WO2008065386A1

WO2008065386A1 - Treatment of disease

Info

Publication number: WO2008065386A1
Application number: PCT/GB2007/004536
Authority: WO
Inventors: Richard Ross
Original assignee: Diurnal Ltd
Current assignee: Neurocrine UK Ltd
Priority date: 2006-11-28
Filing date: 2007-11-27
Publication date: 2008-06-05
Anticipated expiration: 2009-05-28
Also published as: GB0623740D0

Abstract

We describe a medicament for the treatment of diseases or conditions that are typically treatable with steroids, in particular glucocorticoids, wherein the treatment with the steroid results in the suppression of the endogenous adrenal gland circadian secretion of Cortisol.

Description

Treatment of Disease

The invention relates to a medicament for the treatment of diseases or conditions that are typically treatable with steroids, in particular glucocorticoids, wherein the treatment with the steroid results in the suppression of the endogenous adrenal gland circadian secretion of Cortisol.

Cortisol, also called the "stress hormone", is secreted by the adrenal glands which are adjacent the kidneys. Cortisol secretion increases when the body is stressed, either physically or psychologically. Hydrocortisone is the most commonly used drug in Cortisol replacement therapy as it is equivalent to Cortisol, is rapidly absorbed and is inexpensive. Cortisol is released from the adrenal gland under the regulation of ACTH derived from the pituitary gland. There is a circadian rhythm to Cortisol release with high levels first thing in the morning and very low levels around midnight. ACTH and thus Cortisol levels begin to rise between 2 - 3am and peak between 7 - 9 am gradually falling over the day to a nadir between 8pm and 2am, see Figure 1.

Glucocorticoids are commonly used for the treatment of many diseases including inflammatory diseases, asthma, autoimmune disorders, and cancer (chemotherapy regimens often have high dose glucocorticoids). A common side-effect is suppression of the endogenous circadian rhythm of Cortisol. The consequence is that patients may need weaning from glucocorticoids and during this weaning period they may have a flare of their disease or suffer from Cortisol deficiency. Suppression results from the provision of exogenous glucocorticoid that acts to suppress the circadian rhythm of Cortisol. This suppression takes place at all levels of the hypothalamo-pituitary-adrenal axis.

Chronic inflammation is an inflammatory response of prolonged duration which can last weeks, months, or even indefinitely which is provoked by the persistence of the causative stimulus to inflammation within the tissue. The inflammatory process inevitably causes tissue damage. The exact nature, extent and time course of chronic inflammation is variable, and depends on a balance between the causative agent and the attempts of the body to remove it.

There is a vast array of diseases exhibiting a chronic inflammatory component. These include: inflammatory joint diseases (e.g., rheumatoid arthritis, osteoarthritis, polyarthritis, polymyalgia rheumatica and gout), chronic inflammatory connective tissue diseases (e.g., lupus erythematosus, scleroderma, Sjorgen's syndrome, poly- and dermatomyositis, vasculitis, mixed connective tissue disease (MCTD), tendonitis, synovitis, bacterial endocarditis, osteomyelitis and psoriasis), autoimmune disorders and asthma. A feature of some of these diseases is that those that are susceptible to the disease have symptoms that are more severe in the early morning.

A mode of treatment for chronic inflammatory conditions is by administration of nonsteroidal anti-inflammatory drug (NSAID's) such as diclofenac, ibuprofen, aspirin, phenylbutazone, indomethacin, naproxen and piroxicam. Although NSAID's can be effective, they are known to be associated with a number of side effects and adverse reactions. These may include gastro-intestinal problems such as dyspepsia, ulceration and haemorrhage, sleepiness, nausea or vomiting, constipation, allergic reactions and occasionally hepatoxicity.

An alternative treatment regime is the use of steroids to treat the inflammatory condition. A steroid such as prednisolone is used to treat rheumatoid arthritis and is effective at reducing inflammation. It is often used when symptoms are not suppressed by NSAIDs and painkillers and is sometimes directly injected into an inflamed joint. However, the use of steroids is not without problems. If steroids are used for extended periods their side effects include osteoporosis, thinning of skin, weight gain and muscle wasting. In addition the administration of steroids suppresses the endogenous circadian secretion of Cortisol by the adrenal glands and this has consequences for the patient who is treated with the steroid, for example in children glucocorticoid treatment may cause suppression of growth in linear height and for this reason treatment is often given alternate days to avoid suppression of growth and the normal circadian secretion of Cortisol.

In rheumatoid arthritis many patients are treated with prednisolone at between 2.5 to 7.5mg usually first thing in the morning. However as symptoms are worse first thing in the morning, night time dosing has been suggested for example as in US5, 792, 476. A problem associated with US5, 792, 476 is that the release of glucocorticoid will suppress the endogenous circadian release of Cortisol. US5, 792, 476 discloses at treatment regime that administers prednisolone at night with a 1-3 hour delay and then release over a 40 to 80 min period. Therefore, a tablet taken at 10pm will release at 11pm to 2am with then full release between 12am and 3.20am. This release will exactly coincide with the normal start of the circadian rhythm of Cortisol and therefore very likely cause adrenal suppression.

We disclose an alternative regime that utilises hydrocortisone for the treatment of inflammatory diseases that typically have symptoms that are more severe in the early morning. Cortisol has a distinct circadian rhythm with low trough levels from 8pm to 2am with onset of Cortisol secretion between 2-4am and a peak Cortisol level around 6-9am. The treatment regime is also suitable for the treatment of patients who have adrenal suppression following glucocorticoid treatment. It is an object of the invention to provide a delayed and then sustained release formulation of hydrocortisone that allows a circadian delivery of hydrocortisone wherein said delivery does not suppress the endogenous hypothalamo-pituitary-adrenal axis.

According to an aspect of the invention there is provided the use of a preparation comprising hydrocortisone and a delivery vehicle in the manufacture of a medicament to provide a treatment regime for a disease or condition in an animal, preferably a human, which comprises the steps of administering the preparation wherein the vehicle is adapted to delay release of hydrocortisone until about between 03:00 and 06:00am and further wherein said vehicle is further adapted to release hydrocortisone in a sustained release form until about 10:00am.

In a preferred embodiment of the invention said vehicle is adapted to delay release of hydrocortisone until about between 04:00 and 06:00am.

In a preferred embodiment of the invention the administration of hydrocortisone replaces Cortisol levels but does not suppress the endogenous adrenal circadian secretion of Cortisol.

In a preferred embodiment of the invention said disease or condition is an inflammatory disease or condition the symptoms of which are severe in the early morning.

The preparation according to the invention will provide circadian therapy for diseases that are worse first thing in the morning but will reduce the risk of adrenal suppression by delaying the release of hydrocortisone until after the onset of the normal circadian rhythm and clearance before the nadir of Cortisol. The burst of sustained release hydrocortisone will only cover the critical part of the day that includes late sleep and the waking period.

In a preferred embodiment of the invention said inflammatory disease or condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymylagia rheumatica, asthma.

In a preferred embodiment of the invention said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.

In a preferred embodiment of the invention said arthritic disease is rheumatoid arthritis.

In a further preferred embodiment of the invention said disease or condition is a glucocoticoid responsive disease or condition, wherein the glucocorticoid used to treat the disease or condition is not hydrocortisone, and the administration of the glucocorticoid has suppressed the endogenous adrenal gland circadian secretion of Cortisol.

In a preferred embodiment of the invention said glucocorticoid responsive disease is cancer.

In an alternative preferred embodiment of the invention said glucocorticoid disease is an auto-immune disease.

In a further preferred embodiment of the invention said glucocorticoid disease is iatrogenic Cushing's syndrome.

In a further preferred embodiment of the invention said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.

In a further preferred embodiment of the invention said glucocorticoid responsive condition is a patient recovering from a glucocorticoid responsive condition wherein glucocorticoid treatment has resulted in tertiary adrenal insufficiency.

Tertiary adrenal insufficiency describes patients who have been exposed to glucocorticoids and as a consequence have adrenal insufficiency. This is usually temporary or occasionally in some patients permanent. This contrasts with adrenal insufficiency which is usually permanent. There is probably an element of tertiary adrenal insufficiency in any patients treated with steroids but this may be only very brief. In current practice anyone treated with steroids for more than two weeks at high dose has their steroid dose weaned to allow recovery of the adrenal axis.

In a preferred embodiment of the invention said glucocorticoid is selected from the group consisting of: hydrocortisone, cortisone acetate, prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone. In a preferred embodiment of the invention said preparation comprises at least 5mg hydrocortisone.

In a preferred embodiment of the invention said preparation comprises at least 10mg hydrocortisone.

In a preferred embodiment of the invention said preparation comprises between 10 and 60mg hydrocortisone.

In a preferred embodiment of the invention said preparation comprises between 15 and 60mg hydrocortisone.

In a further preferred embodiment of the invention said preparation is provided in unit dosage form.

In a preferred embodiment of the invention said delivery vehicle provides a preparation comprising: i) a core comprising an effective amount of hydrocortisone and means that controls the sustained release of hydrocortisone during a 2-4 hour period after administration; and ii) an outer layer contacting said core and comprising a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer to provide a delayed release of hydrocortisone.

In a preferred embodiment of the invention said delay is about 3-6 hours.

In a preferred embodiment of the invention said delay is about 4-6 hours.

In a preferred embodiment of the invention said preparation is a capsule or tablet.

In a preferred embodiment of the invention said preparation is taken between 2200 and 240Oh; preferably before the patient goes to sleep. According to an aspect of the invention there is provided a method to treat a disease or condition comprising the administration of a preparation comprising hydrocortisone and a delivery vehicle wherein the administration of the preparation does not suppress the endogenous adrenal circadian secretion of Cortisol comprising the steps of: administering the preparation wherein the vehicle is adapted to delay release of hydrocortisone until about between 03:00 and 06:00am and further wherein said vehicle is further adapted to release hydrocortisone in a sustained release form until about 10:00am.

In a preferred method of the invention said vehicle is adapted to delay release of hydrocortisone until about 04:00 and 06:00am.

In a preferred method of the invention wherein said disease or condition is an inflammatory disease or condition the symptoms of which are severe in the early morning.

In a preferred method of the invention said inflammatory condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymyalgia rheumatica, asthma.

In a further preferred method of the invention said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.

In a preferred method of the invention said arthritic disease is rheumatoid arthritis.

In a further preferred method of the invention said disease or condition is a glucocorticoid responsive disease or condition, wherein the glucocorticoid used to treat the disease or condition is not hydrocortisone, and the administration of the glucocorticoid has suppressed the endogenous adrenal gland circadian secretion of Cortisol.

In a preferred method of the invention said glucocorticoid responsive disease is cancer.

In an alternative preferred method of the invention said glucocorticoid responsive disease is an auto-immune disease.

In a further preferred method of the invention said glucocorticoid responsive disease is iatrogenic Cushing's syndrome. In a further preferred method of the invention said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.

In a preferred method of the invention said glucocorticoid is selected from the group consisting of: prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone.

In a preferred method of the invention said preparation comprises at least 5mg hydrocortisone.

In a preferred method of the invention said preparation comprises at least 10mg hydrocortisone.

In a further preferred method of the invention said preparation comprises between 10 and 60mg hydrocortisone.

In a further preferred method of the invention said preparation comprises between.15 and 60mg hydrocortisone.

In a further preferred method of the invention said preparation is provided in unit dosage form.

In a preferred method of the invention said delivery vehicle provides a preparation comprising: i) a core comprising an effective amount of hydrocortisone and an agent that controls the sustained release of hydrocortisone during a 2-4 hour period after administration; and ii) an outer layer contacting said core and comprising a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer to provide a delayed release of hydrocortisone.

In a preferred method of the invention said delay is about 3-6 hours. In a preferred method of the invention said delay is about 4-6 hours.

In a preferred method of the invention said preparation is a capsule or tablet.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

An embodiment of the invention will now be described by example only and with reference to the following Figure, materials and methods;

Figure 1 illustrates the circadian secretion of Cortisol.

Materials and Methods

Examples of delivery vehicles that can provide the required pharmacokinetic release profile are well known in the art of pharmacy. For example Ross et al J Pharm. Pharmacol (2000), 52: 903-909 describes a capsule that is adapted to release a drug after a pre-determined delay e.g. after a 2-12 hour period. The drug is sealed within an insoluble capsule body by an erodible tablet. The release time is determined by the rate of erosion of the tablet thereby regulating the release of the drug. This is commercially available and sold under the trade mark Pulsincap^tm. This is also described in Krogel and Bodmeier (1998) Pharmaceutical Research 15(3): 474; Binns et al (1996) Journal of Controlled Release 38: 151-158; Wilson et al (1997) Drug Delivery 4(3): 201-206. Similar technology that utilises a multiparticulate delayed release system based on coated pellets containing an osmotic active ingredient is described in Schultz and Kleinebudde Journal of Controlled Release (1997) 47: 181-189. By altering the composition of the osmotically active agent the delay in release of the drug contained in the particle can be regulated. A further osmotically activated drug delivery vehicle is described in Herbig et al (1995) 35: 127-136.

A further example is disclosed in WO03/007919, which is incorporated by reference in its entirety, and discloses a drug delivery system that releases one or more active agents at controlled and variable rates. The tablet disclosed in WO03/007919 comprises a bilayer or multilayered tablet core in which at least one of the layers contains one or more pharmaceutical agents and one or more layers contains one or more rate controlling polymers and an insoluble casing extending over the tablet surface but leaving a part of one layer of the tablet core exposed which is in contact with the internal milieu once administered to a subject to be treated.

A still further example of commercially available delivery devices can be found at http://www.alza.com Alza Corporation, in particular see OROS^tm for oral delivery of drugs.

When administered hydrocortisone preparation is administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives and compatible carriers.

Hydrocortisone is administered in effective amounts. An "effective amount" is that amount of hydrocortisone that alone, or together with further doses, produces the desired response. In the case of treating a particular inflammatory disease, for example arthritis, the desired response is ameliorating the symptoms of the disease in the early morning. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.

The hydrocortisone preparation used is preferably sterile and contains an effective amount of hydrocortisone for producing the desired response in a unit of weight or volume suitable for administration to a patient.

The doses of hydrocortisone administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.

Administration of hydrocortisone preparations to mammals other than humans, (e.g. for testing purposes or veterinary therapeutic purposes), is carried out under substantially the same conditions as described above although dosages will vary in accordance with the size of the animal treated. A subject, as used herein, is a mammal, preferably a human, and including a non-human primate, cow, horse, pig, sheep, goat, dog, cat or rodent.

When administered, the hydrocortisone preparation is administered in pharmaceutically- acceptable amounts and in pharmaceutically-acceptable compositions. The term

"pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

Hydrocortisone preparations may be combined, if desired, with a pharmaceutically- acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with hydrocortisone, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

The hydrocortisone preparation may contain suitable buffering agents, including: acetic acid in a salt; citric acid in a salt; boric acid in a salt; and phosphoric acid in a salt. The hydrocortisone preparation also may contain, optionally, compatible preservatives known to those skilled in the art.

Hydrocortisone may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain agents that release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion.

In inflammatory disorders that are worse in the morning there is an imbalance between the anti-inflammatory actions of Cortisol and the pro-inflammatory cytokines such as IL-6. Such that in patients with Rheumatoid arthritis the Cortisol circadian rhythm is depressed and the rise in IL-6 overnight augmented. There is thus a window of opportunity for treatment which is addressed by Contracort without suppressing normal Cortisol release. This will allow glucocorticoid treatment at lower dose effectively steroid sparing therapy with the native hormone Cortisol.

Claims

1. The use of a preparation comprising hydrocortisone and a delivery vehicle in the manufacture of a medicament to provide a treatment regime for a disease or condition in an animal, preferably a human, which comprises the steps of administering the preparation wherein the vehicle is adapted to delay release of hydrocortisone until about between 03:00 and 06:00am and further wherein said vehicle is further adapted to release hydrocortisone in a sustained release form until about 10:00am.

2. Use according to claim 1 wherein said vehicle is adapted to delay release of hydrocortisone until about between 04:00 and 06:00am.

3. Use according to claim 1 or 2 wherein the administration of hydrocortisone replaces Cortisol levels but does not suppress the endogenous adrenal circadian secretion of Cortisol.

4. Use according to any of claims 1-3 wherein said disease or condition is an inflammatory disease or condition the symptoms of which are severe in the early morning.

5. Use according to claim 4 wherein said inflammatory disease or condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymylagia rheumatica, asthma.

6. Use according to claim 5 wherein said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.

7. Use according to claim 6 wherein said arthritic disease is rheumatoid arthritis.

8. Use according to any of claims 1-3 wherein said disease or condition is a glucocorticoid responsive disease or condition, wherein the glucocorticoid used to treat the disease or condition is not hydrocortisone, and the administration of the glucocorticoid has suppressed the endogenous adrenal gland circadian secretion of Cortisol.

9. Use according to claim 8 wherein said glucocorticoid responsive disease is cancer.

10. Use according to claim 8 wherein said glucocorticoid disease is an auto-immune disease.

11. Use according to claim 8 wherein said glucocorticoid disease is iatrogenic Cushing's syndrome.

12. Use according to claim 8 wherein said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.

13. Use according to claim 8 wherein said glucocorticoid responsive condition is a patient recovering from a glucocorticoid responsive condition wherein glucocorticoid treatment has resulted in tertiary adrenal insufficiency.

14. Use according to any of claims 8-13 wherein said glucocorticoid is selected from the group consisting of: hydrocortisone, cortisone acetate, prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone.

15. Use according to any of claims 1-14 wherein said preparation comprises at least 5mg hydrocortisone.

16. Use according to any of claims 1-14 wherein said preparation comprises at least 10mg hydrocortisone.

17. Use according to any of claims 1-14 wherein said preparation comprises between 10 and 60mg hydrocortisone.

18. Use according to any of claims 1-14 wherein said preparation comprises between 15 and 60mg hydrocortisone.

19. Use according to any of claims 1-18 wherein said preparation is provided in unit dosage form.

20. Use according to claim 19 wherein said delivery vehicle provides a preparation comprising: i) a core comprising an effective amount of hydrocortisone and means that controls the sustained release of hydrocortisone during a 2-4 hour period after administration; and ii) an outer layer contacting said core and comprising a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer to provide a delayed release of hydrocortisone.

21. Use according to claim 20 wherein said delay is about 3-6 hours.

22. Use according to claim 20 wherein said delay is about 4-6 hours.

23. Use according to any of claims 20-22 wherein said preparation is a capsule or tablet.

24. Use according to any of claims 1-23 wherein said preparation is taken between 2200 and 2400h.

25. A method to treat a disease or condition comprising the administration of a preparation comprising hydrocortisone and a delivery vehicle wherein the administration of the preparation does not suppress the endogenous adrenal circadian secretion of Cortisol comprising the steps of: administering the preparation wherein the vehicle is adapted to delay release of hydrocortisone until about between 03:00 and 06:00am and further wherein said vehicle is further adapted to release hydrocortisone in a sustained release form until about 10:00am.

26. A method according to claim 25 wherein said vehicle is adapted to delay release of hydrocortisone until about 04:00 and 06:00am.

27. A method according to claim 25 or 26 wherein said disease or condition is an inflammatory disease or condition the symptoms of which are severe in the early morning.

28. A method according to claim 27 wherein said inflammatory disease or condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymyalgia rheumatica, asthma.

29. A method according to claim 28 wherein said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.

30. A method according to claim 29 wherein said arthritic disease is rheumatoid arthritis.

31. A method according to claim 25 or 26 wherein said disease or condition is a glucocorticoid responsive disease or condition, wherein the glucocorticoid used to treat the disease or condition is not hydrocortisone, and the administration of the glucocorticoid has suppressed the endogenous adrenal gland circadian secretion of Cortisol.

32. A method according to claim 31 wherein said glucocorticoid responsive disease is cancer.

33. A method according to claim 31 wherein said glucocorticoid responsive disease is an auto-immune disease.

34. A method according to claim 31 wherein said glucocorticoid responsive disease is iatrogenic Cushing's syndrome.

35. A method according to claim 31 wherein said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.

36. A method according to any of claims 31-35 wherein said glucocorticoid is selected from the group consisting of: prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone.

37. A method according to any of claims 25-36 wherein said preparation comprises at least 5mg hydrocortisone.

38. A method according to any of claims 25-36 wherein said preparation comprises at least 10mg hydrocortisone.

39. A method according to any of claim 25-36 wherein said preparation comprises between 10 and 60mg hydrocortisone.

40. A method according to any of claims 25-36 wherein said preparation comprises between 15 and 60mg hydrocortisone.

41. A method according to any of claims 25-40 wherein said preparation is provided in unit dosage form.

42. A method according to claim 41 wherein In a preferred method of the invention said delivery vehicle provides a preparation comprising: i) a core comprising an effective amount of hydrocortisone and an agent that controls the sustained release of hydrocortisone during a 2-4 hour period after administration; and ii) an outer layer contacting said core and comprising a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer to provide a delayed release of hydrocortisone.

43. A method according to claim 42 wherein said delay is about 3-6 hours.

44. A method according to claim 42 wherein said delay is about 4-6 hours.

45. A method according to any of claims 42-44 wherein said preparation is a capsule or tablet.

46. A method according to any of claims 25-45 wherein said preparation is taken between 2200 and 240Oh.