WO2003009873A2

WO2003009873A2 - Use of pulmonary surfactant as humectant

Info

Publication number: WO2003009873A2
Application number: PCT/GB2002/003374
Authority: WO
Inventors: Derek Woodcock; John Staniforth; Joy Conway; Jim Thompson
Original assignee: Britannia Pharmaceuticals Limited
Priority date: 2001-07-23
Filing date: 2002-07-23
Publication date: 2003-02-06
Also published as: AU2002321402A1; GB0117911D0; WO2003009873A3

Abstract

A surface active phospholipid (SAPL) composition, especially a dry powder blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol, is used as a non-therapeutic pulmonary humectant or anti-irritant by inhalation into the airways and upper respiratory tract of a person experiencing dry or dusty atmospheres.

Description

NON-THERAPEUTIC USES OF PULMONARY SURFACTANT

This invention relates to a composition of SAPL (surface active phospholipids) for administration to the lungs by inhalation to act as a non-therapeutic pulmonary humectant or anti-irritant.

EP- 1082108- A (Britannia Pharmaceuticals) proposes that the lungs and airways of non-asthmatics may contain a natural protective barrier which prevents pollutants and other airborne triggers from reaching receptors whose irritation would then produce an acute attack. Studies have suggested that SAPL masks (covers) most of these receptors in normal lungs but this masking is deficient in asthmatics. The proposal is predicated on the belief that it is possible to restore normal masking by binding surface-active phospholipids (SAPL) to the tissue surface of the lungs, thereby reducing the number of receptors exposed to allergens and reducing hyper- responsiveness of the bronchoconstrictor reflex, common to all forms of asthma.

EP-1082108-A involves the use of a SAPL composition in which one component is capable of binding (absorbing) to the tissue surface (epithelium) of the airways, thereby masking receptors against stimulation by noxious agents or sensitisation by allergenic stimuli. Advantageously another component is a spreading agent, which spreads the composition over the surfaces of the airways. Once in place, one or more components of the composition will migrate across the mucous layer and deposit a thin hydrophobic lining on the tissue surface, and/or supplement the endogenous coating.

WO 02/34270, unpublished at the priority date of this application, describes how a layer of SAPL on pulmonary surfaces has a "dewatering" effect that can be used to alleviate the condition known as "wet lung". The SAPL is believed to be effective against this condition by the formation of ion channels that pump ions in a direction to establish a gradient that moves water out of the as airways and into the body by osmosis. At the same time, the SAPL layer on airway surfaces acts as a semi- permeable membrane, preventing the water returning to the surface. In one aspect, the present invention is based on the finding that this effect keeps the lung epithelium wet or moist. In effect, an SAPL lining on pulmonary surfaces maintains a fluid balance, acting as a "moisturiser" or humectant to keep delicate lung lining moist and preventing the epithelial tissue from drying out.

US Patent 5,698,537 (Clarion Pharmaceutical) suggests that SAPL are useful as a mucolytic to reduce the viscosity of mucus and facilitate its removal from lung airways

In another aspect, the present invention is based on a contrary finding that SAPL, rather than decreasing the viscosity of sputum, decreases the transport of particles through sputum and therefore acts as a means of preventing particulate irritants, such as particles in a dusty atmosphere, from contacting lung tissue.

Accordingly the present invention proposes that SAPL is useful in a non-therapeutic context as a pulmonary humectant to maintain liquid balance and to reduce the adverse effects on the lungs when exposed to dry and also to increase the barrier effect of mucus to impede the passage of particles so as to prevent irritation in dusty atmospheres.

The present invention comprises use of a surface active phospholipid (SAPL) composition as a non-therapeutic inhalable pulmonary humectant or anti-irritant, said composition comprising at least one SAPL.

More specifically, the present invention comprises use of a surface active phospholipid (SAPL) composition in the preparation of a non-therapeutic pulmonary humectant or anti-irritant for administration by inhalation to the airways and upper respiratory tract of a person, said composition comprising at least one SAPL.

From another aspect, the present invention provides a method of providing a non- therapeutic humectant or anti -irritant effect in the lungs of a person which comprises administering to the person by inhalation an effective amount of at least one SAPL. Since the present invention provides a non-therapeutic effect, the SAPL compositions may be administered to healthy persons, free from lung disease.

Suitable SAPL compositions include those described in our above-mentioned patent applications, the disclosure of which is incorporated herein by reference.

The SAPL is preferably administered as a dry powder of SAPL rather than a saline solution or suspension as disclosed in various proposals to use SAPL in the treatment otrespiratory distress syndrome (RDS).

Examples of SAPL which appear to be capable of forming a thin film or coating on surfaces of the lungs include phosphatidyl cholines (PC), especially diacyl phosphatidyl cholines (DAPCs), e.g. dioleyl phosphatidyl choline (DOPC); distearyl phosphatidyl choline (DSPC) and dipalmitoyl phosphatidyl choline (DPPC).

Another preferred component is a spreading agent. This may function to reduce the melting point of PC so that it rapidly spreads as a thin film at normal body temperature. Suitable spreading agents include phosphatidyl glycerols (PG); phosphatidyl ethanolamines (PE); phosphatidyl serines (PS) and phosphatidyl inositols (PI). Another useful spreading agent is chlorestyl palmitate (CP). The above spreading agents, especially PG, are believed to enhance or potentiate the binding of the PC, especially the DPPC, to the epithelial surface.

Phosphatidyl choline (PC), especially dipalmitoyl phosphatidyl choline (DPPC) is a preferred component of the SAPL. Phosphatidyl glycerol (PG) is also a preferred component of the SAPL.

PG has a further important function in compositions employed in the invention because it lowers the transition of blends in which it is used and also may contribute to binding to lung surfaces. In a blend with an SAPL such as PC (or DPPC) to form a very finely-divided, dry powder dispersion in air. Such dispersions may have particle sizes in the range of 0.5 to 20 μm, preferably 0.5 to 5 μm and more preferably 0.5 to 2 μm. Typically, the median particle diameter is about 1.2 μm. Finely divided dry powders of this kind may be adsorbed onto the surfaces of lung tissue, i.e. bound to the epithelium.

Preferably, the SAPL compositions employed in the present invention are blends of phosphatidylcholine (PC), especially dipalmitoyl phosphatidyl choline (DPPC), and phosphatidyl glycerol (PG), or more generally SAPL blends that result in transition temperature below that of body temperature and/or facilitate binding.

The composition is desirably essentially free from animal protein in order to avoid the danger of patient sensitivity to animal proteins and pyrogens. Also, surfactants which are derived from animal proteins are not available in a finely-divided particle form which can be dispersed in a carrier gas stream.

PC is obtainable from commercially available lecithin, which is a mixture of phosphatidyl choline and phosphatidyl ethanolamines, and sometimes used directly as PC.

DPPC can be prepared synthetically by the use of acyl chlorides using the method of Baer & Bachrea - Can. J. Of Biochem. Physiol 1959; 37, page 953 and is available commercially from Sigma (London) Ltd. PG may be prepared from egg phosphatidylcholine by the methods of Comfurions et al and Dawson, Biochem. Biophys Acta 1977; 488; pages 3642 and Biochem J. 1947; 192; pages 205-210.

To obtain a mixture in which the particle size is suitable for use in the invention, the phospholipid components may be dissolved in a suitable solvent, for example ethanol, the solution filtered and vacuum-dried, and the solid product size-reduced, for example by milling or micronising, to obtain particles of the desired size. During size- reduction, care should be taken to protect the mixture from moisture, oxygen, direct heat, electrostatic charge and microbial contamination.

When co-precipitated with DPPC from a common solvent such as chloroform or ethanol, PG forms with DPPC a fine powder which spreads rapidly over the surfaces of the airways and lungs. At a weight ratio of DPPC:PG of about 7:3, the mixture spreads rapidly at a temperature of about 35°C and above. Additional or lesser quantities of PG can be incorporated into the composition and finely-divided compositions obtained. In general, DPPC and PG may be present in a weight ratio of from 9:1 to 1 :9. Other DAPC's and other spreading agents may be used in similar proportions. Compositions employed in currently tested formulations have been in the weight ratio of from about 6:4 to 8:2.

The most preferred composition of the invention contains DPPC and a phosphatidyl glycerol derived from egg phosphatidyl choline and having a mixture of C16, C18 (saturated and unsaturated) and C20 (unsaturated) acyl groups.

It is highly desirable that the SAPL should not break down in the environment of the lungs. One of the factors which will reduce the life of a lining or coating will be the presence of enzymes, such as phospholipase A, capable of digesting DPPC and/or PG. Such enzymes attack only the laevorotatory (L) form, which constitutes the naturally occurring form. Therefore, the composition should preferably contain the dextrorotatory (D) form or at least comprise a racemic mixture, which is obtained by synthetic routes.

The compositions employed in the present invention are generally finely divided dry powders having a particle size distribution which is small enough to be introduced into the airways and, preferably, deeply into the lungs in a gas stream from a dispersion device. Generally, compositions are preferred in which the particle size distribution is such that a major proportion are between 0.5 and 2 micrometres, but larger particle sizes are also inhalable, for example up to 20 - 5- microns or higher. Further information on suitable particle sizes for inhalation is found in WO 00/30654 (Britannia Pharmaceuticals) the contents of which are incorporated herein by reference. Also disclosed therein are useful SAPL components and blends that may be used in this invention. Thus in WO 00/30654 the SAPL blend advantageously comprises a diacyl phosphatidyl choline and a phosphatidyl glycerol. The phosphatidyl glycerol is advantageously a diacyl phosphatidyl glycerol. The acyl groups of the phosphatidyl glycerol, and also of the diacyl phosphatidyl choline, may be the same or different, and are advantageously each fatty acid acyl groups which may have from 14 to 22 carbon atoms. In practice, the phosphatidyl glycerol component may be a mixture of phosphatidyl glycerols containing different acyl groups. The phosphatidyl glycerol is expediently obtained by synthesis from purified lecithin, and the composition of the acylsubstituents is then dependent on the source of the lecithin used as the raw material. It is preferred for at least a proportion of the fatty acid acyl groups of the phosphatidyl glycerol to be unsaturated fatty acid residues, for example, mono-or di- unsaturated C18 or C20 fatty acid residues. Preferred acyl substituents in the phosphatidyl glycerol component are palmitoleoyl, oleoyl, linoleoyl, linolenoyl and arachidonoyl. The blend preferably comprises dipalmitoyl phosphatidyl choline and phosphatidyl glycerol, with the phosphatidyl moiety of the phosphatidyl glycerol advantageously being obtainable from the phosphatidyl moiety of egg lecithin.

Suitable dispersion devices for administration of dry powders may employ a propellant such as a halocarbon to form the gas stream and may include a tapered discharge nozzle baffle or a venturi to accelerate particles through a discharge nozzle, and to remove oversized particles. Suitable halocarbons include hydrofluorocarbons, hydrofluorochlorocarbons and fluorochlorocarbons having a low boiling point, such as those marketed under the trade mark "Freon". The composition may be packaged with a propellant in a pressurised aerosol container within the inhaler. Other inhalers have an impeller which mixes the powder into an air stream and delivers the powder- laden air into the patient's airways - see, e.g. US 5577497.

A preferred method and apparatus for administering the composition involves dispersing the powdered composition in a propellant gas stream. For example, a pressurised canister of a liquefied gas may be connected to a vial containing the composition. By releasing controlled amounts of gas from the canister into the vial, increments of the compositions are ejected from the vial as a cloud of powder and may be inhaled by the user.

Compositions and administration devices suitable for administering inhalant compositions in accordance with this invention are disclosed in the above mentioned EP-1082108-A, the entire contents of which are incorporated herein by reference. The effect of SAPL to prevent irritant particles contacting the surfaces of the lung airways, by reinforcing the barrier properties of mucus, is illustrated by the data obtained in the assay reported below.

Assay of Barrier properties of Sputum and added Surfactants

Method

The barrier assay measures the ability of an agent to increase the transport of fluorescent beads (200 nm in diameter) through a layer of sputum. The structure of the chamber is shown in Figure A. The apparatus consists of a chamber with two compartments (1,2) separated by an 8 μm polycarbonate filter (3). The upper compartment (1) is provided with wells (4) containing sputum, fluorescent beads (5) and the agent under investigation. The lower compartment (2) is provided with wells (6) containing phosphate buffered saline. Following the incubation period the chamber is dismantled and the fluorescence of the solution contained in the lower wells (4) due to the presence of transported beads (7) is measured.

Results A model sputum was used as a barrier to the transport of fluorescent beads in the assay. This model sputum contained DNA, mucin and actin. In each experiment a phosphate buffered saline (PBS) control was performed. This involved the addition of PBS to the upper well in the presence of fluorescent beads to indicate the maximum possible transport of the beads achievable. This represents 100% transport. Two types of model sputum have been used: thick and thin preparations. The composition of these models is detailed below. The assay has been validated using both thick and thin model sputum in the presence of a mucolytic agent, DNase.

Experiment 1

Thin model sputum (3.33 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was treated with DNase and fluorescent beads added (10% v/v). 15 μl of the DNase preparation was added to upper wells of the 48-well chamber in quadruplicate. -The chamber was centrifuged briefly at 1000 rpm to remove air bubbles and incubated at 37°C, with shaking, in the dark for 1 hour. Following incubation the fluorescence of the solution in the lower wells was measured.

Figure 1 shows that thin model sputum acts as a 50% barrier to the transport of fluorescent beads when compared with the PBS control. The DNase mucolytic (2.9 μg/ml DNase) increased transport from 50% to approximately 80%. 50 μg/ml DNase completely restored the transport of beads to the level seen in the PBS control. (* P < 0.05 compared with model sputum only)

Experiment 2

Thick model sputum (5 mg/ml DNA, 30 mg/ml mucin, 0.33 mg/ml actin) was treated with DNase and fluorescent beads added (10% v/v). 15 μl of the preparation was added to upper wells of the 48-well chamber in quadruplicate. The chamber was centrifuged briefly at 1000 rpm to remove air bubbles and incubated at 37°C, with shaking, in the dark for 1 hour. Following incubation the fluorescence of the solution in the lower wells was measured.

Figure 2 shows that thick model sputum allows the transport of only 35% of beads compared with the PBS control. Addition of 2.9 μg/ml DNase increases transport to 63%, and 50 μg/ml DNase almost fully restores transport with 95% compared to the PBS control. (* P < 0.05 compared with model sputum only) This indicates that the two types of model sputum provide different barriers to transport and both are appropriate models for testing barrier properties of added agents.

Surfactants A and B were tested in the barrier assay using the same method. The effect of mixing the Surfactants with the thin model sputum and sprinkling the Surfactants on top of sputum was investigated, as models for administration of powdered SAPL to the airways by inhalation. Incubation periods of 1 hour and 17 hours .were tested to ensure that any time-dependent effects were observed.

Surfactant A:

A 7:3 by wt mixture of DPPC and PG obtained by coprecipitation from a common solvent; mean particle size range of about 10-16 microns with 90% of the particles within about 20-50 microns.

Surfactant B:

A 7:3 by wt mixture of DPPC and PG obtained by coprecipitation from a common solvent; mean particle size of 2 microns with 95% below 5 microns.

Experiment 3

Thin model sputum (3.33 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was mixed with fluorescent beads (10% v/v). This mixture was then mixed directly with Surfactant, or added directly to wells and Surfactant sprinkled on top. In each case 15 μl of the preparation was added to upper wells of the 48-well chamber in quadruplicate. Chamber centrifuged briefly at 1000 rpm to remove air bubbles and incubated at 37°C, with shaking, in the dark for 1 hour. Following incubation the fluorescence of the solution in the lower wells was measured.

Figure 3 shows that after an incubation period of 1 hour, the Surfactants that had been mixed with the model sputum and beads caused a decrease in transport. Surfactant A decreased transport from 30% to 9%, and Surfactant B decreased transport to 12%. The addition of Surfactant powder to the surface of model sputum surprisingly showed little effect, with Surfactant A causing a decrease in transport from 30% to 27%o, and Surfactant B resulting in a slight increase in transport from 30% to 36%. The model was later adjusted to investigate this.

Experiment 4

Thin model sputum (3.33 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was mixed with fluorescent beads (10% v/v). This mixture was then mixed directly with Surfactant, or added directly to wells and Surfactant sprinkled on top. In each case 15 μl of the preparation was added to upper wells of the 48-well chamber in quadruplicate. Chamber centrifuged briefly at 1000 rpm to remove air bubbles and incubated at 37°C, with shaking, in the dark for 17 hours. Following incubation the fluorescence of the solution in the lower wells was measured.

The results obtained following an incubation period of 17 hours are shown in Figure 4. Thin model sputum was less effective as a barrier with a longer incubation time. Over a 1-hour incubation period thin model sputum reduced the transport of beads to 30% of the PBS control (Figure 3), whereas over a 17-hour incubation period thin model sputum only reduced transport to 65% of the PBS control (Figure 4). Shorter incubation periods were therefore used for subsequent assays. In Figure 4 mixing the Surfactants with model sputum caused a decrease in transport; Surfactant A reduced transport from 65% to 29% and Surfactant B reduced it from 65% to 43%. The addition of Surfactant to the surface of model sputum again showed no apparent effect; Surfactant A increased transport from 65% to 66% and Surfactant B caused no change in transport.

The results obtained in Figures 3 and 4 indicated that the effects of sprinkling surfactant on the surface of model sputum required further investigation. For the next experiment a 4-well chamber was used in which each well has a much larger surface area. This allowed a larger quantity of surfactant to be sprinkled on the surface of the sputum. However, as shown in Figure 5, the use of larger wells diminished the barrier function of the thin model sputum. Model sputum only reduced transport of beads to 95%o of that of the PBS control. Addition of 20 mg of Surfactant A and Surfactant B resulted in 95%> and 94% transport respectively.

Experiment 5

_Thin model sputum (3.33 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was mixed with fluorescent beads (10%> v/v) and 500 μl added per upper well. 20 mg

Surfactant was sprinkled on top. The 4-well chamber was incubated at 37°C, with shaking, in the dark for 3.5 hours. Following incubation the fluorescence of the solution in the lower wells was measured.

In an attempt to continue to sprinkle larger quantities of surfactant on the surface of the model sputum the 4-well chambers were re-used. Also the beads were laid on top of the sputum layer in the well prior to sprinkling the surfactant on top. This more closely mimics the in vivo effect of inhaled dust particles and inhaled Surfactant powder. The incubation time was shortened to increase the barrier function of sputum in these large volume chambers.

Experiment 6

500 μl of thin model sputum (3.33 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was added to wells. 50μl beads were added on top of sputum, and 20 mg

Surfactant sprinkled on top of the beads. The 4-well chamber was incubated at 37°C, with shaking, in the dark for 40 mins. Following incubation the fluorescence of the solution in the lower wells was measured.

The addition of beads to the well after model sputum was shown to increase the barrier function of the sputum (Figure 6). Model sputum decreased transport to 54% of the PBS control. This remained unaltered by the addition of 20 mg Surfactant A, however, addition of 20 mg Surfactant B reduced transport to 26% of the PBS control.

This experiment was repeated using a thicker preparation of model sputum to increase the barrier function (Figure 7). Model sputum was added to wells and incubated with

20 mg of pumactant for a range of time periods prior to the addition of beads. This was performed in an attempt to alter the model sputum before the addition of beads and make the assay more sensitive. There was no PBS control in this experiment due tα . shortage of wells in the chamber so the thick sputum model alone is given as the 100%) value in Figure 7. Surfactant A was shown to reduce the transport of beads through the thick model sputum despite pre-incubation of the model sputum and

Surfactant A. 20, 40 and 60 minute pre-incubation times resulted in a reduction in transport from 100% to 54%, 51% and 69% respectively, in contrast to the surprising lack of effect reported above.

Experiment 7

500 μl of thick model sputum (5 mg/ml DNA, 30 mg/ml mucin, 0.33 mg/ml actin) was added to wells. 20 mg Surfactant was sprinkled on top of the beads and incubated at 37°C for a range of time periods. 50 μl of beads were added following the incubation and the 4-well chamber incubated at 37°C, with shaking, in the dark for 10 mins. Following incubation the fluorescence of the solution in the lower wells was measured.

In the next experiment the beads were mixed with surfactant and added on top of the model sputum layer in a 48-well chamber.

Experiment 8

15 μl of thin model sputum (3.3 mg/ml DNA, 8.3 mg/ml mucin, 0.33 mg/ml actin) was added to wells and the chamber centrifuged briefly at 1000 rpm to remove air bubbles. 10 μl of beads, into which had been dissolved 1 mg Surfactant, was added on top of the sputum layer. The 48-well chamber was incubated at 37°C, with shaking, in the dark for 1 hour. Following incubation the fluorescence of the solution in the lower wells was measured.

Figure 8 shows that with the beads added on top of the thin model sputum layer the transport of beads was reduced to 64% of the PBS control. Addition of Surfactant A mixed with beads reduced transport from 64% to 3%, and Surfactant B reduced it to 17%.

Overall the test results show support the concept of the invention that inhaled SAPL powder improves the barrier function of sputum to prevent inhaled particles passing through the sputum to contact the underlying lung surfaces.

Claims

1. Use of a surface active phospholipid (SAPL) composition as a non-therapeutic pulmonary humectant or anti-irritant, said composition comprising at least one SAPL.

2. Use of a surface active phospholipid (SAPL) composition in the preparation of a non-therapeutic pulmonary humectant or anti-irritant for administration by inhalation to the airways and upper respiratory tract of a person free from lung disease, said composition comprising at least one SAPL.

3. Method of providing a non-therapeutic humectant or anti-irritant effect in the lungs of a person free from lung disease which comprises administering to the person an effective amount of a surface active phospholipid (SAPL) composition containing at least one SAPL.

4. Use according to claim 1 or 2, in which the SAPL composition consists of a first component comprising one or more phosphatidyl cholines and optionally a second component comprising one or more compounds selected from phosphatidyl glycerols, phosphatidyl ethanolamines, phosphatidyl serines, phosphatidyl inositols and chlorestyl palmitate.

5. Use according to claim 4, in which the SAPL comprises said first component and said second component in a weight ratio of from 1 : 9 to 9: 1.

6. Use according to claim 4, in which the proportion by weight of said first component exceeds that of said second component.

7. Use according to claim 6, in which said first component and said second component are present in a weight ratio of from 6: 4 to 8: 2.

8. Use according to any one of claims 4 to 7, in which the first component comprises a diacyl phosphatidyl choline.

9. Use according to claim 8, in which the first component comprises a dipalmitoyl phosphatidyl choline.

10. Use according to any one of claims 4 to 8, in which the second component comprises a phosphatidyl glycerol.

11. Use according to claim 1 or 2, in which the SAPL composition comprises a blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a weight ratio ofjfcom 6: 4 to 8: 2.

12. Use according to claim 1 or 2, in which the SAPL composition comprises a blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a weight ratio of about 7: 3.

13. Use according to claim 1 or 2, in which the SAPL composition is a dry powder which is administered as a dry powder.

14. Method according to claim 3, in which the SAPL composition consists of a first component comprising one or more phosphatidyl cholines and optionally a second component comprising one or more compounds selected from phosphatidyl glycerols, phosphatidyl ethanolamines, phosphatidyl serines, phosphatidyl inositols and chlorestyl palmitate.

15. Method according to claim 14, in which the SAPL comprises said first component and said second component in a weight ratio of from 1 : 9 to 9: 1.

16. Method according to claim 14, in which the proportion by weight of said first component exceeds that of said second component.

17. Method according to claim 4, in which said first component and said second component are present in a weight ratio of from 6: 4 to 8: 2.

18. Method according to claim 4 , in which the first component comprises a diacyl phosphatidyl choline.

19. Method according to claim 18, in which the first component comprises a dipalmitoyl phosphatidyl choline.

20. Method according to claim 4, in which the second component comprises a phosphatidyl glycerol.

21. Method according to claim 4, in which the SAPL composition comprises a blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a weight ratio offrom 6: 4 to 8: 2.

22. Method according to claim 4, in which the SAPL composition comprises a blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a weight ratio of about 7: 3.

23. Method according to claim 4, in which the SAPL composition is a dry powder which is administered as a dry powder.

24. Method according to claim 21, in which the SAPL composition is a dry powder which is administered as a dry powder.

24. Method according to claim 22, in which the SAPL composition is a dry powder which is administered as a dry powder.