Administration regimen of compositions of T4 thyroid hormone with high oral absorption

Abstract

New administration regimens of the T4 thyroid hormone are described, characterized by the use of alcohol-free, water-glycerol solutions of said hormone, administered at short temporal distance, i.e. within less than 30 minutes, typically between 15 and less than 30 minutes, from the closest consumed meal.

Claims

1. A method of treating a disease associated with deficiency of one or more thyroid hormones in a patient in need thereof, comprising: administering an effective amount of an oral solution pharmaceutical composition comprising T4 thyroid hormone in an alcohol-free, water-glycerol solution, wherein said composition is administered within a temporal distance of less than 30 minutes from the closest meal consumed by the patient.

2. The method of claim 1, wherein said composition is administered at a temporal distance between 15 minutes and less than 30 minutes from said meal.

3. The method of claim 2, wherein said composition is administered at a temporal distance between 15 minutes and less than 30 minutes before said meal.

4. The method of claim 3, wherein said meal is breakfast.

5. The method of claim 3, wherein said meal provides fewer than 750 calories.

6. The method of claim 3, wherein said water-glycerol solution has a w/w concentration of glycerol in water between 40 and 99%.

7. The method of claim 3, wherein said water-glycerol solution is in the form of a dosage unit, comprising 5 to 1000 μg T4 thyroid hormone.

8. The method of claim 3, wherein said water-glycerol solution is in the form of a dosage unit, comprising 10 to 500 μg T4 thyroid hormone.

9. The method of claim 3, wherein said T4 thyroid hormone is contained in an amount by weight between 2 and 2500 ppm with respect to glycerol.

10. The method of claim 3, wherein said composition is free from stabilizing agents.

11. The method of claim 1, wherein said composition is administered at a temporal distance between 15 minutes and less than 30 minutes before said meal.

12. The method of claim 11, wherein said meal is breakfast.

13. The method of claim 1, wherein said meal provides fewer than 750 calories.

14. The method of claim 1, wherein said water-glycerol solution has a w/w concentration of glycerol in water between 40 and 99%.

15. The method of claim 1, wherein said water-glycerol solution is in the form of a dosage unit, comprising 5 to 1000 μg T4 thyroid hormone.

16. The method of claim 1, wherein said water-glycerol solution is in the form of a dosage unit, comprising 10 to 500 μg T4 thyroid hormone.

17. The method of claim 1, wherein said T4 thyroid hormone is contained in an amount by weight between 2 and 2500 ppm with respect to glycerol.

18. The method of claim 1, wherein said composition is free from stabilizing agents.

19. The method of claim 1, wherein the oral solution pharmaceutical composition consists essentially of T4 thyroid hormone in an alcohol-free solution of water and glycerol, and optionally T3 thyroid hormone.

20. The method of claim 1, wherein the oral solution pharmaceutical composition is administered from a single dose container.

Description

4. DETAILED DESCRIPTION OF THE INVENTION

(1) An object of the invention is a new mode (regimen) of administration of the T4 thyroid hormone, highly effective from the point of view of the absorption into circulation of said hormone, wherein an alcohol-free, water-glycerol solution of T4 thyroid hormone is administered in the treatment or prevention of a disease caused by thyroid hormone deficiency; said administration regimen is characterized in that the administration of the solution is performed within particularly short time intervals with respect to the closest meal consumed by the patient, typically at a temporal distance of less than 30 minutes, e.g. between 15 and 30 minutes from said meal. The administration of the present solution of T4 thyroid hormone can be performed before or after the meal at issue; preferably it occurs before the meal. The term “consumed meal” is herein meant in the broad sense to indicate a meal which can be indifferently consumed before or after administration of the present solution of T4 thyroid hormone, within the above-mentioned temporal distances. The meal can be any meal which is part of the normal food routine, i.e. breakfast, brunch, lunch, happy hour, dinner, etc.; considering that T4 administration occurs preferably early in the morning, the meal at issue will preferably be breakfast. As regards the qualitative and quantitative content of the meal, there are no binding limitations: it is however preferable that the meal at issue has a moderate nutritional content, as it can be generally defined as “light meal”. The nutritionist expert is normally able to select a light meal, with reference to the type and amount of foodstuffs which compose it, in particular the amount of contained fats; a definition of light meal, useful according to the invention, is that of a meal with a caloric content lower than 750 calories, preferably lower than 500 calories, more preferably lower than 300 calories, independently of the type of foodstuffs which compose it. A mean continental breakfast (comprising one among milk/coffee/tea, and further fibers, yogurt, snack food in small amount), is ideally a “light meal” according to the present invention.

(2) Based on the principles explained above, the invention can be defined as a pharmaceutical composition comprising T4 thyroid hormone in an alcohol-free, water-glycerol solution, for use in the treatment or prevention of a disease associated with deficiency of one or more thyroid hormones, characterized in that said composition is administered within less than 30 minutes, e.g. between 15 and less than 30 minutes from the closest consumed meal.

(3) The invention can be equally defined as the use of an alcohol-free, water-glycerol solution of T4 thyroid hormone in the preparation of a medicament for the treatment and/or prevention of diseases caused by a reduced production of one or more thyroid hormones, wherein said medicament is administered (i.e. is part of an administration regimen in which said administration occurs) within less than 30 minutes, e.g. between 15 minutes and less than 30 minutes from the closest consumed meal.

(4) The invention can be equally defined as a method for the treatment and/or prevention of diseases caused by a reduced production of one or more thyroid hormones, characterized by administering an alcohol-free, water-glycerol solution of T4 thyroid hormone within less than 30 minutes, e.g. between 15 and less than 30 minutes from the closest consumed meal.

(5) The invention can be equally defined as the treatment, by administration of an alcohol-free, water-glycerol solution of T4 thyroid hormone, of a subgroup of patients suffering from diseases caused by a reduced production of one or more thyroid hormones, said patients being selected among those who have consumed (or will consume) the closest meal within less than 30 minutes, e.g. between 15 minutes and less than 30 minutes from said administration.

(6) In all above-mentioned forms, the reference time points for calculating the above-mentioned temporal distance are those when: (a) the oral dosage form is ingested, namely it contacted the mouth of the patient and (b) the closest meal has started.

(7) The water-glycerol solution used in the present invention comprises water and glycerol in widely varying amounts; water is not necessarily added, as it can be the one originally comprised in commercial glycerol (the latter is indeed provided with a titer of 85%, i.e. at the concentration of 85% w/w in water); other values in w/w concentration of glycerol in water can be used within the scope of the present invention; for example 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% and any ranges among them.

(8) In the present solutions, the weight ratio between T4 hormone and glycerol [herein meant as pure substance, namely without considering its aqueous component] is generally between 0.002:1000 and 2.5:1000 (i.e. from 2 to 2500 ppm). Preferably, the present water-glycerol solutions are formulated and packaged as single dosage units (single-dose package); in this case, the suitable dose unit will typically contain from 5 to 1000 μg (or preferably from 10 to 500 μg) of T4 hormone.

(9) The term “alcohol-free”, associated with the present solutions of T4 thyroid hormone, means that the solution is free from low molecular weight alcohols; the term “low molecular weight alcohols” means an alkanol with molecular weight lower than 80 Dalton: e.g. methanol, ethanol, propanol, propanediol, isopropanol and similar alcohols; the term “alcohol-free” remains thus compatible with the presence of glycerol in the solution (whose molecular weight is 92.1 Dalton). Examples of water-glycerol solutions in accordance with the above-mentioned parameters and preferably usable in the context of the present invention are described in the co-pending application WO2018/073209 in the name of the Applicant, herein incorporated by reference. In the context of the present invention it is particularly significant that, even if the water-glycerol solutions at issue are free from ethanol or similar alcohols which are able to promote the absorption of the active ingredient through the mucosae, and considering the known difficulty of the T4 hormone when orally administered to be absorbed closely to the meals, the water-glycerol solutions at issue can cause a substantially unchanged absorption of T4 at considerably shortened time intervals from the last meal, e.g. of the order of about 20 minutes.

(10) Although characterized by the presence of T4 thyroid hormone as main active ingredient, the present compositions can optionally contain other active ingredients, in particular further active ingredients useful for the treatment of diseases caused by the deficiency of thyroid hormone and/or related symptomatologies. A typical further active ingredient of this type can be the T3 thyroid hormone: the latter can be intentionally added or be contained in traces (e.g. as by-product from conversion from T4 into T3); in the latter case, T3 amount will typically be very low since the present water-glycerol compositions have a high stability expressed as reduced conversion of T4 hormone into T3 hormone.

(11) Further optional ingredients of the present solutions are those that can be commonly used in the formulation of solutions of active ingredients for oral administration. They can be chosen by the pharmaceutical formulator based on known teachings. It is however to be noted that the high stability of the present alcohol-free T4-water-glycerol solutions makes it advantageously not essential to introduce stabilizers (for example pH-adjusting agents, buffers, chelating agents, etc.); when so formulated, the compositions of the invention entail the further advantage of avoiding unnecessary administration of additives to the patient and reducing the complexity/cost of the final medicament.

(12) The present solutions can be provided to the user in conveniently packaged form. A wide range of choice is allowed with respect to the type of packaging and material used for it. An advantageous mode of packaging is represented by squeezable single-dose containers; in particular, as described in WO2018/073209, multicomponent laminated containers made of layers of polyethylene, ethylene vinyl alcohol copolymer resins, polyvinyl chloride, polyvinylidene chloride, polyvinyl acetate, fluorinated-chlorinated resins, ionomer resins, cyclic olefin copolymers, polyamide, polystyrene, polycarbonate, laminated metals, paper, obtaining containers with an ideal squeezing degree, so as to ensure complete discharge of the dose of solution by manual compression of the container, associated with an excellent protection of the solution; moreover, as it is also shown in WO2018/073209, said protection can be increased using a container as described above, in association to a secondary container which contains it: said secondary container can be e.g. a sachet made by lamination of different materials such as e.g. polyethylene, polyethylene terephthalate, ionomer resins, aluminum, paper, ethylene vinyl alcohol copolymer resins, fluorinated-chlorinated resins, etc.

(13) The present invention is now described by way of the following non-limiting examples.

5. EXAMPLES

(14) A randomized, open-label, pharmacokinetic study, with crossed design, compared the oral levothyroxine solution according to the present invention administered as 600 mcg single dose 20 minutes before breakfast or in total fasted conditions (i.e., fasting from 10 hours before to 4 hours after levothyroxine administration) in 12 healthy volunteers. The study provided the following results.

(15) TABLE-US-00001 TABLE 1 Summary of the pharmacokinetic parameters calculated for serum levothyroxine and adjusted for basal levels oral solution of levo- oral solution of levo- thyroxine administered in thyroxine administered 20 total fasted conditions minutes before breakfast (A) (B) Parameter (unit) N Mean SD CV % N Mean SD CV % AUC.sub.0-48 12 1615.65 317.63 19.66 12 1365.20 386.47 28.31 (h*ng/mL) C.sub.max (ng/mL) 12 65.47 11.21 17.13 12 55.10 11.56 20.98 Parameter (unit) N Median Min Max N Median Min Max T.sub.max (h) 12 1.747 1.494 2.998 12 1.495 0.504 3.998 abbreviations N: number of observations; SD: Standard deviation; CV: Coefficient of variation; Min: Minimum; Max: Maximum; C.sub.max: maximum observed concentration; AUC.sub.0-48: Area under the curve concentration-time from time zero to time of the last measurable concentration; T.sub.max: time of C.sub.max observed treatment conditions Treatment A: oral solution of levothyroxine (600 μg) administered in total fasted conditions. Treatment B: oral solution of levothyroxine (600 μg) administered 20 minutes before breakfast.

(16) TABLE-US-00002 TABLE 2 Geometric least squares mean ratio (B/A) for pharmacokinetic parameters calculated for serum levothyroxine and adjusted for basal levels Geometric LSM Parameter Treatment Treatment Ratio.sup.1 (unit) A B (%) AUC.sub.0-48 1568.86 1315.35 83.84 (h*ng/mL) C.sub.max 64.09 54.11 84.43 (ng/mL) .sup.1Calculated using the least squares means according to the formula: exp.sup.(DIFFERENCE) * 100. abbreviations LSM: least squares mean; C.sub.max: maximum observed concentration; AUC.sub.0-48: Area under the curve concentration-time from time zero to time of the last measurable concentration. treatment conditions Treatment A: oral solution of levothyroxine (600 μg) administered in total fasted conditions. Treatment B: oral solution of levothyroxine (600 μg) administered 20 minutes before breakfast.

(17) The data provided above show that the rate and extent of the absorption of the oral solution of levothyroxine administered 20 minutes before breakfast remain higher than 80% with respect to those of the oral solution of levothyroxine administered in total fasted conditions: it is a very moderate variation, also considering the wide temporal difference of administration of the closest meal in the case of treatment A or B. It is therefore deduced that the bioavailability of the oral solution of levothyroxine according to the present invention is not influenced in a clinically significant manner by the meal ingestion.