MXPA99011675A - Proliposome powders for inhalation stabilised by tocopherol - Google Patents

Abstract

There is described a proliposome powder, said powder comprising discrete particles each comprising in a single phase (1) a biologically active component, (2) a stabilising proportion of tocopherol, and (3) a lipid or mixture of lipids having a phase transition temperature of below 37°C. Also described is a process for the preparation of, and the pharmaceutical use of, the powder.

Description

INHALATION PROLIPOSOME POWDLES, STABILIZED BY TOCOPHEROL Field of the Invention The present invention relates to proliposome powders, particularly for inhalation, a process for producing proliposome powders, compositions containing proliposome powders and methods for their use .

BACKGROUND OF THE ART: Liposomes are vesicles similar to membranes that consist of a series of concentric lipid bilayers alternately with hydrophilic compartments. They can also be made from a variety of natural and synthetic lipids such as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids. One of the main uses of liposomes have been as carriers of different types of pharmaceutically active components, to improve the release of drugs and minimize the side effects of some treatments. The pharmaceutically active compounds can be incorporated into liposomes either by encapsulation in hydrophilic compartments of the liposomes (when the active component is soluble in water), or by encapsulation in the lipid bilayers, when the active component is lipophilic.

REF .: 32252 One of the main problems associated with pharmaceutical liposomal formulations is long-term stability. The dispersions of aqueous liposomes have a limited stability due to aggregation, loss of the active component encapsulated towards the external phase, chemical degradation of the active component or the lipid material, etc. These problems can be overcome to a large extent if a solid composition is used. Such a solid composition may comprise a liposome powder, i.e. a dry liposomal dispersion or a powder of proliposomes. WO 96/19199 describes a variety of literature on liposome and proliposome and describes a proliposome powder. The powder contains, a single phase, discrete particles that contain a biologically active component and a lipid mixing component has a phase transition temperature (Te) of less than 37 ° C. It has now been found that the stability of the proliposome powder of WO 96/19199 can be increased to a considerable degree. Description of the Invention The present invention provides a proliposome powder, the powder contains discrete particles, each of which comprises in a single phase (1) a biologically active component, (2) a stabilizing ratio of tocopherol, and (3) a lipid or lipid mixture having a phase transition temperature of less than 37 ° C. Preferably, tocopherol is α-tocopherol, and more preferably racemic α-tocopherol. The powder is particularly suitable for administration by inhalation. The single-phase powder can alternatively be described as comprising a homogeneous molecular mixture and a biologically active component, a lipid or mixture of lipids having a phase transition temperature lower than 37 ° C, and tocopherol. It should be understood according to the terms "a single phase" and "homogeneous molecular mixture" that there is no non-separated crystalline phase of the active component, the lipid or the tocopherol in the powder of the present invention. The single-phase powder can be inhaled directly, and in situ for examin the upper or lower respiratory system, will form liposomes in which the biologically active component is incorporated. In general, any amphiphatic lipid or lipid mixture known to be suitable for preparing liposomes by known methods could be used in the present invention. The lipid or lipid mixture must have a phase transition temperature lower than the body temperature (37 ° C) so that the product of the proliposome powder is able to hydrate under physiological conditions (i.e. to be able to form liposomes in the body). respiratory system) . The phase transition temperatures for the different lipid mixtures can be easily estimated, using well-established methods, for example DSC methods-see for example J. Suurkuusk et al., Biochemistry, vol. 15, no.7, p. 1393 (1976). In general, any lipid or mixture of natural or synthetic lipids having a phase transition temperature of less than 37 ° C is useful in the present invention. As examples of potentially useful lipids there may be mentioned natural and synthetic lipids as well as natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids. 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 (ePC) and soy phosphatidylcholine (s-PC); and lecithins such as egg yolk lecithin (e-lecithin) and soy lecithin (s-lecithin). Synthetic lipids include dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dilauryl phosphatidylcholine (DLPC), l-myristoyl-2-palmitoyl phosphatidylcholine (MPPC), l-palmitoyl-2 myristoyl 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, DMPC / 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, any of the foregoing may include a charged lipid such as dimyristoyl phosphatidylglycerol (DMPG), diphospalmitoyl phosphatidylglycerol (DPPG), dimyristoyl phosphatidic acid (DMPA), dipalmitoyl phosphatidic acid (DPPA) or stearylamine (SA). Lipids of particular interest in the present invention are DPPC and / or DMPC. The mixture of DPPC and DMPC containing at least 10% (/) of DMPC, for example 10-50% of DMPC is preferred. Especially preferred is a mixture of DPPC and DMPC containing 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 optionally containing at least one charged lipid, and mixtures of cholesterol or e-lecithin or s-lecithin, optionally containing at least one charged lipid, and having a Tc of less than 37 ° C. Other mixtures can be easily selected by one skilled in the art with reference to the example of Gregor Cevc, Phospholipids Handbook, Marcel Dekker, New York (1993) pp 427-435. The tocopherol is preferably present in a proportion of 0.05 to 1.0%, more preferably of O.lal to 0.6%, by weight of the total single phase containing the lipids and the biologically active component. The active component preferably has a molecular structure which can be incorporated into the lipid bilayers, to aid in the encapsulation in the liposomes during hydration. An example of such a molecular structure is a fatty acid ester having a long hydrocarbon chain sufficient to act as a hydrophobic anchor. Suitable active components can be readily identified by a person skilled in the art and can include, for example, anti-inflammatory and broncho-relaxant drugs, antihistamines, cyclooxygenase inhibitors, leukotrin synthesis inhibitors, leukotriene antagonists, phospholipase A2 inhibitors ( PLA2), antagonists of platelet aggregation factor (PAF) and asthma prophylactics. Antiarrhythmic drugs, tranquillizers, cardiac glycosides, hormones, antihypertensive drugs, antidiabetic, antiparasitic and anti-cancer drugs, sedative drugs, analgesics, antibiotics, antirheumatics, immunotherapies, antifungal drugs, antiphypotensive drugs, vaccines, antiviral drugs, proteins, peptides and vitamins, may also be of interest. Specifically, glucocorticosteroids such as budesonide, fluticasone propionate, ciclesonide, rofleponide, for example, as their palmitate, mometasone, for example as their furoate, tipredane, RPR 106541, dexamethasone, betamethasone, fluocinolone, flumethasone, triamcinolone acetonide, flunisolide , Beclomethasone and Acétals 16,17 of pregnane derivatives and compound derivatives thereof and β-2 agonists such as terbutaline, salmeterol, salbutamol, formoterol, fenoterol, clenbuterol, procaterol, bitolterol, and broxaterol, may be useful in present invention. The active component can also be a mixture of pharmaceutically active substances; for example a mixture of glucocorticosteroids with a bronchodilator such as formoterol, salmeterol, terbutaline or salbutamol, may be useful. For the avoidance of doubt, where reference is made here to any active component, the reference is intended to include a reference to pharmaceutically acceptable esters, salts and hydrates thereof. I Where the active component is a steroid this is preferably a steroid ester. The active component is preferably a steroid, preferably a steroid which is Iβ esterified at position 21 with a saturated or unsaturated fatty acid of at least 8, for example and / or 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 steroid-21-palmitate, myristate, laurate, caprate, caprylate or stearate. The most preferred active component according to the invention is the compound (22R) -16a, 17a-butylidenedioxy-6a, 9a-difluoro-11β-hydroxy-21-palmitoyloxypregn-4-en-3,20-dione, i.e. Rylleponide palmitate. When the active component is an ester this must be able to be hydrolyzed the main active component. Surprisingly, the single-phase proliposome powder of the present invention facilitates the necessary hydrolysis in itself, although such crystalline state esters are generally not hydrolyzed. Where release by inhalation is desired, as much as possible 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 such particles. Preferably at least 50% of the powder consists of particles within the range of the desired size. 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 any particles within the desired size range. or of agglomerates of such particles. The proliposome powders of the present invention need not contain other ingredients. However, pharmaceutical compositions comprising the powders of the present invention can also include other pharmaceutically acceptable additives such as a pharmaceutically acceptable adjuvant, diluent or carrier. These can be added to the proliposome composition after any micronization, or before any micronization, provided that the solvent has been completely removed. Any carrier is preferably a hydrophilic, crystalline substance. A preferred carrier is crystalline lactose monohydrate. Other suitable carriers include glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, estoquiosa, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine and betaine. The amount of additive present in the formulation can vary over a wide range. In some circumstances little or no additive may be required, although 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 may constitute additives, the remainder being the polyphosoma powder. The percentage of additives may also depend on the potency of the biologically active compound and the optimum amount of powder for inhalation. Where an additive, for example a carrier, is present, the entire composition may be in the form of a particle within the range of respirable particle size. Alternatively the carrier may comprise larger particles for example with a mass median diameter greater than 20 microns, or may comprise agglomerates of smaller particles, the agglomerates have a mass average diameter of for example greater than 20 microns, so that in any case an ordered mixture of proliposome and carrier is formed. A further object of the present invention is to provide a process for the preparation of the proliposome powder of the present invention, that is, a process that produces the proliposome powder in a single phase. Accordingly, the present invention also provides a process for the preparation of a proliposome powder for inhalation, which comprises dissolving a lipid or mixture of lipids, tocopherol and a lipophilically active component in a solvent, the lipid or lipid mixture has a phase transition temperature less than 37 ° C; obtaining a crystalline solvent matrix and a single lipid phase in its vitreous state to freeze the solution, the freezing is carried out at a temperature lower than the phase transition temperature of the lipid phase; and evaporating the frozen solvent at a temperature lower than the phase transition temperature of the lipid phase. The freezing of the solution and the evaporation of the solvent can be carried out by conventional methods, for example in a conventional lyophilizer. For example, the solution of lipids, tocopherol and biologically active component can be poured into the shelves of a lyophilizer and the temperature can be lowered to freeze the solution. The evaporation of the solvent can then be achieved, for example, by lowering the pressure in the lyophilization chamber; the resulting powder can be detached from the chamber shelves and optionally passed through a sieve. "If necessary, the lyophilized powder can 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. Freezing of the solution of the biologically active component, tocopherol and lipid is carried out in such a way that it 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 speed of the solution, the optimal freezing speed of any particular solution will be somewhere between the time needed for the crystallization of the solvent in question and the time necessary for the crystallization of the lipids, tocopherol and the active component and can be determined by a skilled in the art, simply by trial and error. The optimum final temperature should be 10-20 ° C lower than the vitreous transition temperature of the lipid phase. For example, a powder X-ray method can be used to verify the crystallinity and differential scanning calorimetry can be used to verify the degree of incorporation of the biologically active component into the liposomes after hydration. The solvent must have the capacity to dissolve the lipids, tocopherol and the biologically active component completely, since it is essential that all the components are in solution before freezing to avoid precipitation or separation of phases, which will give rise to dust with more of a phase. In addition, the solvent must be toxicologically acceptable, have an appropriate freezing point and preferably a high vapor pressure. The solvent may be, for example, an organic solvent, for example an alcohol, a mixture of aqueous and organic solvents. The preferred solvent for use in the present invention is tertiary butanol. The powder can be agglomerated optionally in small spheres, to control the cohesiveness of the powder. The spheres should preferably not be larger than 1 mm in diameter; the larger spheres of this can be removed, for example, by sieving. Any agglomerates should be friable, so that they can be easily de-agglomerated, for example in the air flow generated 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 respiratory tract, including through the nasal route. Therefore, the present invention also provides the proliposome powder 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 treating a patient in need of therapy, which comprises administering to the patient a therapeutically effective amount of the 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 can be effected for example using a dry powder inhaler or a pressurized aerosol inhaler. Suitable dry powder inhalers include those inhalers, for example the single-dose inhaler known by the trademark Monohaler® and multi-dose inhalers, for example, a multi-dose, respiratory-powered dry powder inhaler, such as the inhaler known by the Turbuhaler brand. Although the proliposome powder of the present invention is particularly adapted to be administered by inhalation, it may also be included in formulations adapted for other forms of delivery. For example, oral, topical and injectable formulations can be prepared for use in the treatment of, for example, inflammatory diseases of the joints, for example arthritis, skin diseases and intestinal diseases.

The following Examples are intended to illustrate, but not limit, the scope of the present invention. The parts are in weight.

Example 1 Rofleponide palmitate (10 parts), DPPC (63 parts), DMPC (24 parts), NaDPPG (3 parts), and racemic α-tocopherol (0.1 parts) in tertiary butanol (1300 parts) at 80 ° C were dissolved. . The solution was poured onto the shelves of a lyophilizer cooled to -35 ° C. The solution reached this temperature after about 30 minutes; then the pressure of the lyophilizer was reduced to induce the sublimation of the solvent. Although the sublimation speed could be adjusted by lowering the pressure and increasing the temperature, the temperature through the process was allowed to exceed -10 ° C. The lyophilization continued until all the solvent had been removed. The resulting powder was detached from the freeze dryer shelves and passed through a screen. This powder was micronized in an air jet mill at a particle size of the powder of less than 5 μm. The micronized powder was mixed with a lactose hydrate (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 an air jet mill.

The powder mixture was agglomerated into spheres no larger than 1 mm, using standard techniques. The large spheres were removed by sieving. The agglomerated powder was filled in a Turbuhaler® dry powder inhaler. In separate experiments the amount of a-tocopherol in the previous formulation was changed to 0.06 parts and 0.6 parts, respectively. Surprisingly it was found that the proliposome formulations of Example 1 are more stable than equivalent formulations containing other antioxidants.

Dust Analysis The X-ray diffraction of the powder carried out on the powder mixture of Example 1 showed that it was not present in the crystalline state in the powder.

Incorporation of the active component in the liposomes The proliposome powders of Example 1. they were hydrated and the degree of incorporation of the active component was measured using differential scanning calorimetry methods. The DSC showed that the active component was completely incorporated into the liposomes.

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.

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A powder of proliposome, the powder is characterized in that it comprises discrete particles, each of which comprises. in a single phase (1) a biologically active component, (2) a stabilizing ratio of tocopherol, and (3) a lipid or lipid mixture having a phase transition temperature of less than 37 ° C.

2. The powder in accordance with the claim 1, characterized in that the tocopherol is α-tocopherol.

3. The powder in accordance with the claim 2, characterized in that the tocopherol is the racemic α-tocopherol.

4. The powder according to any of the preceding claims, characterized in that the tocopherol is present in a proportion of 0.05 to 1.0% by weight of the single phase.

5. The powder according to claim 4, characterized in that the tocopherol is present in a proportion of 0.1 to 0.6% by weight.

6. The powder according to any of the preceding claims, characterized in that it comprises one or more lipids selected from the group consisting of natural and synthetic phosphoglycerolipids, sphingolipids, and digalactosylglycerolipids.

The powder according to any of the preceding claims, characterized in that it comprises a mixture of lipids selected from the group consisting of SM / PC, SM / Cholesterol, ePC / Cholesterol, sPC / Cholesterol, PC / PS / Cholesterol, DMPC / DPPC, DMPC / 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.

8. The powder according to any of the preceding claims, characterized in that it comprises DPPC or DMPC, or a mixture of DPPC and DMPC.

9. The powder according to claim 8, characterized in that the mixture comprises at least 10% of DMPC.

The powder according to any of the preceding claims, characterized in that it additionally includes a charged lipid.

The powder according to claim 10, characterized in that the charged lipid is selected from the group consisting of dimyristoyl phosphatidylglycerol (DMPG), diphospalmitoyl phosphatidylglycerol (DPPG), dimyristoyl phosphatidic acid (DPPA) and stearylamine (SA).

The powder according to any of the preceding claims, characterized in that the active component comprises a glucocorticosteroid.

13. The powder in accordance with the claim 12, characterized in that the active component comprises a glucocorticosteroid which is esterified at position 21 with a fatty acid of at least 8 carbon atoms.

14. The powder in accordance with the claim 13, characterized in that the active component comprises a glucocorticosteroid which is esterified at position 21 with a fatty acid of at least 10 carbon atoms.

15. The powder according to claim 14, characterized in that the active component comprises a glucocorticosteroid-21-palmitate.

16. The powder according to claim 15, characterized in that the active component comprises rofleponide palmitate.

17. The powder according to any of the preceding claims, characterized in that at least 50% of the powder consists of particles having a diameter less than 10 microns.

18. The powder according to claim 17, characterized in that at least 50% of the powder consists of particles having a diameter of O.Ol-10 microns.

19. The powder according to claim 18, characterized in that at least 50% of the powder consists of particles having a diameter smaller than 0.1-6 microns.

20. The powder according to any of claims 17-19, characterized in that it comprises agglomerated particles.

21. A pharmaceutical composition, characterized in that it comprises a powder according to any of the preceding claims and a pharmaceutically acceptable carrier.

22. The pharmaceutical composition according to claim 21, characterized in that the carrier is crystalline lactose monohydrate.

23. The pharmaceutical composition according to any of claims 21 or 22, characterized in that the carrier comprises particles with an average mass diameter of less than 10 microns or agglomerates of such particles.

24. A dry powder inhaler device, characterized in that it contains a proliposome powder according to any one of the preceding claims.

25. The dry powder inhaler device according to claim 24, characterized in that the inhaler is a single dose inhaler.

26. A method for treating a patient in need of therapy with a given biologically active compound, characterized in that it comprises administering to the patient a therapeutically effective amount of a powder according to any one of claims 1 to 20 or a composition in accordance with any of claims 21 to 23.

27. The use of a powder according to any of claims 1-20 in the preparation of a formulation for use in therapy.