WO2007125295A2

WO2007125295A2 - Treatment of hypothyroidism

Info

Publication number: WO2007125295A2
Application number: PCT/GB2007/001477
Authority: WO
Inventors: Richard Ross
Original assignee: Diurnal Limited
Priority date: 2006-04-28
Filing date: 2007-04-23
Publication date: 2007-11-08
Also published as: WO2007125295A3; GB0608402D0

Abstract

The disclosure relates to a medicament for the treatment of thyroid disorders that typically result from a hypoactive thyroid gland.

Description

.

Treatment of Hypothyroidism

The invention relates to a medicament for the treatment of thyroid disorders that typically result from a hypoactive thyroid gland.

The thyroid gland is an endocrine gland located in the middle of the lower neck below the larynx and above the collar bones. The main function of the thyroid gland is to produce thyroid hormone which has effects on all tissues of an organism to regulate metabolism. Pathologies associated with abnormal thyroid gland function are common and result from either an over active or under active thyroid gland. These are referred to as hyperthyroidism and hypothyroidism respectively.

Hypothyroidism is a condition that results from a failure of the thyroid gland to secrete a physiologically sufficient amount of thyroid hormone. There are many symptoms associated with hypothyroidism and these include fatigue, weakness, weight gain, hair loss, cold intolerance, constipation, depression, abnormal menstrual cycles and decreased libido. There are two common causes of hypothyroidism. The first involves inflammation or autoimmunity to the thyroid gland which results in damage to the hormone secreting cells and failure of thyroid hormone secretion. A common form of thyroid inflammation results from the autoimmune disease Hashimoto's thyroiditis. A second common cause of hypothyroidism results from surgical treatment of other conditions that require removal of all or part of the thyroid gland as, for example after surgical removal of a cancerous thyroid gland. A less common cause of hypothyroidism results from secondary effects produced on a normal thyroid gland that causes a decrease in thyroid hormone secretion. For example, if the pituitary gland fails to produce enough thyroid stimulating hormone (TSH) then the result is a lack of stimulation of the thyroid to produce thyroid hormone.

A further consequence of hypothyroidism is a secondary effect by the pituitary gland to produce large amounts of TSH to stimulate the thyroid gland to produce more thyroid hormone. In this event the thyroid gland becomes enlarged to form a goiter to compensate for reduced hormone secretion. Individuals that suffer from hypothyroidism are commonly prescribed thyroxine (T4) as replacement therapy. It is well recognised that a large proportion of patients persist with specific symptoms and a failure to regain a normal sense of wellbeing despite thyroxine replacement. For example, recent studies, it is estimated that between 30 and 50% of patients reported dissatisfaction with their treatment (Kaplan, 2003).

The thyroid gland secretes two hormones: thyroxine (T4) and triiodothyronine (T3). T3 is the more active thyroid hormone but it is secreted at lower levels and T4 may be at least, in part, converted to T3 in the circulation. For this reason, many physicians do not believe it is necessary to give T3 medication. However, it has been proposed in studies that a combination of T4 and T3 treatment might relieve people of symptoms. However, these studies have major flaws. T3 has a very different pharmacokinetic profile to T4. T4 has a very long half-life whereas T3 has a short half-life. Therefore, just administering a single tablet of T3 may give an acute rise in T3 levels followed by lower levels later on. In addition, the proportion of T3 to T4 remains fairly stable throughout 24 hours whereas giving a burst of T3 will lead to varying T4 to T3 ratios. For this reason, studies have not accurately reflected physiology and may well have found negative results. Consequently patients frequently turn to alternative therapies such has bovine thyroid extract which contain both T4 and T3. It is therefore desirable to provide a treatment for hypothyroidism that provides a physiological dosage regime to entrain thyroid hormone secretion to avoid the disadvantages of current thyroid replacement therapy.

We disclose that there is a distinct circadian rhythm of TSH, total T3 (Tt3) and FreeT3 (Ft3) which has a sinusoidal pattern, whereas FreeT4 (Ft4) levels remain stable throughout 24 hours. The rise in levels of Tt3 and Ft3 lag behind TSH levels by approximately 1 to 1.5 hours suggesting that the circadian rhythm of T3 is generated by TSH stimulation of the thyroid gland. The rise in T3 starts after 200Oh peaks after 240Oh remains high overnight to the time of waking then declines to a nadir around 150Oh. Ft4 shows no clear circadian rhythm and remains at a relatively stable concentration throughout the 24 hours. This disclosure also relates to a medicament which would provide physiological thyroid hormone replacement providing physiological circadian rhythm for T3 and stable concentration of T4. We disclose a medicinal preparation comprising a delivery vehicle and a combined preparation of thyroxine and triiodothyronine.

Delivery vehicles which can be used in the working of the invention are known in the art. An example is disclosed in EPO 1077065, which is incorporated by reference. The controlled release formulation comprises a drug core which is surrounded by a release control layer which breaks down after a predetermined delay. EPO 1077065 also discloses a drug release layer outside the release control layer which provides for an initial rapid release followed by the release of drugs from the drug core. This provides for the delivery of at least two drug doses in a delayed manner.

EP01053752, which is incorporated by reference, discloses a further example of a preparation which shows controlled release. The preparation comprises two parts, a female and male part, the female part is made from a water insoluble polymer and the male part formed from a composition consisting of ethyl acrylate: methyl methacrylate: trimethylammonioethyl methacrylate co-polymer and a methylacrylic.-ethyl acrylate copolymer. The therapeutic agent is contained within the male and female parts. The formulation is pH sensitive only releasing a therapeutic agent at neutral pH thereby passing through the stomach intact and only releasing in the neutral environment of the small intestine.

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. According to an aspect of the invention there is provided a medicament comprising a delivery vehicle and a combined preparation of thyroxine and triiodothyronine wherein delivery vehicle provides for the delayed and sustained release of triiodothyronine.

Typically, a molar ratio of about 14:1 T4:T3, delivering around lOOμg T4 and 6μg T3 per day is desired and the typical dose of T4 for fully hypothyroid individuals is around 1.6μg/kg/day. As physiological replacement is based on weight a range of tablets will be required providing different quantities of T4 and T3 but at the same ratio which would be evident to the skilled person

In a preferred embodiment of the invention at least lOOμg of thyroxine is provided in the combined preparation.

In a preferred embodiment of the invention at least 6 μg of triiodothyronine is provided in the combined preparation.

In a preferred embodiment of the invention thyroxine is provided in the combined preparation at 25 to 200μg per unit dose; preferably triiodothyronine is provided in the combined preparation at 1 to 20μg per unit dose.

In a preferred embodiment of the invention thyroxine is provided at about lOOμg and triiodothyronine is provided at about 6 μg per unit dose.

In a preferred embodiment of the invention said medicament is adapted for the release of thyroxine and the delayed and sustained release of triiodothyronine.

In a preferred embodiment of the invention said delivery vehicle provides a medicament comprising: i) a core comprising at least one layer that includes an effective amount of triiodothyronine and an agent that controls the sustained release of triiodothyronine; and ii) an outer layer contacting said core and comprising an effective amount of thyroxine wherein the core and outer layer is encased in a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer thereby allowing the release of thyroxine from said outer layer when administered to a subject followed by triiodothyronine.

In a preferred embodiment of the invention said medicament is a tablet.

Sustained drug delivery polymers, for example hydrophilic polymers, are known in the art that allow the controlled release of therapeutic agents either by diffusion out of the polymer matrix or by erosion of the polymer or a combination thereof. Polymers are degradable or non-degradable but degradable are preferred since they degrade to smaller molecules that are excreted. Examples of these polymers are polylactide based or cellulose based. Polylactides are typically hydrophobic and take longer to degrade; poly (lactide-co-glycolide) is more hydrophilic. Examples of hydrophilic drug polymers include hydroxypropylmethylcellulose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethylcellulose, poly (ethylene) oxide, polymethyacrylates or polyvinyl alcohol. Polymers that confer modified release profiles are commercially available, for example Methocel products manufactured by The Chemical Company Dow. Polymer morphology can also affect the release properties of the encapsulated drug and typically polymer matrices can be in the form of micro/nanospheres. Moreover, drug delivery polymers may also include excipients that can be added to a polymer drug matrix to further modify drug release, drug stability or polymer degradation kinetics or combinations thereof. For example basic salts can be added that control polymer degradation thereby altering drug release. Hydrophilic excipients can be added that accelerate drug release.

When administered, the medicament of the present invention is administered in pharmaceutically acceptable preparations. Such preparations may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers and supplementary potentiating agents.

The medicament of the invention can be administered by any conventional route, including injection or by gradual infusion over time. The administration may, for example, be oral, intravenous, intraperitoneal, intramuscular, intracavity, subcutaneous, or transdermal. The preferred route of administration is oral.

The medicament of the invention is administered in effective amounts. An "effective amount" is that amount of a medicament that alone, or together with further doses, produces the desired response. In the case of treating a particular disease the desired response is inhibiting the progression of the disease. This may involve only slowing the progression of the disease temporarily, although more preferably, it involves halting the progression of the disease permanently. This can be monitored by routine methods or can be monitored according to diagnostic methods known in the art.

Such amounts will depend, of course, on 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. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons. The medicaments used in the foregoing methods preferably are sterile and contain an effective amount of thyroxine and triiodothyronine for producing the desired response in a unit of weight or volume suitable for administration to a patient.

The doses of thyroxine and triiodothyronine 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. In general the aim of treatment will be to maintain the TSH level in the normal range. Other protocols for the administration of the medicament will be known to one of ordinary skill in the art, in which the dose amount, schedule of injections, sites of injections, mode of administration and the like vary from the foregoing. Administration of the medicament 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. 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 medicament of the invention is applied 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.

The medicament 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 the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy. The medicament 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. Medicaments also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol and parabens.

The medicament 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 medicament is 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.

Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active compound. Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as syrup, elixir or an emulsion.

According to a further aspect of the invention there is provided the combined use of thyroxine and triiodothyronine in the manufacture of a medicament for the treatment of hypothyroidism.

In a preferred embodiment of the invention triiodothyronine is provided as a delayed and sustained release preparation.

In a preferred embodiment of the invention the medicament is administered to a subject wherein the administration pattern of the medicament comprises release of thyroxine followed temporally by the sustained release of triiodothyronine.

In a preferred embodiment of the invention the administration pattern of thyroxine is sustained over a period of 5-60 minutes after administration of the medicament to said subject; preferably triiodothyronine is released in a sustained pattern after administration of thyroxine. In an alternative preferred embodiment of the invention the administration pattern of thyroxine is sustained over a period of 30-120 minutes.

In a preferred embodiment of the invention triiodothyronine is delayed in its release for a period of 2-4 hours after release of thyroxine.

In a preferred embodiment of the invention said medicament is administered between 18:00h and 22:00h.

In an alternative preferred embodiment of the invention said medicament is administered to provide a delay in the release of triiodothyronine and a sustained release pattern wherein triiodothyronine concentration peaks at between 00:00h and 06:00h.

In a preferred embodiment of the invention the administration pattern of the medicament produces a circadian rhythm of thyroxine and triiodothyronine release in said subject.

In a preferred embodiment of the invention hypothyroidism results from inflammation of the thyroid gland, for example Hashimoto's thyroiditis and autoimmune hypothyroidism.

In a further preferred embodiment of the invention hypothyroidism results from surgical removal of all or part of a subject's thyroid gland.

In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of fatigue and impaired quality of life caused by hypothyroidism.

In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of weight gain caused by hypothyroidism.

In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of depression caused by hypothyroidism.

In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of hair loss caused by hypothyroidism. In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of an abnormal menstrual cycle caused by hypothyroidism.

In a further preferred embodiment of the invention there is provided a medicament for use in the treatment of decreased libido caused by hypothyroidism.

According to a further aspect of the invention there is provided a method of treatment of hypothyroidism comprising administering a medicament comprising a combined preparation of thyroxine and triiodothyronine wherein triiodothyronine is provided in a form that allows the delayed and sustained release of triiodothyronine.

In a preferred method of the invention 100 μg thyroxine is provided in the combined preparation.

In a preferred method of the invention 6 μg triiodothyronine is provided in the combined preparation.

In a preferred method of the invention thyroxine is provided in the combined preparation at a concentration of 25 to 200μg; preferably triiodothyronine is provided in the combined preparation at a concentration of 1 to 20μg.

In a preferred method of the invention the administration pattern of thyroxine is sustained over a period of 30-120 minutes after administration.

In a preferred method of the invention triiodothyronine is delayed in its release for a period of 2-4 hours after release of thyroxine.

In a preferred method of the invention said medicament is administered between 18:00h and 22:00h. In an alternative preferred method of the invention said medicament is administered to provide a delay in the release of triiodothyronine and a sustained release pattern wherein triiodothyronine concentration peaks at between 00:00h and 06:00h.

In a preferred method of the invention thyroxine is provided at a concentration of about lOOug and triiodothyronine is provided at a concentration of about 6ug

In a preferred method of the invention hypothyroidism results from inflammation of the thyroid gland, for example Hashimoto's thyroiditis or autoimmune hypothyroidism.

In a further preferred method of the invention hypothyroidism results from surgical removal of all or part of a subject's thyroid gland.

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 figures:

Figure la-d shows the results of measurements of TSH, Ft4, Tt3, and Ft3 in the above subjects. It can be seen that TSH, TO and Ft3 show a distinct circadian rhythm that has a sinusoidal pattern. Changes in levels of T3 lag behind those of TSH by approximately 1 to 1.5 hours. Levels of T3 start to rise after 200Oh peak after 240Oh and remain high till waking and then decline to a nadir at 150Oh. Ft4 shows no distinct circadian rhythm.

Materials and Methods

Sample collection for physiological profiles: The samples used in this study were collected retrospectively from another study (LEC:SOU/00/177) that was closed in 2004. This study examined circadian secretion of pituitary hormones in healthy individuals compared to those who have received cranial irradiation¹⁸. Briefly, the samples in the study SOU/00/177 were collected for 24 hours at 20 minute intervals from a group of 33 healthy subjects (9 females and 24 males), aged 17.3-56.5 yr (median, 22.8 yr), with a Body Mass Index that ranged from 16.3-28.9 kg/m2 (median, 22.9 kg/m2). Thyrotropin Stimulating Hormone (TSH) blood sampling at 20-min intervals was carried out between 0900 and 0840 h next morning. Three standard hospital meals were provided at 0830, 1230, and 1800 h, and physical activity was restricted to within the ward. Sera were separated and immediately frozen at -80 C. TSH estimation was performed on the 24 hourly samples¹⁸.

Measurement of hormones: Total T3, free thyroxine (Ft4) and free triiodothyronine (Ft3) at 20 minute intervals were measured using standard methods with Bayer Centaur Immunoassay analyser.

Pharmacokinetic modelling: The rhythms of T4 and T3 will be used as the input to model the release profiles for a thyroid treatment that will deliver physiological thyroid hormone replacement.

Claims

1. A medicament comprising a delivery vehicle and a combined preparation of thyroxine and triiodothyronine wherein delivery vehicle provides for the delayed and sustained release of triiodothyronine.

2. A medicament according to claim 1, wherein lOOμg thyroxine is provided in the combined preparation.

3. A medicament according to claim 1 or 2, wherein 6 μg triiodothyronine is provided in the combined preparation.

4. A medicament according to any of claims 1-3, wherein thyroxine is provided in the combined preparation at about 25 to 200μg per unit dose.

5. A medicament according to any of claims 1-3, wherein triiodothyronine is provided in the combined preparation at about 1 to 20μg per unit dose.

6. A medicament according to claim 4 or 5, wherein thyroxine is provided at about lOOμg and triiodothyronine is provided at about 6 μg per unit dose.

7. A medicament according to any of claims 1-6, wherein said medicament is provided in unit dosage form.

8. A medicament according to any of claims 1-7, wherein said medicament is adapted for the release of thyroxine and the delayed and sustained release of triiodothyronine.

9. A medicament according to any of claims 1-8, wherein said delivery vehicle provides a medicament comprising: i) a core comprising at least one layer that includes an effective amount of triiodothyronine and an agent that controls the sustained release of triiodothyronine; and ii) an outer layer contacting said core and comprising an effective amount of thyroxine wherein the core and outer layer is encased in a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer thereby allowing the release of thyroxine from said outer layer when administered to a subject followed by the sustained release of triiodothyronine.

10. A medicament according to any of claims 1-9, wherein said medicament is a tablet.

11. The use of a combined preparation of thyroxine and triiodothyronine wherein triiodothyronine is provided as a delayed and sustained release preparation in the manufacture of a medicament for the treatment of hypothyroidism in a subject.

12. Use according to claim 11, wherein the medicament is administered to a subject wherein the administration pattern of the medicament comprises release of thyroxine followed temporally by the sustained release of triiodothyronine.

13. Use according to claim 11, wherein the administration pattern of thyroxine is over a period of at 5-60 minutes after administration of the medicament to a subject.

14. Use according to claim 11 wherein the administration pattern of thyroxine is sustained over a period of 30-120 minutes after administration to a subject.

15. Use according to claim 11 wherein triiodothyronine is delayed in its release for a period of 2-4 hours after release of thyroxine.

16. Use according to claim 11 wherein said medicament is administered between 18:00h and 22:00h

17. Use according to claim 11 wherein said medicament is administered to provide a delay in the release of triiodothyronine and a sustained release pattern wherein triiodothyronine concentration peaks at between 00:00h and 06:00h.

18. Use according to claim 11, wherein triiodothyronine is released in a sustained pattern after the release of thyroxine.

19. Use according to any of claims 12-18, wherein the administration pattern of the medicament produces a circadian rhythm of thyroxine and triiodothyronine release in said subject.

20. Use according to any of claims 12-19, wherein hypothyroidism results from inflammation of the thyroid gland.

21. Use according to claim 20, wherein hypothyroidism is caused by Hashimoto's thyroiditis and or autoimmune hypothyroidism.

22. Use according to any of claims 12-19, wherein hypothyroidism results from surgical removal of all or part of a subject's thyroid gland.

23. Use according to any of claims 12-19, wherein the medicament is for the treatment of fatigue and or impaired quality of life caused by hypothyroidism.

24. Use according to any of claims 12-19, wherein the medicament is for the treatment of weight gain caused by hypothyroidism.

25. Use according to any of claims 12-19, wherein the medicament is for the treatment of depression caused by hypothyroidism.

26. Use according to any of claims 12-19, wherein the medicament is for the treatment of hair loss caused by hypothyroidism.

27. Use according to any of claims 12-19, wherein the medicament is the treatment of an abnormal menstrual cycle caused by hypothyroidism.

28. Use according to any of claims 12-19, wherein the medicament is for the treatment of decreased libido caused by hypothyroidism.

29. A method of treatment of hypothyroidism comprising administering a medicament comprising a combined preparation of thyroxine and triiodothyronine wherein triiodothyronine is provided in a form that allows the delayed and sustained release of triiodothyronine.

30. The use of a delivery vehicle comprising: i) a core comprising at least one layer that includes an effective amount of triiodothyronine and an agent that controls the sustained release of triiodothyronine; and ii) an outer layer contacting said core and comprising an effective amount of thyroxine wherein the core and outer layer is encased in a substantially insoluble layer extending over part of the tablet surface but exposing at least part of said outer layer thereby allowing the release of thyroxine from said outer layer when administered to a subj ect followed by the sustained release of triiodothyronine in the manufacture of a medicament for the treatment of hypothyroidism.