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US-12616736-B2 - Method of diagnosis of adrenal insufficiency

US12616736B2US 12616736 B2US12616736 B2US 12616736B2US-12616736-B2

Abstract

The disclosure relates to a composition comprising adrenocorticotropic hormone (ACTH) or a synthetic ACTH analogue for use in a diagnostic test for adrenal insufficiency. A method to conduct said diagnostic test; a combined diagnostic and method of treatment; and kits comprising the components for said test are also disclosed.

Inventors

  • Neil Peter Wright
  • Charlotte Jane Elder

Assignees

  • SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST
  • UNIVERSITY OF SHEFFIELD

Dates

Publication Date
20260505
Application Date
20181024
Priority Date
20171025

Claims (15)

  1. 1 . A method of diagnosing adrenal insufficiency in a paediatric subject, comprising: i) obtaining a sample of saliva from the paediatric subject and measuring cortisone concentration in said saliva sample; ii) intranasally administering a pharmaceutical composition to the paediatric subject at a dose of between 500-1000 μg, the composition comprising: tetracosactide acetate 0.25% (w/v); chitosan glutamate 0.5% (w/v); sodium chloride 0.54% (w/v); benzalkonium chloride 0.015% (w/v); acetic acid 0.51% (w/v); and sodium acetate trihydrate 0.21% (w/v); and iii) repeating step i) 120 minutes or 180 minutes after the intranasal administration of step ii).
  2. 2 . The method of claim 1 , further comprising: iv) comparing the concentration of cortisone in the saliva sample of step (i) with the cortisone concentration of step (iii); and v) determining if the paediatric subject has adrenal insufficiency.
  3. 3 . The method of claim 1 , wherein the pharmaceutical composition is administered to the paediatric subject at an effective dose selected from the group consisting of 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, and 1000 μg tetracosactide acetate.
  4. 4 . The method of claim 1 , wherein the pharmaceutical composition is administered to the paediatric subject at an effective dose of 500 μg tetracosactide acetate.
  5. 5 . The method of claim 1 wherein step iii) is performed 120 minutes after the intranasal administration of step ii).
  6. 6 . The method of claim 1 wherein step iii) is performed 180 minutes after the intranasal administration of step ii).
  7. 7 . A method of diagnosis of adrenal insufficiency in a neonate subject between 0-28 days old or an infant subject between 1 to 12 months old, comprising: i) obtaining a sample of saliva from the neonate or infant subject and measuring cortisone concentration in said saliva sample; ii) intranasally administering a pharmaceutical composition adapted for nasal administration comprising an effective dose of tetracosactide acetate, chitosan glutamate, and an acid, wherein said composition has a viscosity of between 10 to 300 mPAs; iii) repeating step i); iv) comparing the concentration of cortisone in the saliva sample of step (i) with the cortisone concentration of step (iii); and v) identifying adrenal insufficiency in the neonate or infant subject.
  8. 8 . The method according to claim 7 , wherein step iii) is performed 5, 10, 15, 20, 30, 40, 45, 50, 60, 75, 90, 120 and/or 180 min after intranasal administration of the pharmaceutical composition of step ii).
  9. 9 . The method according to claim 7 , wherein step i) is repeated 2, 3, 4, or 5 times after intranasal administration of the pharmaceutical composition according to step ii).
  10. 10 . The method according to claim 7 , wherein said acid is acetic acid.
  11. 11 . The method according to claim 7 , wherein said pharmaceutical composition comprises an effective dose of between 100-1000 μg tetracosactide acetate.
  12. 12 . The method according to claim 7 , wherein said viscosity is between 20 to 200 mPa·s.
  13. 13 . The method according to claim 12 , wherein said viscosity is between 50 mPa·s to 100 mPa·s.
  14. 14 . A method of diagnosis of adrenal insufficiency in a neonate subject between 0-28 days old or an infant subject between 1 to 12 months old, comprising: i) obtaining a saliva sample from the neonate or infant subject and measuring cortisone concentration in the saliva sample; ii) intranasally administering a pharmaceutical composition to the neonate or infant subject at a dose of between 500-1000 μg, wherein the pharmaceutical composition comprises: tetracosactide acetate 0.25% (w/v), chitosan glutamate 0.5% (w/v), sodium chloride 0.54% (w/v), benzalkonium chloride 0.015% (w/v), acetic acid 0.51% (w/v), and sodium acetate trihydrate 0.21% (w/v); iii) repeating step i); iv) comparing the concentration of cortisone in the saliva sample of step (i) with the cortisol or cortisone concentration of step (iii); and (v) identifying adrenal insufficiency in the neonate or infant subject.
  15. 15 . The method of claim 1 , wherein the pediatric subject is a neonate subject between 0-28 days old or an infant subject between 1 to 12 months old.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This is the U.S. National Stage of International Application No. PCT/GB2018/053073, filed Oct. 24, 2018, which was published in English under PCT Article 21 (2), which in turn claims the benefit of Great Britain Application Nos. 1717509.2, filed Oct. 25, 2017 and 1809456.5, filed Jun. 8, 2018. FIELD OF THE INVENTION The disclosure relates to a composition comprising adrenocorticotropic hormone (ACTH) or a synthetic ACTH analogue for use in a diagnostic test for adrenal insufficiency. A method to conduct said diagnostic test by typically administering a hormone or hormone analogue nasally and measuring response with a non-invasive saliva test; kits comprising the components for said test are also disclosed and the use of the diagnostic test and kits in the diagnosis of patients BACKGROUND TO THE INVENTION The adrenal glands are above the kidneys and are part of the body's endocrine system. They produce a number of different hormones; those involved in metabolism (cortisol), salt and water balance (aldosterone) and sex steroids (oestrogen and testosterone). Cortisol release is regulated by interaction and feedback with the hormones of the hypothalamus and the anterior pituitary gland. Corticotropin releasing hormone (CRH) produced by the hypothalamus stimulates adrenocorticotropin (ACTH) production in the pituitary gland which in turn stimulates the production of cortisol in the adrenal cortex of the adrenal gland. Cortisol has itself a negative feedback on the hypothalamus and the pituitary gland inhibiting the production of CRH and ACTH. Cortisol is referred to as a stress hormone and has several other physiological functions such as maintaining blood pressure, regulating protein, carbohydrate and fat metabolism, regulating the effects of insulin and influencing the immune system's inflammatory responses. Adrenal insufficiency is a rare endocrine disorder and can affect people of all ages and sex and is characterised by insufficient production of cortisol (and in some cases aldosterone) causing symptoms such as muscle weakness, loss of weight, low mood, cramps and exhaustion, and has pronounced effects on mental and physical development in children. Adrenal insufficiency (AI) is caused by an impaired function of either i) the adrenal glands (primary adrenal insufficiency), ii) the pituitary gland (secondary adrenal insufficiency) or iii) the hypothalamus (tertiary adrenal insufficiency) and can present with the slow but progressive loss of cortisol (and in some cases aldosterone) resulting in steadily worsening symptoms which, if undiagnosed and not treated with adequate hormone replacement therapy, can ultimately result in adrenal crises, a potential life threatening condition requiring immediate emergency treatment with hydrocortisone. The most common cause in adults from the developed world is autoimmune destruction of the adrenal gland but worldwide it is tuberculosis. The commonest paediatric cause is the prescription of steroid medication. Adrenal insufficiency is usually permanent but may be transient, especially in children, and therefore periodic diagnostic testing is required in some patients (for example weekly, monthly or 3-monthly). A diagnosis of adrenal insufficiency can be confirmed by the short synacthen test (SST) using the synthetic analogue of ACTH, tetracosactide, to monitor cortisol production. The test is typically conducted at a hospital where a blood sample is obtained from the patient to determine the amount of cortisol present in the blood. Then a dose of tetracosactide is injected to stimulate the adrenal glands and after a short period of time, such as after 20, 30 and/or 60 min, cortisol levels in the blood are measured again to monitor the response of the adrenal glands to the stimulant. A failure to produce cortisol in response to the stimulant can be indicative of adrenal insufficiency and may provide information of the interaction of hypothalamus, pituitary and adrenal glands. In recent years requests for SSTs have risen in line with increased paediatric steroid usage and heightened awareness of the adrenal insufficiency steroids can cause. However, although the SST is a common diagnostic method for adrenal insufficiency, cannulation and blood sampling are required making it invasive, time-consuming and resource-intensive, which, when considering children in particular, is not desirable. The disclosure relates to compositions comprising tetracosactide and chitosan suitable for nasal administration and to a diagnostic test for detecting adrenal insufficiency comprising the delivery of said tetracosactide composition which allows measurement of the cortisol response of a subject in the saliva in a non-invasive manner. STATEMENT OF THE INVENTION According to an aspect of the invention there is provided a liquid pharmaceutical composition adapted for nasal administration comprising adrenocorticotropic hormone (ACTH) or a synthetic ACTH an