Powder for inhalation and its manufacturing method

Abstract

A pharmaceutical composition in the form of a dry powder for inhalation is described, which comprises a local anesthetic, such as procaine, chloroprocaine, lidocaine, prilocaine, mepivacaine, bupivacaine, etidocaine, ropivacaine, and tetracaine, or their salts and / or solvates, and a hydrophilic biocompatible polymer, in particular hyaluronate.The composition of the present invention is useful for the treatment of cough.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a combination of a local anesthetic (LANE) agent and a hydrophilic biocompatible polymer for administration as a dry powder formulation for inhalation by dry powder inhaler (DPI) for the treatment of acute cough, e.g. during or after respiratory tract viral infection, as well as for the prevention of cough induced by pharmacological treatment.The present invention is further directed to a method for its preparation. [Background technology]

[0002] Inhalation therapy is one of the oldest and most effective approaches to the treatment of airway diseases. To date, it is well known that the most effective and safe method for treating the lungs is to administer drugs directly to the airways, resulting in low systemic exposure and rapid onset of pharmacological response.

[0003] Coughing is an important defense mechanism of the respiratory tract and is the most frequently observed sign during diseases involving this district of the organism. Acute coughing refers to cases in which the disorder lasts less than 4 weeks, whereas chronic coughing refers to cases in which the disorder lasts more than 8 weeks (Morice AH et al., Eur Respir J 2020 55: 1901136).

[0004] Chronic cough affects about 10% of the general adult population and is a major health problem due to its negative impact on the quality of life of affected people and due to the possibility of complications. In about 25% of cases, chronic cough is defined as "unknown cause" since it remains unexplained even when patients are subjected to multiple diagnostic tests, or "treatment-resistant" since it is insensitive to various treatments. This type of cough, which we prefer to call "idiopathic", is a challenge from a clinical point of view (Song, W.-J et al., Allergy Asthma Immunol Res 2016, 8 (2), 146-10). To date, there is no approved product for inhalation for this indication. In any case, it is well known that local anesthetics (hereinafter referred to as LANE) can act as peripheral antitussives by blocking neuronal sodium channels, reducing excitability and thus reducing the cough reflex (Karlsson JA Bull Eur Physiopathol Respir. 1987;23 Suppl 10:29s-36s; Dicpinigaitis PV et al. Pharmacol Rev 2014; 66:468-512).

[0005] Off-label use of LANE for local treatment by nebulization of the solution is not an uncommon practice. A retrospective study of adults receiving prescriptions and nursing instructions for administering nebulized lidocaine solutions for chronic cough between 2002 and 2007 (Lim, KG et al., Chest 2013, 143 (4), 1060-1065) demonstrated that adults tolerated self-administration of nebulized lidocaine for difficult-to-manage chronic cough. No serious adverse effects were observed, but most patients were reluctant to undergo the procedure anyway due to the negative effects associated with administration by nebulization, such as unpleasant taste, throat or oral irritation, and loss of sensory function.

[0006] Recently, a clinical trial compared the effectiveness of lidocaine administration in reducing the effects associated with treatment-resistant chronic cough and showed greater efficacy of the spray formulation compared to nebulization (Rayid Abdulqawi et al., The Journal of Allergy and Clinical Immunology: In Practice. 2021, 9(4) 1640-1647).

[0007] Besides these problems, deposition of LANE in liquid dosage form (e.g. nebulized droplets) poses the risk of drug deposition in the deep lung, potentially resulting in its adsorption and systemic distribution, which may lead to depression secondary to CNS excitation, the most common consequence of local anesthetic toxicity (Covino, BG et al., J. Dent. Res. 1981, 60 (8), 1454-1459).

[0008] To date, no solid particle formulations consisting of a combination of LANE and a polymer suitable for deposition in the conductive part of the respiratory tree have been described.

[0009] Excipient-free lidocaine inhalation formulations have been described for the treatment of asthma and to reduce the need for corticosteroids in asthmatic patients (WO 2006 / 6181). In this case, the formulation consists of the drug without a specific manufacturing method. The same assignee claimed pure preparations or benzyl phosphate ester prodrugs of corticosteroids or lidocaine, or related local anesthetic compositions for administration by aerosol to inhibit lung inflammation in asthmatic patients (WO 2005 / 063777). Similarly, N-oxide prodrugs of local anesthetics for inflammation associated with bronchitis and COPD have been described (WO 2005 / 044233).

[0010] Two other applications of local anesthetics for inhalation are available: one is an anti-migraine product in the form of a liquid aerosol (US20040184999) and the other is a formulation in the form of a pressurized metered dose inhaler (US19975679325).

[0011] Thus, there remains a significant need for more effective and safer LANE therapies for the treatment of cough, particularly chronic cough.

[0012] In recent years, within the scope of inhalation therapy, potential alternatives to nebulization have been investigated, and DPIs have been proposed as a promising strategy, as they allow easy administration of sufficient amounts of fine powder containing a therapeutic dose. DPIs involve formulations aerosolized by passive inhalation devices that are activated by the act of inhalation from the patient. DPIs are able to disperse large amounts of drug with a unique and rapid act of inhalation (20 mg in a few seconds); if larger amounts are required, the dose can be inhaled by a subsequent inhalation (Buttini, F et al., Int J Pharm 2018, 548 (1), 182-191).

[0013] In general, the development of powders for inhalation requires overcoming a well-known paradox: the active ingredient (API) should have a very small particle size to reach the lungs, but at the same time exhibit technical properties (flowability, packing, redispersibility) favorable for releasing the correct dose of aerosolized drug and the aerosol. This consideration becomes more important when the API dose is high. The technical properties of powders consisting only of the API are generally unsatisfactory and not suitable for inhalation administration. In fact, particles of a size suitable for inhalation administration are generally obtained by subjecting the API to micronization processes, usually in fluidized bed jet mills. These processes imply an increase in the energy content of the particles and their reactivity, inducing the creation of a highly sticky surface. All these aspects are highly detrimental to inhalation administration. In the case where the API is a LANE, especially a medium-acting LANE such as lidocaine, the low melting point is a further aspect that induces problems and instabilities during the manufacturing process (especially micronization), which often implies an increase in the temperature of the processed material.

[0014] Contrary to what happens with drugs administered to the lungs, which have the bronchoalveolar region as their site of action, in certain cases of cough, especially chronic and treatment-resistant cough, the administration of LANE must maximize deposition at the level of the inducer of the respiratory tree, where the highest excitability occurs and where the cough reflex begins. From the point of view of delivery technology, deposition in the inducer, i.e. in the inducer of 0-15 branching generations according to the Weibel model (Weibel ER. 1963. Morphometry of the human lung. Berlin: SpringerVerlag), means overcoming new problems, substantially different from those related to the administration of drugs that must be deposited at the bronchoalveolar level. In fact, the inducer region has a small number of branches that induce flow modifications resulting in a loss of particle momentum, and is covered by a ciliated epithelium physiologically entrusted with the capture and removal of particles transported by the inspiratory flow. This reduces the likelihood of particle deposition at the site of action by formulation as an adhesive mixture designed to deposit in the deepest parts of the lungs (De Boer, AHD et al., Expert opinion on drug delivery 14, 499-512).

[0015] In general, it is possible to develop particle engineering strategies to control the physical shape and to control the size and morphology in order to optimize the performance of DPIs in terms of maximizing the depositable fraction in the deepest part of the lung and enhancing the flowability (Buttini, F et al., J Control Release 2012, 161 (2), 693-702). In any case, when administering drugs that must act at the level of the conductive part of the respiratory tree, for the reasons mentioned above, the problem of deposition at the site of action of inhaled powders cannot be completely solved by a simple optimization of the particle size.

[0016] However, there is no doubt that it would be highly advantageous to have a LANE-based pharmaceutical product suitable for inhalation administration, which allows for fast and easy drug administration while at the same time causing high deposition of LANE at the target site. In view of this, a formulation is needed that favors deposition of the drug in the respiratory area where the cough receptors are located. Rapidly adapting cough receptors or irritant receptors are mainly located in the posterior aspect of the trachea, the pharynx, and the carina (the branching point from the trachea to the main bronchi). Receptors are few in number in the distal airways and are absent beyond the respiratory bronchioles. Therefore, a more suitable aerodynamic particle size for particles to direct the drug to this area is comprised between 6 and 12 microns.

[0017] The above problems are solved by the present combination and its uses. Summary of the Invention

[0018] In a first aspect, the present invention has as its object a pharmaceutical composition in the form of a dry powder for inhalation comprising a local anesthetic and a hydrophilic biocompatible polymer.

[0019] Advantageously, the powder is in the form of dry microparticles obtained by spray drying, for administration by inhalation with a dry powder inhaler (DPI). After aerosolization by an inhalation device, the microparticles typically have a mass median aerodynamic diameter comprised between 4.0 and 6.0 microns and are characterized by a fine particle fraction of 35% or less by mass.

[0020] The present invention also relates to a method for preparing microparticles comprising the steps of: i) Selecting a hydrophilic biocompatible polymer and dissolving it in a suitable solvent at a suitable concentration. ii) Selecting the LANE drug and dissolving it in water at an appropriate concentration. iii) adding the solution of step ii) to the solution of step i) and keeping the resulting solution stirred. iv) spray drying the solution of step iii) using suitable spray drying equipment. v) collecting the resulting powder in particulate form; and vi) optionally micronizing the particles.

[0021] In a preferred embodiment, particles having a size suitable for use according to the invention are obtained using a spray dryer nozzle having a diameter comprised between 0.7 mm and 3 mm.

[0022] The present invention further relates to a dry powder inhaler filled with the aforementioned dry powder pharmaceutical formulation, and to a kit comprising the dry powder composition and the dry powder inhaler.

[0023] The present invention has as a further object said composition for use as a medicine, in particular for the treatment of cough.

[0024] definition In the present invention: - the term "LANE" advantageously refers to a therapeutic substance belonging to the class of local anesthetics having a water solubility of at least 0.5% w / v by definition and by the determination procedures therefor reported in the United States Pharmacopoeia, the European Pharmacopoeia and the British Pharmacopoeia. - Local anesthetics are drugs that can be classified according to the literature based on their inherent anesthetic potency and duration of activity. For example, procaine and chloroprocaine are drugs with relatively low potency and short duration of action. Lidocaine, mepivacaine, and prilocaine are agents with moderate potency and duration of action. Tetracaine, bupivacaine, and etidocaine are very strong agents with long duration of action. - Coughing is a physiological defense mechanism of the respiratory tract with the purpose of keeping the airways free of excess secretions and accidentally inhaled foreign material. It can be voluntary and involuntary. There are several guidelines in the medical literature for classifying cough (Irwin RS and Madison JM. New England Journal of Medicine 2000, 343 (23, 1715-1721; Morice AH, et al Eur Respir J 2020 55: 1901136; DOI: 10.1183 / 13993003.01136-2019). Cough lasting less than 4 weeks is generally considered "acute", with viral infections of the upper respiratory tract being the most common cause of acute cough. Cough lasting 3-8 weeks is classified as subacute, and cough lasting more than 8 weeks is defined as chronic. - The molecular weight of the polymer is determined by the average molecular mass (M w ) is meant. - The term mucoadhesive polymer defines a hydrophilic polymer capable of interacting with the mucosal layer that covers the respiratory epithelium through weak, reversible bonds (S. Roy, et al. (2009) Polymers in Mucoadhesive Drug-Delivery Systems: A Brief Note, Designed Monomers and Polymers, 12:6, 483-495). - the term "micronized" relates to a powder in which 90% of the particle size distribution exhibits a size smaller than 10 μm; - The term "coarse" relates to materials having a diameter of several hundred microns. - Particle size is typically quantified by measuring the representative diameter of an equivalent sphere, known as the volume diameter, by laser light diffraction. - Particle size can also be quantified by measuring the size of the agglomerates using a suitable instrument such as a sieve analyzer. - The volume diameter (VD) is related to the mass diameter (MD) by the particle density (assuming that density is independent of particle size). In this specification, the particle sizes of the active ingredient and the fine particle fraction are expressed by volume size, whereas the particle size of one of the coarse particles is expressed by mass size. - the particles have a normal or log-normal distribution defined by the volume or mass median diameter (VMD or MMD, respectively) corresponding to the volume or mass diameter of 50 percent of the particles by volume or mass, and optionally by the volume or mass diameter of 10% and 90% of the particles, respectively. - Another common approach to define the particle size distribution consists of using three values: i) the median diameter d(0.5), which is the diameter that divides the distribution into two equal parts; ii) d(0.9) and iii) d(0.1), which correspond to the 90th and 10th percentiles of the distribution, respectively. In general, particles with the same or similar VMD or MMD may have different particle size distributions, in particular different widths of the distributions as expressed by the values ​​d(0.1) and d(0.9). - During aerosolization, particle size is expressed as mass aerodynamic diameter (MAD), whereas particle size distribution is expressed by mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). MAD depends on the ability of suspended particles to be transported in an airstream. MMAD corresponds to the mass aerodynamic diameter of 50 percent of the particles by weight.

[0025] The expression "respirable fraction" refers to the percentage of the mass of active particles, ie particles having an aerodynamic diameter of less than 5 μm, that reach the patient's lungs. - The MMAD, GSD and respirable fraction are assessed using a suitable impactor such as an Andersen Cascade Impactor (ACI), a Multi Stage Liquid Impinger (MLSI) or a Next Generation Impactor (NGI) according to procedures reported in common pharmacopoeias, in particular the European Pharmacopoeia 10th Edition. - The respirable fraction is calculated from the percentage ratio of the fine particle mass (also called the fine particle dose) and the delivered dose, which represents the mass of active ingredient released from the device upon activation. - The delivered dose, which means the metered dose released from the inhaler after the act of inhalation, is calculated from the cumulative deposition in the impactor device, whereas the fine particle mass is calculated by the deposition of particles with an aerodynamic diameter <5.0 μm. - The delivered dose is also assessed using a Dose Unit Sampling Device (DUSA) according to procedures reported in common pharmacopoeias, in particular the European Pharmacopoeia 10th Edition. - Metered Dose (MD) means the powder mass loaded into the inhaler and intended to be expelled (in whole or in part) upon the performance of a device actuation. - "Emitted Fraction" (EF) is the ratio of the emitted dose to the measured dose. - the non-respirable particle fraction is calculated from the percentage ratio of the mass of non-respirable particles (i.e. having an aerodynamic diameter >5 μm) to the delivered dose. - Non-respirable particulate mass (NB-PM) is defined as the amount of drug with an aerodynamic diameter greater than 5 μm, obtained as the difference between the emitted dose and the fine particle mass, expressed in mg. - "Treatment" of cough means reducing the frequency of coughing events and / or reducing the severity of coughing events (compared to an untreated condition). These terms refer to both prophylactic treatment and treatment of ongoing coughing episodes. - A "therapeutically effective amount" of a substance refers to that amount that results in a clinically meaningful reduction in the frequency or severity of coughing events.

[0026] Detailed Description of the Invention The present invention is directed to a combination of a local anesthetic (LANE) and a hydrophilic biocompatible polymer (HBP), where the LANE and HBP are present in a pre-established ratio.

[0027] Advantageously, the LANE may be any active ingredient belonging to the pharmacological class of anesthetics. More advantageously, the LANE has a water solubility of at least 0.05% w / v at standard conditions (15-25° C., 1 atm).

[0028] For example, the LANE drug can be selected from LANEs having short, medium, and long duration of action, such as procaine, chloroprocaine, lidocaine, prilocaine, mepivacaine, bupivacaine, etidocaine, ropivacaine, and tetracaine and / or their salts and / or solvates. If one of these compounds has a chiral center, they can be used in optically pure form or can exist as a diastereomeric or racemic mixture.

[0029] Advantageously, LANE can be used in the form of a free base or in the form of a pharma- ceutically acceptable salt, such as the hydrochloride and hydrobromide salts. In a preferred embodiment, LANE is lidocaine in the form of its hydrochloride salt.

[0030] Advantageously, the hydrophilic biocompatible polymer (HBP) may be selected from the group consisting of safe and pharma- ceutically acceptable substances such as hyaluronic acid (HA) salts, preferably the sodium salt, water-soluble cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, or any mixture thereof.

[0031] Preferably, the hydrophilic biocompatible polymer is sodium hyaluronate (SH) with a molecular weight comprised between 15 and 1500 kDa, preferably between 15 and 200 kDa, more preferably between 20 and 140 kDa, even more preferably between 20 and 100 kDa.

[0032] More advantageously, the LANE is present in a weight percentage of the combination comprised between 1 and 90% by weight of the combination, preferably between 10 and 50% by weight. Preferably, the weight percentage of HA ranges from 90-50% w / w, more preferably from 80-70% w / w.

[0033] Advantageously, the combination of the invention is in the form of microparticles characterised by a defined particle size.

[0034] The particle size distribution of the particulates, expressed as volume diameter, should satisfy the following parameters: d(0.1) comprised between 2.0 and 5.0 microns, d(0.5) comprised between 5.0 and 9.0 microns, and d(0.9) comprised between 11 and 18 microns.

[0035] When expressed as an aerodynamic diameter, the median mass is comprised between 4.0 and 6.0 microns.

[0036] When aerosolized by a typical DPI, the particles exhibit a fine particle fraction (FPF) (<5 microns) in the range of 35-30%, preferably in the range of 25-20%, and more preferably in the range of 15-20%.

[0037] The advantages of the dry powder compositions of the present invention stem from obtaining engineered microparticles comprising LANE in combination with hydrophilic biocompatible polymers, suitable for inhalation and able to meet the requirements deriving from the particular challenges related to the deposition of pharmaceuticals in the conductive tracts of the respiratory tree.

[0038] The powders of the present invention consist of flowable particles of LANE that can be effectively delivered from an inhaler device and deposited in the mucosal layer covering the ciliated epithelium of the conducting airways due to their defined diameter comprised between 2 and 18 microns, preferably between 5 and 14 microns, and even more preferably between 5 and 12 microns.

[0039] The presence of a mucoadhesive hydrophilic biocompatible polymer in the particles favors adhesion of the particles to moist epithelium and local and prolonged release of LANE over time.

[0040] The microparticles of the present invention are stable from both a chemical and physical standpoint.

[0041] The compositions of the present invention exhibit a uniform distribution of the active ingredient in the powder and the possibility of delivering high doses, with the maximum dosage that can be administered with one or more acts of inspiration from the patient being 100 mg, preferably 80 mg, and even 40 mg of powder.

[0042] Although not strictly necessary, the powder formulation according to the invention may further comprise coarse and / or fine particles of a pharma-ceutically acceptable inert excipient such as lactose, preferably alpha-lactose monohydrate, trehalose, mannitol, raffinose, etc.

[0043] The present invention allows the preparation of powders of HA particles that can be effectively aerosolized by adding LANE. According to the present invention, the powder dose delivered from the inhaler is >70% by weight of the loaded dose, preferably >85% by weight of the loaded dose.

[0044] The compositions of the present invention may be loaded into hard capsules, blisters, or reservoir inhalers without the addition of any flow excipients or diluents.

[0045] The microparticles of the present invention consist of a matrix of HBP in which LANE molecules are entrapped, resulting in a pharma- ceutically acceptable time-dependent amorphous, semi-crystalline or crystalline stable structure, and thus the compositions of the present invention can be aerosolized and inhaled using a dry powder inhaler.

[0046] The particle size allows their deposition in areas of the respiratory tree (larynx, trachea, large bronchi) where there is a high concentration of receptors for cough stimuli; this feature makes it possible to maximize the therapeutic effect and minimize systemic adsorption and its associated side effects.

[0047] Furthermore, the HBP-LANE microparticles of the present invention slowly release the active ingredient over an extended period of time.

[0048] The present invention further relates to methods for preparing said engineered microparticles that affect the selection of the type of polymer, its molecular weight, and the polymer:drug ratio.

[0049] In particular, the method of the present invention is carried out by spray drying.

[0050] Typically, spray drying is performed by nebulizing a solution containing the solute to be dried in a preheated drying chamber, where small droplets of the solution are subjected to a hot air current of controlled temperature and converted into powder particles. The resulting powder passes through a powder / gas separator, e.g., a cyclone, in which the powder loses kinetic energy and is collected in a suitable container.

[0051] The adjustable parameters to obtain a powder with the characteristics specified are: i) the type of nebulizer; ii) the temperature of the inlet gas used to dry the material sprayed into the drying chamber (hereinafter referred to as the input temperature); iii) the flow rate of the gas, and iv) the flow rate of the feed solution (hereinafter referred to as the feed flow rate).

[0052] The spray drying process comprises the following steps: i) Selecting a suitable hydrophilic biocompatible polymer (HBP) and dissolving it in a suitable solvent at a suitable concentration. ii) Selecting the LANE drug and dissolving it in water at an appropriate concentration. iii) adding the solution of step ii) to the solution of step i) and keeping the resulting solution stirred. iv) spray drying the solution of step iii) using suitable spray drying equipment. v) collecting the resulting powder in particulate form; and vi) optionally micronizing the particles.

[0053] Advantageously, in step i), the solvent is water or an aqueous alcoholic solution containing ethanol as co-solvent, in a concentration comprised between 0.1 and 99.9% v / v.

[0054] Preferably, step i) is carried out in water at room temperature under stirring, wherein the HBP is comprised between 1 and 6% w / v.

[0055] Advantageously, also in step ii), the solvent is water or an aqueous alcoholic solution containing ethanol as co-solvent, in a concentration comprised between 0.1 and 99.9% v / v.

[0056] The type of HBP and its molecular weight in step i) must be selected by those skilled in the art based on the specific qualitative composition, drug type, and drug content. In a preferred embodiment of the present invention, HA is selected as the polymer.

[0057] Preferably, step ii) is carried out at room temperature and under stirring, wherein the concentration of the drug LANE is comprised between 0.6 and 10%, preferably between 1 and 6% w / v.

[0058] The solution of step iii) should have a solute concentration comprised between 0.5 and 6% w / v, preferably between 3 and 5% w / v.

[0059] The concentration of LANE, expressed as the free base, in the solution resulting from step iii) is comprised between 10 and 50% by weight of the solute, preferably between 20 and 40% by weight.

[0060] Advantageously, the solution resulting from step iii) is kept stirred at at least 50 rpm for 10 minutes.

[0061] Steps i) and ii) can be combined and the solution can be prepared by combining all the components of these two steps and heating the contents at a temperature comprised between 25 and 50°C, preferably between 30 and 44°C, more preferably between 37 and 42°C.

[0062] In step iv), the HBP-LANE is then spray dried with suitable parameters, for example: - an input temperature preferably between 110°C and 160°C, preferably between 115°C and 150°C, even more preferably between 120°C and 140°C; - a flow rate of the feeding solution between 1.0 and 10.0 mL / min, preferably between 1.5 and 5 mL / min, and even more preferably between 2 and 4 mL / min; - a solute concentration of the solution between 1 and 7% w / v, preferably between 2 and 6% w / v, even more preferably between 3 and 5% w / v; - a nebulization gas flow rate between 135 and 820 L / h, preferably between 300 L / h and 750 L / h, even more preferably between 473 and 670 L / h; - 20 to 40 m 3 / h, preferably between 30 and 38 m 3 / h, and more preferably between 33 and 35 m 3 Dry gas flow rate between 100 and 200 / h.

[0063] In step v), the particles can be collected by known methods.

[0064] In step vi), the collected particles can optionally be micronized by known methods. In any case, according to the present invention, it is possible to obtain microparticles of the desired size without further micronization using a spray drying nozzle having a diameter comprised between 0.7 mm and 3.0 mm, preferably between 1.0 mm and 2.5 mm, more preferably between 1.4 mm and 2.0 mm.

[0065] The solution of step iii) is prepared by adding a LANE solution to a HBP solution, and in any case, a person skilled in the art can choose different preparation methodologies and conditions based on his or her own knowledge.

[0066] In step iii), it was found that the preferred molecular weight of HA, which ensures the formation of microparticles with a completely amorphous structure maintained for a pharma- ceutically acceptable time, is in the range of 20-100 kDa, especially in the case of lidocaine powder and 50-90% by weight HA. For higher HA molecular weights, around 750-1000 kDa, the obtained microparticles may show a partially crystalline structure, observed for example by polarized light microscopy, which may be due to an incomplete molecular dispersion of lidocaine between the HA polymer chains.

[0067] The particle size distribution of the powders is significantly affected by the diameter of the nozzle used for the spray drying process. Using a 1.4 mm diameter, d(v,10) was 2.4-2.8 microns and d(v,90) was 11.0-14.0 microns. These particle populations had an MMAD of 3.8-4.1 microns and an FPF of 34%, indicating a percentage of particles in the range of 5-14 microns (66%). When diameters larger than 2.0 mm were used, the microparticles showed an MMAD of 5.7-6.0 microns and an FPF of 14%, indicating a high percentage of particles in the range of 5-17 microns (86%). This observation is confirmed by laser diffraction analysis, which revealed d(v,10) of 3.3-4.6 microns and d(v,90) of 14.2-17.0 microns.

[0068] This unique feature deposits the powder specifically in areas of the respiratory tree where cough receptors are highly localized (larynx, trachea, large bronchi), minimizing deposition in the oral cavity, which can cause unpleasant and / or severe side effects such as loss of sensation or even choking when ingesting food or drink.

[0069] A further advantage of the present invention is represented by the fact that the polymer, e.g., HA, acts as a control element for the release of LANE, thereby prolonging its delivery at the site of action for several hours, compared to the dissolution of LANE, which otherwise takes only a few minutes. This aspect is favorable for obtaining long-term cough suppression.

[0070] Finally, the mucoadhesive potential of HBP favors particle adhesion to the mucosa lining the epithelium of the conducting tracts of the respiratory tree, avoiding particle entry into the lower respiratory tract where systemic adsorption is higher.

[0071] The therapeutic amount of the combination may vary within wide limits depending on the nature of the active substances, the type and severity of the condition to be treated, and the condition of the patient requiring treatment.

[0072] In particular, active agents are carefully added to the compositions of the present invention after the solution preparation and drying steps.

[0073] Excellent distribution uniformity of an active ingredient is achieved when the active ingredient has a drug content within 5% of the theoretical value. The determination of content uniformity must be made by one of ordinary skill in the art using a validated analytical method.

[0074] The compositions of the invention can be used with any dry powder inhaler: i) single dose inhalers (unit dose) for administering single, subdivided doses of active ingredient; ii) metered dose multi-dose inhalers or reservoir inhalers pre-loaded with an amount of active ingredient sufficient for longer treatment cycles.

[0075] The compositions of the invention can be administered to a patient at an established frequency prescribed by a clinician, e.g., in a single dose or multiple doses, typically once, twice, or several times daily. Alternatively, the compositions of the invention can be administered by a caregiver or self-administered by the patient as needed.

[0076] The amount of composite dry powder to be inhaled depends on the concentration of the active ingredient in the spray-dried powder. For example, 16 mg of powder is required to administer 8 mg of LANE from the mixture HBP:LANE 50:50 w / w, or 40 mg of powder is required to administer 8 mg of LANE from the mixture HBP:LANE 80:20 w / w. Preferably, the amount of drug is administered in a single inhalation act (the entire powder dose in a few seconds), but in certain embodiments of the invention, if a larger amount of powder is required, the dose can be inhaled by several successive inhalations with the same inhaler.

[0077] The compositions of the invention are effective in treating acute, subacute, or chronic cough of various origins, such as cough associated with asthma, or cough caused by the administration of another medication, such as an ACE inhibitor or any medication used to treat asthma or chronic obstructive pulmonary disease. [Brief description of the drawings]

[0078] [Figure 1] SEM images are shown. [Diagram 2] Diffraction patterns are shown. [Diagram 3] Drug distribution is shown. [Figure 4] The dissolution profile is shown. [Diagram 5] Images taken under a polarized optical microscope (magnification 10×) are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] The present invention is illustrated in detail by the following examples. EXAMPLES

[0080] Preparation of spray-dried powder of lidocaine hydrochloride-HA with molecular weights comprised between 20 and 50 kDa The optimization was focused on three process parameters: solute concentration in the solution to be dried, feed flow rate, and nozzle diameter. Each of the three variables was optimized for a total of eight (2 3A two-level full factorial design was applied using the software Minitab® 17 (Minitab Inc., State College, PA, USA) to carry out the experiment, with two levels considered.

[0081] The following dried powder quality attributes were evaluated: Residual moisture content of dried powder Particle size as dv50 Non-breathable fraction

[0082] The composite spray-dried powder contained lidocaine hydrochloride (ACEF, Fiorenzuola, Italy) 20% w / w and HA 20-50 kDa (Prymalhyal 50, 20-50 kDa, Givaudan, France) 80% w / w as the mucoadhesive polymer.

[0083] Powders were produced using a Mini Spray Dryer B290 machine (Büchi, Switzerland) while keeping the following process parameters constant: air flow rate (600 L / h), input temperature (130°C), and aspiration flow rate (35 m 3 / h). Under these conditions, the output temperature was about 70°C.

[0084] The mass median diameter, Dv50, was determined by laser diffraction as described in Example 2.

[0085] TGA-DSC 1 STAR e The moisture content of the spray-dried powders was measured by thermogravimetric analysis (TGA) using a system instrument (Mettler Toledo, USA). Approximately 5 mg of each spray-dried powder was subjected to a heating program from 25 to 130 °C at a heating rate of 10 °C / min under a flow of dry nitrogen at 50 mL / min.

[0086] The residual moisture content was expressed as the percentage of weight loss that occurred between 25 and 110°C.

[0087] The non-respirable fraction was evaluated in vitro using a Fast Screening Impactor (FSI, Copley Scientific, UK). This device uses two separation stages, the first named CFC, where particles with aerodynamic diameters larger than 5 μm are deposited, and the other named FFC, which collects particles with aerodynamic diameters less than 5 μm. The FSI consists of an induction port (IP), a CFC filled with 10 mL of the solution methanol-water 70:30 v / v, which acts as a liquid trap for particles with aerodynamic diameters >5 μm, and a FFC equipped with a glass fiber filter (A / E Type, Pall Corporation, USA). After completing the assembly according to the instructions provided by the manufacturer, the FSI was connected to a vacuum pump VP 1000 (Erweka, Germany) and the air flow of 60 mL / min passing through the impactor was measured and recorded by a flow meter (model 3063, TSI, USA). Powder aerosolization was performed with a dry powder device RS01 (Plastiape, Italy) loaded with hypromellose capsule size 3 (Qualicaps, Spain) containing 20 mg of powder. After deposition, the powder amount at each stage, device, and capsule was collected by high performance liquid chromatography (HPLC) using a defined solvent volume. Analysis was performed in triplicate.

[0088] The non-respirable fraction was calculated by dividing the amount deposited on the CFC stage by the total amount of powder emitted from the device, which corresponds to the sum of the amounts deposited on the CFC and FFC.

[0089] Table 1 summarizes the process parameters and corresponding quality attributes obtained for the lidocaine hydrochloride-HA powder.

[0090] [Table 1]

[0091] Statistical analysis (ANOVA) was performed with Minitab® 17 software, and the effects of process parameters and quality attributes were analyzed with linear regression models.

[0092] Regression equations showed that nozzle diameter had a statistically significant effect on particle size distribution and non-respirable fraction. Increasing nozzle diameter increases particle size and non-respirable dose of spray dried powder. EXAMPLES

[0093] Particle size distribution and drug content of spray-dried lidocaine hydrochloride-HA (20-50 kDa) powders The particle size distribution of the spray-dried lidocaine-HA powder prepared according to Example 1 was assessed by laser diffraction using a Spraytech instrument (Malvern, UK).

[0094] Approximately 10 mg of the spray-dried powder was dispersed in a solution of polysorbate 80 (SPAN® 80, Sigma Aldrich, USA) in cyclohexane, in which lidocaine hydrochloride is insoluble (powder concentration 0.1% w / v), and placed in an ultrasonic bath for 5 min before diffraction measurements.

[0095] Each measurement was performed in triplicate. The attenuation of the laser beam was kept between 8 and 10%.

[0096] Particle sizes were expressed as equivalent sphere diameters of equal volume, i.e., dv10, dv50, and dv90.

[0097] Drug content and powder uniformity were assessed by HPLC using an LC Agilent 1200 instrument (Agilent Technologies, USA). Analysis was performed on six samples prepared by weighing 25 mg of powder dissolved in 10 mL of water. Three replicates were performed for each sample.

[0098] Content uniformity determination was performed using a validated analytical method and the following chromatographic conditions: - Column: C18 Agilent® Eclipse (5 μm, 4.6 × 150 mm, Waters Corp, USA); - Wavelength: 230±2nm; - Column temperature: 25°C; - Flow rate: 1mL / min; - Mobile phase: phosphate buffer solution:methanol (25:75 v / v).

[0099] Anhydrous NaH 2 PO 4 A phosphate buffer solution was prepared by dissolving 1.38 g in 500 mL of ultrapure water, and then the pH was adjusted to 8 by adding a few drops of 1 M (40 g / L) aqueous NaOH solution. The solution was filtered through a 0.45 μm PTFE filter. The retention time of the drug was 3 ± 1 min.

[0100] The drug content was uniform in all samples, within 5% w / w of the theoretical value. The coefficient of variation, VC (calculated as the percentage of the ratio of the standard deviation of five measurements to the mean value), was less than 2.5%. The results indicate that the spray drying technique is suitable for preparing lidocaine hydrochloride-HA particles with the established combination.

[0101] [Table 2] EXAMPLES

[0102] Scanning electron microscopy analysis of spray-dried powders according to Example 1 produced using nozzles with different diameters The morphology of the powders dried as described in Example 1 was studied by scanning electron microscopy (SEM) using a SUPRA 40 instrument (Carl Zeiss, Germany). Each powder sample (10 mg) was placed on a sample holder pre-applied with conductive carbon double-sided adhesive to dissipate the charge. Excess particles were removed with a gentle stream of nitrogen.

[0103] 2.75 10 -6Samples were analyzed under high vacuum conditions of 1 Torr, and images were collected at 5000x magnification using an accelerating voltage of 1.0 kV.

[0104] FIG. 1 shows SEM images of dry powders produced using nozzles with diameters of 2 or 1.4 mm.

[0105] In both cases, the composite HA-LANE powders can be seen to be characterized by round particles with largely collapsed surfaces and in a few cases swollen smooth surfaces. In any case, the powders produced with a nozzle diameter of 1.4 mm showed a large number of smaller particles attached to larger particles, compared to the powders produced with a nozzle diameter of 2 mm, which had a smaller number of smaller particles. EXAMPLES

[0106] Powder X-ray diffraction. Two different HAs: - Prymalhyal 50(20~50kDa, Givaudan, France); - PLUS-PH 100kDa European Pharmacopoeia Grade (Altergon, Italy) Powder X-ray diffraction analysis was carried out on two powders produced using

[0107] For both polymers, powders were produced containing 20% ​​w / w lidocaine hydrochloride and 80% w / w HA.

[0108] Starting with a solution containing 3% w / v of solute overall, powders were produced using a Buchi B290 instrument using the following process parameters: Nozzle diameter (2 mm); supply flow rate (2 mL / min); gas flow rate (600 L / h); input temperature (130 °C); output temperature (70 °C); suction flow rate (35 m 3X-ray diffraction of these powders was recorded using a Miniflex diffractometer (Rigaku, Japan) with CuKα radiation at 30 kV at a scan rate of 0.05° / min and a scan range (2θ) of 5–35°. The diffraction patterns (Figure 2) showed that both powders were amorphous. EXAMPLES

[0109] Aerodynamic particle size distribution of particles determined by impaction procedure of spray-dried powders containing lidocaine hydrochloride and HA (20-50 kDa) The composite spray-dried powder contained lidocaine hydrochloride 20% w / w and HA 20-50 kDa 80% w / w.

[0110] The components were dissolved separately in water, then the two solutions were combined to obtain a final solution for drying with a solute content equal to 3% w / v.

[0111] A Büchi B290 spray dryer was used to produce two powders using nozzles with diameters of 2.0 or 1.4 mm, respectively. The following process parameters were used: feed flow rate (4 mL / min); gas flow rate 600 L / h; input temperature 130° C.; output temperature (70° C.); aspiration flow rate 35 m 3 / h.

[0112] Each formulation was loaded into a hypromellose (hydroxypropyl methylcellulose) capsule Quali-VI size 3 (Qualicaps, Spain) and aerosolized with a medium-high resistance dry powder inhaler RS01 (Plastiape, Italy). Each capsule was loaded with 40 ± 0.1 mg of powder, corresponding to a nominal dose of 8 mg of lidocaine. The aerodynamic size of the particles was assessed using a Next Generation Impactor (NGI, Copley Scientific, UK) with an induction port (IP) as described in the United States Pharmacopoeia. Each determination was performed by releasing the contents of four capsules for 4 seconds at a sampling rate of 60 L / min such that 4 L of air was drawn through the device, as recommended in the European Pharmacopoeia 10th edition 2.9.18.

[0113] At the end of the deposition experiment, the NGI was digested and quantification of lidocaine in the powder deposited at each stage was performed using an HPLC validated method.

[0114] Lidocaine hydrochloride deposited at each stage of the impactor was collected using aliquots of water:methanol (25:75 v / v), which were finally transferred to a volumetric flask of appropriate volume and the volume was adjusted with the same solvent mixture. The resulting solution was filtered through a cellulose acetate syringe filter (porosity 0.45 μm and diameter 2.5 cm, GVS Filter Technology, USA) and then injected into the HPLC. A volumetric flask was used to collect the powder remaining in the RS01® device and capsules, and the powder was dissolved in ultrapure water at the end of the experiment to verify the complete recovery of the active ingredient.

[0115] The DUSA (Dose Unit Spray Device) methodology was also used to determine the delivered dose. The delivered lidocaine dose was collected from 10 separate capsules. The RS01® device was used to aerosolize the capsule contents at 60 L / min, with the collected air volume equal to 2.0 L. All powders were tested in triplicate.

[0116] The amount of lidocaine delivered, delivered dose, fine particle dose, fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD) were calculated for each measurement performed with the impactor according to the European Pharmacopoeia (10th edition 2.9.18).

[0117] · Emitted dose (ED) obtained as the sum (in mg) of drug portions retrieved from the induction port and all stages of the NGI and its percentage of the nominal dose. Fine particle dose (FPD), i.e. the amount of drug expressed in mg contained in a particle with a diameter of less than 5 μm calculated by interpolation according to the European Pharmacopoeia Fine particle fraction (FPF), calculated as the ratio of FPD to ED and expressed as a percentage Non-respirable particle dose (NB-PD), i.e. the amount of drug in mg contained in particles with an aerodynamic diameter greater than 5 μm, obtained as the difference between the emitted dose in the NGI and the fine particle dose Non-respirable particle fraction (NB-PF), calculated as the ratio of the non-respirable particle dose to the ED and expressed as a percentage was calculated to evaluate the aerodynamic performance of the two powders.

[0118] As used herein, the term "dose" refers to the amount of active ingredient delivered by one actuation of the inhaler.

[0119] The aerosolization performance of the two powders is summarized in Table 3.

[0120] The mean delivered doses for spray-dried powders obtained with both nozzle diameters, determined by NGI measurements, were between 88 and 95% of the dose (amount of lidocaine recovered from the Hall impactor plus the amount recovered from the capsule and device), whereas they were >97% w / w when the DUSA methodology was used.

[0121] The difference between the fine and non-respirable fractions was a direct consequence of the different particle size (aerodynamic) distributions of the two particles, as highlighted by the MMAD values ​​and the amount of drug contained in the different stages in the NGI device, the particles deposited in the induction port (IP) and the particles remaining in the RS01 device or in the capsule. Figure 3 reports the drug distribution in the NGI stages for two powders produced with different nozzle diameters, 1.40 (white histogram) and 2.00 mm (black histogram), respectively. The bars represent the standard deviation (n=3).

[0122] [Table 3] EXAMPLES

[0123] Comparison of dissolution of spray-dried powder with lidocaine In vitro dissolution studies were performed on lidocaine powder raw material and spray-dried HA-lidocaine powder produced using PLUS-PH 100 kDa European Pharmacopoeia (Altergon, IT, batch number 1000008976), Prymalhyal 50 (20-50 kDa, Givaudan, France) and Contipro Biotech (industrial grade, 750-1000 kDa, Czech Republic) as bioadhesive polymers with a spray dryer (Buchi) using the following process parameters: nozzle diameter (2 mm), flow rate (2 mL / min), air flow rate (600 L / h), input temperature (130 °C), output temperature (70 °C), and aspiration flow rate (35 m). 3 / h).

[0124] The spray dried powder had a solids content of 3% w / v: - 20% (w / w) Lidocaine hydrochloride and 80% (w / w) HA PLUS-PH 100kDa - 60% (w / w) Lidocaine hydrochloride and 40% (w / w) HA Prymalhyal 50 (20~50kDa) - 20% (w / w) Lidocaine hydrochloride and 80% (w / w) HA Contipro Biotech (750~1000kDa) It contained.

[0125] 170cm 3 In vitro dissolution testing was performed to compare powder performance using a RespiCell™ (Sonvico, F et al. Pharmaceutics 2021, 13, 1541), a vertical diffusion cell containing a reservoir, filled with dissolution medium, and with a side arm length of 10 cm.

[0126] The apparatus consists of an upper (donor chamber) and a lower (receiving chamber) connected by a metal clamp but separated by a glass microfiber filter used as a diffusion membrane and placed horizontally in contact with the dissolution medium. The receiving chamber contains a magnetic stirrer inside.

[0127] The dissolution medium used for the analysis was 8 g NaCl, 0.2 g KCl, 1.0 g Na 2 HPO 4 1.44g, and KH 2 PO 4 Phosphate buffered saline (PBS) was prepared by weighing 0.12 g and dissolving in 1 L of distilled water to a final pH of 7.4. The RespiCell™ was thermostatically controlled (Lauda eco silver E4, DE) at 37±0.5° C. during the analysis.

[0128] The receiving chamber was filled with PBS and samples were taken via the side arm of the cell at pre-set time intervals. Prior to analysis, 1 mL of dissolution medium was applied to the filter to thoroughly wet it.

[0129] At the start of the assay, an accurately weighed amount of approx. 8 mg of lidocaine, 40 mg of an accurately weighed amount of spray-dried Lidocaine-HA PLUS-PH 100 kDa European Pharmacopoeia powder (corresponding to approx. 8 mg of lidocaine), 13.3 mg of an accurately weighed amount of spray-dried Lidocaine-HA Prymalhyal 50 powder (corresponding to approx. 8 mg of lidocaine), or 40 mg of an accurately weighed amount of spray-dried Lidocaine-HA Contipro Biotech powder (corresponding to approx. 8 mg of lidocaine) was manually spread onto the wetted filter and 1 mL of the solution was withdrawn from the receiving chamber via the side arm at preset time intervals and replaced with 1 mL of fresh PBS after each withdrawal to maintain a constant volume of liquid in the cell.

[0130] To assess the amount of drug that was undissolved or trapped in the filter, the filters were washed with 5 mL of a 75:25 v / v mixture of methanol:water at the end of the experiment to recover any residual undissolved powder. The amount of drug in the samples was quantified by HPLC analysis.

[0131] Data were expressed as the percentage of lidocaine dissolved. 100% dissolution corresponds to the total amount of drug recovered at the end of the experiment (amount in the cell receiving chamber plus amount on the filter). Total dissolution times were 25 minutes for the LANE powder raw material and 135 minutes for the spray-dried lidocaine-HA powder.

[0132] FIG. 4 shows the dissolution profiles of lidocaine raw material and spray-dried lidocaine-HA powder.

[0133] The results obtained showed different dissolution profiles of the LANE raw material and the lidocaine-HA powder.

[0134] In particular, the dissolution of the spray-dried lidocaine-HA powder is significantly slower. In the case of the lidocaine powder raw material, the entire amount of lidocaine was completely dissolved after 15 minutes, whereas the amount of LANE in the spray-dried powder with PLUS-PH 100 kDa HA was completely dissolved after about 2 hours. In any case, the spray-dried powder containing Prymalhyal 50, with a LANE content of 60%, was completely dissolved in the dissolution medium after 25 minutes, significantly faster than the previous dissolution.

[0135] The spray dried powder containing HA Contipro Biotech had the slowest dissolution with only 70% of the LANE dissolved in the dissolution medium after 2 hours.

[0136] Table 4 summarizes the amount of lidocaine dissolved, the amount of lidocaine retained on and in the filter, and the mass balance (total recovery) of the experiment.

[0137] [Table 4] EXAMPLES

[0138] Characterization by optical microscopy of the mixture LANE-sodium hyaluronate Contipro SD 20:80 The LANE-HA powders prepared according to Example 6 were observed by polarized light microscopy (Optiphor2-POL, Nikon, Japan) to highlight the possible birefringence phenomenon related to the presence of lidocaine microcrystals in the particle structure. From the images obtained, it was observed that the amorphous particles, HA Contipro Biotech (750-1000 kDa), exhibited birefringent microcrystalline lidocaine structures at the surface. Said crystallization was observed in powders with lidocaine:HA ratios equal to 10:90; 20:80 (Figure 5, panel A); 25:75; 30:70.

[0139] Using sodium hyaluronate with a lower molecular weight, i.e. sodium hyaluronate Prymalhyal 50 (20-50 kDa), fully amorphous powders were obtained at both 20 and 60% w / w LANE concentrations. Figure 5 shows polarized optical microscopy (magnification 10x) images of particles obtained by spray drying according to that reported in Example 6: LANE:HA (Contipro) 20:80 w / w (panel A); LANE:HA (Prymalhyal) 20:80 w / w (panel B), and LANE:HA (Prymalhyal) 60:40 w / w (panel C). EXAMPLES

[0140] Stability study of spray-dried HA-lidocaine hydrochloride powder. A stability study was carried out on two spray dried powders prepared according to Example 4 containing lidocaine hydrochloride 20% w / w and two different types of HA: Prymalhyal 50 (20-50 kDa) and PLUS-PH 100 kDa European Pharmacopoeia.

[0141] The powder was stored in Hypromellose capsules size 3 sealed in aluminum bags and after 1 month and 4 months of storage under two different conditions: 25°C - 60% relative humidity 40°C - 75% relative humidity was analyzed.

[0142] Chemical stability was evaluated by quantifying the lidocaine hydrochloride content by HPLC analysis after different storage periods.

[0143] The physical stability was also evaluated by hot stage microscopy (HSM), where samples were observed under a polarized microscope before (T-zero) and after storage (1 and 4 months). Samples were heated from 25°C to 130°C in a nitrogen atmosphere with a heating range of 5°C / min. The data obtained are reported in Table 5.

[0144] Analysis showed that the powder showed no tendency to develop crystalline moieties, both when freshly prepared and at two different storage times, even after heating.

[0145] [Table 5] EXAMPLES

[0146] Cough provocation test. Ten healthy volunteers (8 males, ages ranging from 35 to 70 years) underwent cough provocation tests (Fontana, GA, et al. Eur Respir J 1997; 10: 983-98; Lavorini, F et al. Am J Respir Crit Care Med 2001; 163: 1117-1120) before and after inhalation of placebo powder and lidocaine-HA powder prepared according to Example 4 using sodium hyaluronate PLUS-PH (100 kDa).

[0147] Coughing was induced by inhalation of ultrasonically nebulized distilled water (mist) produced by an ultrasonic nebulizer Mist-O2-Gen (EN143A Model, Timeter, PA, USA). The aerodynamic mass median diameter of the aerosol droplets generated by the nebulizer has been reported in the literature to be 3.6-5.7 μm (Phipps, PR, et al. Chest 1990; 7 1327-1332). The reservoir of the nebulizer was filled with 180 mL of distilled water; the aerosol output was adjusted by a potentiometer and monitored as a direct current (DC) signal on an oscilloscope. The output could be increased incrementally with respect to a level corresponding to 5% of the maximum achievable output level.

[0148] Volunteers inhaled the mist while breathing normally at rest, and inhalation times for each concentration were standardized to 1 min. A 2-3 min rest was scheduled between each inhalation of mist. The output range of the nebulizer used in the experiments could be varied from 30 to 100% of the maximum DC signal, and the corresponding volume of nebulized water (mean value) ranged from 0.08 to 4.45 mL / min.

[0149] The onset of coughing was determined by recording the expiratory flow rate with a Fleish pneumotachograph No. 4. After the appearance of coughing, the test was stopped and the subject was allowed to rest for 30 minutes. The test was then resumed with the inhalation of the mist corresponding to the output value just below the last dose. If coughing could be induced again with the same mist level that had previously been able to induce coughing, the induction was stopped and this mist level was considered as the subject's cough threshold (T). Conversely, if no cough response was obtained, the test was resumed and continued until coughing was induced twice with the same mist level. Thus, the lower mist level that could induce at least coughing between two consecutive tests separated by 30 minutes was considered as the cough threshold.

[0150] During inhalation of each nebulizer output, the intensity of the urge to cough (UTC) was assessed on a 10 cm visual analogue scale (VAS) (Lavorini F, et al. Am J Respir Crit Care Med 2006; 176: 825-32). The extremes of the VAS (i.e., "no desire to cough" and "extreme urge to cough") were displayed at either end of a screen placed in front of the subject. Each participant was informed that "extreme urge to cough" represented an irresistible need to cough. The screen was connected to a linear potentiometer with a cursor, by which the subject could quantify the UTC level. Both the screen and the potentiometer were 10 cm long. Equal distances on the screen and on the potentiometer represented equal changes in the intensity of the UTC.

[0151] After assessing cough threshold, subjects were administered placebo (lactose) or HA-lidocaine powder using the RS01 DPI 24-48 hours later. Trained medical personnel carefully instructed subjects to inhale as quickly as possible starting from a level close to residual volume and then to total lung capacity, followed by a breath hold for approximately 10 seconds. Each subject was asked to inhale the capsule twice to minimize the possibility of residual dry powder. After approximately 5 minutes, the cough induction was repeated in the same manner as in the baseline test. If the subject did not develop a cough, he / she was subjected to inhalation of mist equal to 1.3 x T, 1.6 x T, and 100% of the nebulizer output. The time required to re-establish the subject's baseline (i.e., pre-drug) cough threshold was calculated similarly.

[0152] Inhalation of placebo did not affect the cough threshold and the corresponding UTC. Conversely, HA-lidocaine powder significantly increased the cough threshold and UTC in 10 subjects with a median increase equal to 2.13-fold. The duration of the effect was approximately 50±8 minutes.

Claims

1. A pharmaceutical composition in the form of a dry powder for inhalation, comprising a local anesthetic and a hydrophilic biocompatible polymer.

2. 2. The pharmaceutical composition of claim 1, wherein the local anesthetic is selected from the group consisting of procaine, chloroprocaine, lidocaine, prilocaine, mepivacaine, bupivacaine, etidocaine, ropivacaine, tetracaine, and salts and solvates thereof.

3. 3. The pharmaceutical composition of claim 2, wherein the local anesthetic is lidocaine.

4. 2. The pharmaceutical composition of claim 1, wherein the hydrophilic biocompatible polymer is selected from the group consisting of hyaluronic acid salts or sodium hyaluronate, water-soluble cellulose derivatives, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof.

5. 5. The pharmaceutical composition of claim 4, wherein the hydrophilic biocompatible polymer is sodium hyaluronate.

6. 2. The pharmaceutical composition of claim 1, wherein the dry powder consists of spray-dried microparticles having a defined diameter comprised between 2 and 18 microns, a mass median aerodynamic diameter comprised between 4.0 and 6.0 microns, and a fine particle fraction of 35% by weight or less.

7. The pharmaceutical composition of claim 6, wherein the particle size distribution of the microparticles is characterized by d(0.1) comprised between 2.0 and 5.0 microns, d(0.5) comprised between 5.0 and 9.0 microns, and d(0.9) comprised between 11 and 18 microns.

8. i) selecting a hydrophilic biocompatible polymer and dissolving it in a suitable solvent at a suitable concentration; ii) selecting a local anesthetic and dissolving it in water at an appropriate concentration; iii) adding the solution of step ii) to the solution of step i) and keeping the resulting solution under stirring; iv) spray drying the solution of step iii); v) collecting the resulting powder in particulate form; and vi) optionally, reducing the particle size; 8. A method for preparing microparticles as defined in claim 6 or 7, comprising:

9. The method of claim 8, wherein in step iv) a spray dryer nozzle having a diameter comprised between 0.7 mm and 3 mm is used.

10. A dry powder inhaler comprising the pharmaceutical composition of any one of claims 1 to 7.

11. A kit comprising the pharmaceutical composition according to any one of claims 1 to 7 and a dry powder inhaler.

12. A pharmaceutical composition according to any one of claims 1 to 7 for use in the treatment of cough.

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