is a puncture mechanism (72).

18. The device according to claim 17, wherein the sealed unit dose form includes a blister pack (36) or a capsule (37).

19. The device according to claim 11, which is a nebulizer (500) driven by the propellant energy source (40).

20. The device according to any one of claims 1 to 19, further comprising frit or a filter within the gas discharge portion of the canister (45).

21. The device according to any one of claims 1 to 18, further comprising a valved retaining chamber (VHC) or a spacer, which may be provided separately.

22. The aforementioned drug, i. Long-acting muscarinic antagonists (LAMAs), ii. Long-acting β-agonists (LABAs), iii. Short-acting β2 agonists (SABAs); and iv. Corticosteroids Selected from one or more of the group consisting of, The device according to any one of claims 1 to 21.

23. A method for delivering a drug (30) to a user via a nasal or pulmonary route, the method comprising delivering the drug (30) by administering the drug (30) from a device (20) using a propellant energy source (40), the propellant energy source (40) being or containing an air gas (41) stored at a pressure of at least 2 bar in a canister (45) separate from the drug, adsorbed onto an adsorbent (42), the air gas (41) being released from the adsorbent (42) to administer the drug (30), and the device (20) not having a bag-on valve.

24. A propellant energy source (40) comprising a 10-50 ml canister (45) filled with an airborne gas (41) at a pressure of at least 2 bar, wherein the airborne gas (41) is adsorbed onto an adsorbent (42), the airborne gas (41) is released from the adsorbent (42) to administer a drug (30), and the canister comprises a gas delivery mechanism (50) having a measuring chamber (52) with a capacity of 0.2-5 ml.

25. The propellant energy source (40) according to claim 24, wherein the gas delivery mechanism (50) further comprises a metering valve (51) and a valve stem (53).

26. The propellant energy source according to claim 25, wherein the gas delivery mechanism (50) further comprises a gas inlet orifice (54) and a gas outlet orifice (55) so that the metering chamber (52) can be filled from the canister (45) and delivered to the device (20).

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