WO2005112882A2

WO2005112882A2 - Pharmaceutical compositions

Info

Publication number: WO2005112882A2
Application number: PCT/GB2005/001988
Authority: WO
Inventors: James Anthony Thompson; Robert Price; Paul Michael Young
Original assignee: Britannia Pharmaceuticals Limited
Priority date: 2004-05-22
Filing date: 2005-05-20
Publication date: 2005-12-01
Also published as: GB0411502D0; WO2005112882A3

Abstract

The present invention relates to a method of preparing a composition comprising a phospholipid which composition is free from contamination, more staff a and less hygroscopic, which method comprises: forming a suspension comprising the phospholipid and water; spray drying the suspension; and collecting the dry particles in a cooled chamber.

Description

Pharmaceutical Compositions

The present invention relates to methods of preparing particulate compositions comprising a. phospholipid, the phospholipid acting as a pharmaceutically active agent itself, as a carrier for one or more other pharmaceutically active agents, or as both. The invention also relates to apparatus specifically adapted for carrying out the method.

Phospholipids are the major component of natural surfactant lipids and they have been found to be useful in treating or preventing various medical conditions. In addition to acting as surfactants, phospholipids also act as natural lubricants, de- watering agents and release agents. They are of particular value because they are not recognised by the body as being foreign, and so do not elicit an immune response.

It was first suggested by Avery in 1959 that phospholipids might be used clinically in the treatment of neonates with respiratory distress syndrome. This condition prevents the lungs of an infant from inflating. It has been postulated that the phospholipids assist breathing by reducing the high surface tension of the air-water interface within the alveoli, thereby reducing the pressure needed to expand the lungs, see Milner, Archives of Diseases in Childhood 1993; 68-253. Phospholipids are also administered prophylactically, to prevent the respiratory distress syndrome from occurring.

Following the use of phospholipids in the treatment of respiratory distress syndrome, phospholipids and adjunct formulations that include phospholipids have also been proposed for the treatment of asthma, the treatment of disorders of the middle ear and conditions associated with articulated joints. The various uses of such formulations are discussed in "Surface active phospholipids: a Pandora's box of clinical applications", Hills B. A., Intern Med J 2002; 32(4): 170-178. The use of phospholipids has also been proposed for reducing the occurrence of surgical adhesions, see for example "Spray of phospholipids powder reduces surgically induced adhesions in rabbits", Bhandarkar D. S. et al, Aust N Z J Surg 1999; 69: 388-90.

Both natural and synthetic phospholipids can be used in therapeutic treatments or for prophylaxis. For example, phospholipids suitable for such use include diacyl phosphatidyl cholines, such as dioleyl phosphatidyl choline, distearyl phosphatidyl choline, and dipalmitoyl phosphatidyl choline. Other suitable phospholipids include sphingomyelins, phosphatidyl ethanolamines, phosphatidyl inositols, phosphatidyl serines and lysophosphaαdyl cholines.

Previous studies have shown that the deposition of a phospholipid composition is enhanced when the phospholipid is co-administered with an agent that will reduce the transition temperature of the composition. Below the transition temperature, there is a transition of the acyls chains of the phospholipid composition, so that these chains align at the air-water interface present, allowing the phospholipid composition to rapidly spread as a thin film.

A wide variety of agents are capable of reducing the transition temperature of a phospholipid composition. Such agents include, for example, proteins, peptides, and fatty acids, among others. Preferred agents are capable of reducing the transition temperature of the phospholipid composition to below the body temperature of the animal to which the composition is to be administered. Therefore, the transition temperature is preferably lowered to below 40°C, and ideally to below 37°C.

As phospholipid compositions with a transition temperature of 40°C or less will be more effective, it is desirable to have a method of preparing a particulate composition comprising a phospholipid which is suitable for preparing a composition having a transition temperature which is less than 40°C, and preferably less than 37°C.

Some phospholipids or neutral Upids are capable of reducing the transition temperature of a phospholipid composition. The transition temperature of the composition may also be adjusted using free fatty acids, glycolipids and proteins, which can affect the ultimate structure and function of the phospholipid composition. Particularly preferred agents that facilitate transition temperature reduction and deposition include phosphatidyl glycerols, phosphatidyl ethanolamines, phosphatidyl serines and phosphatidyl inositols. Another useful agent is chlorestyl palmitate.

The advantages of a phospholipid composition including an agent which reduces the transition temperature are discussed in Chen Y. et al, Aust N Z J Surg 2000: 70: 443-7, where it is disclosed that the deposition of dipalmitoyl phosphotidyl choline is enhanced by the addition of phosphatidyl glycerol in the mesothelium at least. It has also been shown that addition of the secondary lipid reduces the transition temperature of the phosphohpid composition, thereby facilitating spreading.

Dipalmitoyl phosphatidyl choline is the major component of lung, gastrointestinal and articulated joints, as disclosed in Hills B. A., Intem Med J 2002; 32(4): 170-8. Thus, one of the preferred phosphohpid compositions comprises a blend of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol. By way of illustration one of the preferred formulations comprises a mixture of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a ratio of 7:3. This formulation has a transition temperature of about 35°C. Other combinations of phospholipids and transition temperature reducing agents are also envisaged, with the different combinations providing the compositions with varied physical, chemical and biological properties.

At least some of the agents capable of reducing the transition temperature of phosphohpid compositions can also have the added advantage of enhancing or potentiating the binding of the phospholipids to the epithelial surface, which is particularly useful where the phosphohpid composition is administered to the lungs. The strong binding of phospholipids to the lung surface observed when the phosphohpid composition includes a transition temperature reducing agent has been demonstrated to withstand repeated saline washings and produce no inflammatory response in rats, Hills B. A., Perit Dial Int (Canada), 2000, 20(5): 503-516). Phosphatidyl glycerol, one of the preferred transition temperature reducing agents, has a further important function in the pharmaceutical compositions. The presence of phosphatidyl glycerol causes the phosphohpid composition to form very finely divided, dry powder dispersion in air. This is particularly advantageous where the composition is to be administered to the lungs.

In light of the various different therapeutic and prophylactic uses of phosphohpid compositions, it is clearly desirable to be able to administer the compositions in a variety of different ways. For example, if the composition is to be used to treat respiratory distress syndrome or asthma, it is preferable to administer it directly to the lungs by inhalation. In contrast, where the composition is used to treat a condition associated with articulated joints, it can, for example, be administered directly to the joint by injection.

Alternative modes for administering phosphohpid compositions include, for example, oral delivery, nasal delivery, sublingual delivery, and buccal delivery. Preferably, the phosphohpid composition is delivered to various internal or external regions of the mammalian structure, i.e. to cavities, fossa, mucosa or membranes or any other body surfaces, preferentially as a dry powder aerosol.

In order for a phosphohpid composition to be suitable for any one of the proposed modes of administration, the composition is preferably aseptic or sterile. Therefore, it is also desirable to have a method of preparing a particulate composition comprising a phosphohpid wherein the composition is sterile.

For storage purposes and for ease of use, a dry powder form is preferable regardless of the manner in which the phosphohpid composition is to be administered.

Where the phosphohpid composition is to be administered by inhalation, the composition is preferably in the form of a dry powder. In order to ensure that the powder particles reach the patient's airways and upper respiratory tract, the particles preferably have a diameter in the range of 0.5 to 20 microns, more preferably 0.5 to 5 microns, and most preferably 0.5 to 2 microns. Therefore, it is desirable to have a method of preparing a particulate composition comprising a phosphohpid wherein the diameter of the particles of the composition can be controlled, and wherein the particles preferably have a diameter in the range of 0.5 to 20 microns, more preferably 0.5 to 5 microns, and most preferably 0.5 to 2 microns.

Although the above particle sizes are preferred, the skilled artisan would appreciate that the appropriate particle size may also be measured as a function of the density of the particles and/or the Mass Median Aerodynamic Diameter (MMAD). Therefore, a particle may be of any size as long as the particle size can be propelled through the pharynx and larynx to reach the trachea. Upon reaching the lungs, the spreading of the composition is dependent on the transition temperature and not the particle size. Therefore, it is also desirable to have a method of preparing a particulate composition comprising a phosphohpid wherein the MMAD of the particles of the composition can be controlled, and wherein the particles preferably have a MMAD which is suitable for effective administration by inhalation.

The particle size, and indeed physiochemical character of the particle, is dependent on the mode of production and processing. Therefore, it is desirable to have a method of preparing a particulate composition comprising a phosphohpid wherein these properties of the particles can be adjusted by making shght changes to the method, that is, the mode of production and the processing of the particles.

In order to achieve the optimal therapeutic or prophylactic effect, it will usually be desirable for the phosphohpid composition to remain present in the body for as long a period after administration as possible. The duration of the effect of the phosphohpid composition may be extended by using specific enantiomer forms of the phospholipids employed. Dextro rotatory (D) forms of the phosphohpids can exist for longer periods within the body because they are not susceptible to degradation by enzymes such as phospholipase A, which are capable of digesting the naturally-occurring laevo rotatory (L) forms of phosphohpids.

Adjusting the relative proportions of the phosphohpid enantiomers may also allow manipulation of the physiochemical properties of the phosphohpid composition. Whilst phosphohpid compositions ate themselves useful in treating a variety of conditions, such as respiratory distress syndrome and asthma, the phosphohpids may also be used as a carrier material. Where there is co-administration of the phosphohpid and another material, the phosphohpid may or may not be intended to also provide the above described therapeutic or prophylactic effects. Indeed, in some instances co-administration may result in a synergistic effect.

When in an aqueous environment and correctly processed, the phosphohpids will spontaneously form liposomes or micelles. If these phosphohpid hposomes or micelles are formed in the presence of other material, that other material can become encapsulated within the hposomes or micelles. As previously mentioned, the phosphohpids do not ehcit an immune response from the patient. Therefore, the material encapsulated within the phosphohpid hposomes is effectively masked and protected, the phosphohpid acting as a shell which masks and protects the encapsulated material. This makes such phosphohpid encapsulation a very attractive way in which to dehver materials to the body which otherwise are difficult to administer, for example because they ehcit an immune response from the patient's body. The encapsulation of material within a phosphohpid liposome or micelle prevents the triggering of such an immune response.

It is envisaged that a wide variety of materials can be administered by phosphohpid protective encapsulation. Such materials include, for example, food supplements and nutrients, but are preferably pharmaceutically active agents that are useful in therapeutic treatments or prophylaxis. These pharmaceutically active agents may provide a locahsed or systemic effect on the body upon administration. The following are just a few examples of the types of pharmaceutically active agents which may be administered by phosphohpid protective encapsulation: proteins, such as insulin; antibiotics; antidiuretics; antibodies; antiviral agents; analgesics; anti- inflammatories; antimicrobials; respiratory drugs, such as β₂-agonists, steroids, cromones, antimuscarinic drugs and leukotriene receptor antagonists. Much work has been done to identify a way to efficiently administer proteins such as insulin. The present invention offers a cheap and efficient pharmaceutical composition wherein the protein is encapsulated and protected, and can be simply administered in simple, conventional ways.

In light of the obvious advantages of phosphohpid encapsulation, it is desirable to have a method of preparing a particulate composition comprising a phosphohpid, wherein the phosphohpid encapsulates a further material.

The use of phosphohpids having a low transition temperature can assist the efficient dehvery of the encapsulated material. Indeed, encapsulation within a phosphohpid composition which has a transition temperature of 40°C or less will ensure prompt and full release of the encapsulated material once inside the body.

It is anticipated that the dehvery of pharmaceutically active agents by phosphohpid encapsulation could increase the percentage of the active agent delivered. Indeed, in the case of peptides such as insulin, the rate of dehvery using conventional methods is relatively low and could be significantly increased by encapsulation in a phosphohpid composition having a low transition temperature.

It is essential for patient safety that a composition administered to the body is generally free from contamination. Contamination can arise during the manufacture of a phosphohpid particulate composition using conventional methods, for example, as a result of residual solvent or exposure to external sources of contamination, such as airborne particles.

Contamination is particularly dangerous if the composition is intended for administration by injection or in surgical operations, although the risk of provoking an adverse reaction is present whatever the mode of administration. The production and use of a sterile particulate composition should, therefore, reduce the potential for serious adverse reactions during administration therapy. The sterile particulate composition will also be a useful starting material for the preparation of other dose forms, i.e. solutions for injection or powders for injection with suitable dehvery devices.

The current methods used to produce the necessary finely divided dry powders of phosphohpid compositions for sterile apphcations generally involve multiple steps and are expensive, with the avoidance of contamination being difficult and frequently requiring extra testing steps. The resultant dry powder tends to be unstable and has a very short storage period, it being intolerant to small changes in temperature and humidity.

Furthermore, compositions that have a transition temperature below that of body temperature, for example a formulation comprising dipalmitoyl phosphatidyl choline and phosphatidyl glycerol in a ratio of 7:3, are generally hygroscopic and tend to be susceptible to changes in humidity and temperature when made using conventional methods. They are not stable within environmental conditions that conventional powder formulations are routinely exposed to.

The main reason for the instability of conventional particulate phosphohpid compositions is their tendency to absorb water from the atmosphere. Certain formulations of lipid mixtures and associated adjuvants facilitate hygroscopic behaviour. When water from the surrounding atmosphere is attracted and absorbed, the complex mixture of the components of the formulation undergoes a change in morphology which makes the formulation difficult to aerosohse and causes chemical degradation.

In one known method for producing dry particulate phosphohpid compositions, the components, for example dipalmitoyl phosphatidyl choline and phosphatidyl glycerol, are dissolved in a suitable solvent, such as ethanol or chloroform. The solution is then sterile filtered, hydrated, and put into vials for freeze-drying. The particle size obtained using this method is generally between 1 and 100 microns in diameter, but the low density of the particles means that these larger diameter particles are still useful in inhalation therapy as they have a MMAD which is acceptable for such administration. However, this method has the disadvantage that it is costly and there is also the requirement to test the resultant composition for traces of the solvent used.

An alternative known method used to produce dry powders comprising phosphohpids involves dissolving the components in ethanol, which is then allowed to evaporate. Water is then added to form a slurry which is freeze-dried and subsequently micronised in order to obtain the desired particle sizes. The resultant composition has the disadvantage that it is unstable and will readily absorb water when exposed to a surrounding atmosphere containing moisture.

Therefore, it is the aim of the present invention to provide a method of manufacturing a particulate composition comprising a phosphohpid which is simple and inexpensive. The method should be able to provide a particulate composition which has one or more of the desirable properties discussed above. Thus, for example, the method should be suitable for preparing a sterile or aseptic particulate composition comprising only a phosphohpid or comprising material encapsulated within phosphohpid hposomes or micelles. It should also be possible to adjust the method to provide a composition with particles having specific desirable properties, such as a diameter suitable for inhalation. Furthermore, the method should be suitable for preparing compositions having a transition temperature of 40°C or lower.

According to a first aspect of the present invention, a method for manufacturing a particulate composition comprising a phosphohpid is provided. The method comprises forming an aqueous solution or suspension of the phosphohpid and any other components to be included in the composition. This solution or suspension is then spray dried, with the resultant particles being transferred to and collected in a cooled chamber. This is a one-step method.

Spray drying is a well known technique for forming particulate compositions from solutions and suspensions and it is extensively used in connection with pharmaceuticals. Spray drying essentially comprises exposing highly dispersed liquid to warm or hot air, so as to cause evaporation of the solvent or liquid and the drying of the airborne droplets. The dried droplets are carried to a collection vessel whilst the evaporated solvent or liquid is removed. In some types of apparatus, the resultant dry particles are sorted into ranges of particle sizes, for example using a cyclone. Particle sizes may be sorted by manipulation of cyclone dimension flow rates of material and associated operating conditions.

The phospholipid-containing dry particulate composition produced using the method according to the first aspect of the invention is free from contamination and is significantly more stable than the particulate composition obtained by conventional methods. The spray dried particulate composition does not attract water from the surrounding atmosphere.

As discussed above, it is highly desirable for the phosphohpids used in therapeutic and prophylactic apphcations to have a low transition temperature. Preferably, the transition temperature is 40°C or lower. This can be achieved by simply selecting appropriate phosphohpids to make the suspension or solution which is fed into the spray drying apparatus. However, the methods for producing phosphohpid powders described in the prior art do not address the problems which are associated with dealing with phosphohpids having a transition temperature of 40°C or less.

Where the phosphohpid composition has a low transition temperature, this will increase the hkehhood of the composition being exposed to temperatures above the transition temperature during the manufacturing process. When this happens, the composition will undergo a phase transition and "melt".

Therefore, the method according to the first aspect of the present application includes the collection of the dry particles in a cooled chamber. If the dry particulate phosphohpid composition produced by the spray drying is not collected in a cooled chamber, the composition will deposit a waxy layer on the interior of the collection chamber. This is clearly undesirable as a proportion of the phosphohpid composition will obviously be lost, rendering the production of the dry particulate composition inefficient. Furthermore, the deposited layer will have to be removed periodically, to ensure that the functioning of the apparatus is not impaired. Preferably, the cooled chamber in which the dry particulate phosphohpid composition is collected has cooled walls. The walls are preferably cooled by a cooling jacket which is arranged around the chamber. In a preferred embodiment, the cooling jacket contains cooling agents that can maintain a desired temperature during production of the dry particulate phosphohpid composition.

Even more preferably, the conducting tubes of the spray drying apparatus, which connect the drying chamber to the collection chamber, are also cooled. This coohng may also be achieved using a cooling jacket.

In another preferred embodiment of the invention, the method is used to prepare a composition with the phosphohpid acting as a carrier, encapsulating other material such as one or more pharmaceutically active agents. The material to be encapsulated is simply included in the aqueous suspension or solution to be spray dried. When this suspension or solution is spray dried, the resultant particles will include the other material encapsulated within a phosphohpid shell.

The method according to the first aspect of the present invention can be used to produce an aseptic particulate composition. This aseptic composition may be administered in any of the usual ways, including inhalation. It can even be administered by injection. In one preferred embodiment of the invention, the aqueous solution or suspension is sterile filtered before it is spray dried. This will further reduce the possibility of contamination. Furthermore, all of the gases used in the spray drying process can also be filtered.

In another preferred embodiment of the first aspect of the invention, the spray drying method is adjusted to ensure that the resultant dry particulate composition particles have a diameter of between 0.5 and 20 microns, preferably between 0.5 and 5 microns and more preferably between 0.5 and 2 microns.

The skilled person will be well aware of the ways in which the spray drying method may be adjusted to provide a given particle size. For example, particle size can be controlled by adjusting the atomising of the suspension, by adjusting the conditions within the drying chamber, or by sorting the resultant particles and selecting those within the desired size range.

In yet another embodiment, the spray drying method is adjusted to ensure that the particles have a MMAD which renders them suitable for administration by inhalation. Once again, the skilled person would have no problem adjusting the spray drying method to provide a particle with the desired MMAD.

The aqueous phosphohpid suspension or solution which is spray dried according to the first aspect of the present invention may include small amounts of salts, acids, bases or organic solvents. These may be required to effect crystallisation, however, they should be kept to a minimum, preferably less than 10% w/w, more preferably 5% w/w of the total formulation, and most preferably less than 1% w/w of the total formulation.

According to a second aspect of the present invention, apparatus is provided for carrying out the method according to the first aspect of the present invention. The apparatus comprises the basic components of a conventional spray drying apparatus, except that the collection vessel is cooled. The basic components of a spray drying apparatus are a feed pump, an atomiser, an air inlet, a drying chamber, an air outlet and a collection vessel. Preferably, the collection vessel is made from a metal.

As with conventional spray drying apparatus, it is desirable for various parameters to be adjustable, in order to ensure that spray dried particles with the desired properties are produced. For example, it is possible to manipulate the feed temperature, and specific blowing agents may be added and specific drying gases may be selected. The apparatus may also provide for filtering of the feed solution, if desired, for example if sterility is required.

As explained above, phosphohpid compositions, and especially those with a low transition temperature, tend to deposit a waxy layer of phosphohpid on the interior surface of the apparatus, and in particular, of the collection vessel. This deposit can be avoided by coohng the collection vessel. Preferably, the walls of the collection vessel are cooled. The walls may be cooled, for example, by positioning a cooling jacket around the outside of the collection vessel.

In some spray drying apparatus, the dry particles are sorted in a collection chamber, which includes a collection vessel. Thus, in another embodiment of the present invention, apparatus is provided comprising a collection chamber, the wall of which is cooled. Indeed the wall of all parts of the apparatus between the drying chamber and the collection vessel may be cooled, in order to avoid deposit of the waxy layer.

The walls of the apparatus may be cooled using a cooling jacket, which is constandy cooled by a cooling agent or heat transfer agent, for example a supply of cold water or liquid nitrogen. This coohng jacket enhances the conduction and convection of heat from the particles surface.

According to a preferred embodiment of the invention, the coohng jacket is porous, allowing water vapour to contact the spray dried particles. This will affect the crystal structure and other intrinsic physiochemical properties of the particles. This can be used to give the particles desirable properties.

An example of an apparatus according to the second aspect of the present invention will now be described, by way of example only, and with reference to the following drawing.

Figure 1 is a schematic, cross-sectional view of an embodiment of a spray drying apparatus in accordance with the present invention.

The apparatus comprises a source 11 of the suspension or solution of water and the phosphohpid, together any other material to be incorporated into the dry particulate composition to be formed. The suspension or solution is preferably constantly stirred by a stirrer 12, to ensure uniform distribution of the components. The suspension or solution is fed to the drying chamber of the spray drying apparatus via a feed pipe 1 which is connected to a peristaltic pump 14.

The source of the suspension or solution, and the feed pipe, are maintained at a predetermined temperature. This area of controlled temperature is indicated by a box 15 in the schematic drawing.

From the feed pipe 13, the solution or suspension is fed into the drying chamber 21. It enters the drying chamber through one or mote spray nozzles 22, which atomise it, creating a cloud of tiny droplets. The drying chamber is also fed with dry gas, such as N₂, CO₂, Ar, He or NO. The selection of the dry gas used in the drying chamber can have an impact on the size of the dry particles produced. This dry gas enters the drying chamber through the first, upper inlet 23.

Dry gas is also fed into the drying chamber from lower inlets 24 and 25, but this gas is cool.

When the droplets of solution or suspension come into contact with the dry gas, the water evaporates and dry particles are formed. These dry particles flow out of the drying chamber via a conducting tube 31 which links the drying chamber 21 to the collection chamber 41.

Both the conducting tube and the collection chamber are surrounded by a coohng jacket. At the base of the collection chamber, there is a collection vessel 42, within which the dry particles are collected. At the upper end of the collection chamber, there is an outlet 43 for the air. This outlet can have a filter, allowing the capture of minute airborne particles.

Within the collection chamber, a cyclone can be generated, in order to allow separation and collection of dry particles according to their size, if desired.

As an example of a method for preparing a particular particulate composition, the suspension fed into the apparatus comprises dipalmitoyl phosphatidyl choline, phosphatidyl glycerol, insulin and water. The spray dried particulate composition collected in the collection vessel of the apparatus will comprise insulin encapsulated in a shell made of dipalmitoyl phosphatidyl choline and phosphatidyl glycerol.

Claims

1. A method of preparing a particulate composition comprising a phosphohpid, comprising: forming a suspension comprising the phosphohpid and water; spray drying the suspension; and collecting the dry particles in a cooled chamber.

2. A method as claimed in claim 1, wherein the particulate composition is sterile or aseptic.

3. A method as claimed in either of the preceding claims, wherein the phosphohpid is a diacyl phosphatidyl chohne.

4. A method as claimed in claim 3, wherein the diacyl phosphatidyl choline is selected from the group consisting of dioleyl phosphatidyl chohne, distearyl phosphatidyl chohne, dipalmitoly phosphatidyl choline,

5. A method as claimed in either of claims 1 and 2, wherein the phosphohpid is selected from the group consisting of sphingomyehns, phosphotidyl ethanolamines, phosphatidyl inositols, phosphotidyl serines and lysophosphatidyl chohnes.

6. A method as claimed in claim 4, wherein the phosphohpid is dipalmitoyl phosphatidyl chohne.

7. A method as claimed in any one of the preceding claims, wherein the suspension also comprises an agent capable of reducing the transition temperature of the phosphohpid.

8. A method as claimed in claim 7, wherein the agent reduces the transition temperature of the phosphohpid to less than 40°C, preferably less that 37°C.

9. A method as claimed in either of claims 7 and 8, wherein the agent is selected from the group consisting of phosphatidyl glycerols, phosphatidyl ethanolamines, phosphatidyl serines, phosphatidyl inositols, and chlorestyl palmitate.

10. A method as claimed in claim 9, wherein the agent is a phosphatidyl glycerol.

1 . A method as claimed in any one of the preceding claims, wherein the suspension comprises dipalmitoyl phosphatidyl chohne, phosphatidyl glycerol and water.

12. A method as claimed in any one of the preceding claims, wherein the suspension also comprises a further material, to be administered with the phosphohpid.

13. A method as claimed in claim 12, wherein the further material is a pharmaceutically active agent.

14. A method as claimed in claim 13, wherein the pharmaceutically active agent is selected from the group consisting of proteins, antibiotics, antidiuretics, antibodies, antiviral agents, analgesics, anti-inflammatories, antimicrobials, and respiratory drugs.

15. A method as claimed in claim 14, wherein the pharmaceutically active agent is insuhn.

16. A method as claimed in any one of the preceding claims, wherein the particles of the dry particulate composition have a diameter of between 0.5 and 20 microns, preferably between 0.5 and 5 microns and more preferably between 0.5 and 2 microns.

17. A method as claimed in any one of the preceding claims, wherein the particles of the dry particulate composition have a Mass Median Aerodynamic Diameter rendering them suitable for administration by inhalation.

18. A method as claimed in any one of the preceding claims, wherein the dry particulate composition is for administration by inhalation, oral dehvery, nasal dehvery, sublingual dehvery, buccal dehvery, or injection.

19. A method as claimed in any one of the preceding claims, wherein the suspension also comprises less than 5% w/w of the total formulation of a salt, acid, base, or organic solvent, and preferably less than 1% w/w of the total formulation.

20. A spray drying apparatus comprising a feed pump, an atomiser, an air inlet, a drying chamber, an air outlet, and a collection vessel, the collection vessel being cooled.

21. An apparatus as claimed in claim 20, wherein the collection vessel is made from metal.

22. An apparatus as claimed in either of claims 20 and 21, wherein the parts of the apparatus connecting the drying chamber and the collection vessel are cooled.

23. An apparatus as claimed in any one of claims 20-22, wherein the walls are cooled.

24. An apparatus as claimed in claim 23, wherein the walls are cooled by a surrounding coohng jacket.

25. An apparatus as claimed in claim 24, wherein the coohng jacket is porous.

26. An apparatus as claimed in claim 25, wherein the porous coohng jacket allows water vapour to come into contact with the material collected in the collection vessel.

27. An apparatus as claimed in any one of claims 20-26, for use in a method as claimed in any one of claims 1-19.

/ 27. A method of preparing an aseptic dry particulate composition comprising a phosphohpid, substantially as hereinbefore described.

28. A spray drying apparatus substantially as hereinbefore described and as illustrated in Figure 1.