EP4704805A2 - Oral solution comprising liothyronine sodium - Google Patents
Oral solution comprising liothyronine sodiumInfo
- Publication number
- EP4704805A2 EP4704805A2 EP24722291.2A EP24722291A EP4704805A2 EP 4704805 A2 EP4704805 A2 EP 4704805A2 EP 24722291 A EP24722291 A EP 24722291A EP 4704805 A2 EP4704805 A2 EP 4704805A2
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- Prior art keywords
- oral pharmaceutical
- pharmaceutical solution
- solution
- solution according
- sodium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An oral pharmaceutical solution comprising liothyronine sodium; water; at least one cosolvent selected from the group consisting of a polyol, and a glycol; and a pharmaceutically acceptable buffer; wherein the pH of the solution is from 3.5 to 6.5, and wherein the solution is obtained by a process comprising the steps of i) dissolving liothyronine sodium in a carrier comprising water at a pH from 10.0 to 13.0, and ii) lowering the pH to a value from 3.5 to 6.5.
Description
ORAL SOLUTION COMPRISING LIOTHYRONINE SODIUM
TECHNICAL FIELD
The present invention refers to oral pharmaceutical solutions comprising liothyronine sodium.
BACKGROUND OF THE INVENTION
Liothyronine is described chemically as (2S)-2-amino-3-[4-(4-hydroxy-3-iodo-phenoxy)- 3,5-diiodo-phenyl]propanoic acid.
Liothyronine is a manufactured form of the thyroid hormone triiodothyronine (T3). It is most commonly used to treat hypothyroidism and myxedema coma. It is commonly administered orally or by intravenous injection.
Liothyronine sodium is the sodium salt form of liothyronine and has the following structural formula:
Liothyronine sodium binds to nuclear thyroid receptors which then bind to thyroid hormone response elements of target genes. As a result, liothyronine sodium induces gene expression that is required for normal growth and development. Liothyronine sodium is more potent and has a more rapid action than thyroxine (T4).
The commercially available liothyronine sodium tablets are formulated as film-coated, tablets for oral administration in strengths of 5 pg, 10 pg, 20 pg, 25 pg and 50 pg of liothyronine sodium.
Although oral solid dosage forms such as tablets are very popular, mainly because of ease of management, for certain users (e.g. children and the elderly) these forms are not necessarily a convenient option, especially due to difficulty in swallowing these
forms. This lack of convenience results in high incidence of non-compliance and ineffective therapy.
Moreover, the Patient Information Leaflet (PIL) of commercially available liothyronine sodium tablets discloses a dosing scheme for children, adolescences, adults and elderlies, according to which dosing is tailored to each different age groups of patients. The concept of tailored treatment sets as prerequisite pharmaceutical forms, such as oral solutions, that enable dose fractioning.
However, the desire for the development of an oral liquid dosage form that comprise liothyronine sodium is complicated by the fact that liothyronine sodium is very unstable, especially, in liquid environments.
According to patent application WO 1999/063969 the instability of liothyronine has been known for a long time. Liothyronine degrades through oxidation and/or de-iodination and other excipient/active interactions in which de-iodination appears to be the predominant degradation pathway. A well-known problem encountered by many manufacturers of these products is also their inherent thermo-labile nature.
Hence, it is challenging to formulate a physicochemically stable oral solution comprising liothyronine sodium as active ingredient.
Patent application EP 0742714 discloses liquid compositions comprising at least one thyroid hormone, such as liothyronine sodium, 40% to 96% v/v ethanol; a pH adjusting agent so that the pH of the composition is from 9 to 12; and 4% to 50% v/v water.
Patent application WO 2022/221480 discloses oral solutions comprising liothyronine sodium; water; at least one buffering agent selected from a citrate buffer, a phosphate buffer or combination thereof to maintain the pH of the oral solution within the target pH of 3.5 to 5.5 during storage; and a solvent.
Liothyronine sodium is also marketed as oral solution under the brand name Liotir® (IBSA Farmaceutici Italia S.r.l.) that contains 5 pg/ml, 10 pg/ml, 15 pg/ml or 20 pg/ml of liothyronine sodium and 28.8 vol% ethanol (alcohol) and glycerol 85%.
However, according to the PIL of Liotir®, each single-dose container contains 233 mg of ethyl alcohol (ethanol), equivalent to 5.8 ml of beer or 2.4 ml of wine. Thus, it can be harmful to alcoholics and should be taken into account in pregnant or lactating women, children and high-risk groups, such as people with liver disease or epilepsy.
Technically the biggest challenge is the development of stable formulations. The most important problem is the use of excipients with low toxicity in the lowest feasible concentrations without compromising the stability of the formulations. In other words, the low concentrations of preservatives contribute in reducing the potential for toxicological effects, but low concentrations may be insufficient for achieving the required stability.
The present invention addresses the problems of the prior art knowledge by advantageously providing physicochemically stable oral pharmaceutical solutions comprising liothyronine sodium.
SUMMARY OF THE INVENTION
The present invention is directed to an oral pharmaceutical solution comprising as active ingredient liothyronine sodium and a process of preparing said solution.
The oral pharmaceutical solution according to the invention comprises liothyronine sodium; water; at least one cosolvent selected from the group consisting of a polyol, and a glycol; and a pharmaceutically acceptable buffer; wherein the pH of the solution is from 3.5 to 6.5, and wherein the solution is obtained by a process comprising the steps of i) dissolving liothyronine sodium in a carrier comprising water and a base, wherein the pH of the carrier is from 10.0 to 13.0, and ii) lowering the pH of the solution obtained in step i) to a value from 3.5 to 6.5.
The oral pharmaceutical solutions according to the present invention provide many advantages over conventional film coated tablet or ethanolic non-aqueous solution dosage forms. Apart from achieving better patient compliance, oral solutions of the present invention offer unique advantages such more reproducible bioavailability and an option of a flexible dosing regimen based on body weight or body surface area.
The oral pharmaceutical solutions according to the present invention is optionally free of ethanol, the presence of which may raise additional safety and toxicity issues. Use of minimum quantities, or absence, of ethanol is extremely important particularly in case of paediatric formulations.
The oral pharmaceutical solutions according to the present invention present excellent physicochemical stability.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an oral pharmaceutical solution comprising liothyronine sodium as active ingredient and a process of preparing said solution.
Patent application WO 2022/221480 describes a process of preparing solutions comprising liothyronine sodium where liothyronine sodium is dissolved in purified water or an aqueous carrier, without controlling the pH of water or the aqueous carrier, and then after the addition of liothyronine sodium the pH of the solution is adjusted to the target pH of 3.5 to 5.5.
Surprisingly, it has been found that when a solution comprising liothyronine sodium is obtained by a process comprising the step of dissolving the liothyronine sodium in a carrier comprising water and a base, wherein the pH of the carrier is from 10.0 to 13.0 and then lowering the pH of the liothyronine sodium solution to a pH from 3.5 to 6.5, the obtained liothyronine sodium solution is more stable during storage.
Furthermore, a liothyronine sodium solution prepared using the process according to the present invention also shows an improved stability in comparison to the marketed oral solution under the brand name Liotir®.
A solution comprising liothyronine sodium according to the present invention comprises less Liothyronine Eur.Ph. Impurity A, (chemical name: (2S)-2-amino-3-[4-(4-hydroxy- 3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid) i.e. Levothyroxine, less unidentified impurities, less total unidentified impurities and less total related substances i.e. the sum of all known (identified) and unknown (unidentified) impurities, when comparing to liothyronine sodium solutions of prior art.
The oral pharmaceutical solution according to the invention comprises liothyronine sodium; water; at least one cosolvent selected from the group consisting of a polyol and a glycol; and a pharmaceutically acceptable buffer; wherein the pH of the solution is from 3.5 to 6.5, and wherein the solution is obtained by a process comprising the steps of i) dissolving the liothyronine sodium in a carrier comprising water and a base, where the pH of the carrier is from 10.0 to 13.0 and ii) lowering the pH of the solution obtained in step i) to a value from 3.5 to 6.5.
The term “pg/ml” used in the present description and claims means pg of the active ingredient per 1 ml of the oral pharmaceutical solution.
The term “mg/ml” used in the present description and claims means mg of the active ingredient, or of an excipient, per 1 ml of the oral pharmaceutical solution.
As used throughout this description and claims, a "glycol" is propylene glycol, or polyethylene glycol, or a mixture thereof. Polyethylene glycol is also known in the art as "PEG".
Preferably the glycol is selected from propylene glycol, polyethylene glycol having an average molecular weight from 150 to 1500, or a mixture thereof. More preferably, the glycol is selected from propylene, glycol, polyethylene glycol having an average molecular weight of 300 (also known as polyethylene glycol 300, or PEG 300), or polyethylene glycol having an average molecular weight of 400 (also known as polyethylene glycol 400, or PEG 400), or polyethylene glycol having an average molecular weight of of 600 (also known as polyethylene glycol 600).
As used throughout this description and claims, the term "polyol" (polyhydric alcohol) refers to a pharmaceutical excipient containing multiple hydroxyl groups. Although the term "polyol" as used in the present invention includes sugar alcohols, it does not include sugars, i.e. carbohydrates, such as sucrose, glucose, dextrose, fructose and galactose. Typical examples of suitable polyols according to the invention are sugar alcohols such as, maltitol, glycerol, mannitol, sorbitol, xylitol, erythritol, isomalt and lactitol, as well as polyvinyl alcohol.
Preferably, the polyol is selected from glycerol, sorbitol, mannitol, maltitol, xylitol, erythritol, isomalt, lactitol, polyvinyl alcohol, or a mixture thereof. More preferably, the polyol is selected from glycerol, sorbitol, mannitol, maltitol, xylitol, or a mixture thereof. Even more preferably, the polyol is glycerol.
The term “carrier” used in step i) of the process of the present invention can comprise only water and a base, or it can comprise water, a base and a further pharmaceutically acceptable excipient, such as a cosolvent as defined above. For example, the carrier can comprise water, a base and a cosolvent; water, a base and a preservative; water, a base, a cosolvent and a preservative; water, a base, a cosolvent, a preservative and a sweetener. According to another example, the carrier can comprise water, a base, and at least one polyol or glycol; or water, a base, at least one polyol or glycol and at least one preservative. According to another example, the carrier can comprise water, a base, and at least one polyol or glycol; water, a base, at least one polyol or glycol and at least one preservative. According to another example, the carrier can comprise water, a base and glycerol; or water, a base, glycerol and at least one preservative.
In step i) of the process of the present invention, liothyronine sodium is dissolved in a carrier comprising water and a base, wherein the pH of the carrier in which liothyronine sodium is dissolved is from 10.0 to 13.0. Preferably the pH of the carrier is from 10.5 to 13.0. Even more preferably the pH of the carrier is from 11.0 to 13.0.
Preferably, the adjustment of the pH of the carrier in which liothyronine sodium is dissolved is accomplished by the addition of a strong base, for example, NaOH (powder, or aqueous solution) or KOH (powder, or aqueous solution).
In step ii) of the process of the present invention, the pH of the solution obtained in step i) is lowered to a value from 3.5 to 6.5. The reduction of the pH can be accomplished, for example, by the addition of an acid, or by the addition of a buffer. Examples of acids include hydrochloric acid and sulfuric acid. With regard to the buffer, any pharmaceutically acceptable system which acts as a buffer in the pH region of the invention can be used in the oral pharmaceutical solution according to the invention to lower the pH of the liothyronine sodium solution to a pH range of 3.5 to 6.5. Examples of a buffering agent include but are not limited to ascorbic acid, acetic acid, tartaric acid, citric acid monohydrate, sodium citrate, potassium citrate, acetic acid, sodium acetate,
sodium hydrogen phosphate, sodium dihydrogen phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, or a mixture thereof.
Preferably, the oral pharmaceutical solution according to the invention comprises from 2 pg/ml to 50 pg/ml of liothyronine sodium. More preferably, the oral pharmaceutical solution according to the invention comprises from 4 pg/ml to 40 pg/ml of liothyronine sodium
Preferably, the total concentration of the cosolvent in the oral pharmaceutical solution according to the invention is from 200 mg/ml to 800 mg/ml. More preferably, the total concentration of the cosolvent is from 400 mg/ml to 700 mg/ml.
Preferably, the pH of the oral pharmaceutical solution according to the invention is from 4.0 to 6.0. More preferably the pH of the oral pharmaceutical solution is from 4.5 to 5.5.
According to a preferred embodiment, the oral pharmaceutical solution according to the invention comprises a) from 2 pg/ml to 50 pg/ml of liothyronine sodium, b) water, c) a cosolvent selected from glycerol, sorbitol, mannitol, maltitol, polyvinyl alcohol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, or a mixture thereof, wherein the total concentration of the cosolvent is from 200 mg/ml to 800 mg/ml, d) a pharmaceutically acceptable buffer, wherein the pH of the solution is from 3.5 to 6.5, and wherein the solution is obtained by a process comprising the steps of i) dissolving liothyronine sodium in a carrier comprising water and a base, wherein the pH of the carrier is from 9.0 to 13.0 and ii) lowering the pH of the solution obtained in step i) to a value from 3.5 to 6.5.
According to another preferred embodiment, the oral pharmaceutical solution according to the invention comprises a) from 2 pg/ml to 50 pg/ml of liothyronine sodium, b) water,
c) a cosolvent selected from glycerol, sorbitol, mannitol, maltitol, polyvinyl alcohol, propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, or a mixture thereof, wherein the total concentration of the cosolvent is from 400 mg/ml to 700 mg/ml, d) a pharmaceutically acceptable buffer, wherein the pH of the solution is from 4.0 to 6.0, and wherein the solution is obtained by a process comprising the steps of i) dissolving liothyronine sodium in a carrier comprising water and a base, wherein the pH of the carrier is from 9.0 to 13.0 and ii) lowering the pH of the solution obtained in step i) to a value from 4.0 to 6.0.
The oral pharmaceutical solution according to the invention may also optionally contain additional excipients commonly used in preparing oral liquid compositions, such as an antimicrobial preservative, an antioxidant, a viscosity adjusting agent, a flavouring agent, or a sweetener.
Examples of antimicrobial preservatives as referred to herein include but are not limited to sodium benzoate, benzoic acid, boric acid, sorbic acid and salts thereof, benzyl alcohol, parahydroxy benzoic acids and their alkyl esters, methyl, ethyl and propyl parahydroxy benzoates or their salts, or a mixture thereof.
Examples of antioxidants as referred to herein include but are not limited to sodium metabisulfite, butylated hydroxyanisole, butylated hydroxytoluene, ethylenediamine tetraacetic acid, ascorbic acid, a-tocopherol, propyl gallate, or a mixture thereof.
Examples of viscosity adjusting agents as referred to herein include but are not limited to sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone or a mixture thereof.
Examples of flavouring agents as referred to herein include but are not limited to fruit flavours such as orange, banana, strawberry, cherry, wild cherry, lemon and the like and other flavourings, such as cardamom, anise, mint, menthol, vanillin, bubble gum, or a mixture thereof.
Examples of sweeteners as referred to herein include but are not limited to sugars, i.e. carbohydrates, such as sucrose, glucose, dextrose, lactose, fructose and galactose as well as other sweetening agents known in the art such as sucralose, aspartame, acesulfame-K, thaumatin, mogroside, saccharin and salts thereof, sodium cyclamate, erythritol, glycyrrhizin, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, or a mixture thereof.
Preferably, the oral pharmaceutical solution according to the invention is free of ethanol. Absence of ethanol provides more palatable solutions, and provides also the opportunity to use less amount of flavouring agents and/or sweeteners to achieve better taste of the solution.
Absence of ethanol is also extremely important particularly in case of paediatric formulations.
Preferably, the oral pharmaceutical solution according to the invention is free of a surfactant.
Preferably, the oral pharmaceutical solution according to the invention is free of ethanol and free of a surfactant.
The oral pharmaceutical solution according to the invention is preferably supplied as a multidose preparation. Each dose from a multidose container, such as amber type III glass 25, 50 or 100 ml bottles sealed with a suitable seal, such as a child resistant, tamper evident screw cap, can be administered by means of a device suitable for measuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof, or an oral syringe for other volumes.
The oral pharmaceutical solution of the present invention may be prepared using for example the following process:
Step 1 : Dilution of buffering agents
In a side vessel, appr. 30% of the total amount of purified water is transferred. The total amount of buffering agents is added and stirred until complete dissolution is achieved.
Step 2: Addition of buffering agents’ premix into the main vessel
In the main vessel, the total amount of buffering agents’ premix is transferred under stirring.
Step 3: Liothyronine Sodium premix solution preparation
In a side vessel, appr. 40% of the total amount of purified water is transferred and the pH is adjusted to 11.0 with NaOH aqueous solution 0.1 N. Under stirring, the total amount of liothyronine sodium is added under stirring until complete dissolution is achieved. Step 4: Liothyronine Sodium premix addition into the main vessel
In the main vessel, the total amount of liothyronine sodium premix solution of the previous step is transferred under stirring until complete dissolution is achieved.
Step 5: Addition of preservative, if present, into the main vessel
In the main vessel, under continuous mixing, slowly add the amount of preservative (if present) under stirring until complete dissolution is achieved.
Step 6: Addition of the cosolvent (polyol and/or glycol)
In the main vessel, under continuous mixing, the total amount of polyol and/or glycol is added under stirring until complete dissolution is achieved.
Step 7: pH adjustment
The pH is measured and adjusted with citric acid aqueous solution 40% w/w or sodium citrate aqueous solution 40% w/w to the desired value.
Step 8: Final bulk
Purified water is added to the final batch size volume/weight.
EXAMPLES
EXAMPLE 1 - Comparative studies with “Liotir 20|jg/ml oral solution, IBSA”
Composition I, which is a composition according to the invention, was prepared through a manufacturing process, where in a side vessel, appr. 30% of the total amount of purified water was transferred under stirring. The total amount of buffering agents (Citric Acid Monohydrate, Sodium Citrate) was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of buffering agents was transferred under stirring. In a side vessel, appr. 40% of the total amount of purified water was added and the pH was adjusted to 11.0 with NaOH aqueous solution 0.1 N. The total amount of liothyronine sodium was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of liothyronine sodium solution of the
previous step was transferred under stirring until complete dissolution was achieved. In the main vessel, the amount of sodium methyl paraben was added under stirring until complete dissolution was achieved. In the main vessel, under continuous mixing, the total amount of glycerol was added until complete dissolution was achieved. The pH was measured and adjusted with citric acid 10% or sodium citrate 10% solutions.
Purified water was added to the final batch size volume/weight.
Composition I was then studied in relation to its stability at storage conditions of 25°C temperature and 60% relative humidity for nine months. The quantitative determination of impurities in the prepared composition, before and after the storage period, was carried out by HPLC.
Commercially available “Liotir 20pg/ml oral solutions” were about nine months old when analyzed in relation to their stability. The quantitative determination of impurities in the “Liotir 20pg/ml oral solutions”, was carried out by HPLC.
Table 1
Impurity A: Levothyroxine
Total RS: Total Related substances
The above results clearly demonstrate that the combination of excipients along with the manufacturing process according to the present invention result in compositions where decomposition of liothyronine to levothyroxine and other impurities is minimum.
EXAMPLE 2 - Comparative studies with compositions disclosed in WO 2022/221480
Compositions A and B were prepared by the following the process described in Example 5 of WO 2022/221480: (i) 40 w/v% of the final amount of purified water was added to a batch tank; (ii) the dibasic sodium phosphate was added to the water in the batch tank of step (i) and stirred for about 10 minutes until the dibasic sodium phosphate was dissolved; (iii) the monobasic sodium phosphate was added to the solution of step (ii) and stirred for about 10 minutes until the monobasic sodium phosphate was dissolved; (iv) glycerol was added to the solution of step (iii) and mixed for about 10 minutes until a uniform composition was obtained; (v) 5% of the batch weight of purified water was added to a separate side tank, (vi) the methylparaben sodium was added to purified water in the side tank of step (v); (vii) a sample of the solution prepared in step (vi) was removed; (viii) the liothyronine sodium was wetted in an appropriate container with a portion of the sample solution from step (vii); (ix) the wet liothyronine of step (vii) was added to the solution in the separate side tank of step (vi) and stirred until liothyronine
sodium was dissolved; (x) the container which held the wet liothyronine was rinsed, 5 times, with the remaining sample solution of step (vii) and the rinse liquid was added into the solution in the side tank of step (ix); (xi) any remaining amounts of the sample from step (vii) were added to the solution prepared in step (ix); (xii) the solution of step (x) and (xi) were added to the solution of step (iv); (xiii) the pH of the prefinal solution of step (xii) was measured and adjusted to a target pH of 4.5, with HCI and/or NaOH solution; (xiv) purified water was added to the solution of step (xiii) to obtain the desired volume; (xv) the final liothyronine solution of step (xiv) was filtered and packaged. The composition was packaged in amber glass bottles and the stability was tested.
In Table 2 below, the concentration of liothyronine sodium in composition A is 0.005169 mg/mL as described in the Example 5 of WO 2022/221480, whereas the concentration of liothyronine sodium in composition B is doubled i.e. 0.010338 mg/mL
Composition II, which is a composition according to the invention, was prepared through a manufacturing process, where in a side vessel, appr. 30% of the total amount of purified water was transferred under stirring. The total amount of buffering agents ( monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate) was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of buffering agents was transferred under stirring. In a side vessel, appr. 40% of the total amount of purified water was added and the pH was adjusted to 11.0 with NaOH aqueous solution 0.1 N. The total amount of liothyronine sodium was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of liothyronine sodium was transferred under stirring until complete dissolution was achieved. In the main vessel, the amount of sodium methyl paraben was added under stirring until complete dissolution was achieved. In the side vessel, under continuous mixing, the total amount of glycerol was added until complete dissolution was achieved. The pH was measured and adjusted with hydrochloric acid solution. Purified water was added to the final batch size volume/weight. The composition was then packaged in amber glass bottles.
The compositions were then studied in relation to their stability at storage conditions of 25°C temperature and 60% relative humidity for 6 months. The quantitative determination of impurities in the prepared compositions, before and after the storage period, was carried out by HPLC.
Table 2
Total RS: Total Related Substances
The above results clearly demonstrate that when the manufacturing process comprises the step of dissolving liothyronine sodium in highly basic environment (i.e. pH 11.0) the decomposition of liothyronine to impurity A (levothyroxine) and other impurities is minimum.
EXAMPLE 3
This composition of Table 3 was prepared through a manufacturing process, where in a side vessel, appr. 30% of the total amount of purified water was transferred under stirring. The total amount of buffering agents (Citric Acid Monohydrate, Sodium Citrate Dihydrate) was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of buffering agents was transferred under stirring. In a side vessel, approximately 40% of the total amount of water was added and the pH was adjusted to 11.5 with NaOH aqueous solution 0.1 N. The total amount of liothyronine sodium was added under stirring until complete dissolution was achieved. The total amount of liothyronine sodium solution of the previous step was transferred to the main vessel, under stirring until complete dissolution was achieved. In the side vessel, under continuous stirring, the total amount of the polyol and the total amount of the sweetener were added until complete dissolution was achieved. The pH was measured and adjusted with citric acid and sodium citrate solution. Purified water was added to the final batch size volume/weight.
The composition was then studied in relation to its stability at storage conditions of 25°C temperature and 60% relative humidity for 6 months. The quantitative determination of
impurities in the prepared compositions, before and after the storage period, was carried out by HPLC.
Table 3:
Total RS: Total Related substances
EXAMPLE 4
This composition of Table 4 was prepared through the manufacturing process outlined in Example 3.
The composition was then studied in relation to its stability at storage conditions of 25°C temperature and 60% relative humidity for 6 months. The quantitative determination of impurities in the prepared compositions, before and after the storage period, was carried out by HPLC.
Table 4:
EXAMPLE 5 This composition of Table 5 was prepared through a manufacturing process, where in a side vessel, appr. 30% of the total amount of purified water was transferred under stirring. The total amount of buffering agents (citric acid monohydrate, sodium citrate dihydrate) was added under stirring until complete dissolution was achieved. In the main
vessel, the total amount of buffering agents was transferred under stirring. In a side vessel, approximately 40% of the total amount of water was added and the pH was adjusted to 11.0 with NaOH aqueous solution 0.1 N. The total amount of liothyronine sodium was added under stirring until complete dissolution was achieved. In the main vessel, the total amount of liothyronine sodium solution was transferred under stirring until complete dissolution was achieved. In the side vessel, under continuous mixing, the total amount of polyethylene glycol was added until complete dissolution was achieved. The pH was measured and adjusted with citric acid and sodium citrate solution. Purified water was added to the final batch size volume/weight.
The composition was then studied in relation to its stability at storage conditions of 25°C temperature and 60% relative humidity for 6 months. The quantitative determination of impurities in the prepared compositions, before and after the storage period, was carried out by HPLC.
Table 5:
Total RS: Total Related Substances
Claims
1. An oral pharmaceutical solution comprising a) liothyronine sodium as active ingredient, b) water, c) a cosolvent selected from the group consisting of propylene glycol, polyethylene glycol, a polyol, and a mixture thereof, d) a pharmaceutically acceptable buffer, wherein the pH of the oral pharmaceutical solution is from 3.5 to 6.5, and wherein the oral pharmaceutical solution is obtained by a process comprising the steps of i) dissolving liothyronine sodium in a carrier comprising water and a base, wherein the pH of the carrier is from 10.0 to 13.0, and ii) lowering the pH of the solution obtained in step i) to a value from 3.5 to 6.5.
2. The oral pharmaceutical solution according to claim 1 , wherein the polyol is selected from the group consisting of glycerol, sorbitol, mannitol, maltitol, xylitol, erythritol, isomalt, lactitol, polyvinyl alcohol, and a mixture thereof.
3. The oral pharmaceutical solution according to claim 1 or 2, wherein the polyol is selected from the group consisting of glycerol, sorbitol, mannitol, maltitol, xylitol, and a mixture thereof.
4. The oral pharmaceutical solution according to any one of the preceding claims, wherein the cosolvent is selected from the group consisting of glycerol, sorbitol, mannitol, propylene glycol, polyethylene glycol, and a mixture thereof.
5. The oral pharmaceutical solution according to any one of the preceding claims, wherein the cosolvent is selected from the group consisting of propylene glycol, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, and a mixture thereof.
6. The oral pharmaceutical solution according to any one of the preceding claims, wherein the total concentration of the cosolvent in the oral pharmaceutical solution is from 200 mg/ml to 800 mg/ml.
7. The oral pharmaceutical solution according to any one of the preceding claims, wherein the total concentration of the cosolvent in the oral pharmaceutical solution is from 400 mg/ml to 700 mg/ml.
8. The oral pharmaceutical solution according to any one of the preceding claims, wherein the concentration of liothyronine sodium in the oral pharmaceutical solution is from 2 pg/ml to 50 pg/ml.
9. The oral pharmaceutical solution according to any one of the preceding claims, wherein the pH of the carrier is from 10.5 to 13.0.
10. The oral pharmaceutical solution according to any one of the preceding claims, wherein the pH of the carrier is from 11 .0 to 13.0.
11. The oral pharmaceutical solution according to any one of the preceding claims, wherein the pH of the oral pharmaceutical solution is from 4.0 to 6.0.
12. The oral pharmaceutical solution according to any one of the preceding claims, wherein the pH of the oral pharmaceutical solution is from 4.5 to 5.5.
13. The oral pharmaceutical solution according to any one of the preceding claims, further comprising an excipient selected from the group consisting of an antimicrobial preservative, an antioxidant, a viscosity adjusting agent, a flavouring agent, a sweetener, and a mixture thereof.
14. The oral pharmaceutical solution according to any one of the preceding claims, wherein the base is a strong base, preferably NaOH or KOH.
15. The oral pharmaceutical solution according to any one of the preceding claims, wherein the solution is free of ethanol and/or free of a surfactant.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP23386032 | 2023-05-02 | ||
| PCT/EP2024/062153 WO2024227895A2 (en) | 2023-05-02 | 2024-05-02 | Oral solution comprising liothyronine sodium |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP4704805A2 true EP4704805A2 (en) | 2026-03-11 |
Family
ID=86386779
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP24722291.2A Pending EP4704805A2 (en) | 2023-05-02 | 2024-05-02 | Oral solution comprising liothyronine sodium |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP4704805A2 (en) |
| WO (1) | WO2024227895A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2025245015A1 (en) * | 2024-05-20 | 2025-11-27 | Regents Of The University Of Minnesota | Thyroid hormone prodrugs and compositions comprising the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9401891D0 (en) | 1994-02-01 | 1994-03-30 | Boots Co Plc | Therapeutic agents |
| US6190696B1 (en) | 1998-06-08 | 2001-02-20 | Pieter J. Groenewoud | Stabilized thyroxine medications |
| US8318712B2 (en) * | 2006-01-06 | 2012-11-27 | Intervet International B.V. | Concentrated liquid thyroid hormone composition |
| DK2683361T3 (en) * | 2011-03-10 | 2016-02-01 | Emp Pharma Gmbh | Process for preparing a levothyroxine solution |
| WO2022221480A1 (en) | 2021-04-15 | 2022-10-20 | Vertice Pharma Llc | Stable liquid oral dosage forms of liothyronine |
-
2024
- 2024-05-02 WO PCT/EP2024/062153 patent/WO2024227895A2/en not_active Ceased
- 2024-05-02 EP EP24722291.2A patent/EP4704805A2/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024227895A2 (en) | 2024-11-07 |
| WO2024227895A3 (en) | 2024-12-26 |
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