MXPA97004406A - Proliposomas powders for inhalac - Google Patents

Abstract

The present invention relates to a powder of proliposomes, the powder comprises in a single phase discrete particles of a biologically active component, together with a lipid or mixture of lipids having a phase transition temperature below 37

Description

INHALATION PROLIPOSOME DUSTS FIELD OF THE INVENTION The present invention relates to proliposome powders, particularly for inhalation, to a process for producing the proliposome powders, to compositions containing the proliposome powders, and to methods for their use. BACKGROUND TECHNIQUE Liposomes are membrane-like vesicles, which consist of a series of concentric lipid bilayers alternating with hydrophilic compartments. They can be made from a variety of natural and synthetic lipids, such as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipiods. One of the main uses for liposomes has been as carriers for different classes of pharmaceutically active components, to improve the distribution of the drug and to minimize the side effects of some treatments. The pharmaceutically active components can be incorporated into the liposomes either by encapsulation in hydrophilic compartments of the liposome a (when the active component is soluble in water), or by encapsulation in the lipid bilayers, when the active component is lipophilic. REF: 24884 One of the main problems associated with pharmaceutical liposomal formulations is long-term stability. Aqueous dispersions of liposomes have limited stability due to aggregation, loss of the active component encapsulated to the external phase, chemical degradation of the active component or lipid material, etc. These problems can be overcome in large part if a solid composition is used. Such a solid composition may comprise a liposome powder, i.e., a dry liposome dispersion or a powder of proliposomes. The drying process of liposome dispersions has the associated risk of damage to the membranes of liposomes. To minimize this risk it is necessary to dry the liposomes in the presence of protective sugars, as described for example in WO 86/01103. U.S. Patent No. 4,906,476 describes liposome formulations for steroid distribution by inhalation. The possibility of distributing dry liposomes as a powdered aerosol using a suitable device is described. Spray distribution is also described from a built-in atomizer using a solvent as a propellant with dry liposomes suspended in a powder, and by spraying dried particles to the lungs with a propellant. Liposomes as such are not present in the proliposome powders, but are formed when the powder is hydrated above the phase transition temperature of the lipids. Compared with dry liposomes, the proliposome powders have the advantage that the risk of damaging the membranes of the liposomes with dehydration is eliminated. The proliposome powders have been previously described. For example, U.S. Patent No. 4,311,712 discloses a potential mixture of lyophilized liposomes, obtained by dissolving an amphipathic lipid that forms liposomes, and a lipid-soluble or lipid-bound biologically active compound, in an organic solvent that remains solid during the process of lyophilized, and lyophilizing the solution. The potential mixture of liposomes can be stored and transformed into an aqueous liposome preparation when desired. The biologically active compound can be any compound that has a property of biological interest. WO 90/00389 describes a potential lyophilized mixture of liposomes having an amphipathic lipid and a cyclosporin or a derivative thereof, for use in a liposome distribution of the cyclosporin in the cells. The lyophilized mixture is reconstituted in an aqueous medium, to provide liposomes that encapsulate substantially all of the cyclosporin present in the lyophilized mixture. WO 92/11842 discloses a preliposomal powder, which forms a liposome suspension containing a polyene drug such as nstatin when reconstituted with water or saline. All of the above patents and the applications related to compositions of proliposomes are related to compositions that are to be hydrated before their administration. EP 309464 describes powdered compositions of proliposomes that can be inhaled. The powder compositions comprise solid particles, in which a biologically active component is in a particulate dispersion in a lipid. OBJECT OF THE INVENTION We have found it advantageous to provide proliposome powders that have only a single phase when distribution by inhalation is desired. Therefore, it is an object of the present invention to provide such proliposome powder. DESCRIPTION OF THE INVENTION The object of the present invention is achieved in the delivery, according to the present invention, of a powder of proliposomes, the powder comprises in a single phase discrete particles of a biologically active component, together with a lipid or mixture of lipids having a phase transition temperature (Tc) below 37 ° C. The powder is particularly suitable for administration by inhalation. The single-phase powder can alternatively be described as comprising a homogeneous molecular mixture of a biologically active component and a lipid or mixture of lipids having a phase transition temperature below 37 ° C. The terms " a single phase "and" homogenous molecular mixture "that there is no crystalline phase separate from either the active component or the lipid in the powder of the present invention. The single-phase powder can be inhaled directly and in situ, for example in the upper or lower respiratory system, will form liposomes in which a biologically active component is fully incorporated. In general, any lipid or mixture of amphipathic lipids which are known to be suitable for preparing liposomes could be used by methods known in the present invention. The lipid or lipid mixture must have a phase transition temperature below body temperature (37 ° C) so that the prodrug product powder is capable of hydration under physiological conditions (i.e., to be able to form liposomes in the respiratory system). The phase transition temperatures for the different lipid mixtures can be easily estimated, using well established methods, for example CBD methods - see for example J. Suurkuusk et al., Biochemistry, Vol. 15, No. 7, page 1393 (1976). In general, any lipid or mixture of natural or synthetic lipids having a phase transition temperature below 37 ° C are useful in the present invention. As examples of potentially useful lipids, natural and synthetic lipids such as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerol lipids can be mentioned. Among the natural lipids can be mentioned sphingolipids (SL) such as sphingomyelin (SM), ceramide and cerebroside; galactosylglycerolipids such as digalactosyldiacylglycerol (DGalDG); phosphoglycerolipids such as egg yolk phosphatidylcholine (e-PC) and soy phosphatidylcholine (s-PC); and lecithins such as egg yolk lecithin (e-lecithin) and soy lecithin (s-lecithin). Among the synthetic lipids may be mentioned dimiristoil phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dilauryl phosphatidylcholine (DLPC), l-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), l-palmitoyl-2 -miristoyl phosphatidylcholine (PMPC), and dioleoyl phosphatidylcholine (DOPC). Among the lipid mixtures, the following can be mentioned: SM / PC, SM / Cholesterol, ePC / Cholesterol, sPC / Cholesterol, PC / PS / Cholesterol, DMPC / DPPC, D PC / DPPC / CH, DMPC / CH, DPPC / DOPC, DPPC / DOPC / CH, DLPC / DPPC, DLPC / DPPC / CH, DLPC / DMPC, DLPC / DMPC / CH, DOPC / DSPC, DPSM / DMSM, e-lecithin / Cholesterol and s-lecithin / Cholesterol. In addition to any of the above, a charged lipid such as dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA) or stearylamine (SA) may be included.

Lipids of particular interest in the present invention are DPPC and / or DMPC. A mixture of DPPC and DMPC containing at least 10% (w / w) of DMPC, for example 10-50% of DMPC is preferred. Especially preferred is a mixture of DPPC and DMPC which also contains at least one charged lipid such as DMPG, DPPG, DMPA or SA, for example in an amount of up to 5% (w / w). Other preferred mixtures include DPSM and DMSM which optionally contain at least one charged lipid, and cholesterol mixtures with either e-lecithin or s-lecithin, which optionally contain at least one charged lipid, and which have a Tc less than 37 °. C. Other mixtures can easily be selected by a person skilled in the art with reference to, for example, Gregor Cevc, Phospholipids Handbook, Marcel Dekker, New York (1993) pages 427-435. The active component preferably has a molecular structure that can be incorporated into the lipid bilayers, to aid encapsulation in the liposomes during hydration. An example of such a structure is a fatty acid ester having a large hydrocarbon chain, sufficient to act as a hydrophobic anchor. Suitable active components can be readily identified by a person skilled in the art, and may include for example anti-inflammatory and bronchoplactor drugs, as well as antihistamines, cyclooxygenase inhibitors, leukotriene synthesis inhibitors, leukotriene antagonists, inhibitors of phospholipase-A2 (PLA2), platelet aggregation factor (PAF) antagonists, and asthma prophylactics. Also may be of interest antiarrhythmic drugs, tranquilizers, cardiac glycosides, hormones, anti-hypertensive drugs, antidiabetics, antiparasitic and anticancer drugs, sedatives, analgesic drugs, antibiotics, antirheumatic drugs, immunotherapies, antifungal drugs, antiphypotensive drugs, vaccines, antiviral drugs, proteins, peptides and vitamins. Specifically, glucocorticosteroids such as budesonide, dexamethasone, betamethasone, fluocinolone, flumethasone, triamcinolone acetonide, flunisolide, beclomethasone and 16,17-acetals of pregnane derivatives and compounds derived therefrom may be useful in the present invention; and β-2 agonists such as terbutaline, salmeterol, salbutamol, formoterol, fenoterol, clenbuterol, procaterol, bitolterol, and broxaterol. The active component can also be a mixture of pharmaceutically active substances; for example a mixture of a glucocortico-steroid with a bronchodilator such as formoterol, salmeterol, terbutaline or salbutamol, may be useful. To avoid doubt, when a reference is made to any active component herein, the reference is proposed to include a reference to pharmaceutically acceptable esters, salts, and hydrates thereof. When the active component is a steroid, it is preferably a steroid ester. The active component is preferably a steroid, preferably a steroid which is esterified at position 21 with a fatty acid of at least 8, for example at least 10 or at least 12 carbon atoms. The fatty acid can have, for example, up to 24 carbon atoms, for example up to 20 carbon atoms or up to 18 carbon atoms. More preferably, the active component is a 21-palmitate, myristate, laurate, caprate, caprylate or steroid stearate. The most preferred active component according to the invention is the compound (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11β-hydroxy-21-palmitoyloxy-pregn-4-ene-3, 20-dione, palmitate rofleponido. When the active component is an ester, it must be hydrolyzed to the main active component. Surprisingly, the single-phase proliposome powder of the present invention facilitates the necessary hydrolysis in situ, while the esters in the crystalline state will not be hydrolyzed. When the distribution by inhalation is desired, as much as possible of the proliposome powder of the present invention should consist of particles having a diameter of less than 10 microns, for example 0.01-10 microns or 0.1-6 microns, for example 0.1-5 microns, or agglomerates of the particles. Preferably, at least 50% of the powder consists of particles within the desired size range. For example, at least 60%, preferably at least 70%, more preferably at least 80%, and more preferably at least 90% of the powder consists of either particles within the desired size range, or agglomerates of the particles. The proliposome powders of the present invention need not contain other ingredients. However, pharmaceutical compositions containing the powders of the present invention can also include other pharmaceutically acceptable additives such as pharmaceutically acceptable adjuvants, diluents and carriers. These can be added to the proliposome composition after any micronization, or before any micronization, provided that the solvent has been completely eliminated. Any carrier is preferably a crystalline, hydrophilic substance. A preferred carrier is crystalline lactose onohydrate. Other suitable carriers include glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, malezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, and betaine. The amount of additives present in the formulation can vary within a very large range. In some circumstances, little or no additive may be required, while for example it is often preferable to dilute a powder with additive, to improve the properties of the powder for use in an inhaler. In the latter case, for example, at least 50%, for example at least 70% or at least 80% of the formulation can be formed of additives, the rest is the proliposome powder. The percentage of additives may also be dependent on the potency of the biologically active compound, and the optimum amount of powder for inhalation. When an additive, for example a carrier, is present, the entire composition may be in the form of particles of a size within the range of respirable particle size. Alternatively, the carrier may comprise thicker particles, for example of a median diameter of mass greater than 20 microns, or may comprise agglomerates of the smaller particles, the agglomerates having a median diameter of mass for example greater than 20 microns, so that in any case an ordered mixture of proliposomes and carrier is formed. A further object of the present invention is the provision of a process for the preparation of the proliposome powder of the present invention, that is, a process that provides the powder of proliposomes in a single phase.

Accordingly, the present invention also provides a process for the preparation of a powder of proliposomes for inhalation, which comprises dissolving a lipid or mixture of lipids and a biologically active lipophilic component in a solvent, the lipid or lipid mixture having a temperature of phase transition below 37 ° C; obtaining a crystalline solvent matrix and a single phase of lipid in its vitreous state by freezing the solution, freezing is carried out at a temperature below the phase transition temperature of the lipid phase; and evaporating the frozen solvent at a temperature below the phase transition temperature of the lipid phase.

Freezing of the solution and evaporation of the solvent can be effected by conventional methods, for example in a conventional lyophilizer. For example, the lipid solution and the biologically active component can be poured onto the reservoirs of a lyophilizer, and the temperature lowered to freeze the solution. The evaporation of the solvent can then be carried out, for example, by lowering the pressure in the lyophilization chamber; The resulting powder can be scraped from the deposits of the chamber, and optionally passed through a sieve. The lyophilized powder can, if necessary, be subjected to further processing, to obtain particles within the range of respirable particle size; for example the lyophilized powder can be micronized to give respirable particles, for example using an air jet mill. The freezing of the solution of the biologically active component and the lipids is carried out in a manner that produces a single lipid phase in the frozen solvent matrix. The production of a single lipid phase is controlled by the final temperature and the freezing rate of the solution; the optimum freezing rate of any particular solution will be somewhere between the time necessary for the crystallization of the solvent in question and the time necessary for the crystallization of the lipids and the active component, and can be determined by a person skilled in the art. , simply by trial and error. The optimum final temperature should be 10-20 ° C below the glass transition temperature of the lipid phase. For example, a powder X-ray method can be used to monitor the crystallinity, and a differential scanning calorimeter can be used to monitor the degree of incorporation of the biologically active component into the liposomes after hydration. The solvent must have the ability to completely dissolve the lipids and the biologically active component, since it is essential that all components are in solution before freezing, to avoid precipitation or phase separation, which will result in a powder with more than one phase. In addition, the solvent must be toxicologically acceptable, have a suitable freezing point, and preferably a high vapor pressure. The solvent may be, for example, an organic solvent, for example an alcohol, or a mixture of aqueous and organic solvents. The preferred solvent for use in the present invention is tert-butanol.

The powder can optionally be agglomerated into small spheres, to control the cohesiveness of the powder. The spheres should preferably not be larger than 1 mm in diameter; Larger spheres than this can be eliminated, for example by sieving. Any agglomerate must be friable, so that it can be easily deagglomerated, for example in a powder inhaler. The proliposome powder of the present invention is useful for the local or systemic treatment of diseases, and can be administered for example via the upper and lower resiratory tract, including the nasal route. As such, the present invention also provides the powder of proliposomes for use in therapy; the use of proliposome powder in the manufacture of a medicament for the treatment of diseases via the respiratory tract; and a method for the treatment of a patient in need of therapy, comprises administering to the patient a therapeutically effective amount of a proliposome powder of the present invention. For example, the proliposome powder of the present invention can be used in the treatment of inflammatory diseases in the respiratory tract, for example asthma, rhinitis, alveolitis, bronchiolitis and bronchitis.

Administration to the respiratory tract may be effected for example using a dry powder inhaler or a pressurized aerosol inhaler. Suitable dry powder inhalers include dose inhalers, for example the single dose inhaler known by the trademark Monohaler ™ and multi-dose inhalers, for example a respiratory-driven, multi-dose dry powder inhaler, such as the inhaler known by the trademark Turbuhaler. "While the proliposome powder of the present invention is particularly adapted for administration by inhalation, it can also be included in formulations adapted for other forms of distribution, for example, oral formulations can be prepared, topical and injectable, for use in the treatment for example of inflammatory diseases of the joints, for example arthritis, skin diseases, and ntestinal diseases The following Examples are proposed to illustrate, but not to limit, the scope of the invention. Example 1 Rofleponide palmitate was dissolved (10 parts), DPPC (63 parts), DMPC (24 parts) and NaDPPG (3 parts) in tert-butanol (1300 parts) at 80 ° C. The solution was poured into the reservoirs of a lyophilizer cooled to -35 ° C. The solution speaks reached this temperature after about 30 minutes; the pressure in the lyophilizer was then reduced, to induce sublimation of the solvent. While the rate of sublimation could be adjusted by decreasing the pressure and increasing the temperature, the temperature was not allowed to exceed during the whole process at -10 ° C. The lyophilization was continued until all the solvent had been removed. The resulting powder was scraped from the lyophilizer tanks, and passed through a screen. This powder was micronized in an air jet mold at a particle size of the powder less than 5 μm. The micronized powder was mixed with lactose monohydrate (20 parts of powder: 80 parts of lactose monohydrate) by a sieving process, and the mixture was further homogenized by micronising at low pressure, in a jet mill. The powder mixture was agglomerated in spheres no larger than 1 mm, using standard techniques. The larger spheres were removed by sieving. The agglomerated powder was deposited in a dry powder inhaler Turbuhaler1.

Example 2 The procedure of Example 1 was repeated, with freezing times of 6 hours, 17 hours and 24 hours. Comparative Example The lipids and the active component of Example 1 are simply dry blended with each other. The resulting powder is a multi-phase system comprising separate particles of the active component and of the lipids. Example 3 The procedure of Example 1 was repeated, using the following lipid mixtures having a phase transition temperature below 37 ° C: DPSM / DPSM e-Lecithin / Cholesterol s-Lecithin / Cholesterol Example 4 The procedure was repeated of Example 1, with the following active components: rofleponide 21-rhoplatin 21-laurate rhapontopide 21-rhoplatinum 21-caprate roflaponate 21-rhoplatinide stearate. Dust Analysis The X-ray powder diffraction performed on the powder mixture of Examples 1 and 2 showed that a crystalline state in the powder was not present. The powder of the Comparative Example contained the active component in the crystalline state. Incorporation of the active component in the liposomes The proliposome powders of Examples 1 and 2 were hydrated, and the degree of incorporation of the active component was measured, using differential scanning calorimetry methods. The CBD showed that the active component was fully incorporated in the liposomes. The CBD performed on the powder of the Comparative Example did not substantially show an incorporation of the active component in the liposomes. Ester hydrolysis The degree of hydrolysis of the proliposome powder of Example 1 and Comparative Example to the main active component was investigated. The proliposome powders of Examples 1 and 2 and Comparative Example (50 μM of the steroid ester in each case) were hydrated with water and heated at 50 ° C for 15 minutes. After that, the samples were incubated at 37 ° C in the presence of porcine pancreas lipase (2 mg / ml) in a buffer solution (1 mM EDTA, 80 mM KCL, 10 mM HEPES, pH 7.4) and sonicated periodically for periods of time variables, up to 120 minutes. The samples were analyzed by HPLC methods, to determine how much of the ester had been hydrolyzed to the main active component. 94% of the proliposome powder of Example 1 was hydrolyzed to the main active component, compared to only 2% of the powder of the Comparative Example. Pharmacological studies The anti-edema efficacy was determined using the Sephadex model on rats as described by L. Kallstrom et al., In Agents and Actions 17 (3/4) 355 (1985). Samples of the powders of Example 1 and Comparative Example were suspended in cold saline, and were given by intratracheal injection to the left lung of male Sprague-Dawley rats. After one hour, an inflammation process was induced by intratracheal instillation of Sephadex beads (5 mg / kg) to both left and right lungs. The resulting interstitial edema was quantified after 20 hours, determining the weight of the right and left lungs. The decrease in lung weight was taken as indicative of the pharmacological effect of the powders. The lung weight of the rats treated with the proliposome powder of Example 1 had decreased 40 times more than the lung weight of the rats treated with the powder of the Comparative Example: that is, the efficacy of the proliposome powder according to the invention was 40 times greater than the effectiveness of the powder of the Comparative Example. Inhalation studies Beagle dogs were anesthetized, intubated, and exposed to a powdered aerosol of the formulation of Example 1 or Comparative Example. The aerosol was generated from a powder tablet, using a Wright apparatus Dust Feed, operated at ^ 00 rpm. The concentration of the aerosol (Casella 950 AMS), tidal volume, inspired current volume and respiration frequency were recorded during inhalation. The target inhaled dose was 25 μg rofleponide palmitate / kg body weight. Plasma samples were taken regularly, following inhalation. Bioavailability was calculated by comparison with rofleponide plasma concentrations following intravenous administration. The bioavailability of the rofleponide following the administration of the powder according to Example 1 was close to 100%, while the bioavailability of the rofleponide following the administration of the powder of the Comparative Example was not measurable.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (42)

1. RE IVINDICAC IONS 1. A pharmaceutical composition characterized in that it comprises a powder of proliposomes, the powder comprises in a single phase discrete particles of a biologically active component together with a lipid or mixture of lipids having a phase transition temperature below 37 ° C, and a pharmaceutically acceptable crystalline and hydrophilic carrier.
2. 2. A pharmaceutical composition according to claim 1, characterized in that the powder comprises one or more lipids selected from natural and synthetic phosphoglycerolipids, sphingolipids and digalactosylglycerolipids.
3. 3 . A pharmaceutical composition according to claim 1 or claim 2, characterized in that the powder corrects a mixture of lipids selected from the mixtures of SM / PC, SM / Cholesterol, ePC / Cholesterol, sPC / Cholesterol,
4. PC / PS / Cholesterol, DMPC / DPPC, EMPC / DPPC / CH, EMPC / CH, DPPC / DOPC, DPPC / DOPC / CH, DLPC / DPPC, DLPC / DPPC / CH, DLPC / r-MPC, DLPC / IMPC / CH, DOPC / DSPC. Four . A pharmaceutical composition according to any of claims 1-3, characterized in that the powder comprises DPPC, DMPC, or a mixture of DPPC and DMPC.
5. 5. A pharmaceutical composition according to claim 4, characterized in that the mixture comprises at least 10% of DMPC.
6. 6. A pharmaceutical composition according to any of claims 1-5, characterized in that the powder further includes a charged lipid.
7. 7. A pharmaceutical composition according to claim 6, characterized in that the charged lipid is selected from DMPG, DPPG, DMPA and SA.
8. 8. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component is selected from anti-inflammatory drugs, bronchorelax drugs before, antihistamines, cyclooxygenase inhibitors, leukotriene antagonists, PLA2 inhibitors, PAF antagonists and asthma prophylactics. .
9. 9. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a glucocorticosteroid.
10. 10. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a β-2 agonist.
11. 11. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a steroid which is esterified in the position 21 with a fatty acid of at least 8 carbon atoms.
12. 12. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a steroid which is esterified in position 21 with a fatty acid of at least 10 carbon atoms.
13. 13. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a steroid which is esterified at position 21 with a fatty acid of at least 12 carbon atoms.
14. 14. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises a steroid 21-palmitate.
15. 15. A pharmaceutical composition according to any of the preceding claims, characterized in that the active component comprises rofleponido palmitate.
16. 16. A pharmaceutical composition according to any of the preceding claims, characterized in that at least 50% of the powder comprises particles having a diameter of less than 10 microns.
17. 17. A pharmaceutical composition according to any of the preceding claims, characterized in that at least 60% of the powder comprises particles having a diameter of less than 10 microns.
18. 18. A pharmaceutical composition according to any of the preceding claims, characterized in that at least 70% of the powder comprises particles having a diameter of less than 10 microns.
19. 19. A pharmaceutical composition according to any of the preceding claims, characterized in that at least 80% of the powder comprises particles having a diameter of less than 10 microns.
20. 20. A pharmaceutical composition according to any of the preceding claims, characterized in that at least 90% of the powder comprises particles having a diameter of less than 10 microns.
21. 21. A pharmaceutical composition according to any of claims 16-20, characterized in that the particles have a diameter of 0.01-10 microns.
22. 22. A pharmaceutical composition according to any of claims 16-20, characterized in that the particles have a diameter of 0.1-6 microns.
23. 23. A pharmaceutical composition according to any of claims 16-20, characterized in that the particles have a diameter of 0.1-5 microns.
24. 24. A pharmaceutical composition according to any of the preceding claims, characterized in that it comprises agglomerated particles.
25. 25. A pharmaceutical composition according to any of the preceding claims, characterized in that the carrier is crystalline lactose monohydrate.
26. 26. A pharmaceutical composition according to any of claims 1 to 24, characterized in that the carrier is selected from glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, malezitose, stachyose, lactitol, palatinate, starch, xylitol , mannitol, myoinositol, and hydrates thereof, and amino acids.
27. 27. A pharmaceutical composition according to any of the preceding claims, characterized in that the carrier comprises particles with a median diameter of mass greater than 20 microns.
28. 28. A pharmaceutical composition according to any of claims 1 to 26, characterized in that the carrier comprises particles of medium diameter of mass less than 10 microns.
29. 29. A process for the manufacture of a proliposome powder according to any of claims 1 to 23, the process is characterized in that it comprises dissolving a lipid or mixture of lipids and a lipophilic biologically active component in a solvent, the lipid or mixture of 'lipids has a phase transition temperature of less than 37 ° C, obtain a crystalline matrix of solvent and a single lipid phase in its glassy state by freezing the solution, the freezing is carried out at a temperature below the temperature of phase transition of the lipid phase; and evaporating the frozen solvent at a temperature below the phase transition temperature of the lipid phase.
30. 30. A process according to claim 29, characterized in that it additionally comprises the step of micronizing the lyophilized powder to obtain particles within the range of respirable particle size.
31. 31. A process according to claim 29 or 30, characterized in that the freezing and evaporation of the solvent are carried out in a lyophilizer.
32. 32. A process according to any of claims 29-31, characterized in that the solvent comprises an organic solvent.
33. 33. A process in accordance with the claim

    32, characterized in that the solvent comprises an alcohol.
34. 34. A process in accordance with the claim

    33, characterized in that the solvent comprises tertiary butanol.
35. 35. A process for the manufacture of a pharmaceutical composition according to any of claims 1 to 28, the process is characterized in that it comprises the process according to any of claims 29 to 34, followed by the step of adding to the powder of proliposomes obtained in this way a pharmaceutically acceptable, crystalline and hydrophilic carrier; and optionally the step of micronizing the powder and carrier mixture, to obtain particles within the range of respirable particle size.
36. 36. A process according to any of claims 29-35, characterized in that it additionally comprises the step of agglomerating the particles into spheres of diameter of 1 mm or less.
37. 37. A pharmaceutical composition according to any of claims 1-28, characterized in that it is for use in therapy.
38. 38. The use of a pharmaceutical composition according to any of claims 1-28, the use is characterized in that it is for the manufacture of a medicament for the treatment of diseases via the respiratory tract.
39. 39. A method of treating a patient in need of therapy, characterized in that it comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any of claims 1-28.
40. 40. A dry powder inhaler device, characterized in that it contains a pharmaceutical composition according to any of claims 1-28.
41. 41. A dry powder inhaler device, according to claim 40, characterized in that the inhaler is an inhaler of a dose.
42. 42. A dry powder inhaler device, according to claim 40, characterized in that the inhaler is a multi-dose inhaler.

    PROLIPOSOMES POWDERS FOR INHALATION SUMMARY OF THE INVENTION The present invention describes a powder of proliposomes, the powder comprises in a single phase discrete particles of a biologically active component, together with a lipid or mixture of lipids having a phase transition temperature by below 37 ° C.