WO2003053406A1

WO2003053406A1 - Fluorinated particles for inhalation & pharmaceutical formulation

Info

Publication number: WO2003053406A1
Application number: PCT/EP2002/014825
Authority: WO
Inventors: Paul Johnson
Original assignee: Glaxo Group Limited
Priority date: 2001-12-21
Filing date: 2002-12-20
Publication date: 2003-07-03
Also published as: GB0130703D0; AU2002364305A1

Abstract

A pharmaceutical formulation for inhalation comprising particles having a substantially fluorinated surface, use and preparation of said formulations and substantially fluorinated particles and populations of said particles prepared according to the invention.

Description

Fluorinated Particles for Inhalation & Pharmaceutical Formulation

The present invention relates to particles for inhalation, methods of preparing the said particles and their use in the preparation of pharmaceutical formulations suitable for filling into inhalation devices.

Drugs for treating respiratory and nasal disorders are frequently administered through the mouth or nose as fine particles incorporated into a formulation. One widely used method for dispensing drug is by use of a metered dose inhaler which contains an aerosol drug formulation wherein the drug is suspended in a liquefied gas propellant.

The suspension is stored in a sealed canister capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispersed by activation of a dose-metering valve affixed to the canister.

A metering valve generally comprises a metering chamber, which is of a set volume and is designed to administer per actuation an accurate predetermined dose of medicament. As the suspension is forced from the canister through the dose-metering valve by the high vapour pressure of the propellant, the propellant rapidly vaporises leaving a fast moving cloud of very fine particles of the drug formulation. This cloud of particles is directed into the nose or mouth of the patient by a channelling device such as a cylinder or open-ended cone. Concurrently with the activation of the aerosol dose-metering valve, the patient inhales the drug particles into the lungs or nasal cavity. Systems of dispensing drugs in this way are known as "metered dose inhalers" (MDI's). See Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL (1990) for a general background on this form of therapy.

Alternatively compositions for topical delivery to the lung may, for example, be presented in formulations generally of a powder mix of drug and a suitable powder base such as lactose or starch. Packaging of the formulation may be in unit dose or multi- dose delivery devices. In the case of multi-dose delivery, the formulation can be pre- metered (e.g. as in Diskus, see GB 2242134 or Diskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (e.g. as in Turbuhaler, see EP 69715). An example of a unit-dose device is Rotahaler (see GB 2064336). The Diskus inhalation device comprises an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein an inhalable formulation containing a drug usually combined with lactose. The strip is sufficiently flexible to be wound into a roll. The lid sheet and base sheet will preferably have leading end portions which are not sealed to one another and at least one of the said leading end portions is constructed to be attached to a winding means. The lid sheet may preferably be peeled from the base sheet in a longitudinal direction from a first end of the said base sheet.

Patients often rely on medication delivered by devices used in inhalation therapy for rapid treatment of respiratory disorders, which are debilitating and in some cases even life threatening. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meets the specifications claimed by the manufacturer and complies with the requirements of the FDA and other regulatory authorities. That is, every dose in the can/device must be capable of delivery within the same within close tolerances.

Formulations of drugs for inhalation have presented the pharmaceutical industry with significant challenges in recent years, for example, the drug may have a tendency to adhere to the internal surfaces of the device, which may result in the reduction in the amount of drug delivered to the patient, which is unacceptable. This is particularly true for MDI devices containing formulations employing so called HFA propellants. Furthermore some work has been done to show that moisture ingression in such devices results in a decrease in the fine particle mass (FPM) distribution, the measure of the amount of drug which reaches the inner lung the target area for treatment, especially after prolonged storage. This may in turn reduce the effectiveness of the treatment.

The FPM of an actuation from an MDI or dry powder device can be, for example, calculated based on the sum of the amount of drug substance deposited on stages 3, 4 and 5 of an Andersen Cascade Impaction stack as determined by standard HPLC analysis.

Various attempts have been made to address these problems in aerosol formulations. Some prior art aerosol devices rely on the dispenser being shaken so as to agitate the liquid propellant and product mixture therein, in an attempt to dislodge the deposited particles. However, while in some cases this remedy can be effective within the body of the drug container itself, it may not be effective for particles deposited on the inner surfaces of other MDI components such as the metering valve. Patent applications WO96/32099, WO96/32150, WO96/32151 and WO96/32345 disclosure the use of a fluorocarbon polymer in combination with a non-fluorocarbon polymer to coat the internal surfaces of metered dose inhaler canisters. However this has the disadvantage that the canisters must often be made from reinforced material to withstand the stressful curing process used when the coating is applied. This has cost implications. Furthermore, it does not address the issue of the effect of moisture on formulation properties.

Modification of other components used in the preparation of MDIs has been disclosed in, for example, UK patent application GB-A-2,328,932 which discloses the use of a liner of a material such as fluoropolymer, ceramic or glass to line a portion of the wall of the metering chamber in a metering valve of an MDI. Although this alleviates the problem of deposition in these types of dispensers, it does require the re-design or modification of mouldings and mould tools for producing the valve members to allow for insertion of the liner. Alternatively the coating of the metering chamber with a fluorocarbon polymer has been proposed. In addition ethylene propylene diamine monomer in valve gaskets to reduce moisture ingression and the incorporation of a desiccant material in to the device has been investigated.

WOOO/53248 discloses a dose protector which may be incorporated into a dry powder device to limit the ingression of water in use.

Furthermore many inhalation devices are sealed in a foil pouch containing desiccant to ensure that the patient receives a product of the required standard, even after storage.

Surprisingly the inventors have found that formulations with improved stability are obtained when the pharmaceutical formulation for inhalation comprises particles having a substantially fluorinated surface (herein after "modified particles").

Such formulations appear to be less susceptible to the effects of water ingress.

Furthermore reduced drug deposition may be achieved without the requirement to fluorinate, for example, by coating each surface the formulation is likely to come into contact with before or during a dose being dispensed from a device to a patient. Additionally other physical properties of the particles may be improved, for example, the flow properties of the bulk material. Furthermore the absorption of the medicament into the body of the patient may be affected advantageously.

Preferably the pharmaceutical formulations according to the invention comprise particles of medicament having a substantially fluorinated surface.

Preferably when the formulation according to the invention comprises particles of medicament having a substantially fluorinated surface, generally greater than 10% by weight of the particles of the medicament will have a substantially fluorinated surface, more preferably greater than 50% by weight, especially greater than 75% by weight, particularly greater than 90% by weight.

Medicaments for administration by inhalation desirably have a controlled particle size. The optimum particle size for inhalation into the bronchial system is usually 1-1 Oμm, preferably 2-5μm. Hence particles of medicament should preferably have a mass median diameter (MMD) of 1-1 Oμm, especially 2-5μm. Particles having a size above 20μm are generally too large when inhaled to reach the small airways. To achieve these particle sizes the particles of drug as produced may be size reduced by conventional means, for example, by micronisation. The desired fraction may be separated out by air classification or sieving. Preferably, the particles will be crystalline, prepared, for example, by a process which comprises mixing in a continuous flow cell in the presence of ultrasonic radiation a flowing solution of medicament in a liquid solvent with a flowing liquid antisolvent for said medicament (eg as described in International Patent Application PCT/GB99/04368) or else by a process which comprises admitting a stream of solution of the substance in a liquid solvent and a stream of liquid antisolvent for said substance tangentially into a cylindrical mixing chamber having an axial outlet port such that said streams are thereby intimately mixed through formation of a vortex and precipitation of crystalline particles of the substance is thereby caused (e.g. as described in International Patent Application PCT/GB00/04327). When an excipient such as lactose is employed, in one aspect according to the invention, generally the particle size of the excipient will be much greater than the inhaled medicament. When the excipient is lactose it will typically be present as milled lactose, wherein not more than 85% of lactose particles will have a size of 60-90μm and not less than 15% will have a MMD of less than 15μm. Other example excipients include sugars such as trilactose. In an alternative aspect the excipient such as lactose will be in the form of a lactose pellet having a diameter of from 10 to 1500 micrometres, which pellet comprises a plurality of lactose particles, of which at least 90% by weight have a diameter less than 15μm, as disclosed in EP0750492.

The pharmaceutical formulations according to the invention may further or alternatively comprise a particulate excipient, for example lactose as discussed above, having a substantially fluorinated surface and a medicament.

Preferably wherein the formulation according to the invention comprises a particulate excipient having a substantially fluorinated surface generally greater than 10% by weight of the particles of the excipient will have a substantially fluorinated surface, more preferably greater than 50% by weight, especially greater than 70 or 75% by weight.

Thus in a first aspect the pharmaceutical formulation is a dry powder formulation wherein the modified particles may be excipient and/or medicament particles.

Preferably the excipient is lactose.

A final powder composition desirably contains 0.1 % to 90%w/w such as 0.5% to 75% w/w, for example, 1 to 50% w/w of medicament relative to the weight of excipients.

Preferably the concentration of medicament in dry powder formulations according to the invention is generally from 0.001 to 10% by weight, especially, for most types of preparations the proportion used will be within the range of from 0.005 to 5% and most preferably 0.01 to 0.1%.

In dry powder formulations containing particulate medicament and particulate excipient, preferably particles of both medicament and excipient will have a substantially fluorinated surface.

In another aspect of the invention the pharmaceutical formulation is a pharmaceutical aerosol formulation comprising particles of medicament having a substantially fluorinated surface and a liquefied propellant gas. Preferably the particles of medicament will be substantially insoluble in the propellant system in such formulations.

Advantageously modified medicament particles may be less soluble in the propellant system of such formulations than corresponding untreated/unmodified particles of medicament. This may in turn result in a reduction in so called Ostwald Ripening" a process which can lead to particle size growth, which is undesirable.

In this aspect preferably the liquefied propellant gas is a fluorocarbon or hydrogen containing fluorocarbon propellant.

Suitable propellants include, for example, C-| ^hydrogen-containing chlorofluorocarbons such as CH₂CIF, CCIF₂CHCIF, CF₃CHCIF, CHF₂CCIF₂, CHCIFCHF₂, CF₃CH₂CI and CCIF CH3; C-₎ ^hydrogen-containing fluorocarbons such as CHF CHF , CF3CH₂F, CHF₂CH3 and CF3CHFCF3; and perfluorocarbons such as CF3CF3 and CF3CF₂CF₃.

Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are employed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chlorofluorocarbons, for example, CHCIF₂, CH₂F₂ and CF3CH3. Preferably a single fluorocarbon or hydrogen-containing chlorofluorocarbon is employed as the propellant. In this aspect of the invention particularly preferred as propellants are C-| ^hydrogen- containing fluorocarbons such as 1 ,1 ,1 ,2-tetrafluoroethane (CF3CH₂F) or 1 ,1 ,1 ,2,3,3,3- heptafluoro-n-propane (CF3CHFCF3) or mixtures thereof. 1 ,1 ,1 ,2-Tetrafluoroethane is of particular interest.

Preferably the pharmaceutical formulations according to this aspect of the invention contain no components covered by the Montreal Protocol which provoke the degradation of stratospheric ozone. In particular the formulations are substantially free of chlorofluorocarbons such as CCI3F, CCI₂F₂ and CF3CCI3.

A polar co-solvent such as C₂_β aliphatic alcohols and polyols e.g. ethanol, isopropanol and propylene glycol, preferably ethanol, may be included in the aerosol drug formulation in the desired amount to improve the dispersion of the formulation, either as the only excipient or in addition to other excipients such as surfactants. Suitably, the aerosol drug formulation may contain 0.01 to 5% w/w based on the propellant of a polar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1 to 1% w/w.

Preferably aerosol formulations according to the invention will be substantially free of co-solvent. A surfactant may also be employed in the aerosol formulation. Examples of conventional surfactants are disclosed in EP-A-372,777. The amount of surfactant employed is desirable in the range 0.0001% to 50% weight to weight ratio relative to the medicament, in particular, 0.05 to 5% weight to weight ratio. Preferred surfactants are lecithin, oleic acid and sorbitan trioleate. Preferred formulations, however, are free or substantially free of surfactant.

Pharmaceutical formulations generally may contain 0.0001 to 50% w/w, preferably 0.001 to 20%, for example, 0.001 to 1% of sugar relative to the total weight of the formulation. Generally the ratio of medicament to sugar falls within the range of 1 :0.01 to 1 :100 preferably 1 :0.1 to 1 :10. Typical sugars, which may be used in the formulations, include, for example, sucrose, lactose and dextrose, preferably lactose, and reducing sugars such as mannitol and sorbitol, and may be in micronised or milled form.

Preferably the aerosol formulations according to the invention are free or substantially free of particulate excipients.

In a further preferred embodiment of the first aspect of the invention the pharmaceutical formulation according to the invention consists essentially of particles of medicament having a substantially fluorinated surface and a fluorocarbon or hydrogen-containing fluorocarbon propellant.

The aerosol formulations according to the invention desirably contains 0.005-10% w/w, preferably 0.005 to 5% w/w, especially 0.01 to 2.0% w/w, of medicament relative to the total weight of the formulation.

Medicaments which may be administered in formulations according to the invention include any drug useful in inhalation therapy.

Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate (e.g. s the sodium salt), ketotifen or nedocromil (e.g. as the sodium salt); antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. as the propionate ester), flunisolide, budesonide, rofleponide, mometasone e.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as the acetonide) or 6α, 9α-difluoro-11 β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy- androsta-1 ,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g. noscapine; bronchodilators, e.g. albuterol (e.g. as free base or sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate), isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride), rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or 4- hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl] ethyl]amino]ethyl-2(3H)- benzothiazolone; adenosine 2a agonists, e.g. 2R,3R,4S,5R)-2-[6-Amino-2-(1 S- hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro- furan-3,4-diol (e.g. as maleate); α₄ integrin inhibitors e.g. (2S)-3-[4-({[4-(aminocarbonyl)- 1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy) acetyl]amino}pentanoyl)amino] propanoic acid (e.g. as free acid or potassium salt), diuretics, e.g. amiloride; anticholinergics, e.g. ipratropium (e.g. as bromide), tiotropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines, e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g. insulin or glucagon; vaccines, diagnostics, and gene therapies. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament.

Preferred medicaments are selected from albuterol, salmeterol, fluticasone propionate and beclomethasone dipropionate and salts or solvates thereof, e.g. albuterol sulphate or salmeterol xinafoate.

Medicaments can also be delivered in combinations. Preferred formulations containing combinations of active ingredients contain albuterol (e.g. as the free base or the sulphate salt) or salmeterol (e.g. as the xinafoate salt) or formoterol (e.g. as the fumarate salt) in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g. the dipropionate) or a fluticasone ester (e.g. the propionate) or budesonide. A particularly preferred combination is a combination of fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt). A further combination of particular interest is budesonide and formoterol (e.g. as the fumarate salt). Suitable fluorinated materials for use according to the invention include fluorocarbon materials such as fluorinated or perfluorinated molecule or monomer or polymer with a desirable toxicology profile. If the material has too many consecutive perfluorinated carbon atoms the body may have difficulties metabolising the material which may then bioaccumulate, which is undesirable. Whilst not wishing to be bound by theory it is thought that the body has difficulty metabolising molecules with greater than 3 consecutive perfluorinated carbon atoms.

In the context of this specification the terms fluorocarbon, fluorinated and fluorine containing substance will be used interchangeably.

Toxicity of a material can be tested by methods well known to person skilled in the relevant art. A suitable method for accessing the bioaccumulation of compounds for use according to the invention includes intravenously dosing a Wistar Han rat (B30603) with 10mg per Kg of the desired compound in a suitable carrier, for example, 25% DMSO 75% saline carrier. Plasma samples may then be taken at desired intervals, for example, 10, 20, 40, 90 150 minutes, and 6, 24 and 32 hours. The samples may be prepared by extraction using protein precipitation and then analysed using high- performance liquid chromatography using a suitable detector such as a liquid chromatography tandem mass spectrometer. The half-life of the compound can then be calculated by known methods.

Suitable materials include those derived from a monomer of selected from tetrafluoroethylene, fluorinated ethylene propylene, vinylidiene fluoride and chlorinate ethylene tetrafluoroethylene. However, the polymeric materials used, during some of the processes described below may in fact be deposited as monomer radicals. Other suitable materials include trifluoropolysiloxanes as disclosed in USP 5,118 496 which are commercially available from Grant Industries Inc under the name Gransil known for its good lubrication and hydrophobic properties.

Preferably the coating obtained will be thin, for example, 0.01 μm to 5μm preferably 0.01 μm to 1μm.

A further aspect of the invention are processes for preparing modified particles according to the invention. Preferably the particles have a substantially fluorinated surface obtained by treating, for example, by coating an unmodified particle with a fluorine containing substance. One method of coating particles is physical vapour deposition (PVD). The means of vaporising the material used in the coating can vary, for example, suitable means include: thermal means such as a filament or plate and electromagnetic means such a laser as used in laser ablation.

Thus in one aspect is provided a method of preparing fluorinated particles for inhalation by laser ablation wherein the laser in used energise a material such that discrete particles thereof are generated such as radicals which are rapidly vaporised. It is advantageous that the "coating" material is vaporised quickly as this minimises the amount of degradation it experiences during the process. The discrete particles generated can then be deposited on the surface of the substrate to be coated. The size of the coating particles can be controlled by varying the physical condition the process is performed under. Under poorly controlled conditions the coating particles may agglomerate which is undesirable. The laser parameters such as number of pulses, power density, laser spot size and gas pressure in the chamber and length of treatment can all be varied to give a coating with the desired characteristics.

Lasers suitable for use in processes according to the invention emit light in the wavelength range of 190 to 1100nm.

Suitable lasers are well known to persons skilled in the art, such as, Spectra-Physics DCR11 Nd-Yag operating at 266nm, Lambda Physik model 305i operating at a wavelength of, for example, 248nm or KrF, ArF excimer lasers at wavelengths of 248nm and 193 nm respectively. Suitable energy densities in the range 0.05-1 OJ/cm², more typically 0.1-2J/cm². A pulse width of approximately 10^"12 to 10^"6 seconds is appropriate which should be repeated with a frequency of 0-1000Hz. The laser may be set such that the beam approaches the target at a 45° incident angle. It may be more precisely targeted by using focal mirrors.

The longer the substrate particles are exposed to the discrete particles of coating the larger the amount of coating deposited thereon will be. Furthermore the larger the number the of laser pulses the substrate is exposed to the "thicker" the coating will be. The chamber may be under reduced pressure and/or in a inert atmosphere such as argon or nitrogen. Generally the lower the pressure the faster the rate of deposition because the ratio of discrete coating particles to atmosphere atoms or molecules is larger and therefore the coating particles are less diluted as the number of atmosphere molecules are reduced. Collisions of the discrete coating particle with the atmospheric gas atoms or molecules reduces/slows the deposition process which can be used advantageously to provide a thinner coating. Preferably the amount of coating on each substrate particle is minimised by the presence of an inert gas. This reduces any toxicology issues related to the coating. Pressure in the chamber may be in the range 0.05-760 Torr, such as 10-760 Torr preferably 0.05 to 50 Torr.

When the coating material is a polymer then it may be necessary to first mix the material with a solvent and then freeze the mixture which can then be ablated as described in USP 4 920 264 (Becker). Alternatively the polymer may be incorporated in a matrix such as glycerol to facilitate the energy transfer from the laser to the polymer.

It is necessary for the generated discrete particles of coating to have access to the individual substrate particles to be coated. This can be done by, for example, introducing the substrate into the coating chamber such that they move under the influence of gravity from one point to another in the chamber to coincide with the laser cycle. Alternatively mechanical vibration, stirring or energisation can be used to agitate and separate the substrate particles. Additionally the flow of an inert gas through the chamber in a desired direction may be used to disrupt the substrate particles for the purpose of coating them, as in a fluidiser. In a preferred embodiment the chamber is designed such that the continuous processing of substrate particles is facilitated, for example, wherein the substrate particles are introduced under gravity this may be by means of an inlet opening/valve in an the top or upper portion of the chamber. Substrate particles may leave the chamber via an exit opening/valve in the base or lower portion of the chamber after the coating process. Optionally the substrate may be recycled to the inlet valve for a second pass to ensure the particles are adequately coated. The particles may be held in a pre-treatment region such as a hopper before the entry into the coating chamber.

Preferably the coating chamber will be isolatable such that the environment therein can be controlled. More preferably the laser will have access the chamber via an area transparent to the beam, for example, a UV transparent quartz region. Although lasers are known which are suitable for incorporating in the chamber. The former enables the laser to energise the coating material whilst remaining physically separate and thereby avoiding interactions with the substrate particles to be coated. Apparatus as described in USP 4200669 may be adapted for use in the present invention.

A drying step may be employed for example using an inert gas to ensure the coated particles do not agglomerate, for example, using an inert gas.

In another aspect the invention provides a method of preparing a particle with a substantially fluorinated surface for inhalation using thermal energy, for example, hot filament or hot plate vapour deposition, wherein a fluid is heated to form discrete particles, such as radicals, which are deposited on the surface of a substrate particle to be coated. In a further aspect the fluid is gas such as perfluoroethane or perfluoromethane which when heated by a filament or a plate forms radicals of, for example, CF₂. Alternatively the fluid may be a liquid which is heated by a metal plate.

Optionally after the coating material is deposited on the substrate particle the product may be further processed by cooling or exposure to the flow of an inert gas, to aid the bonding of the coating to the substrate.

The coating may be present as monomer units or as polymers. Generally the processes have the advantage that substrates of irregular shapes can be coated without modification of the process and furthermore the substrate is not damaged during coating.

Substantially fluorinated surface, in the context of this specification, will be understood to mean wherein about 30% or more of the surface of the particle is fluorinated. Preferably greater than 50%, especially greater than 75% of the particle surface will be fluorinated.

The apparatus for providing coated particles according to the invention comprises in general a vacuum chamber which provides access of the particles to be coated to a vapour generated by an energy source. Preferably the particles to be coated will be located near the production source of the vapour because this is a physical technique. After a certain distance the efficiency of the coating process is reduced with increasing distance moved away from the source.

In an alternative aspect the substrate particles are coated using a plasma process. The plasma coating may comprise a fluorinated polymer laid down on the surface of the particle, by polymerisation or direct modification of the material surface by interchange of hydrogen ions in the material with fluorine ions. The coating process typically takes place in a vacuum at ambient temperature. The particles to be coated are placed inside a chamber which is evacuated. The particles require agitation during the coating process and suitable means are described above. The fluorine monomer or fluorine source is introduced into the chamber at a controlled rate. The plasma is ignited within the chamber and maintained for a given time at a chosen power setting. At the end of the treatment the plasma is extinguished, the chamber flushed and the particles retrieved. Filters may be necessary to ensure that particles are not lost during the coating process, especially at the final stage. In the polymerisation process, a thin layer of plasma polymer will be bonded to the surface of the particle.

For plasma polymerisation typically temperatures in the range of about 20°C to about 100°C may be employed. Suitable plasma processes also include continuous wave radio frequency/microwave frequency cold plasma.

More appropriately the plasma process used will be pulsed wave cold plasma technology which provides a number of advantages over the continuous wave plasma processes. The former is more controllable since the average energy is lower. This results in less damage to the substrate and more control over the radical polymerisation. Pulses are applied on and off at intermittent intervals, suitably the 'off' time being longer than the 'on' time. Generally, the ratio of 'off time to 'on' time is such that the average power applied is less than 10 Watts, preferably less than 1 W. The power may be applied, for example, for 20 μS followed by no power for 10000μS to 20000 μS. The 'off time allows the radicals a finite amount of time for the radical generated to interact with the substrate particles.

Pulsed wave plasma coating may also include regimes where an inert/noble gas, nitrogen, or carbon dioxide is pulsed.

Suitable apparatus for a pulsed cold plasma procedure may be an electrodeless cylindrical glass reactor enclosed in a Faraday cage. The reactor may be pumped by a two stage rotary pump (such as an Edwards E2M2) via a liquid nitrogen cold trap (base pressure of 5 x 10^"3 mbar). A suitable power source would be 13.56 MHz supplied to a copper coil (e.g. 10 turns) wound the plasma chamber via an L-C matching unit and power meter. The RF generator may be modulated by pulses with a 5V amplitude supplied by the pulse driver used to drive the gas pulsing valve. The output of both may be monitored by an oscilloscope.

Where gas pulsing is used the gas may be pulsed into the system by a gas pulse valve, for example, General Valve Corporation 91-110-900 which can be driven by a pulse driver.

In an alternative process the coating material is dissolved in a solvent, for example supercritical CO₂, the substrate particles are then introduced into the solution and mixed to form a homogenous suspension. The solvent is then rapidly evaporated to leave particles with a substantially fluorinated surface. Furthermore aqueous suspension of fluorinated ethylene propylene are available and may be used in similar methodology.

In another alternative the substrate particles are coated by an adaptation of a spray drying process using, for example, a Wurster™ fluidised bed granulation coater by Glatt, a K.K, SPIR-A-FLOW granulation coater by Freund Industrial Co. Ltd, a Multiplex tumbling fluidised bed coater by Powrex Corporation or a Precision Coater by Niro (Aeromatic Division, Columbia). The coater may have a top, bottom or tangential spray. The design and type of coater used may vary the characteristics of the products obtained. In the invention in suit preferably the coated particles have a size which makes them suitable for inhalation.

In one embodiment of this type the substrate particles to be coated are placed in a cylindrical column placed in the centre of a container employed to fluidise the particles in a single direction by an upward gas stream, the coating solution is then sprayed in fine droplets from a nozzle, for example, at the bottom of the column. It may be necessary to heat the gas stream to allow for evaporation of the solvent the coating is suspended in.

It is necessary to control the apparatus to prevent aggregation of the coated particles and agglomeration of the coating particles. This can be done by minimising the diameter of the coating aspirated from the nozzle and increasing the speed at which the substrate particles collide with the said droplets.

Useful spray rates include 1 to about 50ml/min, such as 25 to about 50ml/min, using a single spray gun. Static inlet pressure should be controlled to be in the range 2 to about 10 bars. The inlet temperature should be 60 to about 100°C and the product temperature should be about 20 to about 60°C. The substrate particles will usually be micronised before processing.

The period of time the particle spends in the stream is proportional to the thickness of the coating obtained. Preferably, the particles spend the minimum amount of time in stream being coated, for example, 1 to 10 seconds.

Scanning electron microscope technology using, for example, a Stereoscan 250 MK3 microscope form Cambridge Instruments can be used to analyse whether a satisfactory coat has been obtained.

Preferably greater than 10%w/w or more of the "target" particles will be coated, more preferably greater than 30%w/w or more, especially 50%w/w or more, particularly 75%w/w or more.

Thus the invention includes a process for the preparation of a pharmaceutical formulation wherein said formulation is an aerosol formulation or dry powder formulation which process comprises the step of; a) coating particles of medicament and/or excipient with a fluorinated material.

When the formulation is an aerosol formulation the method may further include suspending said coated medicament particles in a fluorocarbon or hydrogen containing fluorocarbon propellant; and filling the formulation into a container capable of withstanding the pressure exerted thereon.

The formulation may be filled into a "metered dose inhaler" or "MDI", that is a unit comprising a can, a crimped cap covering the mouth of the can, and a drug metering valve situated in the cap, while the term "MDI system" also includes a suitable channelling device. The terms "MDI can" means the container without the cap and valve. The term "drug metering valve" or "MDI valve" refers to a valve and its associated mechanisms, which delivers a predetermined amount of drug formulation from an MDI upon each activation. The channelling device may comprise, for example, an actuating device for the valve and a cylindrical or cone-like passage through which medicament may be delivered from the filled MDI can via the MDI valve to the nose or mouth of a patient, e.g. a mouthpiece actuator. The relation of the parts of a typical MDI is illustrated in US Patent 5,261 ,538 incorporated herein by reference. Metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.

The gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of large scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is added to a charge vessel and liquefied propellant is pressure filled through the charge vessel into a manufacturing vessel, together with liquefied propellant containing the surfactant. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.

In an alternative process, an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure formulation does not vaporise, and then a metering valve crimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filled canister is check- weighed, coded with a batch number and packed into a tray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channeling device prior to use to form a metered dose inhaler system for administration of the medicament into the lungs or nasal cavity of a patient. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff, for example, in the range of 10 to 5000 micrograms of medicament per puff.

When the formulation is a dry powder formulation it may be filled into a pre-metered delivery device, as described in the introduction, such as Diskus or Diskhaler including a unit-dose inhaler such as Rotahaler. Alternatively the powder may be filled into the multi-dose reservoir/ bulk container of a reservoir device, for example, Turbuhaler® where the powder/formulation is metered by volume from the bulk container into a dose metering cavity.

The pharmaceutical formulation of the present invention are particularly suitable for use in multi-dose reservoir type inhalers.

The invention also provides use of formulations according to the invention in the treatment of respiratory disorders such as disorders of the lungs and bronchial tracts including asthma and chronic obstructive pulmonary disorder (COPD).

The invention also extends to use of particles of medicament and/or excipient with a substantially fluorinated surface and populations of medicament particles and/or excipient particles where 30 to 90% of said particles have a substantially fluorinated surface, especially wherein the excipient is lactose.

Fig 1 shows apparatus in a block diagram form where 1 represents a suitable laser, 2 represents a quartz window, 3 represents a coating chamber, 4 represents a vessel for containing the coating material with access to the coating chamber, 5 represents a beam, 6 represents an inlet valve, 7 represents access to a means for creating a vacuum such as a vacuum pump and 8 represents an outlet valve.

Fig 2 shows an alternative appendage to the coating chamber of Fig 1 , (such that the apparatus in Fig 2 replaces the laser the vessel for containing the coating and the quartz window in Fig. 1) wherein 20 represents a filament that is connected to a source of electrical output, 21 represents a heating sleeve for maintaining the temperature in the unit sufficient to prevent condensation of the coating and 22 represents a heated baffle.

Fig 3 shows another alternative appendage, to the one shown in Fig 2, wherein the filament is replaced by a hotplate 30.

Claims

I . A pharmaceutical formulation for inhalation comprising particles having a substantially fluorinated surface.

2. A pharmaceutical formulation for inhalation according to claim 1 comprising particles of medicament having a substantially fluorinated surface.

3. A pharmaceutical formulation according to any one of claim 2 wherein greater than 90% w/w of the medicament particles have a substantially fluorinated surface.

4. A pharmaceutical formulation according to claim 2 or 3, further comprising a particulate excipient substance.

5. A pharmaceutical formulation according to claim 4, wherein the particulate excipient comprises particles of excipient having a substantially fluorinated surface.

6. A pharmaceutical formulation according to any one of claim 5, wherein greater than 70% w/w of the excipient particles have a substantially fluorinated surface.

7. A pharmaceutical formulation according to claim 4 to 6 wherein the particulate excipient is lactose.

8. A pharmaceutical formulation according to claim 1 comprising particles of excipient having a substantially fluorinated surface and a medicament.

9. A pharmaceutical formulation according to claim 8, wherein the particulate excipient is lactose.

10. A pharmaceutical formulation according to any preceding claim wherein said medicament particles and/or excipient particles are coated with a fluorocarbon coating.

I I . A pharmaceutical formulation according to claim 10, wherein the coating is derived from a monomer of selected from tetrafluoroethylene, fluorinated ethylene propylene, vinylidiene fluoride or chlorinate ethylene tetrafluoroethylene.

12. A pharmaceutical formulation according to claim 11 , wherein the coating is derived from a monomer of tetrafluoroethylene.

13. A pharmaceutical aerosol formulation according to claim 2, further comprising liquefied propellant gas.

14. A pharmaceutical aerosol formulation according to claim 13 wherein the liquefied propellant gas is 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,12,3,3,3-heptafluoro-n-propane or mixtures thereof.

15. A pharmaceutical formulation according to claim 14, wherein the medicament is present in the amount 0.005 to 10%w/w relative to the total weight of the formulation.

16. A pharmaceutical formulation according to any one of claims 13 to 15 that consists essentially of a particles of medicament having a substantially fluorinated surface and a fluorocarbon or hydrogen containing fluorocarbon propellant.

17. A pharmaceutical formulation or pharmaceutical aerosol formulation according to any preceeding claim wherein the medicament particles have mass median diameter in the size range 1 to 10 microns.

18. Use of substantially fluorinated particles in the preparation of a pharmaceutical formulation for inhalation.

19. Use of substantially fluorinated particles according to claim 18, wherein the particles are medicament particles.

20. Use of substantially fluorinated particle according to claim 18, wherein the particles are excipient particles.

21. Use of substantially fluorinated particles according to claim 18 to 20, wherein said particles are coated with a fluorocarbon coating.

22. Use of substantially fluorinated particles according to claim 21 , wherein the coating is derived from a monomer of selected from tetrafluoroethylene, fluorinated ethylene propylene, vinylidiene fluoride or chlorinate ethylene tetrafluoroethylene.

23. Use of substantially fluorinated particles according to claim 22, wherein the coating is derived from a monomer of tetrafluoroethylene.

24. A population of medicament particles wherein 30-99% of the particles have a substantially fluorinated surface.

25 A population of medicament particles according to claim 24, wherein said medicament particles are coated with a fluorocarbon coating.

26. A population of medicament particles according to claim 25, wherein the coating is derived from a monomer of selected from tetrafluoroethylene, fluorinated ethylene propylene, vinylidiene fluoride or chlorinate ethylene tetrafluoroethylene.

27. A population of excipient particles wherein 30-99% of the particles have a substantially fluorinated surface.

28. A population of excipient particles according to claim 27, wherein the excipient is lactose.

29. A population of A population of excipient particles according to claim 27 or 28 wherein said excipient particles are coated with a fluorocarbon coating.

30. A population of excipient particles according to claim 29, wherein the coating is derived from a monomer of selected from tetrafluoroethylene, fluorinated ethylene propylene, vinylidiene fluoride or chlorinate ethylene tetrafluoroethylene.

31. A method of treating respiratory disorders which comprise administration of a pharmaceutical formulation according to any one of claims 1 to 17.

32. A process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 17 which comprises; a) coating particles of medicament and/or excipient with a fluorinated material.

33. A process according to claim 32 for preparing a pharmaceutical aerosol formulation which further comprises the steps: b) suspending said coated medicament particles in a fluorocarbon or hydrogen containing fluorocarbon propellant; and c) filling the formulation into a container capable of withstanding the pressure exerted thereon.

34. A process according to claim 32, for preparing a pharmaceutical dry powder formulation which comprises the further step of filling the particles from step (a) into a delivery device.