Another aspect of the invention is concerned with a pulmonary drug delivery composition based on biodegradable microparticles, said microparticles containing 6a alkyl and/or 7a alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs.

BACKGROUND OF THE INVENTION Methods of treating androgen deficiency comprising the administration of androgens, such as testosterone, dihydrotestosterone, dehydroepiandrosterone and various esters of testosterone, or derivatives and analogues such as mesterolone are known in the art.

Three types of androgen deficiency in males are usually distinguished, i. e. primary androgen deficiency (testicular insufficiency), secondary androgen deficiency (hypothalamo- hypophyseal insufficiency) and androgen deficiency in aging males (ADAM), also known as "male menopause"or"andropause".

As regards the long-term administration of androgens to males, a distinction can be made between therapy and supplementation. Therapy typically requires relatively high doses that usually correspond to the normal rate of production of endogenous androgen (s).

Supplementation on the other hand is suitably done with dosages that are below the rate of production of endogenous androgen (s). These endogenous androgens typically include testosterone, dihydrotestosterone and dehydroepiandrosterone.

Because of concerns about undesirable side effects, androgens are only sparingly used in both therapy and hormone supplementation. Indeed, androgens are normally only used for therapy in human males when primary or secondary androgen deficiency has been diagnosed.

It is known that androgens affect the liver metabolism, particularly when administered orally.

This is why, in existing protocols, androgens are generally administered in the form of 2-3 weekly depot injections or implants. Only a few androgens, e. g. dehydroepiandrosterone and 17a-alkylated derivatives of testosterone, are suitable for oral administration because, unlike testosterone, they are largely resistant to hepatic metabolism. As mentioned before, however, a disadvantage of oral administration is associated with the fact that the androgen will exert a relatively high effect on the liver and particular the liver metabolism. The aforementioned 17a-alkylated derivatives of testosterone, for instance, are not recommended for clinical oral use because of their potential hepatoxicity (Bhasin et al. (1997) J. Clin. Endocr. Metab. 82 : 3- 8). Adverse hepatic effects associated with prolonged use of these androgens include cholestasis, peliosis hepatis (blood-filled hepatic cysts), hepatocellular hyperplasia, hepatic adenomas, and hepatocellular carcinoma.

Furthermore, oral administration is rather unreliable in that the effective dosage is significantly influenced by the efficiency of intestinal uptake and/or metabolisation in the liver, both of which are largely dependent on an individual's physiology and even his/her diet.

When administered orally, androgen is usually applied in relatively high dosages in order to ensure that the minimum effective dosage is achieved in each individual. Naturally such high dosages have the disadvantage that they lead to relative overdosing in some individuals, which in turn is likely to produce pronounced side effects.

Parenteral administration, particularly intramuscular administration, is a feasible alternative for oral administration. However, this mode of administration has the disadvantage that it becomes quite burdensome in case of prolonged therapies. Intramuscular or subcutaneous injection can be painful and self-administration of an injectable composition typically suffers from low user acceptance. Hence depot injections or implants are sometimes used to partly overcome this disadvantage. However, both depot injections and implants suffer from the drawback that release of the active androgen is uneven, i. e. initially there is a much higher increase in serum androgen level than is required and indeed desirable. Another disadvantage associated with (depot) injections resides in the fact that it is not possible to retrieve the injected drug from the body, e. g. in case an allergic reaction occurs or prostate cancer is diagnosed. This is particularly disadvantageous since with this mode of administration it takes a long time before the drug has disappeared from the body.

A recently developed method of treating androgen deficiency in males makes use of transdermal administration of testerone by means of patches. The transdermal testosterone delivery systems provide adequate testosterone replacement for hypogonadal men. An obvious inconvenience of these testosterone patches is the need to remove the old patch and to apply a new one each night. Skin irritation at the application site occurs frequently. A study has shown that approximately 50% of men who participated in clinical trials reported transient, mild to moderate erythema at the application site during therapy, and burn-like blister reactions occurred in 12% of men during the clinical trials.

US 5,855, 905 (Oettel et al. ) describes a method of treating hypogonadism or hypophyseal disease in a man comprising administering a pharmaceutical preparation containing an androgen and an estrogen. According to the US-patent these preparations can be presentations for oral application such as tablets, capsules and lozenges, presentations for percutaneous application such as transdermal therapeutic systems (TTS) or gels, sprays or ointments, preparations for intranasal applications such as nasal sprays or nose drops, preparations for rectal application such as suppositories, and parenterals such as implants or compacts and ampules. In a list of examples of pharmaceutical preparations a preparation containing 125 mg dihydrotestosterone (DHT) and 1 mg estradiol in the form of a spray is mentioned.

As will be apparent from the above, there is a need for a new, sophisticated method of treating androgen deficiency in male mammals which has less drawbacks than the existing methods that employ oral, intramuscular or transdermal administration of androgens.

SUMMARY OF THE INVENTION The inventors have established that the disadvantages associated with existing methods for treating androgen deficiency, are associated primarily with the mode of administration used. Surprisingly it was found that these disadvantages are largely negated if an adequate amount of 6a alkyl and/or 7a allkyl-androgen is administered in a pulmonary fashion.

The pulmonary administration offers several advantages over known methods of androgen administration, particularly oral and intramuscular administration. Firstly, pulmonary delivery is highly effective, i. e. a large fraction of the alkyl-androgen that is inhaled is indeed absorbed. Secondly, pulmonary administration is a very convenient and

user-friendly method, as is demonstrated by the widespread use of pulmonary administration of several agents (i. e. anti-inflammatory, bronchodilatation) used in asthma therapy. Thirdly, pulmonary administration, unlike oral administration, has minimum impact on liver metabolism since only a minor fraction of the administered alkyl-androgen will pass through the liver.

Since pulmonary administration is so facile, it is quite feasible to design protocols that require a relatively high administration frequency, e. g. at least once daily. Such high administration frequencies are required for alkyl-androgens which, like all known androgens, have a relatively short half-life. Also short administration intervals make it possible to avoid undue high serum concentrations.

Because of the convenient way of administration, the present invention also facilitates the utilisation of androgens in the treatment or prevention of a variety of disorders and diseases such as: wasting syndrome, anti-retroviral drug induced lipodystrophia, lack of well- being or fatigue in HIV infected individuals; catabolic state; leydig cell dysfunction and germinal epithelial damage following cytotoxic chemotherapy; fatigue; reduction in hemoglobine or neutrophil count during or subsequent to cytotoxic chemotherapy or radiotherapy; benign gynaecological disorders; delayed puberty or in a method of weight maintenance. Although it is known that these disorders may be treated with androgens, the lack of a convenient way of administration has so far prevented widespread therapeutic and prophylactic use of androgens in the treatment of these disorders.

6a alkyl and 7a-alkyl-androgens are relatively potent androgens which are metabolised in vivo into estrogen, but unlike testosterone and testosterone esters cannot be metabolised by 5a-reductase into DHT. These properties make said alkyl-androgens particularly suitable for pulmonary administration to androgen deficient males. The relatively low amount of alkyl-androgen that is required in androgen therapy or androgen supplementation, makes it possible to employ relatively small pulmonary dosages, thereby eliminating the need for repeated administrations. The partial in vivo metabolisation of the alkyl-androgen (s) into estrogen is advantageous in androgen deficient males because androgen deficiency is normally accompanied by estrogen deficiency. Estrogens in males are known to have an important effect on bone (help to prevent osteoporosis resulting from estrogen deficiency), spermatogenesis, as well as on carbohydrate and lipid metabolism. The fact that these alkyl-androgens are not metabolised into DHT is also beneficial because DHT has been associated with benign prostate hypertrophy and prostate cancer.

The present invention also offers the advantage that it provides a convenient way of administering alkyl-androgen. The only convenient method which has been practised on some scale for androgens, i. e. oral administration, is not effective for 6a-alkyl or 7a-alkyl- androgens, since said androgens are not bioavailable orally. Thus, the present invention enables a method of treating androgen deficiency in male mammals that is both convenient and effective and that uses an androgen, i. e. a 6a-alkyl or 7cx-alkyl-androgen, that is particularly suited for such treatment.

DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention is concerned with a method of treating or preventing androgen deficiency in male mammals, wherein the method comprises pulmonary administration of 6Oe-alkyl andlor 7Oz-alkyl-androgen to a male suffering from androgen deficiency in a therapeutically effective amount to reduce or prevent symptoms of androgen deficiency. The terms"6a-alkyl-androgen and 7a-alkyl-androgen"as used throughout this document encompass androgens comprising an alkyl-substituent on the 6cx or 7cx position as well as precursors thereof that are capable of liberating such an alkyl-androgen in vivo when used in accordance with the present invention. Preferably the alkyl radical is a C1-C4 alkyl.

More preferably the alkyl radical is methyl or ethyl. Most preferably the alkyl radical is methyl.

Pronounced symptoms of androgen deficiency are found particularly in chemically castrated and orchiectomised males. A significantly less dramatic form of androgen deficiency is observed in ageing males. Furthermore, androgen deficiency may be caused by a disease or a disorder, e. g. AIDS or wasting (cachexia).

Androgen deficiency in ageing males (ADAM) is typically observed in human males from the age of 45 onwards, with continuously varying symptoms. The Saint Louis University (ADAM) Questionnaire which was developed to facilitate the diagnosis of ADAM, recognises the following symptoms of ADAM 1. Decreased libido 2. Lack of energy 3. Decrease in strength and/or endurance 4. Weight loss 5. Decreased'enjoyment of life'

6. Feelings of sadness or grumpiness 7. Less strong erections 8. Recent deterioration in ability to play sports 9. Falling asleep after dinner 10. Deterioration in work performance ADAM is diagnosed if a yes answer is obtained to questions 1,7 or any three other questions. In addition to the aforementioned symptoms, androgen deficiency has been associated with loss of bone mass, along the lines of osteoporosis, ischaemic heart disease, obesity and reduced haemoglobin levels.

The present method is particularly effective when used to treat or prevent androgen deficiency in ageing males, and in particular when it is used to treat androgen deficiency in ageing males exhibiting symptoms of androgen deficiency. Since symptoms of ADAM usually do not become apparent until males have reached the age of about 45, the present method is particularly suitable for treating males at an age of least 45, preferably at an age of at least 50.

Another aspect of the invention relates to a method of treating or preventing wasting syndrome; a method of treating or preventing anti-retroviral drug induced lipodystrophia, lack of well-being or fatigue in HIV infected individuals; a method of treating or preventing catabolic state caused by a chronic illness, surgical intervention, oncological condition, trauma and/or malnutrition; a method of treating or preventing leydig cell dysfunction and germinal epithelial damage following cytotoxic chemotherapy; a method of treating or preventing fatigue or maintaining weight, a method of maintaining hemoglobine or neutrophil count during or subsequent to cytotoxic chemotherapy or radiotherapy; a method of treating or preventing benign gynaecological disorders; or a method of treating or preventing delayed puberty, wherein the method comprises pulmonary administration of an effective amount of an alkyl-androgen selected from the group consisting of 6a-alkyl-androgen, 7a-alkyl- androgen and combinations thereof.

Examples of alkyl-androgens which may advantageously be employed in the present method include 7a-methyl-19-nortestosterone, 7cx-methyl-14-dehydro-19-nortestosterone, 7a- methyltestosterone, 7a-methyl-11-hydroxytestosterone, 7cx, 17-dimethyltestosterone, 7a, 17- dimethyl-11-hydroxytestosterone, 7a, 17-dimethyl-19-nortestosterone, 7a, 17-dimethyl-11- hydroxy-19-nortestosterone, 6a-methyltestosterone, 6a-methyl-19-nortestosterone, 6a methyl-11-hydroxytestosterone, 6a, 17-dimethyltestosterone, 6a, 17-dimethyl-11-

hydroxytestosterone, 6a, 17-dimethyl-19-nortestosterone, 6Ot, 17-dimethyl-11-hydroxy-l9- nortestosterone.

Particularly preferred for use in the present method are 7a-alkyl-androgens, especially 7a-methyl-androgens. Most preferably the alkyl androgen employed in the present method is 7a-methyl-19-nortestosterone (MENT).

In the present method the pulmonary drug delivery composition is typically administered in an amount of 1-500 mg, preferably of 5-250 mg. These amounts may be administered in a single metered dose or alternatively in a few doses that are administered within a short time interval, e. g. within 10 minutes, preferably within 5 minutes.

The present methods suitably employ continuous pulmonary administration of the alkyl-androgen during a period of at least 60 days, preferably of at least 150 days. The term "continuous"as used in here, means that the alkyl-androgen is administered at relatively regular intervals, with no (therapeutically) significant interruptions. Naturally, minor interruptions may occur that do not affect the overall effectiveness of the present method, and indeed such aberrations are encompassed by the present invention. In a preferred embodiment, and more arithmetically, the administration regimen is deemed to be continuous if the longest interval between 2 subsequent administrations is not more than 3.5 times as long as the average interval. Even more preferably said longest interval is not more than 2.5 times as long as the average interval.

The present invention also encompasses the pulmonary administration of a precursor of the present alkyl-androgens. These precursors are preferably selected from the group of derivatives of the present alkyl-androgens, wherein the hydrogen atom of at least one hydroxyl-group has been substituted by an acyl radical of a hydrocarbon carboxylic, sulfonic or sulfamic acid of 1-25 carbon atoms; tetrahydrofuranyl; tetrahydropyranyl; or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue. Typical examples of precursors which can suitably be used in accordance with the invention are esters that can be obtained by reacting the hydroxyl group present in the alkyl-androgen-molecule with substances that contain one or more carboxyl (M+-OOC-) groups, wherein M+ represents a hydrogen or (akali) metal cation. Hence, in a preferred embodiment, the alkyl-androgen- precursors are derivatives of a 6cx-alkyl or 7a-alkyl-androgen, wherein the hydrogen atom of the hydroxyl group has been substituted by-CO-R, wherein R is a hydrocarbon radical comprising from 1-25 carbon atoms. Preferably R is hydrogen, or an alkyl, alkenyl or aryl radical comprising from 1-20 carbon atoms.

The advantages of the present invention are particularly appreciated in therapeutic methods that employ at least once daily pulmonary administration of the alkyl-androgen. A particularly preferred administration regimen comprises once daily pulmonary administration of alkyl-androgen in the morning, preferably between 5: 00 a. m. and 10: 00 a. m. This regimen offers the advantage that it mimics the natural plasma serum testosterone profile (circadian rhythm) as observed in non-androgen deficient males. By replicating the natural testosterone profile, the symptoms of androgen deficiency are most effectively treated.

The present invention also encompasses the pulmonary administration of alkyl- androgen in combination with one or more other active principles. An example of an active principle that may suitably be co-administered in accordance with the present method is aromatase inhibitor (e. g. aminoglutethimide, anastrozole, exemestane, vorozole, letrozole, fadrozole, rogletimide, atamestane, formestane, liarozole, YM 511, TZA-2237, CGS 16949A, MEN 11066). The co-administration of an aromatase inhibitor offers the advantage that it assists in restoring the male's androgen/estrogen balance to normal levels. Thus the present method may be used to not only restore the androgen serum concentration to a physiological level, but to additionally achieve a normal androgen/estrogen ratio.

As regards pulmonary administration it is possible to distinguish two different techniques, i. e. one which uses dry particulates and another that utilises liquid compositions.

Liquid aerosol compositions may be prepared by dissolving the alkyl-androgen in a suitable solvent (e. g. ethanol), combining it with a suitable propellant (e. g. a hydrofluoroalkane) and filling it into an aerosol container provided with a metering valve. In addition a dispersing agent such as oleic acid, sorbitan trioleate, dioctyl sodium or calcium sulphoscuccinate may be incorporated. Usually the liquid aerosol composition will comprise between 0.1 and 5 wt. % of alkyl-androgen. The aerosol system is preferably so arranged that each metered dose or'puff of aerosol contains between 0.01 and 5 mg alkyl-androgen. In order to effectively administer such a dose of alkyl-androgen the discharge volume of the aerosol system is typically between 5 and 250 ptL.

Since alkyl-androgens may display limited stability in solvents that can be used for pulmonary administration, it is preferred to use a pulmonary alkyl-androgen containing composition in the form of dry particulates, in particular in the form of biodegradable microparticles having a number weighted average diameter of 0.5 to 10 um, which microparticles contain alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs. Examples of procedures for the preparation of aerodynamically

light microparticles that may advantageously be employed in accordance with the present invention may be found in US 6,136, 295, which is included herein by reference.

Best results are obtained with pulmonary administration of androgen if the aforementioned microparticles contain relatively high concentrations of alkyl-androgen.

Preferably, the alkyl-androgen content of the microparticles is between 1 and 50 wt. %, more preferably between 5 and 40%. Together alkyl-androgen and carrier will normally constitute at least 50 wt. %, preferably at least 75 wt. % of the microparticles.

The microparticles are advantageously provided in the form of a capsule containing between zug and 100 mg of the drug delivery composition as described in this document. The invention also encompasses a unit comprising two or more discrete capsules, such as a disk comprising a plurality of capsules from which the contents may be released for pulmonary administration in a sequential fashion.

The present method preferably comprises pulmonary administration of 6a alkyl- and/or 7a-alkyl-androgen in an average daily amount of at least 0.01 mg, more preferably of a least 0.1 mg. Generally the daily administered amount of alkyl-androgen will not exceed 20 mg. Preferably the administered average daily amount does not exceed 10 mg.

In case the present method is used to treat androgen deficiency in a chemically castrated or orchiectomised mammalian male, it is desirable to administer relatively high dosages of androgen. Consequently, in such a method alkyl-androgen is preferably administered in an average daily amount of 0.5-10 mg, more preferably in an average daily amount of 1-8 mg.

The treatment of androgen deficiency in ageing males requires relatively low dosages, meaning that alkyl-androgen is suitably administered in an average daily amount of 0.1-4 mg, more preferably in an average daily amount of 0.2-2 mg.

The present method is particularly advantageous when used in human males.

Another aspect of the invention relates to a pulmonary drug delivery composition based on biodegradable microparticles having a number weighted average diameter between 0.5 and 10/mi, said microparticles containing between 1 and 50 wt. % of 6a-alkyl and/or 7a alkyl-androgen and a pharmaceutically acceptable carrier for administration to the lungs. The present drug delivery composition is suitably administered by means of an inhaler. Thus the present invention also comprises an inhaler containing the present pulmonary drug delivery composition.

An inhaler suitable for administering the present pulmonary drug delivery composition typically comprises a receptacle for receiving the drug delivery composition, which receptacle

contains at least two apertures, a first aperture that is designed for releasing the contents of the receptacle into the mouth and another second aperture that is designed for allowing entry of atmospheric air at the same time as the contents are released from the receptacle. The receptacle may furthermore contain protruding elements that are designed to puncture, cut or tear capsules that contain a pulmonary drug delivery composition after insertion into the receptacle. Preferably the device is constructed in such a way that the user's action of closing the receptacle automatically results in the puncturing, cutting or tearing of the capsule, thereby releasing the drug delivery composition contained in the capsule.

A further aspect of the invention relates to a capsule containing between 5g and 100 mg of the drug delivery composition as described herein before. As explained above, the capsule is suitably designed in such a way that it can be easily be punctured, cut or torn when used in inhalers that are well-known in the pharmaceutical art.

Yet another aspect of the invention is concerned with an aerosol drug delivery system comprising an aerosol delivery device and a liquid pharmaceutical composition containing between 0.1 and 5 wt. % of 6a-alkyl and/or 7a alkyl-androgen and a pharmaceutically acceptable liquid carrier for administration to the lungs. Typically, the aerosol drug delivery device contains a nozzle for producing the aerosols. The pressure required for releasing the composition through the nozzle may be provided by a pumping system or by a propellant that is contained within the device, especially as a component of the liquid pharmaceutical composition.

It is noted that the present invention also encompasses so called kits of parts that comprise an inhaler in combination with the drug delivery composition based on microparticles as defined above, or alternatively an aerosol delivery device in combination with the liquid pharmaceutical composition as described above.

The invention is further illustrated by means of the following examples.

EXAMPLES Example 1 Synthesis of MENT containing micro-particles Aerodynamically light MENT-containing microparticles are prepared according to the following procedure:

2.0 g poly (D, L-lactic-co-glycolic acid) with a molar ratio of 50: 50 (PLGA 50: 50, <BR> <BR> Resomer RG503, B. I. Chemicals, Montvale, N. J. ) and 0.50 g MENT are completely dissolved in 100 mL dichloromethane at room temperature. The mixture is subsequently spray-dried through a 0.5 mm nozzle at a flow rate of 5 mL/min using a Buchi laboratory spray-drier (model 190, Buchi, Germany). The flow rate of compressed air is 700 nl. The inlet temperature is set to 30°C. and the outlet temperature to 25°C. The aspirator is set to achieve a vacuum of-20 to-25 bar. The yield is 51% and the mean particle size is approximately 5 ym. Larger particle size can be achieved by lowering the inlet compressed air flow rate, as well as by changing other variables. The particles are aerodynamically light, as determined by a tap density less than or equal to 0.4 g/cm3. Porosity and surface roughness can be increased by varying the inlet and outlet temperatures, among other factors.

Example 2 Preparation of a MENT containing aerosolforfnulation An aerosol formulation is prepared from the following ingredients: % w/w MENT 0.37 Oleic acid 0.03 Ethanol absolute 20.0 Propellant (1,1, 1,2, tetrafluoroethane) 79.6 The formulation is filled into a metered dose inhaler vial equipped with a metering valve. The vial is made of epoxy-phenolic lacquer coated aluminium (ex Cebal Printal U. K.

Ltd.).

Example 3 Pulmonary administration of MENT to ageing males The microparticles obtained from the process described in example 1 are administered once daily to ageing males in the age of 50-65, between 5: 00 and 10: 00 a. m. , in a pulmonary dose of 2 mg (0.4 mg MENT) during a period of 8 weeks. It is found that the pulmonary administration of MENT assists in suppressing symptoms of testosterone deficiency.

Example 4 Pulmonary administration ofMENT to orchiectomised males The microparticles obtained from the process described in example 1 are administered in the same fashion as described in example 2 to males who are androgen deprived as a result of castration. This time the pulmonary dose is increased to 10 mg (2 mg MENT). Again it is found that the pulmonary administration of MENT helps to suppress symptoms of testosterone deficiency.