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WO2008065386A1 - Traitement d'une maladie - Google Patents

Traitement d'une maladie Download PDF

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Publication number
WO2008065386A1
WO2008065386A1 PCT/GB2007/004536 GB2007004536W WO2008065386A1 WO 2008065386 A1 WO2008065386 A1 WO 2008065386A1 GB 2007004536 W GB2007004536 W GB 2007004536W WO 2008065386 A1 WO2008065386 A1 WO 2008065386A1
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WO
WIPO (PCT)
Prior art keywords
hydrocortisone
disease
glucocorticoid
condition
use according
Prior art date
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Ceased
Application number
PCT/GB2007/004536
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English (en)
Inventor
Richard Ross
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurocrine UK Ltd
Original Assignee
Diurnal Ltd
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Filing date
Publication date
Application filed by Diurnal Ltd filed Critical Diurnal Ltd
Publication of WO2008065386A1 publication Critical patent/WO2008065386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • 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"
  • 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.
  • 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
  • MCTD mixed connective tissue disease
  • 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.
  • NSAID's nonsteroidal anti-inflammatory drug
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • said vehicle is adapted to delay release of hydrocortisone until about between 04:00 and 06:00am.
  • hydrocortisone replaces Cortisol levels but does not suppress the endogenous adrenal circadian secretion of Cortisol.
  • 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.
  • said inflammatory disease or condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymylagia rheumatica, asthma.
  • said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.
  • said arthritic disease is rheumatoid arthritis.
  • 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.
  • said glucocorticoid responsive disease is cancer.
  • said glucocorticoid disease is an auto-immune disease.
  • said glucocorticoid disease is iatrogenic Cushing's syndrome.
  • said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.
  • 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.
  • said glucocorticoid is selected from the group consisting of: hydrocortisone, cortisone acetate, prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone.
  • said preparation comprises at least 5mg hydrocortisone.
  • said preparation comprises at least 10mg hydrocortisone.
  • said preparation comprises between 10 and 60mg hydrocortisone.
  • said preparation comprises between 15 and 60mg hydrocortisone.
  • said preparation is provided in unit dosage form.
  • 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.
  • said delay is about 3-6 hours.
  • said delay is about 4-6 hours.
  • said preparation is a capsule or tablet.
  • said preparation is taken between 2200 and 240Oh; preferably before the patient goes to sleep.
  • 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.
  • said vehicle is adapted to delay release of hydrocortisone until about 04:00 and 06:00am.
  • said disease or condition is an inflammatory disease or condition the symptoms of which are severe in the early morning.
  • said inflammatory condition is selected from the group consisting of: arthritic disease, ulcerative colitis, bronchitis, Crohns disease, fibromyalia, polymyalgia rheumatica, asthma.
  • said arthritic disease is selected from the group consisting of: rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, reactive arthritis or psoriatic arthritis.
  • said arthritic disease is rheumatoid arthritis.
  • 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.
  • said glucocorticoid responsive disease is cancer.
  • said glucocorticoid responsive disease is an auto-immune disease.
  • said glucocorticoid responsive disease is iatrogenic Cushing's syndrome.
  • said glucocorticoid responsive condition is the suppression of the inhibition of childhood growth as a result of glucocorticoid administration.
  • said glucocorticoid is selected from the group consisting of: prednisolone, prednisone, methylprednisolone, betamethasone, triamcinolone, fluticasone or dexamethasone.
  • said preparation comprises at least 5mg hydrocortisone.
  • said preparation comprises at least 10mg hydrocortisone.
  • said preparation comprises between 10 and 60mg hydrocortisone.
  • said preparation comprises between.15 and 60mg hydrocortisone.
  • said preparation is provided in unit dosage form.
  • 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.
  • said delay is about 3-6 hours. In a preferred method of the invention said delay is about 4-6 hours.
  • said preparation is a capsule or tablet.
  • FIG 1 illustrates the circadian secretion of Cortisol.
  • Examples of delivery vehicles that can provide the required pharmacokinetic release profile are well known in the art of pharmacy.
  • 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 .
  • WO03/007919 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.
  • hydrocortisone preparation 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.
  • 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.
  • 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.
  • hydrocortisone preparation When administered, the hydrocortisone preparation is administered in pharmaceutically- acceptable amounts and in pharmaceutically-acceptable compositions.
  • the term When administered, the hydrocortisone preparation is administered in pharmaceutically- acceptable amounts and in pharmaceutically-acceptable compositions.
  • “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.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human.
  • 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.
  • 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.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un médicament pour le traitement de maladies ou d'états qui peuvent habituellement être traités par des stéroïdes, en particulier par des glucocorticoïdes, le traitement par le stéroïde conduisant à la suppression de la sécrétion circadienne par la glande surrénale endogène de Cortisol.
PCT/GB2007/004536 2006-11-28 2007-11-27 Traitement d'une maladie Ceased WO2008065386A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0623740.8 2006-11-28
GBGB0623740.8A GB0623740D0 (en) 2006-11-28 2006-11-28 Treatment of disease

Publications (1)

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WO2008065386A1 true WO2008065386A1 (fr) 2008-06-05

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WO (1) WO2008065386A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010115615A1 (fr) * 2009-04-07 2010-10-14 Duocort Pharma Ab Amélioration de la thérapie par les glucocorticoïdes
US8425937B2 (en) 2004-04-22 2013-04-23 Duocort Pharma Ab Pharmaceutical compositions for glucocorticoid replacement therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10012555A1 (de) * 2000-03-15 2001-09-20 Merck Patent Gmbh Glucocorticoide in einer Modified Release-Formulierung
WO2003015793A1 (fr) * 2001-08-15 2003-02-27 University Of Sheffield Liberation retardee et prolongee de medicaments
WO2005065692A1 (fr) * 2004-01-03 2005-07-21 University Of Sheffield Traitement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10012555A1 (de) * 2000-03-15 2001-09-20 Merck Patent Gmbh Glucocorticoide in einer Modified Release-Formulierung
WO2003015793A1 (fr) * 2001-08-15 2003-02-27 University Of Sheffield Liberation retardee et prolongee de medicaments
WO2005065692A1 (fr) * 2004-01-03 2005-07-21 University Of Sheffield Traitement

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MOELLER H: "CHRONOPHARMACOLOGY OF HYDROCORTISONE AND 9ALPHA-FLUORHYDROCORTISONE IN THE TREATMENT FOR CONGENITAL ADRENA HYPERPLASIA", EUROPEAN JOURNAL OF PEDIATRICS, SPRINGER VERLAG, vol. 144, no. 4, June 1985 (1985-06-01), pages 370 - 373, XP001117602, ISSN: 0340-6199 *
SMOLENSKY M H ET AL: "CHRONOPHARMACOLOGY. USING THE BODY CLOCK IN DRUG THERAPY", LABORATORY MEDICINE, AMERICAN SOCIETY OF CLINICAL PATHOLOGISTS, CHICAGO, IL, US, vol. 25, no. 9, 1994, pages 561 - 565, XP000913915, ISSN: 0007-5027 *
VYAS ET AL: "Circadian rhythm and drug delivery design", PHARMAZIE, DIE, GOVI VERLAG, ESCHBORN, DE, vol. 52, no. 11, 1997, pages 815 - 820, XP002160128, ISSN: 0031-7144 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8425937B2 (en) 2004-04-22 2013-04-23 Duocort Pharma Ab Pharmaceutical compositions for glucocorticoid replacement therapy
US10583146B2 (en) 2004-04-22 2020-03-10 Shire Viropharma Incorporated Pharmaceutical compositions for glucocorticoid replacement therapy
WO2010115615A1 (fr) * 2009-04-07 2010-10-14 Duocort Pharma Ab Amélioration de la thérapie par les glucocorticoïdes
JP2012522816A (ja) * 2009-04-07 2012-09-27 デュオコート ファーマ エービー 改良されたグルココルチコイド療法

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