HK1067552A

HK1067552A - Inhalation compositions comprising tricyclic 5,6-dihydro-9h-pyrazolo (3,4-c)-1,2,4-triazolo (4,3-alpha) pyridines

Info

Publication number: HK1067552A
Application number: HK05100049.6A
Authority: HK
Inventors: 迈克尔．J．汉弗莱; 保罗．R．米勒; 迈克尔．T．谢珀德
Original assignee: 美国辉瑞有限公司
Priority date: 2001-09-12
Filing date: 2002-09-02
Publication date: 2005-04-15

Description

Inhalation compositions comprising tricyclic 5, 6-dihydro-9H-pyrazolo (3, 4-C) -1, 2, 4-triazolo (4, 3-alpha) pyrimidines

The present invention relates to an inhalation formulation comprising a compound selected from a specific 5, 6-dihydro-9H-pyrazolo (3, 4-C) -1, 2, 4-triazolo (4, 3-a) pyrimidine class, which formulation is capable of delivering the compound to the lungs in the form of solid particles, and to the use of the formulation in the treatment of certain diseases, such as respiratory diseases.

The compounds useful in the present invention are of formula (I)

And pharmaceutically acceptable salts thereof; wherein

R¹Is hydrogen, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₂-C₄) Alkenyl, phenyl, dimethylamino, (C)₃-C₆) Cycloalkyl group, (C)₃-C₆) Cycloalkyl (C)₁-C₃) Alkyl or (C)₁-C₆) Acyl, wherein the alkyl, phenyl or alkenyl groups may be substituted with two hydroxy groups, (C)₁-C₃) Alkyl, or trifluoromethyl, or tri-halo;

R²and R³Each is independently selected from hydrogen and (C)₁-C₁₄) Alkyl, (C)₁-C₇) Alkoxy (C)₁-C₇) Alkyl, (C)₂-C₁₄) Alkenyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₂) Alkyl, saturated or unsaturated (C)₄-C₇) Heterocycle (CH)₂) n, wherein n is 0, 1 or 2, including one or two groups selected from oxygen, sulfur, sulfonyl, nitrogen and NR⁴Wherein R is⁴Is hydrogen or (C)₁-C₄) An alkyl group; or is selected from the group consisting of

Wherein a is an integer of 1 to 5; b and c are 0 or 1; r⁵Is hydrogen, hydroxy, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkenyl, (C)₁-C₅) Alkoxy group, (C)₃-C₆) Cycloalkoxy, halogen, trifluoromethyl, CO₂R⁶、CONR⁶R⁷、NR⁶R⁷、NO₂Or SO₂NR⁶R⁷Wherein R is⁶And R⁷Each independently of the other is hydrogen or (C)₁-C₄) An alkyl group; wherein Z is oxygen, sulfur, SO₂CO or NR⁸Wherein R is⁸Is hydrogen or (C)₁-C₄) An alkyl group; y is (C)₁-C₅) Alkylene or (C)₂-C₆) Alkenyl, optionally two of them (C)₁-C₇) Alkyl or (C)₃-C₇) Cycloalkyl substitution; wherein 1 to 14 alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups each selected from (C)₁-C₂) Alkyl, trifluoromethyl or halogen; and R⁹And R¹⁰Each is independently selected from hydrogen and (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryl, and (C)₆-C₁₀) An aryloxy group.

These compounds are described in international patent application WO-A-96/39408 and are selective PDE4 inhibitors. It is described that diseases which can be treated by inhalation of the tricyclic 5, 6-dihydro-9H-pyrazolo [3, 4-C ] -1, 2, 4-triazolo [4, 3-a ] pyrimidines described above include respiratory diseases such as asthma and chronic obstructive airway disease (COAD, also known as Chronic Obstructive Pulmonary Disease (COPD)).

The aforementioned applications mention that the optimal therapeutic dose of the compounds described therein is generally in the range of 0.1 to 400mg per day for an average adult patient. This means that the dose for administration by the inhaler is generally formulated as a 0.1-1% (w/v) solution. Although not explicitly shown, a typical dosage form for such solutions would be Metered Dose Inhalation (MDI).

Based on studies on multidose patients, i.e. small doses of the compound administered at multiple intervals throughout the day using a solution MDI (via a 'spacer'), it has been calculated that inhalation of 3mg of the active compound per day is effective in treating asthma and COAD. However, attempts to administer MDI solutions in more reasonable doses, typically not more than four times a day, invariably produce a moderate cough response in most patients. Cough levels varied, but some asthma patients worsened symptoms and were accompanied by more severe cough during treatment. The cough response may prevent absorption of sufficient drug to the intended site to produce the desired therapeutic effect, and most importantly may have a severe impact on patient compliance.

We have surprisingly found that when the active compound is administered in the form of solid fine particles, particularly with a dry powder inhaler, the patient experiences little or no cough response and cough can be caused with the same dose of solution MDI. The patient may receive the entire therapeutic amount of the compound or a substantial reasonable fraction thereof, i.e., the number of doses to which the patient is eligible (typically no more than 4 doses per day). This is completely unexpected because the cough response is often associated with the compound itself, whereas powder or suspension formulations are potentially irritating.

Accordingly, the present invention provides an inhaled formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above, characterised in that the formulation is capable of releasing the compound in the form of solid particles into the lungs.

In addition, the invention provides the use of such an inhaled formulation in the manufacture of a medicament for the treatment of a disease treatable by the inhibition of PDE4, particularly a respiratory disease, for example asthma or chronic obstructive pulmonary disease.

Furthermore, the present invention provides a method of treating a disease treatable by the inhibition of PDE4, in particular a respiratory disease such as asthma or chronic obstructive pulmonary disease, which comprises administering to a mammal such an inhaled formulation.

Preferred compounds for use in the present invention are water soluble at physiological pH's of less than 0.15 mg/ml. Particularly preferred are water soluble compounds having a pH of less than 0.05 mg/ml. For the purposes of the present invention, "physiological pH" is defined as 6.0-8.0. Solubility can be determined by diluting a weighed amount of test compound with an appropriate pH buffer, shaking the mixture for 24 hours, filtering the mixture and determining the saturated solubility of the filtrate by LC-MS (liquid-chromatography-mass spectrometry).

Preferred compounds of formula (I) include those wherein the alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic group may each be substituted with 1 to 5 substituents selected from (C)₁-C₂) Alkyl, trifluoromethyl and hydrogen substituted.

Preferably, R¹Is methyl, ethyl or isopropyl.

Preferably, R³Is (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl group, (C)₁-C₂) Alkyl or phenyl optionally substituted with 1 or 2 hydrogen, hydroxy, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkenyl, (C)₁-C₅) Alkoxy, halogen, trifluoromethyl, CO₂R⁶、CONR⁶R⁷、NR⁶R⁷、NO₂Or SO₂NR⁶R⁷Is substituted in which R⁶And R⁷Each is hydrogen or (C)₁-C₄) An alkyl group.

Preferred individual compounds of formula (I) are:

9-cyclopentyl-5, 6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3- ] pyrimidine;

9-cyclopropyl-5, 6-dihydro-7-ethyl-3- (furan-2-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-pyridyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (4-pyridyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (3-thienyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

3-benzyl-9-cyclopentyl-5, 6-dihydro-7-ethyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3-propyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

3, 9-dicyclopentyl-5, 6-dihydro-7-ethyl-9S pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (1-methylcyclohex-1-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

3- (tert-butyl) -9-cyclopentyl-5, 6-dihydro-7-ethyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-methylphenyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-methoxyphenyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ]1, 2, 4-triazolo [4, 3-a ] pyrimidine;

3- (2-chlorophenyl) -9-cyclopentyl-5, 6-dihydro-7-ethyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3- α ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-iodophenyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (2-trifluoromethylphenyl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine; and

5, 6-dihydro-7-ethyl-9- (4-fluorophenyl) -3- (1-methylcyclohex-1-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula (I) are 3- (tert-butyl) -9-cyclopentyl-5, 6-dihydro-7-ethyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine and 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thien-2-yl) -9H-pyrazolo [3, 4-c ]1, 2, 4-triazolo [4, 3-a ] pyrimidine, and pharmaceutically acceptable salts thereof.

Most preferred are 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ]1, 2, 4-triazolo [4, 3-a ] pyrimidine, and pharmaceutically acceptable salts thereof, especially the free base.

For the purposes of the present invention, "fine" solid drug particles may be those less than 20 microns in diameter. Preferably, the powdered medicament used has a particle size wherein 90% of the particles are less than 10 microns in diameter and 50% of the particles are less than 5 microns in diameter. More preferably, the powdered medicament used has a particle size wherein 90% of the particles are less than 6 microns in diameter and 50% of the particles are less than 3 microns in diameter. Most preferably, the powdered medicament used has a particle size wherein 95% of the particles are less than 5 microns in diameter and 50% of the particles are less than 2.5 microns in diameter.

Suitable particle size distributions can be obtained by comminuting (grinding) large volumes of the drug or by particle engineering. Examples of particle engineering are supercritical fluid crystallization and microsphere preparation (e.g. by spray drying).

Devices that can release solid particulates produced by the above processes into a patient's lungs include dry powder inhalers, suspension metered dose inhalers, suspension nebulizers, and suspension nebulizers. Dry powder inhalers are preferred. Suitable dry powder inhalers for use in the present invention include capsule devices such as Spinhaler (trade mark), Rotahaler (trade mark), Handihaler (trade mark), Aerohaler (trade mark), Eclipse (trade mark), Turbopin (trade mark) and Flowcaps (trade mark) inhalers. Other dry powder inhalers for use in the present invention include multi-dose inhalers, for example, Turbuhaler (trade mark), Ultrahaler (trade mark), dishhaler (trade mark), novolier (trade mark), Easyhaler (trade mark), Taifun (trade mark), Clickhaler (trade mark), twitchaler (trade mark) and Aspirair (trade mark).

The compounds of formula (I) may be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the mode of inhalation chosen and standard pharmaceutical practice.

When generating an aerosol spray from a pressurised container, pump, spray, nebuliser (for example a nebuliser which utilises hydrodynamics to generate an excellent spray) or nebuliser, a suitable propellant may be used, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane, such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A [ trade mark ]) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227EA [ trade mark ]), carbon dioxide, and also perfluorinated hydrocarbons such as Perflubron (trade mark) or other suitable gases. In a pressurized aerosol, the dosage unit may be determined by providing a metered delivery valve. The drug will be dispersed in a suitable agent such as water or aqueous ethanol. A lubricant such as sorbitan oleate may also be included.

Capsules, blisters and cartridges (made, for example, from gelatin or HPMC) for use in an inhaler may be formulated as a powder mix comprising a compound of formula (I), a suitable powder base such as lactose or starch, and a performance modifier such as I-leucine, mannitol, trehalose or magnesium stearate. For the purposes of the present invention, preferred dry powder formulations consist of a dry powder mixture of a compound of the formula (I) or a salt thereof, and lactose, preferably lactose monohydrate. Lactose should be of a sufficiently fine grade with 90% of the lactose particles having a diameter of less than 1000 microns and 50% of the lactose particles having a diameter of less than 500 microns. Preferably, 90% of the lactose particles are less than 300 microns in diameter and 50% of the lactose particles are less than 100 microns in diameter. Most preferably, 90% of the lactose particles have a diameter of less than 100-200 microns, 50% of the lactose particles have a diameter of less than 40-70 microns, and 10% of the lactose particles have a diameter of less than 10 microns. The drug loading may vary from 0.1 to 100% w/w of the dry powder mixture, preferably from 5 to 100% w/w, most preferably from 5 to 40% w/w.

Preferably, an aerosol or dry powder formulation is prepared containing 1-10000 μ g of a compound of formula (I) per metered or "puff" dose delivered to the patient. The total daily aerosol dose is in the range of 1. mu.g to 20mg, and this dose may be administered in a single dose, or usually in divided doses throughout the day.

Another method of delivering fine solid drug particles into the lungs is to use microspheres containing poly (D, L-lactic-co-glycolic acid), wherein such microspheres are generated in situ after delivery from a solution metered dose inhaler.

According to the present invention, the fine solid drug particles released can be optionally released in the form of liposomes to adjust their release properties.

The formulations of the present invention may include one or more pharmacologically active agents, including:

(a) an A2A agonist, such as one of the compounds generally and specifically disclosed in WO-A-00/23457, WO-A-00/77018, WO-A-01/27131, WO-A-01/27130, WO-A-01/60835, WO-A-02/00676 and WO-A-01/94368, preferably 9- [ (2R, 3R, 4S, 5R) -3, 4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl ] -6- [ (2, 2-diphenylethyl) amino ] -N- [2- (1-piperidinyl) ethyl ] -9H-purine-2-carboxamide or A pharmaceutically acceptable salt or solvate thereof, or 6- [ (2, 2-diphenylethyl) amino ] -9- { (2R, 3R, 4S, 5S) -5- [ (ethylamino) carbonyl ] -3, 4-dihydroxytetrahydro-2-furanyl } -N- {2- [ ({ [1- (2-pyridinyl) -4-piperidino ] amino } carbonyl) amino ] ethyl } -9H-purine-2-carbonyl amide or a pharmaceutically acceptable salt or solvate thereof;

(b) a parasympathetic neurophysiologically acting agent, such as a tiotropium salt, ipratropium salt, or oxitropium salt, or a solvate thereof;

(c)β₂an adrenergic receptor agonist, such as salmeterol or formoterol or a pharmaceutically acceptable salt or solvate thereof;

(d) a corticosteroid; or

(e) Dopamine D2 receptor agonists.

It should be understood that all treatments referred to herein include curative, palliative and prophylactic treatments.

Examples

In each of examples 1-3, the lactose monohydrate particle size distribution has 90% of a diameter less than 190 microns, 50% of a diameter less than 55 microns, and 10% of a diameter less than 6 microns, and the drug particle size distribution has 90% of a diameter less than 5.8 microns, 50% of a diameter less than 2.9 microns, and 10% of a diameter less than 1.0 micron.

EXAMPLE 1- - -Dry powder inhalation Capsule (0.5mg)

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine (0.5mg, crushed by a spiral air jet mill) and lactose monohydrate (9.5mg, Pharmatose 150M (DMV) Ph. Eur) were mixed by hand and filled into number 3 opaque capsule shells (supplied by Capsugel, product code 1505).

EXAMPLE 2- - -Dry powder inhalation Capsule (1mg)

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine (1.0mg, comminuted by a spiral air jet mill) and lactose monohydrate (19mg, Pharmatose 150M (DMV) Ph. Eur) were mixed by hand and filled into number 3 opaque capsule shells (supplied by Capsule, product code 1505).

EXAMPLE 3- - -Dry powder inhalation Capsule (2mg)

9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine (2.0mg, comminuted by a spiral air jet mill) and lactose monohydrate (38mg, Pharmatose 150M (DMV) Ph. Eur) were mixed by hand and filled into number 3 opaque capsule shells (supplied by Capsule, product code 1505).

EXAMPLE 4 Dry powder inhaler

Capsules produced according to examples 1-3 were loaded in a single dose inhaler (supported by plastics espa) for patient use.

Example 5- -clinical data

The formulations of examples 1-3 were tested for tolerance and safety in clinical trials in healthy volunteers. The volunteers were dosed with a dry powder inhaler as described in example 4, capsules containing 0.5mg, 1mg and 2mg doses of examples 1, 2 and 3, respectively, or placebo capsules containing lactose only. The number, severity, duration and nature of each cough was determined by increasing the dose. Some results are shown in table 1.

Dosage form	Percentage of cough in the patients within the first 5 minutes after the following dose was taken
			Placebo (Dry powder)	Active ingredient (Dry powder)
	1×0.5mg	-	Placebo (Dry powder)	Active ingredient (Dry powder)	0(0/9)
2×0.5mg	1×0.5mg	-	-	11(1/9)	0(0/9)
2×0.5mg	1×1mg	0(0/6)	-	11(1/9)	22(2/9)
2×1mg	1×1mg	0(0/6)	0(0/6)	22(2/9)	22(2/9)
2×1mg	1×2mg	0(0/3)	0(0/6)	22(2/9)	33(3/9)
2×2mg	1×2mg	0(0/3)	0(0/3)	11(1/9)	33(3/9)
2×2mg	3×2mg	0(0/3)	0(0/3)	11(1/9)	29(2/7)

When a dose corresponding to 1X 0.5mg of dry powder is administered via a solution MDI, approximately 80-100% of patients develop cough within the first 5 minutes after administration. Not only is the percentage of coughs greatly reduced with dry powder inhalers compared to solution metered dose inhalers, but the severity of these coughs is also greatly reduced. Also, the incidence of cough with dry powder inhalers is acceptable within the therapeutic dose range.

Claims

1. A composition comprising a compound of formula (I)

Or a pharmaceutically acceptable salt thereof; wherein

R²and R³Each is independently selected from hydrogen and (C)₁-C₁₄) Alkyl, (C)₁-C₇) Alkoxy (C)₁-C₇) Alkyl, (C)₂-C₁₄) Alkenyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₂) Alkyl, saturated or unsaturated (C)₄-C₇) Heterocycle (CH)₂)_nWherein n is 0, 1 or 2, including one or two selected from oxygen, sulfur, sulfonyl, nitrogen and NR⁴Wherein R is⁴Is hydrogen or (C)₁-C₄) An alkyl group; or is selected from the group consisting of

Wherein a is an integer of 1 to 5; b and c are 0 or 1; r⁵Is hydrogen, hydroxy, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkenyl, (C)₁-C₅) Alkoxy group, (C)₃-C₆) Cycloalkoxy, halogen, trifluoromethyl, CO₂R⁶、CONR⁶R⁷、NR⁶R⁷、NO₂Or SO₂NR⁶R⁷Wherein R is⁶And R⁷Each independently of the other is hydrogen or (C)₁-C₄) An alkyl group; wherein Z is oxygen, sulfur, SO₂CO or NR⁸Wherein R is⁸Is hydrogen or (C)₁-C₄) An alkyl group; y is (C)₁-C₅) Alkylene or (C)₂-C₆) Alkenyl, optionally two of them (C)₁-C₇) Alkyl or (C)₃-C₇) Cycloalkyl substitution; wherein 1 to 14 alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic groups each selected from (C)₁-C₂) Of alkyl, trifluoromethyl or halogenSubstituted by groups; and R⁹And R¹⁰Each is independently selected from hydrogen and (C)₁-C₆) Alkyl, (C)₁-C₆) Alkoxy group, (C)₆-C₁₀) Aryl, and (C)₆-C₁₀) An aryloxy group;

characterized in that the formulation is capable of releasing the compound into the lungs in the form of solid fine particles.

2. An inhalation preparation according to claim 1, wherein 1 to 5 groups of each of the alkyl group, alkenyl group, cycloalkyl group, alkoxyalkyl group and heterocyclic group are selected from (C)₁-C₂) Alkyl, trifluoromethyl and hydrogen.

3. An inhalation formulation according to claim 1 or 2, wherein R¹Is methyl, ethyl or isopropyl.

4. An inhalation formulation according to any preceding claim, wherein R³Is (C)₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₃-C₇) Cycloalkyl group, (C)₃-C₇) Cycloalkyl (C)₁-C₂) Alkyl or phenyl optionally substituted with 1 or 2 hydrogen, hydroxy, (C)₁-C₅) Alkyl, (C)₂-C₅) Alkenyl, (C)₁-C₅) Alkoxy, halogen, trifluoromethyl, CO₂R⁶、CONR⁶R⁷、NR⁶R⁷、NO₂Or SO₂NR⁶R¹Wherein R is⁶And R⁷Each independently of the other is hydrogen or (C)₁-C₄) An alkyl group.

5. An inhalation formulation according to claim 1, wherein the compound of formula (I) is selected from:

9-cyclopentyl-5, 6-dihydro-7-ethyl-3-phenyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine;

and pharmaceutically acceptable salts thereof.

6. An inhalation formulation according to claim 1, wherein the compound of formula (I) is 3- (tert-butyl) -9-cyclopentyl-5, 6-dihydro-7-ethyl-9H-pyrazolo [3, 4-c ] -1, 2, 4-triazolo [4, 3-a ] pyrimidine.

7. An inhalation formulation according to claim 1, wherein the compound of formula (I) is 9-cyclopentyl-5, 6-dihydro-7-ethyl-3- (thiophen-2-yl) -9H-pyrazolo [3, 4-c ]1, 2, 4-triazolo [4, 3-a ] pyrimidine.

8. An inhalation formulation according to claim 1, wherein the compound of formula (I) has water solubility at a physiological pH of less than 0.15 mg/ml.

9. An inhalation formulation according to claim 8, wherein the compound of formula (I) has water solubility at a physiological pH of less than 0.05 mg/ml.

10. An inhalation formulation according to any preceding claim, wherein the solid drug fine particles have a size distribution such that 90% are less than 10 microns in diameter and 50% are less than 5 microns in diameter.

11. An inhalation formulation according to claim 10, wherein the solid drug fine particle size distribution is 90% less than 6 microns in diameter and 50% less than 3 microns in diameter.

12. An inhalation formulation according to any preceding claim in which the fine solid particles are released into the lungs by a dry powder inhaler.

13. An inhalation formulation according to claim 12 in which the dry powder mixture comprises lactose, preferably in the form of its monohydrate.

14. An inhalation formulation according to any of claims 1 to 11 in which the fine solid particles are delivered by suspension metered dose inhalers, suspension nebulisers and suspension nebulisers.

15. An inhaled formulation according to any one of claims 1 to 11 wherein the fine solid particles consist of microspheres comprising poly (D, L-lactic-co-glycolic acid).

16. An inhalation formulation according to any preceding claim for use as a medicament.

17. Use of an inhaled formulation according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of a disease treatable by the inhibition of PDE 4.

18. Use according to claim 17, wherein the disease is a respiratory disease.

19. Use according to claim 18 wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

20. A therapeutic method for treating a disease treatable by the inhibition of PDE4 comprising administering to a mammal an inhaled formulation according to any one of claims 1 to 15.

21. A method of treatment according to claim 20 wherein the disease is a respiratory disease.

22. A method of treatment according to claim 21 wherein the respiratory disease is asthma or chronic obstructive pulmonary disease.

23. Use of a compound of formula (I) having water solubility at physiological pH less than 0.15mg/ml for the manufacture of a medicament for inhalation administration according to claim 1, wherein the medicament is in the form of a dry powder inhaler or other device capable of releasing low solubility particles.

24. Use according to claim 23, wherein the medicament is in the form of a device other than a dry powder inhaler capable of delivering low solubility particles, the device being a suspension metered dose inhaler or a device capable of delivering liposomes, micronised/engineered particles, or microspheres.

25. Use according to claim 24, wherein the device is a device capable of releasing microspheres comprising poly (D, L-lactic-co-glycolic acid).

26. A dry powder inhaler containing a compound of formula (I) as claimed in claim 23.

27. A device other than a dry powder inhaler capable of delivering low solubility particles, comprising a compound of formula (I) as claimed in claim 23.