MXPA06002952A - Mucoactive agents for treating a pulmonary disease - Google Patents

Abstract

The present invention relates to mucoactive agents, such as heparin which are useful in the treatment of diseases where excess mucus is present in the respiratory tract, such as cystic fibrosis and chronic obstructive pulmonary disease. In particular, the invention relates to pharmaceutical compositions for administration by pulmonary inhalation. It also relates to methods for producing particles suitable for pulmonary inhalation, such as spray drying or jet milling.

Description

- before the expiration of the time limit for amending the For two-letter codes and other abbreviations, refer to the "Guidclaims and to be republished in the event of receipt of ance Notes on Codes and Abbreviations" appearing at the begin- issue ofthe PCT Gazette. (SS) Date of publication of the international search report: 16 June 2005 MUCOACTIVE AGENTS TO TREAT A PULMONARY DISEASE FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions which are useful in the treatment of diseases in which an excess of mucus is present in the respiratory tract, such as cystic fibrosis and chronic obstructive pulmonary disease. In particular, the invention relates to pharmaceutical compositions for administration by pulmonary inhalation.

BACKGROUND OF THE INVENTION Mucus is a viscous gel, whose properties depend on a variety of factors. The mucus consists mainly of a mixture of variable amounts of mucosal glycoproteins, water, low molecular weight ions, proteins and lipids. These components interact in a number of ways and these interactions create the three-dimensional structure of the gel and determine the viscosity and elasticity of the gel. Mucin is the main polymeric component of the mucus gel and consists of a peptide base structure with glycosylated and non-glycosylated domains and oligosaccharide chains. The presence of sulphated and sialic terminals makes the molecule highly poly-anionic. The mucins form a poly-dispersed group of densely charged linear polymers, some of which have a length of up to 6 μm, with random entanglements. The rheological properties depend mainly on the density of entanglement, which in turn is determined by the degree of hydration of the mucus and by the length of the mucin molecule. Necrotic activated neutrophils release large amounts of DNA, aotine and proteins which also polymerize and interact with mucin. This process considerably increases the density of entanglement to form highly viscoelastic mucus gels. A variety of different types of bonds within the mucus of the airways affect the chemical and physical properties of mucus, such as viscoelasticity. Disulfide bridges are covalent bonds that link glycoprotein subunits to form the large, extended macromolecular chains known as mucins. The entanglements are formed between adjacent mucin polymers, probably as a result of their large size. The sugar units, which constitute the oligosaccharide side chains and account for approximately 80% of the weight of the mucin, form hydrogen bridges with the complementary units in the surrounding mucins. Although each individual link is weak and dissociates easily, very large numbers of binding sites are present, constituting it as a significant type of binding within the mucus. In addition, the mucins are also ionized, containing both positively charged amino acid residues as well as negatively charged sugar units, mainly sialic acid and sulphated residues. The degree of ionization of mucin can actually increase in airway disease. For example, in cystic fibrosis (CF) the proportion of sulphated residues also rises due to alterations in glucosyl transferase activities within the Golgi apparatus. The ionic interactions between fixed negative charges result in a more extended, more rigid macro-molecular conformation, effectively increasing the size of the polymer and increasing the numbers of entanglements. Finally, in diseases of the airways characterized by infection and inflammation, such as CF, the agonizing leukocytes release high molecular weight DNA and actin filaments, and the exopolysaccharides are released by bacteria. This adds extra bulk and volume to the mucus. Mucus is a critical component of the primary defense mechanism of the respiratory tract, which traps particulate and microbial material for its removal through the mucociliary system. However, when this mechanism fails to eliminate enough, the mucus accumulates and must be expelled as sputum by coughing, otherwise it is retained in the respiratory tract and can encourage colonization by micro-organisms which can lead to chronic inflammation and obstruction of the lung. The retention of mucus in the respiratory tract presents a particular problem because it not only obstructs the airways but also facilitates infection and promotes a self-perpetuating cycle of infection and inflammation. Pathological agents such as bacteria (for example Pseudomonas aeruginosa) are often able to establish colonies within the mucus. Problems tend to arise when the initial bacterial infection stimulates neutrophil chemotaxis, but neutrophils do not have the ability to completely eliminate it. Apoptosis of defective neutrophils and phagocytosis and impaired phagocytosis are key factors in the pathogenesis of pulmonary disease in CF. Neutrophil proteases and oxidants are released during the process and these have a number of effects: they cause both cellular damage as well as deterioration of ciliary motion. These are also potent secretagogues and actually increase the additional secretion of mucus. The proteases also cut anti-proteases and cell surface markers, further deteriorating host defense mechanisms. Therefore, the cycle is perpetuated because these effects further deteriorate mucus elimination while increasing mucus secretion, promoting bacterial stasis and promoting inflammation of the airways. Therefore, the failure of neutrophils to eliminate the original infection actually leads to a rapid deterioration of the situation and the process explains much of the morbidity and mortality observed in patients with CF. There are two main causes of mucus retention. The first is hyper-secretion of mucus from the airways, in which the body produces and secretes high levels of mucus and the mucociliary system can not cope with, and dislodge large amounts of mucus fast enough. The second cause is one in which the mucus has abnormal viscoelasticity. In cases where the mucus has an unusually high viscoelasticity, it is much more difficult for the mucociliary system to move the mucus and evacuate it from the airways. Agents that affect mucus in a way that helps its elimination have traditionally been referred to as "mucolytic" agents. However, this term may be inaccurate, because the agents in question do not exert their effect on the mucus by lysis. Therefore, agents that aid in the elimination of mucus are referred to in the present invention as mucoactive agents. Classical courses of action taken to treat afflicted individuals with hyper-secretion of the airways and / or abnormal viscoelasticity of the mucus include antibiotic therapy, administration of bronchodilators, use of systemic or inhaled corticosteroids, or oral administration of expectorants. for mucus liquefaction. It is also known to treat patients with mucolytic agents "delivered by aerosol, such as water and hypertonic saline." Human recombinant DNase I (rhDNAase) has been used to treat those suffering from CF. It is believed that the DNAse enzymatically digests naked DNA released on the surface of the airways from bacteria, neutrophils, and other cellular debris, which is believed to be the DNA that contributes to the elevated viscoelasticity of mucus in individuals with CF. However, these conventional strategies have only had limited success and there is a need for Low cost and effective treatment for mucus retention in the lungs. further, it is an object of the present invention to provide a treatment that leads to the reduction of the elasticity and viscosity of the mucus and that results in cough and improved mucus removal in the airways and also allows the elimination by ciliary action. It has been shown that agents such as DNase, which digests DNA in the mucus, and gelsolin, which digests actin in the mucus, affect the elasticity components of the network, as opposed to viscosity. In studies in models, this tends to improve the action of coughing and elimination from the airways, instead of helping the elimination by means of ciliary action. It has been suggested that agents that alter the entanglements in the mucus cause a reduction in both elasticity and viscosity. This is the preferred result, since it leads to an improvement in ciliary clearance, in accordance with studies in models. Dextrans have been identified as a potentially useful agent for improving mucus clearance in International Publication No. WO 99/01141. In this patent application, it is suggested, based on models in vitro, that dextrans reduce mucus viscoelasticity and increase mucociliary clearance capacity. It is believed that dextrans have this effect by altering the formation of hydrogen bonds between the mucins within the three-dimensional structure of the mucus. It is hypothesized that dextrans compete with mucin for hydrogen binding sites, which results in the substitution, with dextran carbohydrate moieties, of oligosaccharide moieties bound to high-weight mucin peptides. Molecular constituents that make up the mucus gel. The dextrans used have significantly lower molecular weight and therefore these new hydrogen bridges are, from a structural and rheological point of view, ineffective, thus reducing the overall entanglement density within the mucus and it is believed that this improves the mucus elimination by ciliary mechanisms and coughing action. In a subsequent patent application, International Publication No. WO 01/15672, it is also suggested that the action of the dextrans can be further increased by using charged forms. It is believed that a charged dextran, for example dextran sulfate, has double activity. First, it is said to have the effects due to competition for hydrogen bonding sites as discussed above. Secondly, it is believed that the ionic nature of the charged dextran has an additional effect, protecting some of the fixed charges along the macromolecular center of the mucin polymer, making it less rigid and reducing the number of entanglement entanglements with the neighboring macromolecules within the mucus and thus reducing the viscoelasticity due to ionic interactions. In WO 01/15672 it is also suggested that the heparin-loaded oligosaccharide is not suitable for treating lung diseases such as CF, because its production is very expensive and, more significantly, because it could potentially have side effects. toxicities such as pulmonary hemoptysis, such as bleeding from the tracheo-bronchial mucosa. Heparin is a linear polysaccharide which, together with related proteoglycans such as heparan sulfate, is a member of the group of macromolecules referred to as glycosaminoglycans. Due to their linear anionic poly-electrolyte structure, these macromolecules are involved in several biological processes. Although heparin has been used to a large extent for its anticoagulant effects based on its binding to plasma anti-thrombin III, there is evidence that heparin and other glycosaminoglycans also possess various anti-inflammatory and immunoregulatory properties, including modulation of T lymphocytes, complement activation, inhibition of neutrophil chemotaxis, smooth muscle growth and reduction of the intrinsic viscosity of DNA. Heparin is a heterogeneous mixture of sulfated polysaccharide chains in varying degrees with a molecular weight range of 6,000 to 30,000 daltons. Intact or unfractionated heparin (UFH) can be fractionated to produce high and low molecular weight fractions, as is well known in the art. It has been shown that fractionated, low molecular weight heparin (LMWH) reduces the viscoelasticity of canine mucus and improves mucociliary clearance in a frog palate model. The effects of inhaling an aqueous solution of heparin using a nebulizer on bronchial asthma have been the subject of several studies. However, the results of these studies have been inconsistent, possibly due to the difficulty in quantifying the doses of inhaled heparin that reach the lower respiratory tract. N-acetyl-L-cysteine, which is also commonly called acetylcysteine or NAC, is a chemical compound produced by the body that increases the production of the enzyme glutathione, a powerful antioxidant. It is known that NAC It is a mucoactive agent and is used to dissociate the thick mucus that often occurs in people suffering from chronic respiratory diseases. It can be obtained in oral solution such as Mucomyst (trade name) that can be ingested or converted into an aerosol and inhaled. Although the prior art discusses the possibility of combining competition for hydrogen bridges and ionic protection in order to provide a dual mode for reducing viscoelasticity, there are even additional mechanisms by which viscoelasticity can be reduced and the present invention seeks use these other mechanisms to provide even more efficient means to aid in the elimination of mucus, especially in patients suffering from conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, acute asthma, or bronchiectasis. The elimination of mucus can be improved by reducing the viscosity and elasticity of the mucus gel. There are a number of mechanisms by which these properties can be affected to assist in elimination, by coughing, ciliary movement or by a combination of the two. First, the entanglements within the mucus gel structure can be broken.

This can be achieved by using agents that dissociate the di-sulfide bridges between the glycoproteins within the mucus. Alternatively or additionally, the entanglements within the mucus gel structure can be disrupted by agents competing for hydrogen bonding sites, as described above with respect to dextran. Also, the ionic bonds that exist inside the gel can also break, protecting charges using an ionic agent. This has been described in connection with the use of a charged dextran. Second, the mucus can be diluted by increasing its water content. This reduces the viscosity of the gel and also facilitates the elimination of mucus. This can be done by administering an agent to the mucus which attracts water to the mucus exerting an osmotic effect. Alternatively, the water content of the mucus can be increased by using agents that control the sodium channels or lung epithelium and can therefore block the absorption of salt and water through the epithelium of the airways. Third, the digestion of naked DNA and other cellular debris, such as filamentous actin, found in the mucus also reduces mucus viscosity and elasticity.

SUMMARY OF THE INVENTION Therefore, in a first aspect of the present invention there is provided a composition for aiding mucus removal, the composition comprising one or more mucoactive agents to reduce entanglement within the mucus; to dilute the mucus; and / or to digest naked DNA and cell debris within the mucus. The compositions according to the invention are preferably administered directly to the lung by inhalation. Mucoactive agents have a local effect on mucus in the lungs. It is not intended that these agents have a systemic effect and neither are they intended to be absorbed into the bloodstream through the lung. In a preferred embodiment of the invention, the composition comprises two or more mucoactive agents and has at least two of the effects listed on the mucus. Preferably, the composition according to the invention also has the effect of reducing inflammation. In one embodiment of the present invention, the composition comprises one or more mucoactive agents together with an additional active agent. The additional active agent can be an agent that has a therapeutic effect that help in the treatment of the underlying cause or symptoms of conditions involving hyper-secretion of the airways and / or abnormal viscoelasticity of the mucus. Alternatively, the additional active agent may be included to treat or prevent a different condition. In a particularly preferred embodiment, the additional active agent is an anti-inflammatory agent, such as one of the anti-inflammatory agents listed below. Therefore, the composition may comprise, for example, a combination of NAC and ibuprofen. In another embodiment of the invention, the mucoactive agent to reduce entanglement within the mucus is an agent that has hydrogen binding sites that competes with the hydrogen bonding sites of the side chains of the mucins which form hydrogen bonds with complementary units in surrounding mucins. Especially useful are the charged mucoactive agents which, in addition to protecting some of the fixed charges along the macromolecular center of the mucin polymer, also compete for the hydrogen bonding sites. This double effect makes the mucus less rigid and reduces the number of entanglement entanglements with surrounding macromolecules within the mucus, thereby reducing viscoelasticity due to ionic interactions. In one modality, the agent mucoactive that has this double effect is not dextran. In a particularly preferred embodiment of the present invention, the mucoactive agent for reducing the entanglement is a glycosaminoglycan. Glycosaminoglycans are a group of heteropolysaccharides containing an N-acetylated hexosamine in a characteristic repeating disaccharide unit. Heparin is a preferred glycosaminoglycan. In one embodiment of the present invention, the heparin used in the compositions comprises UFH, ie high molecular weight heparin. Surprisingly, it has been discovered that this form of high molecular weight heparin is effective in aiding mucus clearance and has even been found to be more effective than low molecular weight fractions in reducing the viscoelasticity of human mucus in vitro. . In an alternative embodiment, the heparin used as a mucoactive agent in the compositions of the present invention are the low molecular weight fractions of heparin. In addition, heparin analogs are commercially available and can also be used as mucoactive agents in the present invention. Such analogs include sulfated heparin and glycosylated heparin. Surprisingly, the inventors have discovered that sulfated heparin is more effective than unsulfated heparin in reducing the elasticity of human mucus. Accordingly, in a preferred embodiment of the present invention, the composition comprises sulfated heparin as a mucoactive agent. Heparin derivatives are commonly referred to as heparinoids and these can also be used in the compositions of the present invention. Heparinoids are closely related to heparin and share many of their properties. Heparinoids are useful for reducing entanglement in mucus and these also exhibit inflammatory properties. Chondroitins are another group of glycosaminoglycans that can be used in the present invention, and these include dermatan sulfate and chondroitin sulfates. Keratin sulfate and hyaluronic acid are additional glycosaminoglycans that can be used as mucoactive agents in the compositions of the present invention, as can heparitin sulfates such as heparan proteoglycan sulfate. In one embodiment of the present invention, the mucoactive agent is sodium danaparoid. This low molecular weight heparinoid contains a mixture of the sodium salts of heparan sulfate, dermatan sulfate and Chondroitin sulfate and is useful to reduce entanglement in mucus. Another heparinoid that can be used comprises a combination of heparin, dermatan sulfate and chondroitin sulfate. The highly sulfated glycosaminoglycans of natural origin and synthetic are also examples of mucoactive agents that can be included in the compositions of the present invention. These compounds, which are also known as glycosaminoglycan polysulfate compounds, or sulfated mucopolysaccharides are also useful for reducing entanglement within the mucus to be removed. Other polysaccharides in addition to glycosaminoglycans can be used as mucoactive agents that reduce entanglement within the mucus, such as dextrans. Preferably, the polysaccharide type mucoactive agent should have a relatively low molecular weight. For example, the agent must have an average molecular weight of less than 30,000, preferably less than 20,000, and even more preferred less than 10,000. Finally, an additional group of mucoactive agents that can help mucus clearance are amino acids. Particularly effective amino acids include basic amino acids such as lysine, arginine and histidine, and their derivatives. It is believed that these amino acids they help the elimination of the mucus increasing the trans-epithelial potential difference, causing a stimulation of the transport of chlorine, which induces the movement of water inside the fluid of the epithelial lining and also increases the fluidification of the mucus. It is believed that other amino acids, such as cysteine, break the disulfide bridges in the mucus. Amino acids, including hydrophobic amino acids such as leucine, also reduce entanglement within the mucus.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows a schematic diagram representing the manner in which a standard USN operates. Figure 2 shows a schematic drawing of the ultrasonic equipment. Figure 3 shows the decrease in logG * as a function of the dose of heparin. Figure 4 shows the decrease in logG * as a function of the dose / type of heparin.

DETAILED DESCRIPTION OF THE INVENTION Acetylcysteine (NAC) and the acetylcysteine salt derivative Nacysteline (or NAL) are also agents effective mucoactive agents that are suitable for inclusion in the compositions of the present invention. In effect, the efficacy of NAL is indicated in the experimental data discussed below. In a further preferred embodiment, a charged agent is used to reduce entanglement by protecting the charges in the mucins, thereby reducing the ionic interactions between adjacent mucins. Suitable charged agents include charged glycosaminoglycans, such as those discussed above, including, for example, heparin sulfate, heparan sulfates, or sodium danaparoid. Other sulfates or phosphates or polysaccharide phosphates, such as dextran sulfates or phosphates, can also be used. An alternative mucoactive agent that can reduce entanglement by protecting the charges in the mucins is a solution of sodium chloride or the like. Suitable mucoactive agents to alter the entanglement within the mucus by breaking the disulfide bridges between the glycoprotein subunits are compounds having sulfhydryl groups such as cysteine. These agents include the cysteine derivative NAC, the acetylcysteine salt derivative NAL and dithiothreitol.

In another embodiment of the present invention, preferably in which the composition comprises only one mucoactive agent or in which the composition does not include an additional active agent, the mucoactive agent is not dextran or a charged dextran, such as dextran sulfate or Dextran phosphate. In another embodiment, the agent for reducing entanglement is a dextran having a molecular weight greater than 5,000. Even in another embodiment of the present invention, preferably in which the composition comprises only one mucoactive agent or in which the composition does not include an additional active agent, the mucoactive agent is not either heparin or heparin sulfate, or is not heparin low molecular weight. In another embodiment, preferably in which the composition comprises only one mucoactive agent or in which the composition does not include an additional active agent, the mucoactive agent is not rhADNase or is not NAC. Various mucoactive agents help to eliminate mucus by increasing the water content of the mucus. Some of these agents act by attracting additional water into the mucus, and are often known as osmolar agents or even non-destructive mucolytics. Alternatively, these agents work by blocking the absorption of salt and water through of the epithelium of the airways. Suitable mucoactives to be included in the compositions of the present invention that act by attracting water into the mucus include low molecular weight sugars such as dextrans, dextrin, mannitol, glucose or urea. Many other monosaccharides, disaccharides and oligosaccharides also have an osmolytic effect. Amiloride is an agent that is supposed to block the absorption of salt and water through the epithelium of the airways, which increases hydration and dilutes the macromolecular components of mucus. Some of the amiloride derivatives have a similar activity including fenamil and bezamil. Examples of mucoactive agents that can aid mucus removal by digestion of naked DNA and cellular debris within the mucus include rhADNase, which digests the naked DNA. Filamentous actin can be degraded by de-polymerizing agents such as gelsolin and thymosin β4. Mucoactive agents that reduce inflammation include the glycosaminoglycans discussed above, and in particular heparin, heparinoids and chondroitins. The use of said mucoactive agents allows the compositions of the present invention to simultaneously attack the excess of mucus in the pathways. air, but also that relieves one of the particularly unpleasant results of excess mucus, in specific inflammation, which is often the result of infection that is effectively promoted by excess mucus, as discussed above. As will be apparent from the above discussion of mucoactive agents suitable for use in the present invention, many of these agents actually present two or more of the desired effects on the mucus. For example, heparin reduces entanglement within the mucus and has an anti-inflammatory effect. Dextrans can alter the entanglement in the mucus as well as induce mucus dilution. It should be noted that heparin products such as unfractionated heparin include in a single product both high molecular weight and low molecular weight heparin. These different forms of heparin can have, as previously discussed different effects on the mucus, so that combinations of hydrogen bridge break, ionic interference and osmotic effect are observed from the administration of this individual product. In one embodiment of the invention, the composition comprises a glycosaminoglycan, and preferably a charged glycosaminoglycan. In another embodiment of the present invention, the composition comprises at least two mucoactive agents. In one embodiment, at least one of the mucoactive agents is a glycosaminoglycan. In another embodiment, said two or more mucoactive agents have different effects on the mucus relative to each other, as discussed above. The combination of different types of effects on the mucus, thanks to the different mechanisms to help eliminate the mucus discussed above, is surprisingly effective. It is believed that the combined effects to reduce the viscosity and elasticity of the mucus, allow the elimination of mucus from the lungs both through the action of coughing and through ciliary movement. In addition, some combinations of mucoactive agents have a synergistic effect. For example, in the past it was discovered that rhDNAase has limited effect on some patients and it was thought that this is the result of rhDNAase having difficulty in penetrating the mucus. However, when the rhDNAase is co-administered with another mucoactive agent that can alter the entanglements within the mucus, for example heparin, the rhADNase could penetrate more adequately the gel structure and therefore is more effective. Therefore, the effect of the combination of mucoactive agents is greater than the sum of the effects of the agents when they are administered individually. In a preferred embodiment of the invention, the composition includes a combination of an agent to reduce entanglement and an agent to dilute mucus. For example, the agent for reducing the entanglement can be heparin or heparin sulfate, cysteine, NAC or NAL, while the agent for diluting the mucus can be a low molecular weight sugar such as dextran. Another combination comprises a mixture of different heparins or heparinoids. Alternatively, the combination may comprise an agent for reducing entanglement, such as a glycosaminoglycan, plus dextran, mannitol and / or lactose, in order to increase the osmotic or hydrogen bridge breaking effect. In another embodiment, the composition comprises an agent for reducing entanglement, such as heparin, a heparinoid or another glycosaminoglycan and an amino acid such as lysine, cysteine or leucine. Another combination comprises heparin, dermatan sulfate and chondroitin sulfate. In another embodiment of the invention, the mucoactive agents are administered, either simultaneously or in sequence, with an antibiotic. For example, to treat CF, the antibiotic can be selected from tobramycin, gentamicin, ciprofloxin or colomycin. To treat COPD, the antibiotic can be amoxicillin, cotrimixazole or doxycycline. One or more antibiotics may be included in the composition with said one or more mucoactive agents. Even in another embodiment of the invention, the mucoactive agents are administered, either simultaneously or in sequence, with an anti-inflammatory agent. For example, the anti-inflammatory agent can be selected from diclofenac sodium, ketoprofen, ibuprofen, nedocromil and cromoglycate. The composition may include one or more anti-inflammatory agents with said one or more mucoactive agents. Even in another embodiment of the invention, the mucoactive agents are administered, either simultaneously or in sequence, with a surfactant. It is known that surfactants reduce the adherence of mucus and help it to be eliminated or can help spread the mucoactive composition once it is in the lungs. Surfactants such as lecithin, lung surfactants of natural or synthetic origin, or phospholipids such as DPPC, DPPE and other such lipids as are known in the art, they can conveniently affect the surface tension of the mucus and therefore help its elimination. Alternatively, the combinations may be one or more mucoactive agents with any one or more active agents that are selected from: 1) steroid drugs such as, for example, alcometasone, beclomethasone, beclomethasone dipropionate, betamethasone, budesonide, clobetazol, deflazacort, diflucortolone, deoximetasone, dexamethasone, fludrocortisone, flunisolide, fluocinolone, fluometholone, fluticasone, fluticasone propionate, hydrocortisone, triamcinolone, nandrolone decanoate, neomycin sulfate, rimexolone, methylprednisolone and prednisolone; 2) antibiotics and antibacterial agents such as, for example, metronidazole, sulfadiazine, triclosan, neomycin, amoxicillin, amphotericin, clindamycin, aclarubicin, dactinomycin, nystatin, upirocin and chlorine exidine; 3) anti-histamines such as, for example, azelastine, chlorpheniramine, astemizole, cetirizine, cinnarizine, desloratadine, loratadine, hydroxyzine, diphenhydramine, fexofenadine, ketotifen, promethazine, trimeprazine and terfenadine; 5) anti-inflammatory agents such as, for example, piroxicam, nedocromil, benzydamine, diclofenac sodium, ketoprofen, ibuprofen, nedocromil, cromoglycate, fasafungin and yodoxamide; 6) anti-cholinergic agents such as, for example, atropine, benzatropine, biperiden, cyclopentolate, oxybutynin, orfenadine hydrochloride, glycopyrronium, glycopyrrolate, procylidine, propantheline, propiverine, tiotropium, tropicamide, trospium, ipratropium bromide and oxitropium bromide; 7) bronchodilators, such as salbuta ol, fenoterol, formoterol and salmeterol; 8) sympathomimetic drugs, such as adrenaline, noradrenaline, dexamfetamine, dipirefin, dobutamine, dopexamine, phenylephrine, isoprenaline, dopamine, pseudoephedrine, tramazoline and xylometazoline; 9) anti-fungal drugs such as, for example, amphotericin, caspofungin, clotrimazole, econazole nitrate, fluconazole, ketoconazole, nystatin, itraconazole, terbinafine, voriconazole and miconazole; 10) local anesthetics such as, for example, amethocaine, bupivacaine, hydrocortisone, methylprednisolone, prilocaine, proxymetacaine, ropivacaine, thyrothricin, benzocaine and lignocaine; 11) pharmaceutically acceptable salts of any of the foregoing. The doses of mucoactive agents required for Having the desired effect of aiding mucus elimination depends clearly on the agents used. In general, the dose may comprise no more than 250 mg of one or more mucoactive agents, preferably no more than 200 mg, more preferred no more than 150 mg, more preferred still no more than 100 mg, no more than 50 mg or more. no more than 20 mg. In the case of glycosaminoglycans such as heparin and heparinoids, the preferred dose given tends to be high, because large amounts of these agents are required for the desired effect on the mucus. It is probable that the required daily dose is in the order of 100 to 200 mg per day and therefore the individual doses of these mucoactive agents should be in the region of 20-120 mg, preferably 40-80 mg or 50-60 mg. Other mucoactive agents, such as NAC and NAL can be effective at lower concentrations and therefore can be used at lower doses or can be administered less frequently. These are relatively large doses, even at the lower ends of the intervals and this presents some supply problems which are discussed below. The compositions of the present invention are quite suitable for the treatment of pulmonary diseases and other diseases, while overcoming the problems associated with current treatments of said diseases. Preferably, the compositions are used to treat diseases that have as a symptom the excessive formation of secretions of mucus in the airways, including chronic bronchitis, acute asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), bronchiectasis, hypersecretion resulting from damage to the epithelium such as allergic stimuli or mechanical abrasions, and nasal hypersecretion. In a particularly preferred embodiment of the first aspect of the invention, the composition for aiding mucus removal is in the form of a dry powder. Preferably, the size of the powder particles is selected for deposition within the lung in which the active agents have a local effect. In particular, particles with a MMAD of less than 10 μm, less than 8 μm, less than 7 μm, less than 5 μm, less than 3 μm or less than 2 μm are preferred. There is a general predisposition in this technical field against treating excess mucus in the lungs of a patient suffering from CF, COPD or the like with a dry powder formulation. In the past, these conditions were treated almost exclusively with solutions. Despite this predisposition, it has been found that formulating compositions comprising one or more mucoactive agents as a dry powder is linked to a number of significant advantages that they allow the invention to be carried out and to be practiced in a commercially attractive manner. When the solutions or suspensions are to be administered to the lung by inhalation, this is done by the use of nebulizers. These devices dispense the solutions or suspensions in the form of a fine mist, and these typically have a mask attached, so that the individual can inhale fine mist through the mouth or nose. However, nebulizers tend to be large devices and these are usually not portable, often because they are pressurized by an oxygen tank. For this reason, nebulizers tend to be used to dispense drugs to immobile patients and these are often unsuitable in situations where the easy and convenient (self-) administration of a drug is desired, as in the case of the present invention . An additional problem associated with the use of nebulizers is the difficulty in obtaining accurate information regarding the dose actually delivered to the patient. There is also a general lack of precision, reproducibility and efficiency in the supply of the drug, which leads to the need to increase the dose administered to ensure that the effect is achieved. desired therapeutic, which results in waste of medication and an increased risk of adverse effects. Finally, in cases where relatively large doses of an active agent are to be administered to a patient, this often requires the inhalation of fine mist over a prolonged period of time. For example, in a study of the effect of inhaled heparin, a relatively small dose of 8,000 IU of heparin has to be administered over a period of 15 minutes. This is obviously not a convenient mode of administration. In contrast, the devices used to deliver dry powder formulations are simple and relatively inexpensive, so that they can even be disposable. Also, the devices are small and therefore are easily portable. These are also very easy to use by the patient. However, there are problems associated with formulating the compositions of the present invention as a dry powder. Firstly, due to their poly-anionic nature, glycosaminoglycans are "sticky" molecules and it has been found that they readily form aggregates when provided in the form of particulate material. These aggregates are too large to reach the lung deep after they are inhaled. Secondly, in order to help the elimination of mucus from the airways, a large dose of mucoactive agent is required. For a dose of the order of tens of milligrams of active agent to be administered by inhalation of dry powder, a high dosing efficiency is required or an unacceptable amount of dust would have to be inhaled into the lungs. Dry powder inhalers that are currently available commercially tend to have a relatively low dosing efficiency. It has been discovered, with many of these dry powder formulations, that often only a small amount (typically only about 10%) of the active particles exiting the device in the inhalation is deposited in the lower lung. This is totally unacceptable in cases where it is necessary to administer a large dose. The present invention provides methods and compositions that allow the mucoactive agents to be dispensed efficiently as dry powders. These aspects of the invention are discussed in more detail below. Formulating dry powder formulations for use in the present invention presents problems, especially in cases where the composition includes a "sticky" glycosaminoglycan such as heparin or heparinoids. The nature of these compounds means that they do not carry themselves properly to formulations in the form of fine particulate material. Thus, it is necessary to employ special formulation techniques in order to produce a powder that can be dispensed in an efficient manner so that it can help in the elimination of mucus. If a simple dry powder formulation is used, the dosage efficiency should be such that it is possible to administer a sufficient amount of the mucoactive agent or agents to the lungs to obtain the desired effect of aiding mucus removal. The dosage efficiency is quite dependent on the fine particle fraction (FPF) of the dry powder formulation and it is necessary to add several excipients in order to ensure that a high enough FPF is achieved. A further obstacle to be able to deliver the composition of the present invention as a dry powder is the high dose of the mucoactive agents required to have an effect. The only way in which a sufficiently high dose can be administered without exposing the lungs to too much dry powder is that the dosage efficiency is high. The maximum common dose of drugs supplied using a dry powder is in the order of 5 mg. In the present invention, the doses often far exceed that level and, unless the dosing efficiency is very high, it simply will not be possible to deliver the required large doses of the mucoactive agent. Therefore, the present invention is not solely the decision to use certain mucoactive agents or combinations of these agents. Rather, there is a significant amount of work required to be able to bring the invention into practice so that it can be a pharmaceutical product. The composition according to the present invention can be dispensed using any device that is suitable for the pulmonary administration of a dry powder. Preferably, the composition is suitable for administration using a dry powder inhaler (DPI). The compositions of the present invention may also include other substances, such as stabilizers or excipient materials. The mucoactive agent particles generally comprise at least 1% mucoactive agent, at least 50%, at least 75%, at least 90%, at least 95%, or at least 99% agent mucoactive The mucoactive agent particles they may also include other substances such as stabilizers or excipient materials. Other particles or materials included in the composition are intended to assist in the efficient and reproducible delivery of active particles from the delivery device to the lower respiratory tract or deep lung and these will be discussed in more detail below. It is known that the provision of pharmaceutical compositions of dry powder to the respiratory tract presents certain problems. The inhaler device (usually a DPI) should provide the maximum possible proportion of active particles expelled to the lungs, including a significant proportion to the lower lung, preferably at low inhalation capacities to which some patients are limited. As a result, much work has been done to improve the dry powder formulations to increase the proportion of the active particles that are delivered to the lower respiratory tract or deep lung. The type of dry powder inhaler used affects the efficiency of delivery of active particles to the respiratory tract. In addition, the physical properties of the powder affect both the efficiency and the reproducibility of the supply of the active particles and the site of deposition in the respiratory tract. After leaving the inhaler device, the active particles must form a physically and chemically stable aerocolloid that remains in suspension until it reaches a conductive bronchiole or smaller branch of the respiratory tree or other absorption site, preferably in the lower lung. Preferably, active particles are not exhaled from the absorption site. When a formulation is supplied to the lung for local action, the size of the active particles within the formulation is very important in determining the site of absorption in the body. For the formulations to reach the deep lung by inhalation, the active agent in the formulation must be in the form of particles (active particles) that are very thin, for example having an aerodynamic diameter of the mass median (MMAD) less than 10 μm. It has been well established that particles with a MMAD greater than 10 μm are likely to collide in the walls of the throat and usually do not reach the lung. Particles that have a MMAD of 5 to 2 μm will usually be deposited in the respiratory bronchioles while particles that have a MMAD of 3 to 0.05 μm are likely to be deposited in the alveoli and are absorbed into the bloodstream. Because the mucoactive agents are going to act directly on the mucus in the airways, the dry powder composition should be formulated for supply to the lower respiratory tract. Therefore, the dry powder formulation should preferably comprise particles of the mucoactive agent having a MMAD less than 10 μm or about 2-5 μm. Preferably, at least 90% by weight of the mucoactive particles have a diameter within this range. Due to the poly-anionic nature of glycosaminoglycans, they readily form aggregates when provided in particulate formation. These aggregates are very large so that they reach the deep lung. However, the inventors have been able to provide formulations of particulate material comprising mucoactive agents such as glycosaminoglycans that can be converted into aerosol in a dry powder inhaler and delivered to the deep lung. Conveniently, the compositions of the present invention comprise at least 30%, at least 50%, at least 75%, at least 90%, at least 95% or at least 99% by weight of the agent mucoactive based on the total weight of the formulation.

In addition to the "sticky" nature of the mucoactive agents, the fine particles are also unstable from the thermodynamic point of view due to their high ratio of surface area to volume, which provides a significant excess of surface free energy and encourages the particles agglomerate. In the inhaler, the agglomeration of small particles and the adherence of said particles to the walls of the inhaler are problems that result in the fine particles coming out of the inhaler as stable, large agglomerates, or that can not leave the inhaler and remain adhered to the inhaler. inside the inhaler or even obstruct or block the inhaler. The uncertainty as to the degree of formation of stable agglomerates of the particles between each actuation of the inhaler and also between different inhalers and different batches of particles, leads to a low reproducibility of the dose. Also, the formation of agglomerates means that the MMAD of the active particles can be greatly increased, so that the agglomerates of the active particles do not reach the desired part of the lung for the required therapeutic effect. In accordance with a preferred embodiment, the compositions of the present invention provide first place a fine particle fraction (FPF) and a high fine particle dose (FPD) after aerosolizing the formulation. Additionally, the compositions comprise particles with the correct MMAD that will be deposited in the correct part of the lung. Conveniently, the present invention has identified a number of simple methods for preparing these compositions having suitable FPF and FPD values and exact particle size range. The measured dose (MD) of a dry powder formulation is the total mass of active agent present in the measured form presented by the inhaler device in question. For example, the MD should be the mass of active agent present in a capsule for a Cyclohaler device (trademark), or in thin metal foil bubble packaging in an Aspirair device (trademark). The emitted dose (ED) is the total mass of the active agent emitted from the device after actuation. This does not include the material remaining on the internal or external surfaces of the device, or in the dosing system including, for example, the capsule or bubble pack. The ED is measured by collecting the total mass emitted from the device in an apparatus frequently identified as a sampling device of dose uniformity (DUSA), and recovering it by means of a validated quantitative wet chemical test. The fine particle dose (FPD) is the total mass of active agent that is emitted from the device after the drive that is present in a smaller aerodynamic particle size than that of a defined boundary. In general, this limit is considered as 5 μm if it is not expressly stated that there is an alternative limit, such as 3 μm or 2 μm, etc. FPD is measured using an impact meter or collider, such as a twin-deck collision (TSI), multiple-platform liquid collision (MSLI), an Andersen cascade impact meter (ACI), or an impact measuring device. new generation (NGI). Each impact or collision meter has predetermined aerodynamic particle size collection cutoff points for each platform. The value of FPD is obtained by interpreting the recovery of active agent platform by platform, quantified by a validated quantitative wet chemical test, whether an individual platform cut is used to determine the FPD or a mathematical interpolation is used more complex platform-by-platform deposition. The fine particle fraction (FPF) is usually defined as the FPD divided by the ED and expressed as a percentage. In the present invention, the FPF of ED is referred to as FPF (ED) and is calculated as FPF (ED) = (FPD / ED) x 100%. The fine particle fraction (FPF) can also be defined as the FPD divided by the MD and expressed as a percentage. In the present invention, the FPF of MD is referred to as FPF (MD), and is calculated as FPF (MD) = (FPD / MD) x 100%. The tendency of fine particles to agglomerate means that the FPF of a given dose is highly unpredictable and that as a result a variable proportion of the fine particles is administered to the lung, or to the correct part of the lung. In an attempt to improve this situation and to provide consistent FPF and FPD, dry powder formulations often include additive material. The additive material is intended to reduce the cohesion between the particles in the dry powder formulation. It is believed that the additive material interferes with the weak bonding forces between the small particles, helping to keep the particles separate and reducing the adhesion of said particles to each other, to other particles in the formulation if present and to the interior surfaces of the particles. inhaler device. In cases in which particle agglomerates are formed, the addition of particles of additive material reduces the stability of said agglomerates so that these are most likely broken in the turbulent airflow created by operating the inhaler device, after which the particles are expelled from the device and inhale As the agglomerates break, the active particles return to the form of small individual particles which can reach the lower lung. In the prior art, dry powder formulations are discussed that include different particles of additive material (generally of a size comparable to that of the fine active particles). In some embodiments, the additive material can form either a continuous coating or a discontinuous coating on the active particles and / or any carrier particles. Preferably, the additive material is an anti-adherent material and can have a tendency to reduce the cohesion between particles and also can prevent the fine particles from adhering to the interior surfaces of the inhaler device. Conveniently, the additive material is an anti-friction or slip agent and produces a more adequate flow of the pharmaceutical composition in the inhaler. The materials Additives used in this way may not necessarily be referred to in the usual manner as anti-adherents or anti-friction agents, but rather they have the effect of reducing the cohesion between the particles or improving the flow of the powder. Additive materials are often known as force control agents (FCA) and these usually lead to more suitable dose reproducibility and higher fine particle fractions. Therefore, as used in the present invention, an FCA is an agent whose presence on the surface of a particle can modify the adhesive and cohesive surface forces experienced by said particle, in the presence of other particles. In general, its function is to reduce both forces, the adhesive and the cohesive. In general, the optimum amount of additive material to be included in a dry powder formulation depends on the chemical composition and other properties of the additive material and the active material, as well as on the nature of other particles such as carrier particles. , if these are present. In general, the effectiveness of the additive material is measured in terms of the fine particle fraction of the composition.

The known additive materials usually consist of physiologically acceptable material, although the additive material may not always reach the lung. For example, in cases where the additive particles are attached to the surface of the carrier particles, these are usually deposited, together with said carrier particles, in the back of the user's throat. In a further attempt to reduce agglomeration of fine active particles and to provide consistent FPF and FPD, dry powder formulations often include coarse carrier particles of excipient material mixed with fine particles of active material. Instead of adhering to each other, the fine active particles tend to adhere to the surfaces of the coarse carrier particles while in the inhaler device, but these must be released and dispersed after actuation of the dispensing device and inhalation to the inside the respiratory tract, to produce a fine suspension. These carrier particles preferably have MMAD values greater than 60 μm. The inclusion of coarse carrier particles is attractive in cases in which relatively small doses of active agent are supplied. It is very difficult Exactly and reproducibly supplying very small amounts of powder and small variations in the amount of powder dispensed mean large variations in the dose of active agent in cases where the powder mainly comprises active particles. Therefore, the addition of a diluent, in the form of large excipient particles, makes the dosage more reproducible and accurate. However, the doses of mucoactive agents such as heparin required to achieve an effect on mucus clearance are relatively large. This means that the inclusion of carrier particles in some of the compositions according to the invention to increase FPF and FPD values is not attractive or simply not an option. If included in the compositions of the present invention, the carrier particles could be of any acceptable excipient material or combination of materials. For example, the carrier particles may be constituted by one or more materials that are selected from sugar alcohols, polyols and crystalline sugars. Other suitable vehicles include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate and other organic compounds such as polysaccharides and oligosaccharides. Conveniently, the Carrier particles are constituted by a polyol. In particular, the carrier particles can be crystalline sugar particles, for example mannitol, dextrose or lactose. Preferably, the carrier particles are constituted by lactose or mannitol, which is a mucoactive agent, as discussed above. Conveniently, substantially all (by weight) the carrier particles have a diameter that is between 20 μm and 1000 μm, more preferably 50 μm and 1000 μm. Preferably, the diameter of substantially all (by weight) the carrier particles is less than 355 μm and is between 20 μm and 250 μm. Preferably, at least 90% by weight of the carrier particles have a diameter between 40 μm to 180 μm. The relatively large diameter of the carrier particles improves the opportunity for other, smaller particles to adhere to the surfaces of the carrier particles and provide suitable flow and entrapment characteristics, as well as the improved release of the active particles in the carriers. airways to increase the deposition of active particles in the lower lung. The proportions in which the carrier particles (if present) are mixed and the active particles of mixed material depend, of course, on the type of the inhaler device used, the type of active particles used and the dose required. The carrier particles can be present in an amount of at least 50%, preferably 70%, conveniently 90% and most preferably 95% based on the combined weight of the active particles of mixed material and the particles carriers. However, an additional difficulty is encountered when adding coarse carrier particles to a composition of fine active particles and said difficulty is to ensure that the fine particles are released from the surface of the large particles after the supply device is operated. The step of dispersing the active particles from the other active particles and the carrier particles, if present, to form an aerosol of fine active particles for inhalation is significant in determining the proportion of the dose of active material reaching the active ingredient. desired site of absorption in the lungs. In order to improve the efficiency of said dispersion it is known that additive materials, including FCAs of the nature discussed above, must be included in the composition. Compositions comprising fine active particles and additive materials are described in WO 97/03649 and WO 96/23485.

In view of the above problems associated with the known dry powder formulations, even when these include additive material and / or carrier particles, it is an object of the present invention to provide dry powder compositions having physical and chemical properties that lead to an FPF. and improved FPD. This leads to a higher dosage efficiency, in which a greater proportion of the active agent dispensed reaches the desired part of the lung to achieve the required therapeutic effect. In particular, the present invention seeks to optimize the preparation of active agent particles used in the dry powder composition by designing the particles that make up the dry powder composition and, in particular, by designing the active agent particles. Also, the cohesion between particles must be reduced in order to increase the FPF and the FPD of the dry powder compositions. This is done by preparing the heparin particles in the presence of an ACF. Although the FPF and FPD of a dry powder formulation depend on the nature of the powder itself, these values are also influenced by the type of inhaler used to dispense the powder. Dry powder inhalers can be "passive" devices in which the patient's breath is the only source of gas that provides a driving force in the device. Examples of "passive" dry powder inhaler devices include the Rotahaler and Diskhaler (GlaxoSmithKline) devices and the Turbohaler (Astra-Draco) and Novolizer (trademarks) devices (Viatris GmbH). Alternatively, "active" devices can be used, in which a source of compressed gas or an alternative energy source is used. Examples of suitable active devices include Aspirair (trademark) (Vectura Ltd-see WO 01/00262 and GB2353222) and the active inhaler device produced by Nektar Therapeutics (as covered by US Patent No. 6,257,233). As a rule, FPF obtained using a passive device tends to not be as adequate as that obtained with the same powder but using an active device. In one embodiment of the invention, the dry powder composition has an FPF of at least 40%, and preferably has an FPF of at least 50%. The FPF (ED) can be between 50 and 99%, more preferably between 70 and 99% and even more preferred between 80 and 99%. The FPF (MD) can be at least 35%. Preferably, the FPF (MD) is between 40 and 99%, more preferred between 50 and 95% and even more preferred between 70 and 90%. Even in another modality, the composition Pharmaceutical comprising at least one mucoactive agent and a force control agent, the force control agent is preferably present on the surface of the mucoactive agent particles. In a further embodiment, the pharmaceutical composition comprises at least one mucoactive agent in combination with an active agent that is selected from the above list and an agent for strength control, the force control agent is preferably present on the surface of the mucoactive agent particles. The preferred ACFs to be included in the compositions of the invention can be any of the additive materials discussed above. Preferably, the FCA is selected from amino acids, and especially amino acids, peptides and hydrophobic polypeptides having a molecular weight between 0.25 and 1000 kDa and derivatives thereof, dipolar ions such as zwitterions, phospholipids such as lecithin, and metal stearates such as magnesium stearate. Particularly preferred are amino acids and especially leucine, lysine and cysteine. The known FCAs usually consist of physiologically acceptable material, although the FCA does not always reach the lung. For example, in cases where the FCA particles are attached to the surface of the carrier particles, these are usually deposited, together with said carrier particles, in the back of the user's throat. The FCAs used in the present invention can be film-forming agents, fatty acids and their derivatives, lipids and lipid-type materials, and surfactants, especially solid surfactants. Conveniently, the FCA includes one or more compounds that are selected from amino acids and derivatives thereof, and peptides and derivatives thereof. The amino acids, peptides and peptide derivatives are physiologically acceptable and produce the acceptable release of the active particles upon inhalation. It is particularly convenient that the FCA comprises an amino acid. The FCA may comprise one or more of any of the following amino acids: leucine, isoleucine, lysine, cysteine, valine, methionine, and phenylalanine. The FCA can be a salt or a derivative of an amino acid, for example aspartame, acesulfame K, or acetyl cysteine. Preferably, the FCA consists substantially of an amino acid, preferably of leucine, conveniently L-leucine. The D ~ and DL- forms can also be used. As indicated above, it has been discovered that L-leucine produces particularly efficient dispersion of active particles after they are inhaled. Lysine and cysteine are also useful as FCA. As discussed above, these amino acids are also mucoactive agents. In another embodiment, the amino acid is not glycine or alanine. The FCA may include one or more water soluble substances. This helps the absorption of the substance by the body if the ACF reaches the lower lung. The FCA may include dipolar ions, which may be zithers. Alternatively, the FCA may comprise a phospholipid or a derivative thereof. It has been discovered that lecithin is a suitable material to be used as an FCA. The FCA may comprise a metal stearate, or a derivative thereof, for example, sodium stearyl fumarate or sodium stearyl lactylate. Conveniently, the FCA comprises a metal stearate. For example, zinc stearate, magnesium stearate, calcium stearate, sodium stearate or lithium stearate. Preferably, the FCA comprises magnesium stearate. The FCA may include or consist of one or more surfactant materials, in particular materials that are surfactants in the solid state. These may be soluble in water or may form a suspension in water, for example lecithin, in particular soy lecithin, or substantially insoluble in water, for example fatty acids in the solid state such as oleic acid, lauric acid, palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives (such as esters and salts) thereof, such as glyceryl behenate. Specific examples of such materials are: phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, phosphatidylinositol and other examples of surfactants of natural and synthetic origin for lung; lauric acid and its salts, for example, sodium lauryl sulfate, magnesium lauryl sulfate; triglycerides such as Dynsan 118 and Cutina HR; and sugar esters in general. Alternatively, the FCA may be cholesterol or natural cell membrane materials, including pollen or cell wall components of spores such as sporo-pollenins. Other possible FCAs include sodium benzoate, hydrogenated oils that are solid at room temperature, talcum, titanium dioxide, aluminum dioxide, silicon dioxide and starch. In the embodiments, a plurality of different FCAs may be used. In accordance with a second aspect of the present invention, methods are provided for producing compositions in accordance with the first aspect of the invention. invention. Spray drying is a well-known and widely used technique to produce particles of material. To briefly summarize, the material to be converted into particles is dissolved or dispersed in a liquid or it can be processed as a liquid which is sprayed through a pressure nozzle to produce a mist or flow of fine liquid droplets. These fine droplets are normally exposed to heat which rapidly evaporates the excess volatile liquid in the droplets, effectively leaving dry powder particles. In accordance with another aspect of the present invention, the compositions of the present invention are prepared by spray drying. In one embodiment, the spray drying process involves co-spraying said one or more mucoactive agents with one or more agents for strength control. The combination or mixture of one or more mucoactive agents, optionally one or more other additional active agents, and FCA which is subjected to spray drying to form a dry powder formulation can be a solution or suspension in a liquid host. In some embodiments, all or at least a proportion of the mucoactive agent and / or FCA is or are in solution in the host liquid before it is subjected to spray drying. Substantially all of the mucoactive agent and FCA may be in solution in the host liquid before they are subjected to spray drying. Said one or more mucoactive agents are preferably at least 1.5, 2, 4 and, more preferred, at least 10 times more soluble than the FCA in the host liquid at the temperature and pressure of sprinkling. In preferred embodiments, this relationship exists at a temperature between 30 and 60 ° C and atmospheric pressure. In other embodiments, this relationship exists at a temperature between 20 to 30 ° C and atmospheric pressure, or, preferably, at 20 ° C and atmospheric pressure. In addition to the spray drying technique discussed above, alternative techniques can be used to produce fine particles, such as freeze and spray drying and freeze drying. In another embodiment of the invention, said one or more mucoactive agents are subjected to spray drying using an unconventional spray drying device comprising means for producing droplets moving at a controlled rate and of a predetermined size. The advantages of this control of the formation of tiny droplets and drying profile is discussed in more detail later. Finally, the spray drying process may also include an additional step in which the moisture content of the particles subjected to spray drying is adjusted, in order to "fine-tune" the properties of the particles. This is also discussed in more detail later. It has been found that the FPF and FPD of the dry powder formulation is affected by the means used to create the tiny droplets that are spray-dried. Different means for forming the droplets can affect the size and size distribution of the tiny droplets as well as the speed at which tiny droplets travel when formed and the flow of gas around the droplets. In this sense, the velocity at which the droplets travel when formed and the gas flow (which is usually air) around the droplets can dramatically affect the size, size and shape distribution of the resultant dry particles. A method is provided for preparing a dry powder composition, wherein said one or more mucoactive agents are subjected to spray drying using a spray drying device comprising means for producing droplets moving at a controlled rate and a droplet size predetermined. The The speed of the droplets is preferably controlled in relation to the body of the gas in which they are sprayed. This can be achieved by controlling the initial velocity of the droplets and / or the velocity of the body of the gas within which they are sprayed. It would clearly be desirable to be able to control the size of the droplet formed during the spray drying process and the size of the droplet affects the size of the dry particle. Preferably, the means for droplet formation also produce a relatively narrow droplet, and hence a particle size distribution. This leads to a dry powder formulation with a more uniform particle size and therefore more predictable and consistent FPF and FPD values. Being able to control the speed of the droplet also allows additional control over the properties of the resulting particles. In particular, the velocity of the gas around the droplets affects the speed at which the droplet dries. In the case of tiny, rapidly moving drops, such as those formed using a two fluid nozzle arrangement (airborne spray), the air around the droplet is constantly replaced. As the solvent evaporates from the tiny droplets, moisture enters the air around the tiny droplets. If this humid air is replaced constantly by dry air, new, the evaporation rate increases. Conversely, if the droplet moves through the air slowly, the air around the tiny droplet is not replaced and the high humidity around the tiny droplet slows down the drying rate. As discussed in more detail below, the speed at which a droplet dries affects various properties of the formed particles, including FPF and FPD. Preferably, the speed of the droplets at 10 mm from their point of generation is less than 100 m / s, more preferred less than 50 m / s and more preferred even lower than 20 m / s. Preferably, the gas velocity, used in the generation of the droplets, at 10 mm from the point at which the tiny droplets are generated is less than 100 m / s, more preferred less than 50 m / s and more preferred still lower of 20 m / s. In one embodiment, the velocity of the droplets relative to the body of the gas in which they are sprayed, at 10 mm from their point of generation, is less than 100 m / s, more preferred less than 50 m / s and more preferred still less than 20 m / s. Preferably, the means for producing droplets that move at a controlled rate and of a predetermined size is an alternative to the commonly used two fluid nozzle. In one modality, it is used an ultrasonic nebulizer (USN for its acronym in English) to form the droplets in the process of spray drying. Although ultrasonic nebulizers (USNs) are known, these are conventionally used in inhaler devices, for the direct inhalation of solutions containing a drug, and previously these have not been widely used in a pharmaceutical spray drying apparatus. It has been discovered that the use of said nebulizer in a process for spray-drying particles for inhalation has a number of important advantages and these have not been previously recognized. Preferred USNs control the speed of the droplets and therefore the rate at which the particles are dried, which in turn affects the shape and density of the resulting particles. The use of USNs also provides an opportunity to perform spray drying on a larger scale than hitherto possible using conventional spray drying apparatuses with conventional types of nozzles used to create the droplets, such as the two fluid nozzles. Because the USNs do not require a high gas velocity to generate the droplets, the dryer can provide more control of the shape, velocity and direction of the plume that are possible with atomizers, pressurized or rotating of two conventional fluids. Therefore, the advantages include reduced wall deposition of the dryer, better controlled and more consistent drying speed. The reduced velocity of the plume means that smaller drying units are possible. Preferred USNs use an ultrasonic transducer which is immersed in a liquid. The ultrasonic transducer (a piezoelectric crystal) vibrates at ultrasonic frequencies to produce the short wavelengths required for atomization of the liquid. In a common form of USN, the glass base is held in such a way that the vibrations are transmitted from its surface to the nebulizer liquid, either directly or through a coupler liquid, which is normally water. When the ultrasonic vibrations are intense enough, a liquid source forms on the surface of the liquid in the nebulizer chamber. Large drops are emitted from the apex and a "mist" of tiny droplets is emitted. Figure 1 shows a schematic diagram representing the way in which a standard USN works. Preferably, the performance for each individual piezoelectric unit (for a unit that oscillates to > 1. 5 MegaHz) is greater than 1.0 cm3 / min, greater than 3.0 cm3 / min, greater than 5.0 cm3 / min, greater than 8.0 cm3 / min, greater than 10.0 cm3 / min, greater than 15.0 cmVmin or greater than 20.0 cm3 / min . Then said units must produce dry particles in which at least 90% by weight of the particles have a size of less than 3 μm, less than 2.5 μm or less than 2 μm, as measured using a Malvern Mastersizer apparatus from of a dry powder dispersion unit. Preferably, the performance for each individual piezoelectric unit (for a unit that oscillates at> 2.2 MegaHz) is greater than 0.5 cirrVmin, greater than 1.0 cm3 / min, greater than 3.0 cm3 / min, greater than 5.0 cm3 / min, higher of 8.0 cm3 / min, greater than 10.0 cm3 / min, greater than 15.0 cm3 / min or greater than 20.0 cm3 / min. These units should then produce dry particles with d (90) less than 3 μm, less than 2.5 μm, or less than 2 μm, as measured using a Malvern Mastersizer from a dry powder dispersion unit. The attractive characteristics of USNs for producing dry powders of fine particles for inhalation include: low spray speed; the small amount of carrier gas required to operate the nebulizers; the comparatively small droplet size and the narrow droplet size distribution produced; the simple nature of the ÜSN (the absence of moving parts that can wear out, contamination, etc.); the ability to accurately control the flow of gas around the droplets, thereby controlling the speed of drying; and the high rate of yield that makes the production of dry powders using the USNs commercially viable in a way that is difficult and expensive when using a conventional two-fluid nozzle arrangement. This is because the scaling of conventional spray drying apparatuses is difficult and the use of space is inefficient in conventional spray drying apparatuses which means that spray drying on a large scale requires many appliances and much more. space on the floor. The USN does not separate the liquid into droplets increasing the speed of the liquid. Instead, the necessary energy is provided by the vibration caused by the ultrasonic nebulizer. Also, USNs can be used to adjust droplet drying and to control the expression of the agent for force control on the surface of the resulting particles. In cases where the active agent itself can act as an agent for force control, spray drying with a USN can also help control the positioning of the hydrophobic portions so that the effect of including an agent for force control even without one being included. Therefore, as an alternative to the conventional two-fluid Büchi nozzle, an ultrasonic nebulizer can be used to generate droplets, which are then dried inside the Büchi drying chamber. In one arrangement, the USN is placed in the supply solution comprising an active agent in a specially designed glass chamber that allows the introduction of the cloud of droplets generated by the ÜSN directly into the hot drying chamber of the dryer by aspersion. The two-fluid nozzle is left in place-to seal the hole in which it normally sits, but does not ignite the compressed air. The drying chamber is then heated to an inlet temperature of 150 ° C, adjusting the vacuum cleaner to 100%. Due to the negative pressure of the Büchi system, the cloud of nebulized droplets is easily attracted to the interior of the drying chamber, where the droplets are dried to form particles, which are subsequently classified by the cyclone, and are collected in the container for harvesting. It is important that the level of the supply solution in the chamber is regularly filled to the marked level to avoid over concentration of the supply solution as a result of continuous fogging. When a spray drying process involves the use of a conventional nozzle to form the droplets to be dried, such as a two fluid nozzle, the high rates of flow velocity of the gas around the droplets lead to a velocity of quick drying In comparison, because the velocity of the gas around the droplets that are formed using an ÜSN is low in comparison, the droplets that are formed using a USN are dried more slowly than those produced using the conventional two fluid nozzles. This has several marked effects on the particles produced. In cases where the droplets dry quickly, a wrinkled particle morphology is observed, especially when the active agent is co-dried by spraying with an FCA. It is considered that the reduced rate of evaporation of the solvent from the droplets formed using a USN leads to a reduced "blowing" which is the phenomenon that leads to the wrinkled morphology of the particle. Therefore, primary particles physically smaller and smoother than those observed when the particles are produced using a USN.

It is also speculated that the slower drying speed than that expected when the droplets are formed using the USN allows the ACF that co-dries by spray to migrate to the surface of the droplet during the drying process. This migration can also be aided by the presence of a solvent (polar) that encourages the hydrophobic portions of the FCA to be positioned on the surface of the droplet. For example, in this sense it is believed that an aqueous solvent will be useful. With the FCA able to migrate to the surface of the droplet so that it is present on the surface of the resulting particle, it is evident that a greater proportion of the FCA that is included in the droplet will actually have the effect of controlling the force (because the ACF must be present on the surface so that it has its effect). Therefore, it is also concluded that the use of USNs has the additional advantage that it requires the addition of a smaller amount of FCA to produce the same force control effect in the resulting particles, as compared to the particles that are present. They produce using conventional spray drying methods. Naturally, in cases where the active agent itself has hydrophobic portions which can be presented as a dominant composition on the surface of the particle, excellent values of FPF and FPD can be obtained with little or no separate FCA. In effect, in such circumstances, the active agent by itself acts as an FCA, due to the arrment of its hydrophobic portions on the surfaces of the particles. Previously it was thought that wrinkled particle morphology was desirable since it was believed that it would help reduce the adhesion and cohesion of the particle. Previously it was also speculated that this particle morphology could even help the particles to fly when they are expelled from the inhaler device. However, despite this speculation, the inventors actually believe that the chemical nature of the particle surfaces can even more influence the performance of the particles in terms of FPF, ED, etc. In particular, it is believed that the presence of hydrophobic portions on the surface of the particles is more significant to reduce cohesion than the presence of craters or corrugations. Therefore, contrary to the suggestion in the prior art, it is not necessary to seek to produce extremely wavy or wrinkled particles in order to provide adequate FPF values. Indeed, it is really convenient not to produce severely wavy or wrinkled particles, because these can produce low density powders, with a very high amount of empty space between particles. Said powders occupy a large volume in relation to their mass as a consequence of this form, and can result in packaging problems, that is, bubble or very large capsules are required for a given mass of powder. High density powders, such as those produced using the USNs in a spray drying process may, therefore, be beneficial, especially in the present invention in cases where the dose of active agent that is going to administer is high. Even, as indicated above, the effect of the FCA included in the spray-dried particles is amplified when the droplets are formed using alternative means, such as a USN, due to the migration of the additive towards the surface of the particle. This in turn means that less FCA needs to be included and, in cases where high doses of active agent are required, this is an additional advantage. Preferably, the powder according to the present invention has a packed density of at least 0.1 g / cm3, at least 0.2 g / cm3, at least 0.3 g / cm3, at least 0.4 g / cm3 or per at least 0.5 g / cm3. As discussed above, at least some of the mucoactive agents that will be included in the compositions of the present invention are required in large quantities. Therefore, it is not desirable to include additional materials such as vehicles or agents for volume in the compositions or in the particles. Therefore, in one embodiment of the invention, the spray drying method for producing the particles to be used in the compositions of the present invention does not involve the joint drying by spraying the active agent with a vehicle or bulking agent. One would expect to obtain results similar to those shown above using the ÜSN when using other means that produce low speed droplets at high production rates. For example, additional alternative nozzles can be used, such as electro-spray nozzles or nozzles with vibrating orifice. These nozzles, like the ultrasonic nozzles, are free of momentum, which results in a spray that can be easily directed by a flow of carrier air. However, its production speed is generally lower than that of the ÜSN described above. Another attractive type of nozzle to be used in a spray drying process is one that uses electro-hydrodynamic atomization. It is created a cone tailored, for example, in a fine needle applying high voltage at the tip. This disperses the drops in an acceptable monodispersion. This method does not use a gas flow, except to transport the droplets after drying. An acceptable monodispersion can also be obtained using a rotating disk generator. Nozzles such as ultrasonic nozzles, electro-spray nozzles or nozzles with vibrating orifice can be arranged in a multiple nozzle arrangement, in which many individual nozzle orifices are arranged in a small area and provide a high total solution yield of catering. The ultrasonic nozzle is an ultrasonic transducer (a piezoelectric crystal). If the ultrasonic transducer is located in an elongated container, the performance can be significantly increased. When the mucoactive particles are produced by spray drying, a certain amount of moisture remains in the particles. This is. especially the case in which the mucoactive agent is sensitive to temperature and does not tolerate elevated temperatures during the prolonged time interval that is normally required to remove additional moisture from the particles. The amount of moisture in the particles affects various particle characteristics, such as density, porosity, flight characteristics and the like. Therefore, a method for preparing a dry powder composition is also provided, wherein the method comprises a step of adjusting the moisture content of the particles. In one embodiment, the moisture setting or the profile formation step involves the removal of moisture. Said secondary drying step preferably involves freeze drying, in which the additional moisture is removed by sublimation. An alternative type of drying is vacuum drying. In general terms, secondary drying takes place after the active agent has been spray dried together by spraying with an FSA. In another embodiment, secondary drying occurs after the nebulized mucoactive agent has been spray dried, in which the active agent is optionally in a mixture with an FCA. The secondary drying step has two particular advantages. First, it can be selected to avoid exposing heparin to high temperatures for prolonged periods. Also, the removal of residual moisture by secondary drying can be significantly more economical than the removal of all moisture from the particle by drying by aspersion. Therefore, a combination of spray drying and freeze drying or vacuum drying is economical and efficient, and is suitable for pharmaceutically active agents sensitive to temperature. Secondary drying significantly reduces the moisture content of the mucoactive particles (from about 8.5% to about 2%). This implies that the mucoactive particles are dried in such a way that a hard outer shell is present which retains the residual moisture, which is expelled by secondary drying, and the additional moisture is trapped within a central core. It can be inferred that the residence time of the particle in the drying chamber is very short, and that the outer shell is formed quickly and is very hard to allow moisture to escape easily during the initial spray drying process. Secondary drying can also be beneficial for the stability of the product, by reducing the moisture content of a powder. This also means that drugs that can be very sensitive to heat can be spray-dried at lower temperatures to protect them, and then subjected to secondary drying to further reduce the moisture and thus protect the drug. In another embodiment of the third aspect of invention, the formation of the moisture profile involves increasing the moisture content of the particles subjected to spray drying. Preferably, moisture is added by exposing the particles to an atmosphere of humidity. The amount of added moisture can be controlled by varying the humidity and / or the length of time during which the particles are exposed to this moisture. After spray drying which optionally may also include secondary drying, it would be convenient to grind the powders, for example in an air jet mill, in order to separate any agglomerates of particles that have formed strong bridges between the particles. Even in a further embodiment of the present invention, instead of spraying said one or more mucoactive agents to form a dry powder formulation, it is also possible to use other methods to prepare a dry powder. For example, many dry powders are formed by micronization, that is, by grinding larger particles to form small particles of a desired size. Techniques known as co-grinding and mechano-fusion, such as those described in more detail in International Publication No. WO 02/43701, produce Active particles of mixed material and are also suitable for preparing the dry powder formulations of the present invention. The active particles of mixed material formed by co-grinding and mechano-fusion in the present invention are very fine particles of one or more mucoactive agents having, on their surfaces, an amount of an FCA. The FCA is preferably in the form of a coating on the surfaces of the particles of one or more mucoactive agents. The coating can be a discontinuous coating. The FCA may be in the form of particles that adhere to the surfaces of the particles of one or more mucoactive agents. As explained below, at least some of the active particles of mixed material may be in the form of agglomerates. When the active particles of mixed material are included in a pharmaceutical composition, the FCA promotes the dispersion of the active particles of mixed material by administering said composition to a patient, by actuation of an inhaler, as discussed above. Therefore, again, the presence of FCA can increase the FPF and FPD of dry powder formulations. It has also been discovered that the grinding of particles of one or more mucoactive agents in the presence of an FCA produces significantly smaller particles and / or requires less time and less energy than the equivalent procedure carried out in the absence of the FCA. This allows active particles of mixed material to be produced which have an aerodynamic diameter of the mass median (MMAD) or a median diameter of the volume (VMD) less than 5, 4, 3 or 2 μm. It is often much easier to obtain small particles by this method than by other grinding methods. It is known that a milling process tends to generate and increase the level of amorphous material on the surfaces of the ground particles thereby making them more cohesive. In contrast, it is often found that the mixed material particles of the invention are less cohesive after the milling treatment. The word "grinding" as used in the present invention refers to any mechanical process that applies sufficient force to particles of active material that can break coarse particles (e.g., particles having aerodynamic diameter of the mass median). greater than 100 μm) to fine particles with an aerodynamic diameter of the mass median no greater than 50 μm or applying a relatively controlled compression force as described below with relationship to the methods of mechano-fusion, cycle-mixing and similar methods. A high degree of force is required to separate the individual particles from one or more mucoactive agents (which tend to agglomerate, especially if these include heparin which is adhesive) to achieve effective mixing and effective application of the FCA to the surfaces of said particles. It is believed that a particularly desirable aspect of the milling process is that the FCA can be deformed in the mill and can be extended over or fused to the surfaces of the mucoactive particles. However, it should be understood that, in the case where the particles of one or more mucoactive agents are already fine, for example, having a MMAD less than 20 μm before the milling step, the size of said particles could not significantly reduced The important aspect is that the milling process applies a sufficiently high degree of force or energy to the particles. The method generally involves bringing the FCA particles into close contact with the surfaces of the mucoactive particles in order to obtain coated particles. A degree of intensive mixing is required to ensure a sufficient dissociation of the agglomerates of both constituents, the dispersion and including the distribution of ACF on mucoactive particles. As a consequence of the milling step, porous or non-porous, continuous or discontinuous, complete or partial coatings can be formed. The coatings originate from a combination of heparin and FCA particles. These are not coatings such as those formed by wet processes that require the dissolution of one or both components. In general, such wet coating processes are likely to be more expensive and more labor-intensive than the milling processes of the invention and also suffer from the disadvantage that it is less easy to control the location and structure of the coating. A wide range of milling devices and conditions are suitable for use in the method of the invention. Grinding conditions, for example, grinding intensity and duration, should be selected to provide the required degree of strength. Grinding with a ball mill is an appropriate grinding method. Grinding with a centrifugal and planetary ball mill are especially preferred methods. Alternatively, a high pressure homogenizer may be used in which a fluid containing the particles is forced to pass through a high pressure valve that produces conditions of tangential cut and high turbulence. Tangential shear forces on particles, impacts between particles and surfaces of the machine or other particles and cavitation due to fluid acceleration can all contribute to fracture of the particles and can also provide a compressive force. Such homogenizers may be more suitable than ball mills for use in large-scale preparations of active particles of mixed material. Suitable homogenizers include EmulsiFlex high pressure homogenizers which have a capacity for pressures up to 4000 bars, Niro Soavi high pressure homogenizers (with a capacity of pressures of up to 2000 bars), and Microfluidics micro-fluidification devices (maximum pressure 2750 bars). Alternatively, the milling step may involve a mill with high-energy means or a mill with stirring pellets, for example, the Netzch high-energy mill, or the DYNO-mill mill (Willy A. Bachofen AG, Switzerland ). Alternatively, milling may be a high energy dry coating process such as a mechano-fusion system (Hosokawa Micron Ltd), a Hybridizer device (Nara) or any highly intense compressive procedure. Other possible milling devices include air jet mills, pin mills, hammer mills, knife mills, ultra-centrifugal mills and pestle and mortar mills. The especially preferred methods are those involving the MechanoFusion, Hybridiser and Cyclomix equipment. An air jet mill is also especially preferred. Other suitable methods include ball mills and high energy media which can also provide the desired high shear stress and compression stress between the surfaces, although because the tolerance space is not controlled, the coating process can be control in a less suitable way than that for the milling by mechano-fusion and may present some problems such as the degree of unwanted re-agglomeration. These mills with means may be of a rotating, vibrating, agitating, centrifugal or planetary nature. It has been observed in some cases that when grinding the mucoactive particles with additive material with a ball mill, no fine powder is produced. Instead the powder is compacted on the walls of the mill by the action of the mill. This inhibits the grinding action and avoids the preparation of active particles of mixed material. Said problem occurs particularly when certain additive materials are used, in cases where the additive material is present in small proportions (typically <; 2%), in cases where the mill balls are relatively small (typically <3 mm), in cases where the milling speed is very slow and in cases where the starting particles are very fine. To prevent this from happening, it is convenient to grind with a ball mill in a liquid medium. The liquid medium reduces the tendency to compaction, helps in the dispersion of the additive material and improves any grinding action. The liquid medium may be of low or high volatility and of any solids content as long as it does not dissolve the mucoactive particles to any significant degree and its viscosity is not so high that it prevents effective milling. Preferably the liquid medium is non-aqueous. The liquid of preference is one in which the additive material is substantially insoluble but some degree of solubility may be acceptable as long as sufficient additive material is present so that particles of additive material remain undissolved. Suitable liquid media include diethyl ether, acetone, cyclohexane, ethanol, isopropanol or dichloromethane. Preferred are liquid media which are non-flammable, for example dichloromethane and fluorinated hydrocarbons, especially fluorinated hydrocarbons which are suitable for use as propellants in inhalers. The results of heparin spray drying and heparin jet milling with an FCA (heparin + leucine (95: 5)) are indicated below in Table 1.

TABLE 1 Study of heparin particle size with FCA subjected to spray drying and jet milling Heparin and leucine (95: 5) are spray-dried in a 2% (w / w) solution using a SL10 spray-drying apparatus with a conventional two-fluid atomizer. The powder is subjected to spray drying at a temperature of 250 ° C and an air pressure at the nozzle of 5,624 kg / cm2. The liquid flow rate used is 32 ml / min. The resulting powder is collected in a cyclone. This powder is then subjected to secondary drying under vacuum. The powder is then used to fill capsules to 20 mg, and then fired from a Monohaler device into a twin-deck collider. The resulting FPF (MD) is 37%. The FPF (MD) is increased up to 40% after a subsequent grinding with air jet of the powder to reduce any solid bridges between the particles in the agglomerates. The powder is also analyzed using a Malvern particle size meter. The combination of heparin and leucine (95: 5) is also subjected to air jet milling using a Micron AS50 mill from Hosokawa. The material is passed through the mill twice. The powder is also analyzed by the Malvern particle size meter. The value d (50) and the FPF (MD) are similar to the results obtained in the powders subjected to drying by previous spray. Pure heparin powder is subjected to grinding with air jet with two passes and produces an FPF (MD) of only 7%. The d (50) of this powder is substantially larger than that of the sample containing leucine subjected to air jet grinding. In a further example, a USN is used to prepare dry powders using a solution providing an active agent (heparin) alone, and a combination of active agent with 1% to 5% and 10% w / w FCA (L-leucine) The output speed of the ultrasonic nebulizer is 130 ml / hr. The oven temperature of the nebulized powders is adjusted to 350 ° C. Figure 2 shows a schematic drawing of the ultrasonic equipment. In order to evaluate the processing of the powders, work is done using a Monohaler device and a capsule filled with 20 mg of powder and it is fired into a twin-platform collider (TSI) in the manner previously explained. The study uses a TSI flow rate of 60 Ipm with a cutoff fraction of approximately 5 μm. Three measurements are made for each combination and the results are presented in summary form below, providing the average values of the three sets of results obtained.

TABLE 2 Rapid TSI results using dry powder that is produced using a USN with varying amounts of FCA Formulation FPF% (dose FPD (mg) measured) Heparin (0% leucine) 1.1 0.22 Heparin + leucine (1% w / w) 17.4 3.5 Heparin + leucine (2% w / w) 30.2 6.0 Heparin + leucine (3% W / W) 28.6 5.7 Heparin + leucine (4% w / w) 48.4 9.7 Heparin + leucine (5% W / W) 41.5 8.3 Heparin + leucine (10! * P / P) 55.8 11.8 The results of rapid TSI using the dry powder that is produced using the USN indicate a very low efficiency of aerosol conversion for pure heparin particles, but an improvement in FPF appears with the addition of L-leucine as an FCA. In a particle size study, the particle size of particles subjected to spray drying that are formed using the USN is analyzed. The dry powders are dispersed at 4 bars in the Sympatec particle size meter (dry dispersion Helos). The values of d (10), d (50) and d (90) of the nebulized powders are measured with ultrasound and are indicated in the following table (10% by volume of the particles are one size, measured Using Sympatec, which is less than the value d (10), 50% by volume of the particles are of one size, measured using Sympatec, which is less than the value d (50) etc.). The values are an average of three measurements. In addition, the mass percentage of particles with a size smaller than 5 μm is obtained from the particle size data and expressed as FPF.

TABLE 3 Particle size study of particles subjected to spray drying using USN It can be seen that it has been discovered that the particles that are formed using a spray drying process involving an ultrasonic nebulizer have a higher FPF than those that are produced using a standard spray drying apparatus, for example. with a two fluid nozzle configuration. Also, it has been found that particles that are formed using a spray drying process using a USN have a narrower particle size distribution than those that are produced using a standard spray drying apparatus, for example with a configuration of two fluid nozzle. Clearly there are other known techniques for forming fine particles comprising a mucoactive agent and an FCA. Such techniques include, for example, techniques using super-critical fluids (SCFs), which have been explored for many years for particle production purposes. Similar to the spray drying technique, this technique provides direct formation of particles with size in the range of microns suitable for inhalation powders. The super-critical fluid technologies used most commonly for particle production are the rapid expansion of super-critical solutions (RESS) and super-critical anti-solvent (SAS) or anti-solvent gas (GAS) methods. . RESS is based on a rapid expansion of an SCF. The procedure involves dissolving the drug mixture in a SCF, followed by a rapid expansion of the fluid which causes the compound to precipitate. This technique can produce uniform particles, with control over the particle size and morphology distribution. However, this technique is limited by the fact that most drugs have low solubility in SCFs. SAS is a recrystallization process that is based on the ability of SCFs to act as an anti-solvent to precipitate the particles within a liquid solution. Unlike the RESS technique, SAS does not require a high solubility of the drug compounds in the SCFs. Therefore, SAS is commercially more viable for the production of dust. Recently, an increased dispersion in solution using super-critical fluids (SEDS) was introduced, see for example patent publications GB 2322326, WO 95/01324, WO 95/01221, E.U.A 5,851,453 and WO 96/00610. This technique is based on dispersion, solvent extraction and simultaneous particle formation in a highly turbulent flow. SEDS can generate crystalline and uncharged product, with the ability to control particle size and size distribution by manipulating the process conditions. Another strategy is the technique known as emulsion precipitation. This method can be used to prepare fine particles of mucoactive agent and one or more FCA. An experimental program is carried out to evaluate the mucolytic activity of selected mucoactive agents. The primary objective of this initial protocol is to determine the mucolytic activity (capacity to reduce the viscosity and elasticity and therefore affect the elimination capacity) of heparin in cystic fibrosis sputum at concentrations of potential clinical relevance. This constitutes the stage 1 experiment, following. The secondary objective is to compare heparin with other fractions of heparin in an evaluation test regarding activity, incorporated in the stage 2 experiment. The experiments are carried out using a protocol similar to that described by Sun. et al. (Sun F, Tai S, Lim T, Baumann U, King M (2002) "Additive effect of alpha alpha and Nacystelyn on transportability and viscoelasticity of cystic fibrosis sputum" Can Respir J, 9: 401-406). In stage 1, several concentrations of heparin are investigated, and the results are compared with vehicle control (normal saline solution 0.15M) and a control (Nacisteline). Sputum samples are collected from adult patients suffering from cystic fibrosis. The magnetic micro-rheometer is described by King (King M (1988) "Magnetic microrheometer" Methods in Bronchial Mucology, pp. 73-83). This instrument is used to measure the apparent viscosity and elasticity of microlitre quantities of mucus. A 100 μm steel pellet is carefully placed in a sample of 1-10 μl of mucus and oscillated by means of an electromagnetic field gradient. The movement of this sphere is tracked with the help of a photocell. Graphs of displacement of the pellet against magnetic force are used to determine the viscosity and elasticity of the mucus as a function of the applied frequency (1-100 rad / s). These rheological properties can be used to predict the effectiveness of mucus in elimination, both by ciliary action and by elimination by interaction of air flow. This instrument is particularly appropriate for the proposed studies that involve multiple sputum treatments due to the minimum sample requirement. Studies of mucociliary frog palate removal are also used in these studies. The epithelium of the frog's palate is coated with cilia and secretes and removes the mucus in a manner very similar to that of the mammalian trachea. Mucociliary clearance continues at a constant rate for several hours after sacrifice and extirpation of the palate (King M, Festa E (1998) "The evolution of the frog palate model for mucociliary clearance" Cilia, Mucus and Mucociliary Interactions, pp. 191-201). During this period, the mucociliary clearance rate of the palate can be modulated using agents that alter ciliary activity or that change the properties of the superficial fluid layer (mucus and peri-ciliary fluid). Waiting a little longer (1-2 days in the bull frog) the mucus secretion ceases while the ciliary activity continues for at least 5-6 days. During this prolonged period, mucus from endogenous or exogenous sources (for example cystic fibrosis) or mucus mimics are transported at speeds that are a reflection of their viscoelastic properties. The mucociliary velocity (MCV) is measured by observing the speed of movement of the endogenous mucus, using a calibrated macroscope and a chronometer. The MCV is calculated as the distance that the marker particle travels divided by the elapsed time (irati / s). An average of five consecutive runs is used for each test solution to calculate each MCV value. When interpreting the results of the studies discussed in the present invention, the primary variable of interest is the reduction in mucus viscoelasticity, expressed as delta log G * (corrected for vehicle treatment). A significant reduction in log G * is considered at a given concentration of heparin as a test that supports mucolytic activity. Mucociliary clearance capacity (speed of mucus removal treated sputum with respect to sputum treated with vehicle) is a second variable of interest. Mucolytic treatments that reduce the degree of entanglement without destroying the basic gel structure of the mucus should result in an improvement in its ability to eliminate in vi tro.

Step 1 (heparin dose-response) From each of the 10 CF sputum samples, up to 6 aliquots of approximately 10-15 mg each are incubated for 30 minutes at 37 ° C with either 0.9% NaCl. or with one of the concentrations of heparin or L-lysinate of N-acetylcysteine (NAL) (309 mcg / ml). Before and after the incubation, sputum viscoelasticity at 10 rad / s is determined by magnetic micro-reometry. The mucolytic effect of each solution is defined by the average fractional reduction in G * (vector sum of viscosity and elasticity) through the 10 samples analyzed. The results are presented in summary form in Figure 3. From the graph it can be seen that the agents analyzed have the desired activity and act as mucoactive agents. Also, while the lower dose of heparin has little effect, the activity of heparin is dose dependent and the increased doses are clearly effective and help in the elimination of mucus. It should also be mentioned that NAL is effective at a lower concentration compared to heparin.

Stage 2 (heparin fractions and / or heparin formulation) The design of this experiment is similar to that of stage 1, except for the use of fractions by heparin size and control of Nacisteline. The results are shown in figure 4. Data points 1 and 2 are for the heparin decasaccharide, points 3 and 4 are for heparin polysaccharide, and points 5 and 6 are for heparins without fractionating each to 1.6 mg / ml and 5 mg / ml respectively. The results show that there is little difference in the rheological effect of the two fractions of heparin against unfractionated heparin. Each of these results in a mucolytic effect dose dependent, ie a reduction in log G * that is greater for 5 mg / ml than for 1.6 mg / ml. At 5 mg / ml, the reduction in log G * for the original unfractionated heparin is a little greater than for the two new preparations. The dry powder compositions of the present invention are preferably delivered using an inhaler device, most preferred using a dry powder inhaler (DPI). This type of inhaler is commonly used for the pulmonary administration of a dry powder formulation. Therefore, in accordance with a further aspect of the invention, a DPI is provided to supply the composition of the present invention. The DPI may include a reservoir to contain the powder formulation and a metering mechanism to measure individual doses of the formulation from the reservoir. Examples of such devices include Turbohaler (trademark) (AstraZeneca) or Clickhaler (trademark) (Innovata Biomed Ltd). Alternatively, the dry powder inhaler may be arranged to use pre-measured doses of the packaged formulation, for example, in hard or soft gelatin capsules or in bubble packs. The Rotahaler (trademark) (GlaxoSmithlline), Spinhaler (trademark) (Rhóne-Poulenc Rorer), Cyclohaler (trademark) (Pharmachemie B.V.) and Monohaler (trademark) (Miat) are examples of this type of dry powder inhaler. The invention also provides a metered dose of the formulation contained, for example, in a hard or soft gelatin capsule or in a bubble pack. The aforementioned devices are passive devices, but active devices can also be used, such as an Aspirair device (trademark) (see - WO 01/00262 and GB 2353222). Preferably, the inhaler is arranged to dispense one or more doses. of the formulation, each dose comprising an effective amount of one or more mucoactive agents that will be made available for inhalation. The dose may comprise no more than 250 mg of one or more mucoactive agents, preferably not more than 100 mg, more preferred not more than 50 mg and more preferred not more than 20 mg of one or more mucoactive agents. The dose may comprise at least 5 mg of one or more mucoactive agents, preferably at least 20 mg, more preferred at least 50 mg. A preferred dose comprises 70-80 mg of one or more mucoactive agents. In another embodiment of the present invention, the DPI is adapted to deliver one or more mucoactive agents to the deep lung of a patient at a dose of at least 5,000 Ul. In accordance with another aspect of the present invention, a package is provided for use in an DPI containing an amount of the composition comprising at least 20 mg of one or more mucoactive agents. Preferably, the DPI according to the invention is arranged to use a packet according to the invention. In accordance with a still further aspect of the present invention, the compositions according to the invention are used for use in therapy. Preferably, these are for use in the treatment of lung diseases involving excess mucus in the airway areas or problems of mucus removal from the airways, of which the examples discussed above.

Claims (40)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS 1. - A composition to help eliminate mucus, the composition comprises one or more mucoactive agents to reduce entanglement within the mucus; to dilute the mucus; and / or to digest naked DNA and cell debris within the mucus.
2. 2. A composition according to claim 1, characterized in that one or more of the mucoactive agents can reduce inflammation.
3. 3. A composition according to claim 1 or 2, comprising two or more mucoactive agents.
4. 4. A composition according to any of the preceding claims, characterized in that the mucoactive agent or agents reduce the interlacing within the mucus and dilute the mucus.
5. 5. A composition according to any of the preceding claims, comprising one or more glycosaminoglycans.
6. 6. A composition according to claim 5, characterized in that the glycosaminoglycan is heparin and / or a heparinoid.
7. 7. A composition according to claim 6, characterized in that the heparinoid is sodium danaparoid, or dermatan sulfate. 8. - A composition according to claim 6, characterized in that the heparinoid contains heparin, dermatan sulfate and chondroitin sulfate. 9. A composition according to any of the preceding claims, comprising sulfated glycosaminoglycans, glycosaminoglycan polysulfate compounds, or sulfated mucopolysaccharides. 10. A composition according to any of the preceding claims, comprising a monosaccharide, a disaccharide and / or an oligosaccharide. 11. A composition according to any of the preceding claims, comprising dextran, dextrin, glucose and / or mannitol. 12. A composition according to any of the preceding claims, comprising an amino acid. 13. - A composition according to any of the preceding claims, comprising rhDNAase, gelsolin and / or thymosin β4. 14. A composition according to any of the preceding claims, comprising acetylcysteine and / or Nacysteine. 15. A composition according to any of the preceding claims, characterized in that the composition is a dry powder for pulmonary inhalation. 16. A composition according to claim 15, characterized in that the composition has a fine particle fraction (< 5 μm) of at least 50%, and preferably between 70 and 99% or between 80 and 99%. 17. A composition according to claim 15 or claim 16, characterized in that the composition has a fine particle dose between 50 and 90%, and preferably between 60 and 70%. 18. A composition according to any of claims 15-17, comprising particles of at least one mucoactive agent and an agent for force control. 19. A composition according to claim 18, characterized in that the agent for Force control is an amino acid or peptide, or derivatives thereof, a phospholipid or a metal stearate. 20. A composition according to claim 19, characterized in that the agent for strength control is leucine, lysine, cysteine, or mixtures thereof. 21. A composition according to claim 18, characterized in that the agent for force control is included in an amount of up to 50% w / w, preferably less than 10% w / w, and more preferably less than 5% p / p. 22. A composition according to any of claims 15-21, characterized in that the composition comprises particles of mucoactive agent having a MMAD less than 10 μm. 23. A composition according to claim 22, characterized in that the mucoactive agent particles have a MMAD of 2-5 μm. 24. A composition according to any of claims 15-23, characterized in that the composition also comprises carrier particles, in which, preferably, the carrier particles have a particle size of at least 20 μm. 25.- A pharmaceutical composition in accordance with any of claims 1-24, for use in therapy. 26. A pharmaceutical composition according to claim 25, for treating a lung disease. 27. A pharmaceutical composition according to claim 26, characterized in that the lung disease involves hyper-secretion of mucus or abnormal viscoelasticity of the mucus. 28. A pharmaceutical composition according to any of claims 26 or 27, characterized in that the lung disease is chronic bronchitis, acute asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) or bronchiectasis. 29. A method for treating a lung disease comprising administering a therapeutically effective amount of a pharmaceutical composition according to any of claims 1-24 to an individual in need of said treatment. 30. A method for producing particles for use in a composition according to any of claims 1-24, the method comprising spraying said one or more mucoactive agents. 31.- A method according to claim 30, characterized in that drying by Spraying involves the use of an apparatus for spray drying comprising means for producing droplets that move at a controlled rate. 32. A method according to claim 31, characterized in that the speed of the droplets at 5 mm from their point of generation is less than 20 m / s. 33.- A method according to claim 31 or 32, characterized in that the apparatus for spray drying comprises an ultrasonic nebulizer. 34.- A method according to any of claims 31-33, characterized in that said one or more mucoactive agents are dried together by spraying with an agent for force control. A method for producing particles for use in a composition according to any of claims 1-24, the method comprises subjecting the particles of said one or more mucoactive agents to jet milling in the presence of air or a gas or compressible fluid. 36.- A method according to claim 35, characterized in that the particles are subjected to jet milling in the presence of an agent for force control. 37. - A method according to any of claims 35 and 36, characterized in that the jet mill is operated at an inlet pressure between 0.1 and 3 bar. 38.- A method according to any of claims 35 and 36, characterized in that the jet mill is operated at an inlet pressure between 3 and 12 bars. 39.- A method according to any of claims 35-38, characterized in that at least 90% by volume of the active particles have a diameter smaller than 20 μm before jet milling. 40. A method according to any of claims 30-39, characterized in that 90% of the resulting dry particles have a size smaller than 10 μm, as measured by laser diffraction.