GB2454480A - Pulmonary inhalation of levodopa containing compositions in the treatment of Parkinsons disease and other central nervous system disorders - Google Patents

Abstract

A composition comprising levodopa (L-dopa) for the treatment of diseases and disorders of the central nervous system, such as Parkinson's disease, wherein the composition is administered via pulmonary inhalation and provides a therapeutic effect within 10 minutes of administration. The composition may be used in combination with or comprise one or more additional therapeutic agents including a peripheral DOPA decarboxylase inhibitor, a catechol-o-methyl transferase (COMT) inhibitor or a monoamine oxidase type B (MAOB) inhibitor. In addition to the therapeutic agent(s) the composition may include other materials such as additives including amino acids, metal stearates, phospholipids, lecithin, colloidal silicon dioxide and sodium fumarate and/or inert excipients including sugar alcohols, polyols, crystalline sugars, inorganic salts, organic salts, polysaccharides and oligosaccharides. The composition may be administered when needed as a form of rescue therapy through use of a dry powder inhaler, a pressurised meter dose inhaler (pMDI) or via a nebulised system.

Description

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Compositions for Treating Parkinson's Disease and Other CNS Disorders

Description

The present invention relates to compositions comprising levodopa (L-dopa) for providing improved treatment of diseases and disorders of the central nervous system, including Parkinson's disease. In particular, the L-dopa is to be administered via puJmonary inhalation.

Parkinson's Disease Parkinson's disease was first described in England in 1817 by Dr James Parkinson.

The disease affects approximately 2 of every 1,000 people and most often develops in those over 50 years of age, affecting both men and women. It is one of the most common neurological disorders of the elderly, and occasionally occurs in younger adults. In some cases, Parkinson's disease occurs within families, especially when it affects young people. Most of the cases that occur at an older age have no known cause The specific of symptoms that an individual experiences vary, but may include tremor of the hands, arms, legs, jaw and face; rigidity or stiffness of the limbs and trunk, bradykinesia or slowness of movement; postural instability or impaired balance and coordination as well as severe depression Untreated, Parkinson's disease progresses to total disability, often accompanied by general deterioration of all brain functions, and may lead to an early death.

The symptoms of Parkinson's disease result from the loss of dopamine-secreting (dopaminergic) cells, in the substantia nigra of the upper part of the brainstem. The exact reason for the wasting of these cells is unknown, although both genetic and environmental factors are known to be important.

There is no known cure for Parkinson's disease. The goal of treatment is to control symptoms, and medications aim to do this primarily by increasing the levels of dopamine in the brain. The most widely used treatment is L-dopa in various forms.

L-dopa (3,4-dihydroxy.L..phenylalanjne) is an intermediate in dopamine biosynthesis and it is used as a prodrug to increase dopamine levels for the treatmeiit of Parkinson's disease, since L-dopa is able to cross the blood brain barrier whilst dopamine is not. Once L-dopa has entered the central nervous system, it is metabolised to dopamine by aromatic L-amino acid decarboxylase. However, conversion to dopamine also occurs in the peripheral tissues, causing adverse effects.

The treatment of Parkinson's disease with L-dopa has a number of drawbacks, the most significant being that, due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa (and hence dopamine), and so eventually becomes counterproductive Over time, patients start to develop motor fluctuations, which oscillate between "off" times, a state of decreased mobility, and "on" times, or periods when the medication is working and symptoms are controlled. It is estimated that 4O% of Parkinson's patients will experience motor fluctuations within 4-6 years of onset, increasing by 10 percent per year after that.

The average Parkinson's disease patient experiences 2-3 hours of "off-time" each day. These include handwriting problems, overall slowness, loss of olfaction, loss of energy, stiffness of muscles, walking problems, sleep disturbances, balance difficulties, challenges getting up from a chair, and many other symptoms not related to motor functions, such as sensory symptoms (e.g. pain, fatigue, and motor restlessness); autonomic symptoms (e.g. urinary incontinence and profuse sweats); and psychiatric disorders (e.g. depression, anxiety and psychosis).

In spite of the problems highlighted above, the systemic administration of L-dopa remains of great benefit to the patient. However, orally administered L-dopa is associated with an onset period of about 20 to 60 minutes during which the patient suffers unnecessarily Whilst other drugs can be used in combination with L-dopa, the usual Jfltention in the lntei-stages of the disease is to wean patients off L-dopa, as by this stage they will probably be cxperiencing significant discomfort from off-periods. L-dopa has superior efficacy to dopamine agonists but it accelerates the onset of motor complications. Therefore, patients diagnosed with Parkinson's disease at a young age tend to be prescribed Dopamine Agonists (DAs) whereas older patients are prescribed L.. dopa.

As the disease progresses these older patients will be prescribed L-dopa in combination with a peripheral DOPi\ decarboxylase inhibitor, such as carbidopa or benserazide, a catechol-O-methyl transferase (COMT) inhibitor and/or a monoamine oxidase Type B (MAOB) inhibitor. All these additional agents promote the availability of L-dopa and dopamine, thereby helping to reduce the overall needed L-dopa dose.

The direct administration of L-dopa has a low incidence of neuropsychiatric problems, and it has thus been used in patients with severe neuropsychiatric complications due to oral anti-Parkinsoman drugs.

The usual oral dose of L-dopa is in the region of 100-8000 mg per day, and it is not recommended to exceed 8000 mg because the risk of sensitisation to L-dopa does not outweigh the benefit of the larger doses.

The adverse effects observed with L-dopa administration include adventitious movements such as choreiform and/or dystonic movements. Other, less prevalent adverse reactions includeS cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, bradykinetic episodes (also know as the "on-off" phenomena), mental changes including paranoid ideation and psychotic episodes, mild and severe depression (with or without the development of suicidal tendencies), dementia and urinary retention, anorexia, nausea and vomiting with or without abdominal pain and distress, dry mouth, dysphagia, sialorrhea, ataxia, increased hand tremor, headache, dizziness, numbness, weakness and faintness, bruxism, confusion, insomnia, nightmares, hallucinations and delusions, agitation, anxiety, malaise, fatigue and euphoria. Less frequent adverse effects include, muscle twitching and blepharospasm, trismus, burning sensation of the tongue, bitter taste, diarrhoea, constipation, flatulcnce, flushing, skin rash, increased sweating, atypical -4.

breathing patterns, urinary incontinence, diplopia, blurred vision, dilated pupils. hoc flashes, veight gain or loss, dark sweat and/or urine.

The term "parkinsonism" refers to any condition that involves a combination of the types of changes in movement seen in Parkinson's disease and often has a specific cause, such as the use of certain drugs or frequent exposure to toxic chemicals.

Generally, the symptoms of parkinsonism may be treated with the same therapeutic approaches that are applied to Parkinson's disease.

Both intranasal and pulmonary delivery of L-dopa have previously been proposed.

The nasal cavity presents a significantly reduced available surface area compared to the lung (1.8 m2 versus 200 m2). The nasal cavity is also subjected to natural clearance, which typically occurs every 1 5-20 minutes, where ciliated cells drive mucus and debris towards the back of the nasopharynx. This action results in a proportion of the L-dopa which is administered to the nose being swallowed, whereupon it is subjected to first-pass metabolism. This would be the same as an oral dose and therefore a proportion would result in systemic exposure and convert to dopamine in the brain. A potential advantage of intranasal administration is the speed of onset compared to oral administration. In spite of the advantages offered by intranasal administration, pulmonary administration is not encumbered by these clearance mechanisms but additionally offers rapid systemic delivery of higher doses via transfer across the alveolar membrane.

Nasal administration of L-dopa results in a Tm, of approximately 1 5 minutes.

Pulmonary administration of L-dopa results in a Tm,.. of less than 1 minute in some patients. Pulmonary administration also exhibits greater bioavailability than nasal administration. This, in turn, means that nasal doses need to be increased in order to compensate for the lower bioavailability.

The present invention seeks to provide a way of providing "rescue therapy" in the treatment of Parkinson's disease in which particles of L-dopa are delivered to the pulmonary system. Rescue therapy normally refers to non-surgical medical treatment in life-threatening situations. Howevet, despite the unpleasantness of Parkinson's disease, the symptoms are not life threatening and this patent would therefore appear to relate to "rescue" from off-period symptoms.

The known dopamirie compositions and the methods of treating Paikinson's disease involve administering fixed doses of L-dopa at or prior to the onset of off-period symptoms. This does not provide the optimal treatment. It would be highly beneficial to be able to readily determine the appropriate dose of L-dopa to Suit the specific needs of an individual patient. This would ensure that the minimum necessary dose is administered Such a self-titrating system should be flexible, to enable the dose to be tailored to the patient without the need for different strength presentations. The system should also allow the self-titrating to be on-going, with the patient able to constantly change the dose of L- dopa to meet his or her symptoms and needs. This is desirable for a number of reasons, not least in order to minimise the adverse side effects associated with the treatment (including ernesis) and to reduce the risk of L-dopa sensitisation.

It is a further aim of the present Invention to reduce "off-periods" experienced by the patient as much as possible and, if possible, to avoid such off-periods altogether. It is desirable to achieve this without the need to administer excessively large doses of L-dopa (especially in terms of the daily dose administered to the patient over a 24-hour period).

It is also clearly desirable to provide a composition or treatment regimen which the patient is able to self-administer, reducing the burden on the care-giver. L-dopa is delivered via surgically inserted catheter to the duodenum (DuoDopa rM) which provides a continuous infusion to the patient, thereby attempting to avoid overdosing. A safe and convenient, pain-free route of administration is clearly preferable to constant and frequent Injections or a permanent infusion pump. A medication which alleviates this dependency while allowing ease of delivery for frequent administration of L-dopa would clearly be an advantage.

A formulation that is capable of maintaining an extended duration of response would provide the patient with a window in which they could self administer the next dose, thereby negate the need for caregiver assistance.

A method of administration which reduces the adverse effects of L-dopa would obviously be advantageous.

It is also desirable to provide L-dopa compositions which are stable over time under normal storage conditions, in order to avoid the significant expense associated with the disposal of spoiled medicine.

In particular, therefore, there is a need fox a composition comprising L-dopa in a stable, dry powder form suitable for the straightforward administration of low doses of drug with a sufficiently low induction of side effects and rapid onset of pharmacological effects to facilitate self-titration and optimisation of levels of medication.

It is possible for L-dopa to be delivered to the lung and still, via conversion to dopamme have a central effect. Natural systemic metabolic processes result in the further conversion of dopamine making its direct systemic administration unfeasible. L-dopa is converted to dopamine within the brain but conversion from L-dopa to dopamine is also known to occur at other sites within the body, especially where large neutral decarboxylase activity is present. This conversion is assisted by the enzymes dopamine D-carboxylase and catechol-O-rnethyl transferase (COM1).

Inhibitors of both these enzymes would minimize the metabolism of L-dopa peripherally and increase the L-dopa half-life by reducing metabolism in the plasma.

The enzymes convert L-dopa to non-active analogues. Without these inhibitors, approximately only 5% of the L-dopa dose will cross the blood brain barrier (BBB).

Carbidopa (a decarboxylase inhibitor) does not cross the BBB and therefore does not inhibit conversion of L-dopa to dopamine in the brain.

Dopamine may be removed from the brain and voided in the urine intact or as homovanillic acid (HVA) due to the enzyme monoamine oxidase Type B (MO.AB) The systemic delivery of L-dopa currently requires high levels (1 00-250 mg three times daily) to be administered orally, either as a tablet or dispersible preparation) in oi-der to ovel-come the natural conversion of L-dopa to dopamine prior to absorption into the brain.

Orally administered L-dopa is concomitantly administered with carbidopa and COMT inhibitors to inhibit the breakdown of L-dopa and thereby maximise the amount of L-dopa available to cross the BBB. Once the L-dopa has crossed the BBB the MAOB inhibitors further inhibit the breakdown of L-dopa and thereby maximise the amount of L-dopa that can be converted to dopamine Furthermore, it is postulated that MAOBs are also able to Increase the amount of endogenous dopamine.

These combinations result in prolonged L-dopa exposure, improved therapeutic effect and a lower overall L-dopa dose compared to the administration of L-dopa alone.

Currently oral marketed products for L-dopa include a combination with carbidopa, and in addition to this L-dopa may be prescribed in combination with separate MAOBs and COMT inhibitors.

The products containing L-dopa include; L-dopa alone (marketed as Dopar 1M (in the US)), Comtan fM which contains L-dopa iii combination with the COMT inhibitor, entacapone. Stalevo 1M which contains carbidopa, L-dopa and entacapone.

Azilect i" which contains the MAOB inhibitor rasagiline, and Eldepryl IN which contains the MAOB inhibitor selegiline only.

Summary of the Invention

In a first aspect of the present invention, a dry powder composition comprising L-dopa or derivatives thereof for administration by pulmonary inhalatjon is provided, for creating conditions of the central nervous system, including Parkinson's disease.

Pulmonary administration of L-dopa or derivatives thereof described herein may be accompanied by the administration of a dopamine D-carboxylasc inhibitor, such as carbidopa.

Pulmonary administration of L-dopa or derivatives thereof described herein may be accompanied by the administration of a catcchol-O-methyl transferase (COMT) inhibitor, such as entacapone or tolcapone or any combination thereof.

Pulmonary administration of L-dopa oi derivatives thereof described herein may be accompanied by the administration of a monoamine oxidase Type B (MOAB) inhibitor, such as selegiline or rasagiline or any combination thereof. The administration of a MOAB inhibitor would prevent the breakdown of dopamine to undesirable compounds and thereby prolong the therapeutic effect elicited by dopamine Pulmonary administration of L- dopa or derivatives thereof may be accompanied by the administration of a dopamine D-carboxylase inhibitor, such as carbidopa, a catechol-O-methyl transferase (COMT) inhibitor, such as entacapone or tolcapone or any combination thereof, a monoamine oxidase Type B (MOAB) inhibitor, such as selegiline or rasagiline or any combination thereof.

The pulmonary administration of L-dopa would minimise the drug's exposure to the harsh environment associated with oral delivery. Furthermore, when L-dopa is administered in combination with the above inhibitors, which may be delivered via a variety of routes, for example, via the lung, orally, subcutaneously, rectally, opthalmically, or by infusion, the dose of L-dopa may be dramatically reduced.

Another benefit derived from the pulmonary administration of L-dopa is a more rapid onset of the therapeutic effect combined with the ability to provide consistent prolonged delivery. The onset of effect may within less than 10 minutes compared to 20-60 minutes observed following the oral delivery of L-dopa.

Levodopa, (-)-3-(3,4-dihydroxy-phenyl)-L-alanine is a colourless, crystalline compound, which is slightly soluble in water and insoluble in alcohol, with a molecular weight of 197 2. L-dopa can exist in a free basc form or as an acid addition salt. For the purposes of the present invention L-dopa methyl ester, L-dopa ethyl ester, L-dopa hydrochloride and the L-dopa free base are preferred forms, but other pharmacologically acceptable forms of L-dopa can also be used.

The term "L-dopa" as used herein includes the free base form of this compound as well as the pharmacologically acceptable salts or esters thereof.

in a preferred embodiment, the pulmonary administration of methyl esters of levodopa in combination with dopamine D-carboxylase inhibitor, a COMT inhibitor, a MAOB inhibitor or any combination thereof confers a specific advantage of delivering a modified precursor of dopamine which is significantly more soluble than L-dopa thereby disclosing an embodiment with a more rapid absorption and onset of action.

The combination of lung pathophysiology and inhaled L-dopa attributes result in rapid and consistent systemic exposure which translate to a rapid and predictable therapeutic effect, both of which are key requirements when considering improved treatments of Parkinson's disease. Preferably, a Tma of as little as 1 minute is observed. The majority of patients achieved conversions (that is, the onset of the therapeutic effect) within 10 minutes of inhaling L-dopa. Some patients reported conversion as quickly as 1-2 minutes after administration of the L-dopa by pulmonary inhalation.

in one embodiment, the composition comprises a dose of L-dopa to be administered to a patient, the amount of L-dopa being up to 35 mg, 34 mg, 33 mg, 32 mg, 31 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26 mg, 25 mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg or up to 5 mg. Preferably the dose is at least 3 mg, 6 mg, 9 mg or 12 mg.

The Nominal Dose is the amount of drug metered in the receptacle (also known as the Metered Dose). This is different to the amount of drug that is delivered to the patient which is referred to a Delivered Dose.

l'he fine particle fraction (FPF) is normally defined as the FPD (the dose that is <5 i.tm) divided by the Emitted Dose (ED) which is the dose that leaves the device.

The FPF is expressed as a percentage Herein, the FPF of ED is referred to as FPF (ED) and is calculated as FPF (ED) = (FPD/ED) x 100%.

The fine particle fraction (FPF) may also be defined as the FPD divided by the Metered Dose (MD) which is the dose in the blister or capsule, and expressed as a percentage. Herein, the FPF of MD is referred to as FPF (MD), and is calculated as FPF (MD) (FPD/MD) x 100%.

In a preferred embodiment, the dose is administered to the patient as a single dose requiring just one inhalation. In one embodiment, the dose is preferably provided in a blister or capsule which is to be dispensed using a dry powder inhaler device.

Alternatively, the dose may be dispensed using a pressurised metered dose inhaler (pMDI). Typically, administration of a dose of the compositions according to the present invention will result in a fine particle dose (FPD) of about 5 mg to about 20 mg, and preferably of about 9 mg of L-dopa. These doses are administered to the pulmonary mucosa and the L-dopa is absorbed In yet another embodiment, the doses of the L-dopa composition are to be administered to the patient as needed, that is, when the patient experiences or suspects the onset of an off-period. This provides an "on-demand" treatment. In this embodiment, a single effective dose of L-dopa may be administered.

Alternatively, multiple smaller doses may be administered sequentially, with the effect of each dosing being assessed by the patient before the next dose is administered. This allows self-titration and optimisation of the dose.

In another embodiment, the composition provides a typical daily dose, which is the dose administered over a period of 24 hours, preferably of between about 300 mg and about 750 mg. These daily doses may be administered at a single instance (usually involving multiple inhalarions), but it is expected that the daily dose will be spread Out over the 24 hour penod with patients receiving, on average, 100-250 mg separate single administrations, although some patients may receive 1 6 doses, with a daily extreme of 8000 mg doses of 500 mg per dose. It is impoitant to note that the dose recommendations vary depending on medical authority with a single dose of 250 mg and 500 mg and a maximum daily dose of 800 mg and approximately 8000 mg being recommended in Europe and the United States olAmerica respectively In another embodiment, the composition allows doses to he administered at regular and frequent intervals, for example intervals of about 180 minutes, about 120 minutes, about 90 minutes, about 60 minutes, about 45 minutes or about 30 minutes, providing maintenance therapy to avoid the patient experiencing off-periods comparable to the effect of the infusion pump mentioned above. In such an embodiment, the individual doses administered at the chosen intervals will be adjusted to provide a daily dose within safe limits, whilst hopefully providing the patient with adequate relief from symptoms. For example, each individual fine particle dose would preferably provide in the order of about 5 mg to about 20 mg L-dopa and preferably about 9 mg.

According to one embodiment of the present invention, a composition comprising L-dopa is provided, wherein the administration of the composition by pulmonary inhalation provides a Cm, within less than about 10 minutes and preferably within about 5 minutes of administration, with about 2 minutes of administration or even within 1 minute of administration. Preferably, the Cm,, is provided within I to 5 minute.

In a further embodiment of the present invention, the administration of the composition by pulmonary inhalation provides a dose dependent Cm.

In accordance with another embodiment of the present invention, a dose of L-dopa is inhaled into the lungs and said dose is sufficient to provide a therapeutic effect in about 10 minutes or less. In some cases, the therapeutic effect is experienced within as little as about 5 minutes, about 2 minutes or even about 1 minute from admini strati on.

In another embodiment of the invention, the administration of the composition by -12 -pulmonary inhalation provides a terminal elimination half-life of betwcen at least 60 minutes.

In yet another embodiment, the administration of the composition by pulmonary inhalation provides a therapeutic effect with duration of at least 200 minutes, or at least 180. 150, 120, 90, or preferably at least 50 minutes In a further embodiment, the composition comprises at least about 7O% (by weight) L-dopa, or at least about 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% (by weight) L-dopa.

In a yet further embodiment, the compositions according to the present invention are for use in providing treatment of the symptoms of Parkinson's disease or for preventing the symptoms altogether. The patient is preferably able to administer a dose and to ascertain within a period of no more than about 10 minutes whether that administered dose is sufficient to treat or prevent the symptoms of Parkinson's disease. If a further dose is felt to be necessary, this may be safely administered and the procedure may be repeated until the desired therapeutic effect is achieved.

This self-titration of the L-dopa dose is possible as a result of the rapid Onset of the therapeutic effect, the accurate and relatively small dose of L-dopa and the low incidence of side effects, including reduced incidence of previously identified after effects. It is also important that the mode of administration is painless and convenient, allowing repeated dosing without undue discomfort or inconvenience.

According to a second aspect of the present invention, blisters, capsules, reservoir dispensing systems and the like are provided, comprising doses of the compositions according to the first aspect of the invention.

According to a third aspect of the present invention, inhaler devices are provided for dispensing doses of the compositions according to the first aspect of the invention In one embodiment of the present invention, the inhalable compositions are administered via a dry powder inhaler (D1l). In an alternative embodiment, the -13 -compositions are administered via a pressurized metered dose inhaler (pMDI), or via a nebulised system.

According to a fourth aspect of the present Invention, processes are provided for preparing the compositions according to the first aspect of the invention.

According to a fifth aspect of the present invention, methods of treating diseases of the central nervous system, such as Parkinson's disease are provided, the treatment involving administering doses of the compositions according to the first aspect of the invention by pulmonary inhalation.

Alternatively, the use of L-dopa in the manufacture of a medicament for treating diseases of the central nervous system, such as Parkinson's disease is provided, wherein the L-dopa is to be administered by pulmonary inhalation. In a preferred i embodiment, the L-dopa is in the form of a composition according to the first aspect of the present invention.

New methods of treating diseases of the central nervous system, such as Parkinson's disease are provided, using new pharmaceutical compositions comprising L-dopa which are administered by pulmonary inhalation. These methods achieve the desired therapeutic effect whilst avoiding the side effects associated with the administration of L-dopa discussed above, especially when L-dopa is administered in the relatively large doses usually associated with treating conditions such as Parkinson's disease.

Detailed Description of the Invention

The present invention relates to high performance inhaled delivery of L-dopa, which has a number of significant and unexpected advantages over previously used modes of administration. The mode of administration and the compositions of the present Invention make this excellent performance possible. However, it is important that the L-dopa is delivered in such a way that vill allow rapid absorption of an accurate and consistent amount of L-dopa to provide a predictable therapeutic -14 -effect This is made more difficult because of the relatively large amount of drug that must be administered The advantages for this pulmonary route of administration are improved safety, reduced exposure variability resulting in i-educed incidence of dyskinesia, more rapid onset of action compared to oral administration.

L-dopa Compositions for Pulmonary Inhalation Since the effective treatment of Parkinson's disease requires the delivery of a relatively large dose of L-dopa there are significant technical hurdles to overcome.

To date, dry powder inhaler devices have tended to deliver doses of up to 3 mg of powder or occasionally up to 20 mg. Doses delivered by pressurised metered dose inhalers are of the order of I.tg to 3 mg. In contrast, it is intended to provide a dose of some 10-25 mg of a dry powder composition comprising L-dopa in a single inhalation in order to provide ar effective and user-friendly treatment of Parkinson's disease. The volume of the dry powder formulations according to the invention to be administered by inhalation may be as high as 100-800 mg. When the dose is so large, it is envisaged that the Nominal Dose will be in the region of 10-80 mg and the FPD approximately 7-60 mg In the past, many of the commercially available dry powder inhalers exhibited very poor dosing efficiency, with sometimes as little as 10% of the active agent present in the dose actually being properly delivered to the user so that it can have a therapeutic effect. This low efficiency is simply not acceptable where a high dose of active agent is required for the desired therapeutic effect.

The reason for the lack of dosing efficiency is that a proportion of the active agent in the dose of dry powder tends to be effectively lost at every stage the powder goes through from expulsion from the delivery device to deposition in the lung. For example, substantial amounts of material may remain in the blister/capsule or device Material may be lost in the throat of the subject due to excessive plume velocity. However, it is frequently the case that a high percentage of the dose delivered exists in particulate forms of aerodynamic diameter in excess of that required.

It is well known that particle impaction in the upper airways of a subject is predicted by the so-called impaction parameter. The impaction parameter is defined as the velocity of the particle multiplied by the square of its aerodynamic diameter.

Consequently, the probability associated with delivery of a particle through the upper airways region to the target site of action, is related to the square of its aerodynamic diameter. Therefore, delivery to the lower airways, or the deep lung is dependant on the square of its aerodynamic diameter, and smaller aerosol particles are very much more likely to reach the target site of administration in the user and therefore able to have the desired therapeutic effect.

Particles having aerodynamic diameters of less than 10 p.m tend to be deposited in the lung. Particles with an aerodynamic diameter in the range of 2 p.m to 5 p.m will generally be deposited in the respiratory bronchioles whereas smaller particles having aerodynamic diameters in the range of 0.05 to 3 p.m are likely to be deposited in the alveoli. So, for example, high dose efficiency for particles targeted at the alveoli is predicted by the dose of particles below 3 l.Lm, with the smaller particles being most likely to reach that target site.

The term active particles may comprise L-dopa or L-dopa derivatives aiscussed herein, either in isolation or in combination with any or all of the enzymatic inhibitors discussed herein.

In one embodiment of the present invention, the composition comprises active particles comprising L-dopa, at least SO%, at least 70% or at least 90% of the active particles having a Mass Median Aerodynamic Diameter (MMAD) of no more than about 10 p.m. In another embodiment, at least 50%, at least 70% or at least 90% of the active particles have an MMAD of from about 2 p.m to about 5 p.m. In yet another embodiment, at least 50%, at Jeast 7�% or at least 90% of the active particles have aerodynamic diameters in the range of about 0.05.irn to about 3 p.m. -16-

In one embodiment of the invention, at least about 90Db of the particles of L-dopa have a particle size of 5.Lm or less.

Particles having a diameter of less than about 10 tm are, however, thermodynamically unstable due to their high surface area to volume ratio, which provides significant excess surface free energy and encourages particles to agglomerate. In a dry powder inhaler, agglomeration of small particles and adherence of particles to the walls of the inhaler are problems that result in the active particles leaving the inhaler as large agglomerates or being unable to leave the inhaler and remaining adhered to the interior of the device, or even clogging or blocking the inhaler.

The uncertainty as to the extent of formation of stable agglomerates of the particles between each actuation of the inhaler, and also between different inhalers and different batches of particles, leads to poor dose reproducibility. Furthermore, the formation of agglomerates means that the MMAD of the active particles can be vastly increased, with agglomerates of the active particles not reaching the required part of the lung. Consequently, it is essential for the present invention to provide a powder formulation which provides good dosing efficiency and reproducibility, delivering an accurate and predictable dose.

Much work has been done to improve the dosing efficiency of dry powder systems comprising active particles having a size of less than 10 xm, reducing the loss of the pharmaceutically active agent at each stage of the delivery. In the past, efforts to increase dosing efficiency and to obtain greater dosing reproducibility have tended to focus on preventing the formation of agglomerates of fine particles of active agent. Such agglomerates increase the effective size of these particles and therefore prevent them from reaching the lower respiratory tract or deep lung, where the active particles should be deposited in order to have their desired therapeutic effect.

Proposed measures have included the use of relatively large carrier particles. The fine particles of active agent tend to become attached to the surfaces of the carrier particles as a result of interparricle forces such as Van der Waals forces. Upon actuation of the inhaler device, the active particles are supposed to detach from the -17 -carrier particles and are then present in the aerosol cloud in inhalable form, in addition or as an alternative, the inclusion of additive materials that act as force control agents that modify the cohesion and adhesion between particles has been proposed However, where the dose of drug to be delivered is very high, the options for adding materials to the powder composition are limited, especially where at least 70% of the composition is made up of the L-dopa as is preferred in the present invention. Nevertheless, it is imperative that the dry powder composition exhibit good flow and dispersion properties, to ensure good dosing efficiency.

The term "ultra fine particle dose" (UFPD) is used herein to mean the total mass of active material delivered by a device which has a diameter of not more than 3 j.tm.

The term "ultrafrne particle fraction" is used herein to mean the percentage of the total amount of active material delivered by a device which has a diameter of not more than 3.tm. The term percent ultrafine particle dose (%UFPD) is used herein to mean the percentage of the total metered dose which is delivered with a diameter of not more than 3 m (i.e, %UFPD 100*UFPD/total metered dose).

The terms "delivered dose" and "emitted dose" or "ED" are used interchangeably herein. These are measured as set out in the current EP monograph for inhalation products.

"Actuation of an inhaler" refers to the process during which a dose of the powder is removed from its rest position in the inhaler. That step takes place after the powder has been loaded into the inhaler ready for use.

In one embodiment of the present invention, the composition used for treating conditions of the central nervous system, including Parkinson's disease via inhalation comprises a dose of from about 7-17.5 mg FPD of L-dopa The dose may comprise from about 100 to 1 500 g FPD of said L-dopa or derivatives thereof as mentioned previously In another embodiment of the present invention, the dose of the powder composition delivers, in vitro, a fine particle dose of from about 7 mg to about 17.5 mg of L-dopa (based on the weight of the salt), when measured by a Multistage Liquid impinger, United States Pharmacopoeia 26, Chapter 601, Apparatus 4 (2003), an Andersen Cascade Impactor or a New Generation Impactor.

The tendency of fine particles to agglomerate means that the FPF of a given dose can be highly unpredictable and a variable proportion of the fine particles will be administered to the lung, or to the correct part of the lung, as a result. This is observed, for example, in formulations comprising pure drug in fine particle form.

Such formulations exhibit poor flow properties and poor FPF.

In an attempt to improve this situation and to provide a consistent FPF and FPD, dry powder compositions according to the present Invention may include additive material which is an anti-adherent material and reduces cohesion between the particles in the composition.

The additive material is selected to reduce the cohesion between particles in the dry powder composition. It is thought that the additive material interferes with the weak bonding forces between the small particles, helping to keep the particles separated and reducing the adhesion of such particles to one another, to other particles in the formulation if present and to the internal surfaces of the inhaler device. Where agglomerates of particles are formed, the addition of particles of additive material decreases the stability of those agglomerates so that they are more likely to break up in the turbulent air stream created on actuation of the inhaler device, whereupon the particles are expelled from the device and inhaled. As the agglomerates break up, the active particles may return to the form of small individual particles or agglomerates of small numbers of particles which are capable of reaching the lower lung.

The additive material may be in the form of particles which tend to adhere to the surfaces of the active particles, as disclosed in WO 97/03649. Alternatively, the additive material may be coated on the surface of the active particles by, for example a co-milling method as disclosed in WO 02/43701.

Prefeiably, the additive material is an anti-adherent material and it will tend to s reduce the cohesion between particles and will also prevent fine particles becoming attached to surfaces within the inhaler device. Advantageously, the additive material is an anti-friction agent or glidant and will give the powder formulation better flow properties in the inhaler. The additive materials used in this way may not necessarily be usually referred to as anti-adherents or anti-friction agents, but they will have the effect of decreasing the cohesion between the particles or improving the flow of the powder. The additive materials are sometimes referred to as force control agents (FCAs) and they usually lead to better dose reproducibility and higher FPFs.

is Therefore, an additive material or FCA, as used herein, is a material whose presence on the surface of a particle can modify the adhesive and cohesive surface forces experienced by that particle, in the presence of other particles and in relation to the surfaces that the particles are exposed to. In general, its function is to reduce both the adhesive and cohesive forces.

The reduced tendency of the particles to bond strongly, either to each other or to the device itself, not only reduces powder cohesion and adhesion, but can also promote better flow characteristics. This leads to improvements in the dose reproducibility because it reduces the variation in the amount of powder metered out for each dose and improves the release of the powder from the device, It also increases the likelihood that the active material, which does leave the device, will reach the lower lung of the patient.

It is favourable for unstable agglomerates of particles to be present in the powder when it is in the inhaler device. As indicated above, fox a powder to leave an inhaler device efficiently and reproducibly, the particles of such a powder should be large, prefeiably larger than about 40.tm. Such a powder ma)' be in the form of either individual particles having a size of about 40 j.im or laiger and/or agglomerates of finer particles, the agglomerates having a size of about 40 p.m or larger. The agglomerates formed can have a size of 1 00 p.m or 200 p.m and, depending on the type of device used to dispense the formulation, the agglomerates may be as much as about 1000 p.m. With the addition of the additive material, those agglomerates are more likely to be broken down efficiently in the turbulent airstream created on inhalation Therefore, the formation of unstable or "soft" agglomerates of particles in the powder may be favoured compared with a powder in which there is substantially no agglomeration. Such unstable agglomerates are stable whilst the powder is inside the device but are then disrupted and broken up upon inhalation.

It is particularly advantageous for the additive material to comprise an amino acid.

Ammo acids have been found to give, when present as additive material, high respirable fraction of the active material and also good flow properties of the powder. A preferred amino acid is leucine, in particular L-leucine, di-leucine and tn-leucine. Although the L-form of the amino acids is generally preferred, the D-and DL-forms may also be used. The additive material may comprise one or more of any of the following amino acids: aspartame, leucine, isoleucine, lysine, valine, methionine, cysteine, and phenylalanine. Additive materials may also include, for example, metal stearates such as magnesium stearate, phospholipids, lecithin, colloidal silicon dioxide and sodium stearyl fumarate, and are described more fully in WO 96/23485, which is hereby incorporated by reference.

Advantageously, the powder includes at least 80%, preferably at least 90% by weight of L-dopa (or its pharmaceutically acceptable ester(s) or salts) based on the weight of the powder. The optimum amount of additive material will depend upon the precise nature of the additive and the manner in which it is incorporated into the composition. In some embodiments, the powder advantageously includes not more than 8%, more advantageously not more than 5% by weight of additive material based on the weight of the powder. As indicated above, in some cases it will be advantageous for the powder to contain about 1% by weight of additive material In other embodiments, the additive material or FCA may be provided in an amount fiom about 0 lOb to about 10% by weight, and preferably from about O.1S°/c to 5%, most preferably from about 0 5% to about 2°/o.

-21 -When the additive material is micronised leucine or lecithin, it is preferably provided in an amount from about 0.1% to about 10% by weight. Preferably, the additive material comprises from about 3% to about 7%, preferably about 5%, of rriicronised leucine Preferably, at least 95% by weight of the micronised leucine has a paiticle diameter of less than 150 jim, preferably less than 100 j.tm, and most preferably less than 50 jim. Preferably, the mass median diameter of the micronised leucine is less than 10 jim.

If magnesium stearate or sodium stearyl fumarate is used as the additive material, it is preferably provided in an amount from about O. O5% to about 10%, from about 0.15% to about 5%, from about 0.25% to about 3%, or from about 0.5% to about 2.0% depending on the required final dose.

In a further attempt to improve extraction of the dry powder from the dispensing device and to provide a consistent FPF and FPD, dry powder compositions according to the present invention may include particles of an inert excipient material, which act as carrier particles. These carrier particles are mixed with fine particles of active material and any additive material which is present. Rather than sticking to one another, the fine active particles tend to adhere to the surfaces of the carrier particles whilst in the inhaler device, but are supposed to release and become dispersed upon actuation of the dispensing device and inhalation into the respiratory tract, to give a fine suspension.

The inclusion of carrier particles is less attractive where very large doses of active agent are to be delivered, as they tend to significantly increase the volume of the powder composition. Nevertheless, in some embodiments of the present invention, the compositions include carrier particles.

Carrier particles may be of any acceptable inert excipient material or combination of materials For example, the carrier particles may be composed of one or more matcrials selected from sugar alcohols, polyols and crystalline sugars. Other suitable carriers include inorganic salts such as sodium chloride and calcium carbonate, organic salts such as sodium lactate and other organic compounds such as polysaccharides and oligosaccharides. .Advantageously, the carrier particles comprise a poiyol. In particular, the carrier particles may be particles of crystalline sugar, for example mannitol, trehalose, melezitose, dextrose or lactose. Preferably, the carrier particles are composed of lactose.

Thus, in one embodiment of the present invention, the composition comprises active particles comprising L-dopa and carrier particles. The carrier particles may have an average particle size of from about 5 to about 1000.tm, from about 4 to about 40 tm, from about 60 to about 200 pm, or from 150 to about 1000 pm Other useful average particle sizes for carrier particles are about 20 to about 30 pm or from about 40 to about 70 pm.

Preferably, the carrier particles are present in small amount, such as no more than 90%, preferably 80%, more preferably 70%, more preferably 60% more preferably 50% by weight of the total composition, in which the total L-dopa and magnesium stearate content would be 45 and 5% respectively.

In an alternate embodiment, the carrier particles are present in small amount, such as no more than 50%, preferably 60%, more preferably 70%, more preferably 80% by weight of the total composition, in which the total L-dopa and magnesium stearate content would be 18 and 2% respectively. As the amount of carrier in these formulations changes, the amounts of additive and L-dopa will also change, but the ratio of these constituents preferably remains approximately 1:9.

In an alternate embodiment, the formulation does not contain carrier particles and comprises L-dopa and additive, such as at least 30%, preferably 60%, more preferably 80%, more preferably 90% more preferably 95% and most preferably 97% by weight of the total composition comprises of pharmaceutically active agent.

The active agent may be L-dopa alone or it may be a combination of the L-dopa and an anti-emetic drug oi another drug which would benefit Parkinson's disease patients. The remaining components may comprise one or more additive materials, such as those discussed above.

In a further embodiment the formulation may contain carrier particles and comprises L-dopa and additive, such as at least 30%, preferably 60%, more preferably 80%, more preferably 90% more preferably 95% and most preferably 97% by weight of the total composition comprises the pharmaceutically active agent and wherein the remaining components comprise additive material and larger particles. The larger particles provide the dual action of acting as a carrier and facilitating powder flow.

In a preferred embodiment, the composition comprises L-dopa (30% w/w) and lactose having an average particles size of 45-65 p.m.

The compositions comprising L-dopa and carrier particles may further include one or more additive materials. The additive material may be in the form of particles which tend to adhere to the surfaces of the active particles, as disclosed in WO 97/03649 Alternatively, the additive material may be coated on the surface of the active particles by, for example a co-milling method as disclosed in WO 02/43701 or on the surfaces of the carrier particles, as disclosed in WO 02/00197.

In one embodiment, the additive is coated onto the surface of the carrier particles.

This coating may be in the form of particles of additive material adhering to the surfaces of the carrier particles (by virtue of interparticle forces such as Van der Waals forces), as a result of a blending of the carrier and additive. Alternatively, the additive material may be smeared over and fused to the surfaces of the carrier particles, thereby forming composite particles with a core of inert carrier material and additive material on the surface. For example, such fusion of the additive material to the carrier particles may be achieved by co-jet milling particles of additive material and carrier particles. In some embodiments, all three components of the powder (active, carrier and additive) are processed together so that the additive becomes attached to or fused to both the carrier particles and the active particles. In one illustrative embodiment, the compositions include an additive material, such as magnesium stearate (up to 1 0% w/v) or leucine, said additive being jet-milled with the particles of J_-dopa and/or with the lactose.

-24 -In certain embodiments of the present invention, the L-dopa formulation is a "carrier free" formulation, which includcs only the L-dopa or its pharmaceutically acceptable salts oi esters and one or more additive materials.

Advantageously, in these "cariier free" formulations, at least 90% by weight of the particles of the powder have a particle size less than 63 p.m, preferably less than 30 .tm and more preferably less than 10 tm. As indicated above, the size of the active (comprising pharmaceutically acceptable base, salts or esters of L-dopa with inhibitor combinations) particles of the powder should be within the range of about from 0.1 im to 5 tm for effective delivery to the lower lung. Where the additive material is in particulate form, it may be advantageous for these additive particles to have a size outside the preferred range for delivery to the lower lung.

The powder includes at least 60% by weight of the L-dopa or a pharmaceutically acceptable base, salt or ester(s) thereof based on the weight of the powder.

Advantageously, the powder comprises at least 70%, or at least 80% by weight of L-dopa or a pharmaceutically acceptable base, salt or ester(s) thereof based on the weight of the powder. Most advantageously, the powder comprises at least 90%, at least 95%, or at least 97% by weight of L-dopa or a pharmaceutically acceptable base, salt ox ester(s) thereof based on the weight of the powder. It is believed that there are physiological benefits in introducing as little powder as possible to the lungs, in particular material other than the active ingredient to be administered to the patient. Therefore, the quantities in which the additive material is added are preferably as small as possible. The most preferred powder, therefore, would comprise more than 99% by weight of L-dopa or a pharmaceutically acceptable base, salt or ester(s) thereof in combination with disclosed inhibitor combinations.

in a preferred embodiment, at least some of the L-dopa is in amorphous form. A formulation containing amorphous L-dopa will possess preferable dissolution characteristics. A stable form of amorphous L-dopa may be prepared using suitable sugars such as trehalosc and mclezitose.

In addition to the hydrochloride salt, other acceptable acid addition salts include the hydrobromide, the hydroiodide, the bisulfate, the phosphate, the acid phosphate, the lactate, the citrate, the tartrate, the salicylare, the succinate, the maleate, the gluconaic, and the like.

As used herein, the term "pharmaceutically acceptable esters" of L-dopa refers to esters formed, and which hydrolyse in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable ahphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include formates, acetates, propionates, butryates, acrylates and ethyl succinates.

The free base of L-dopa is particularly attractive in the context of the present invention as it crosses the lung barrier very readily and so it is anticipated that its administration via pulmonary inhalation will exhibit extremely fast onset of the therapeutic effect. Thus, any of the compositions disclosed herein may be formulated us-mg the L-dopa free base. Alternatively, L-dopa hydrochloride hemi-hydrate is also a preferred form.

Preparing Dry Powder Inhaler Formulations Where the compositions of the present invention include an additive material, the manner jo which this is incorporated will have a significant impact on the effect that the additive material has on the powder performance, rncluding the FPF and FPD.

in one embodiment, the compositions according to the present invention are prepared by simply blending particles of L-dopa of a selected appropriate size with particles of additive material and/or carrier particles. The powder components may be blended by a gentle mixing process, for example in a tumble mixer such as a Turbula (trade mark). In such a gentle mixing process, there is generally substantially no reduction in the size of the particles being mixed. In addition, the powder particles do not tend to become fused to one another, but they rather -26 -agglomerate as a result of cohesive forces such as Van der Waals forces These loose or unstable agglomerates readily break up upon actuation of the inhaler device used to dispense the composition.

Compressive Milling Processes In an alternative process for preparing the compositions according to the present Invention, the powder components undergo a compressive milling process, such as processes termed mechanofusion (also known as Mechanical Chemical Bonding') and cyclomixing.

As the name suggests, mechanofusion is a dry coating process designed to mechanically fuse a first material onto a second material. It should be noted that the use of the terms "mechanofusion" and "mechanofused" are supposed to be interpreted as a reference to a particular type of milling process, but not a milling process performed in a particular apparatus. The compressive milling processes work according to a different principle to other milling techniques, relying on a particular interaction between an inner element and a vessel wall, and they are based on providing energy by a controlled and substantial compressive force. The process works particularly vell where one of the materials is generally smaller and/or softer than the other.

The fine active particles and additive particles are fed into the vessel of a mechanofusion apparatus (such as a Mechano-Fusion system (Hosokawa Micron Ltd) or the Nobilta or Nanocular apparatus, where they are subject to a centrifugal 2.5 force and are pressed against the vesseJ inner wall. The powder is compressed between the fixed clearance of the drum wall and a curved inner element with high relative speed between drum and element. The inner wall and the curved element together form a gap or nip in which the particles are pressed together. As a result, the particles experience very high shear forces and very strong compressive stresses as they are trapped between the inner drum wall and the inner element (which has a greater curvature than the inner drum wall). The particles are pressed against each other with enough energy to locally heat and soften, break, distort, flatten and wrap the additive particles around the core particle to form a coating. The energy is -27 -generally sufficient to brcak up agglomerates and some degree of size reduction of both components may occur.

These mechanofusion and cyclomixing processes app))' a high enough degrce of force to separate the individual particles of active material and to bieak up tightly bound agglomerates of the active particles such that effective mixing and effective application of the additive material to the surfaces of those particles is achieved. An especially desirable aspect of the processes is that the additive material becomes deformed in the milling and may be smeared over or fused to the surfaces of the active particles.

However, in practice, these compression milling processes produce little or no size reduction of the drug particles, especially where they are already in a micronised form (i.e. <10 p.m). The only physical change which may be observed is a plastic deformation of the particles to a rounder shape.

In a preferred embodiment, the milling process may also be adapted to produce microparticles comprising L-dopa and derivatives disclosed herein and inhibitors disclosed herein, exhibiting delayed dissolution for use in a pharmaceutical composition for either pulmonary or nasal administration, comprising the step of combining particles of a active substance with particles of a hydrophobic material by milling particles of the active substance in the presence of particles of hydrophobic material so that the particles of the hydrophobic material become fused to the surfaces of the particles of active substance.

In a preferred embodiment, the milling process may also be adapted to produce particles that comprise the active agents dispersed or suspended within a material that provides the controlled release properties.

Other Milling Procedures The process of milling may also be used to formulate the dry powder compositions according to the present invention The manufacture of fine par Licles by milling can be achieved using conventional techniques. in the conventional use of the word, "milling" means the use of any mechanical process which applies sufficient force to the particles of active material that it is capable of breaking coarse particles (for example, particles with a MMAD greater than 100 i.tm) down to fine particles (for example, having a MMAD not more than 50 rim). In the present invention, the term "milling" also refers to deagglomeration of particles in a formulation, with or vithout particle size reduction-The particles being milled may be large or fine prior to the milling step. A wide range of milling devices and conditions are suitable for use in the production of the compositions of the inventions. The selection of appropriate milling conditions, for example, intensity of milling and duration, to provide the required degree of force will be within the ability of the skilled person.

Impact milling processes may be used to prepare compositions comprising L-dopa according to the present invention, with or without additive material. Such processes include ball milling and the use of a homogenizer.

Ball milling is a suitable milling method for use in the prior art co-milling processes.

Centrifugal and planetary ball milling are especially preferred methods.

Alternatively, a high pressure homogeniser may be used in which a fluid containing the particles is forced through a valve at high pressure producing conditions of high shear and turbulence. Shear forces on the particles, impacts between the particles and machine surfaces or other particles, and cavitation due to acceleration of the fluid may all contribute to the fracture of the particles. Suitable homogenisers include EmulsiFlex high pressure homogenisers which are capable of pressures up to 4000 bar, Niro Soavi high pressure homogenisers (capable of pressures up to 2000 bar), and Microfluidics Microfluidisers (maximum pressure 2750 bar). The milling process can be used to provide the microparticles with mass median aerodynamic diameters as specified above. Homogenisers may be more suitable than ball mills for use in large scale preparations of the composite active particles.

The milling step may, alternatively, involve a high energy media mill or an agitator bead mill, for example, the Netzsch high energy media mill, or the DYNO-mill (Willy A Bachoferi AG, Switzerland).

If a significant reduction in particic size is also required, co-jet milling is preferred, as disclosed in the earlier patent application published as \X/O 2005/025536. The co-jet milling process can result in composite active particles with low micron or sub-micron diameter, and these particles exhibit particularly good FPF and FPD, even when dispensed using a passive DPI.

The milling processes apply a high enough degree of force to break up tightly bound agglomerates of fine or ultra-fine particles, such that effective mixing and effective application of the additive material to the surfaces of those particles is achieved.

These impact processes create high-energy impacts between media and particles or between particles. In practice, while these processes are good at making very small particles, it has been found that neither the ball mill nor the homogenizer was particularly effective in producing dispersion improvements in resultant drug powders in the way observed for the compressive process. It is believed that the second impact processes are not as effective in producing a coating of additive material on each particle Conventional methods comprising co-milling active material with additive materials (as described in WO 02/43701) result in composite active particles which are fine particles of active material with an amount of the additive material on their surfaces.

The additive material is preferably in the form of a coating on the surfaces of the particles of active material. The coating may be a discontinuous coating. The additive material may be in the form of particles adhering to the surfaces of the particles of active material. Co-milling or co-micronising particles of active agent and particles of additive (FCA) or excipient will result in the additive or excipient becoming deformed and being smeared over or fused to the surfaces of fine active particles, producing composite particles made up of both materials. These resultant composite active paiticles comprising an additive have been found to be less cohesive after the milling treatment.

-30 -At least some of the composite active particles may be in the form of agglomerates.

However, when the composite active particles are included in a pharmaceutical composition, the additive material promotes the dispersal of the composite active particles on administration of that composition to a patient, via actuation of an inhaler.

Milling may also be carried out in the presence of a material which can delay or control the release of the active agent.

The co-milling or co-micronising of active and additive particles may involve compressive type processes, such as mechanofusion, cyclornixing and related methods such as those involving the use of a 1-lybridiser or the Nobilta. The principles behind these processes are distinct from those of alternative milhng techniques in that they involve a particular interaction between an inner element and a vessel wall, and in that they are based on providing energy by a controlled and substantial compressive force, preferably compression within a gap of predetermined width.

In one embodiment, if required, the microparticles produced by the milling step can then be formulated with an additional excipient This may be achieved by a spray drying process, e.g. co-spray drying with excipients. In this embodiment, the particles are suspended in a solvent and co-spray dried with a solution or suspension of the additional excipient. Preferred additional excipients include trehalose, melezitose and other polysaccharides. Additional pharmaceutical effective exclpients may also be used.

In another embodiment, the powder compositions are produced using a multi-step process. Firstly, the materials are milled or blended. Next, the particles may be sieved, prior to undergoing mechanofusion. A further optional step involves the addition of carrier particles The mechanofusion step is thought to "polish" the composite active particles, further rubbing the additive material into the active particles. This allows one to enjoy the beneficial properties afforded to particles by - 31 -mechanofusion, in combination with the very small particles sizes made possible by the)Ct milling.

The reduction in the cohesion and adhesion between the active particles can lead to equivalent performance with reduced agglomerate size, or even with individual particles.

High shear blending Scaling up of pharmaceutical product manufacture often requires the use one piece of equipment to perform more than one function. An example of this is the use of a mixer-granulator which can both mix and granulate a product thereby removing the need to transfer the product between pieces of equipment. In so doing, the opportunity for powder segregation is minimised High shear blending often uses a high-shear rotor/stator mixer (HSM), which has become used in mixing applications. Homogenizers or "high shear material processors" develop a high pressure on the material whereby the mixture is subsequently transported through a very fine orifice or comes into contact with acute angles. The flow through the chambers can be reverse flow or parallel flow depending on the material being processed. The number of chambers can be increased to achieve better performance. The orifice size or impact angle may also be changed for optimizing the particle size generated. Particle size reduction occurs due to the high shear generated by the high shear material processors while it passes through the orifice and the chambers. The ability to apply intense shear and shorten mixing cycles gives these mixers broad appeal for applications that require agglomerated powders to be evenly blended. Furthermore conventional HSMs may also be widely used for high intensity mixing, dispersion, disintegration, emulsification and homogenization.

It is vell known to those skilled in the production of powder formulations that small particles, even with high-power, high-shear, mixers a relatively long period of "aging" is required to obtain complete dispersion, and this period is not shortened appreciably by increases in mixing power, or by increasing the speed of rotation of the stirrer so as to increase the shear velocity. I-ugh shear mixers can also be used if the auto-adhesive properties of the drug particles are so that high shear forces are -32 required together with use of a force-controlling agent for forming a surface-energy-reducing particulate coating or film.

Spray Drying and Ultrasonic Nebulisers Spray drying may be used to produce particles of inhalable size comprising the L-dopa. The spray drying process may be adapted to produce spray-dried particles that include the active agent and an additive material which controls the agglomeration of particles and powder performance. The spray drying process may also be adapted to produce spray-dried particles that include the active agent dispersed or suspended within a material that provides the controlled release properties. Furthermore the dispersal or suspension of the active material within a an excipient material may impart further stability to the active compounds. In a preferred embodiment the L-dopa may reside primarily in the amorphous state. A formulation containing amorphous L-dopa will possess preferable dissolution characteristics. This would be possible in that particles are suspended in a sugar glass which could be either a solid solution or a solid dispersion. Preferred additional excipients include trehalose, melezitose and other polysaccharides.

Spray drying is a well-known and widely used technique for producing particles of active material of inhalable size. Conventional spray drying techniques may be improved so as to produce active particles with enhanced chemical and physical properties so that they perform better when dispensed from a DPI than particles formed using conventional spray drying techniques. Such improvements are described in detail in the earlier patent application published as WO 2005/025535.

In particular, it is disclosed that co-spray drying an active agent with an FCA under specific conditions can result in particles with excellent properties which perform extremely well when administered by a DPI for inhalation into the lung.

It has been found that manipulating or adusung the spray drying process can result in the FCA being largely present on the surface of the particles. That is, the FCA is concentrated at the surface of the particles, rather than being homogeneously distributed thioughout the particles. This clearly means that the FCA will be able to -33 -reduce the tendency of the particles to agglomerate. This will assist the formation of unstable agglomerates that are easily and consistently broken up upon actuation of a DPI It has been found that it may be advantageous to control the formation of the droplets in the spray drying process, so that droplets of a given size and of a narrow size distribution are formed Furthermore, controlling the formation of the droplets can allow control of the air flow around the droplets which, in turn, can be used to control the drying of the droplets and, in particular, the rate of drying. Controlling the formation of the droplets may be achieved by using alternatives to the conventional 2-fluid nozzles, especially avoiding the use of high velocity air flows.

In particular, it is preferred to use a spray drier comprising a means for producing droplets moving at a controlled velocity and of a predetermined droplet size. The i.5 velocity of the droplets is preferably controlled relative to the body of gas into which they are sprayed. This can be achieved by controlhng the droplets' initial velocity and/or the velocity of the body of gas into which they are sprayed, for example by using an ultrasonic nebuliser (USN) to produce the droplets.

Alternative nozzles such as electrospray nozzles or vibrating orifice nozzles may be used.

In one embodiment, an ultrasonic nebuliser (USN) is used to form the droplets in the spray mist. USNs use an ultrasonic transducer which is submerged in a liquid.

The ultrasonic transducer (a piezoelectric crystal) vibrates at ultrasonic frequencies to produce the short wavelengths required for liquid atomisation. In one common form of USN, the base of the crystal is held such that the vibrations are transmitted from its surface to the nebuliser liquid, either directly or via a coupling liquid, which is usually water. When the ultrasonic vibrations are sufficiently intense, a fountain of liquid is formed at the surface of the liquid in the nebuliser chamber. Droplets are emitted from the apex and a "fog" emitted which may be either inhaled directly by the patient, or may be further processed.

Whilst ultrasonic nebulisers (IJSNs) are known, these are conventionally used in inhaler devices, for the direct inhalation of solutions containing drug, and they have not previously bcen widely used in a spray drying apparatus. It has been discovered that the use of such a nebuliser in spray drying has a number of important advantages and these have not previously been recognised. The preferred USNs control the velocity of the particles and therefore the rate at which the particles are dried, which in turn affects the shape and density of the resultant particles. The use of USNs also provides an opportunity to perform spray drying on a larger scale than is possible using conventional spray drying apparatus with conventional types of nozzles used to create the droplets, such as 2-fluid nozzles.

The attractive characteristics of USNs for producing fine particle dry powders include: low spray velocity; the small amount of carrier gas required to operate the nebulisers; the comparatively small droplet size and narrow droplet size distribution produced; the simple nature of the USNs (the absence of moving parts which can wear, contamination, etc.); the ability to accurately control the gas flow around the droplets, thereby controlling the rate of drying; and the high output rate which makes the production of dry powders using USNs commercially viable in a way that is difficult and expensive when using a conventional two-fluid nozzle arrangement.

USNs do not separate the liquid into droplets by increasing the velocity of the liquid. Rather, the necessary energy is provided by the vibration caused by the ultrasonic nebuliser.

Further embodiments, may employ the use of ultrasonic nebuliser (USN), rotary atomisers or electrohydrodynamic (EHD) atomizers to generate the particles.

Delivery Devices The inhalable compositions in accordance with the present invention are preferably administered ia a dry powder inhaler (DPI), but can also be administered via a pressurized metered dose inhaler (pMDI), or even via a nebulised system In a dry powder inhaler, the dose to be administered is stored in the form of a non-pressurized dry powder and, on actuation of the inhaler, the particles of the powder are expelled from the device in the form of a cloud of finely dispersed particles that may be inhaled by the patient.

Dry powder inhakrs can be "passive" devices in which the patient's breath is the only source of gas which provides a motive force in the device. Examples of "passive" dry powder inhaler devices include the Rotahaler and Diskhaler (GlaxoSmithKline), the Monohaler (MIAT), the Gyrohaler (trademark) (Vectura) the Turbohaler (Astra-Draco) and Novohzer (trade mark) (Viatris GmbH).

Alternatively, "active" devices may be used, in which a source of compressed gas or alternative energy source is used. Examples of suitable active devices include Aspirair (trade mark) (Vectura Ltd) and the active inhaler device produced by Nektar Therapeutics (as covered by US Patent No 6,257,233) It is generally considered that different compositions perform differently when dispensed using passive and active type inhalers. Passive devices create less turbulence within the device and the powder particles are moving more slowly when they leave the device. This leads to some of the metered dose remaining in the device and, depending on the nature of the composition, less deagglomeration upon actuation. However, when the slow moving cloud is inhaled, less deposition in the throat is often observed. In contrast, active devices create more turbulence when they are activated. This results in more of the metered dose being extracted from the blister or capsule and better deagglomeration as the powder is subjected to greater shear forces. However, the particles leave the device moving faster than with passive devices and this can lead to an increase in throat deposition.

It has been surprisingly found that the compositions of the present invention with their high proportion of L-dopa perform well when dispensed using both active and passive devices. Whilst there tends to be some loss along the lines predicted above with the different types of inhaler devices, this loss is minimal and still allows a substantial proportion of the metered dose of L-dopa to be deposited in the lung.

-36 -Once it reaches the lung, the L-dopa is rapidly absorbed and exhibits excellent bioavaila bi lity.

Particular))' preferred "acuve" dry powder inhalers are referred to herein as Aspirair� inhalers and are described in more detail in WO 01 /00262, \X/O 02/07805, WO 02/89880 and WO 02/89881, the contents of which are hereby incorporated by reference. It should be appreciated, however, that the compositions of the present invention can be administered with either passive or active inhaler devices.

In an alternative embodiment, the composition is a solution or suspension, which is dispensed using a pressurised metered dose inhaler (pMDI). The composition according to this embodiment can comprise the dry powder composition discussed abovc, mixed with or dissolved in a liquid propellant such as HFA 134a or HFA 227.

Where the composition is to be dispensed using a pMDI, the composition comprising L-dopa preferably further comprises a propellant. In embodiments of the present invention, the propellant is CFC-12 or an ozone-friendly, non-CFC propellant, such as 1,1,1,2-tetrafluoroethane (HFC 134a), 1,1,1,2,3,3,3-heptafluoropropane (H FC-227), HCFC-22 (difluororchloromethane), HFA -152 (difluoroethane and isobutene) or combinations thereof. Such formulations may require the inclusion of a polar surfactant such as polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, propoxylated polyethylene glycol, and polyoxyethylene lauryl ether for suspending, solubilising, wetting and emulsifying the active agent and/or other components, and for lubricating the valve components of the MDI.

In a yet further embodiment, the composition is a solution or suspension and is administered using a pressurised metered dose inhaler (pMDI), a nebuliser or a soft mist inhaler. Examples of suitable devices include pMDls such as Modulite� (Chiesi), SkyeFine" and SkyeDry'M (SkyePharma). Nebulisers such as Porta-Neb�, Inquaiieb'M (Pan) and Aquilon', and soft mist inhalers such as eFlow' (Pan), -37 -AerodoseTM (Aerogen), Respimat� Inhaler (Bochringer Ingeiheim GmbH), AERx� Inhaler (Aradigm) arid Mystic'M (Ventaira Pharmaceuticals, Inc.).

Summ ay s In conclusion the advantages of pulmonary delivery may be summarised as follows.

The increased delivery efficiency and bioavailability achieved by pulmonary delivery present the opportunity to achieve required efficacy at an L-dopa dose level approximately three-times lower than that studied with rntranasal delivery and ultimately a superior risk:benefit profile.

Pulmonary delivery via oral inhalation, not being subject to some of the complexities surrounding nasal administration, results in more rapid and consistent systemic exposure which translates to an accelerated and predictable therapeutic response. These parameters are key unmet clinical needs when considering the treatment of many disorders of the central nervous system, and Parkinson's disease in particular.

Pulmonary delivery constitutes a more patient friendly administration route, which is associated with a superior local tolerability profile, with no evidence of the administration site adverse events reported with intranasal delivery.

Claims (18)

1. -38 -Claims 1. A pharmaceutical composition suitable for inhalation comprising a theiapeutically effective dose of levodopa
2. 2. A composition as claimed in claim 1, for treating conditions of the central nervous system, including Pai-kin son's Disease.
3. 3. A composition as claimed in either of the preceding claims, comprising a dose of levodopa of up to 3Smg and at least 3mg.
4. 4. A composition as claimed in either of the preceding claims, wherein the composition provides a fine particle fraction (FPF) dose of about 5 to about 20 mg upon administration.
5. 5. A composition as claimed in any one of the preceding claims, wherein doses of the levodopa composition are to be administered to the patient as needed.
6. 6. A composition as claimed in any one of preceding claims, wherein doses may be administered sequentially, with the effect of each dosing being assessed by the patient before the next dose is administered to allow self-titration and optimisation of the dose.
7. 7. A composition as claimed in any one of the preceding claims, wherein doses of the levodopa composition are to be administered sequentially, simultaneously or separately to doses of one or more of a peripheral DOPA decarboxylase inhibitor, a catechol-O-methyl transferase (COMT) inhibitor and a monoamine oxidase Type B (MAOB) inhibitor
8. 8. A composition as claimed in any one of the preceding claims, the composition further comprising one or more of a peripheral DOPA decarboxylase inhibitor, a catechol-O-methyt transferase (COMT) inhibitor and a monoamine oxidase Type B (MAOB) inhibitor.

   -39 -
9. 9. A composition as claimed in any one of the preceding claims, wherein the composition allows doses to be administered at regular and frequent intervals providing maintenance therapy.
10. 10. A composition as claimed in any one of the preceding claims, wherein the composition provides a therapeutic effect in about 10 mInutes oi less following administration by pulmonary inhalation.
11. 11. A composition as claimed in any one of the preceding claims, wherein, the composition comprises at least about 70% (by weight) levodopa.
12. 12 A composition as claimed in any one of the preceding claims, further comprising an additive material.
13. 13. A composition as claimed in any one of the preceding claims, further comprising particles of an Inert excipient material.
14. 14. A blister or capsule containing a composition as claimed in any one of the preceding claims.
15. 15. An inhaler device comprising a composition as claimed in any one of claims Ito 13.
16. 16. An inhaler device as claimed in claim 15, wherein the device is a dry powder inhaler, a pressurized metered dose inhaler or a nebuliser.
17. 17. A process for preparing a composition as claimed in any one of claims I to 13.
18. 18. Use of a composition as claimed in any one of claims I to 13 in the manufacture of a medicament for treating diseases of the central nervous system, such as Parkinson's Disease by pulmonary inhalation.