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Review Article

Rayapuram Mallikarjuna Bhavyasree,1* Beny Baby, Subramanian Rajarajan, Niraj Kumar Panday2 , Ashwini Durai

1.Department of Pharmaceutics, Karnataka College of Pharmacy, Thirumenahalli, Bangalore 560064, India 2.Department of Pharmaceutical Analysis. National Institute of Pharmaceutical Education andResearch, Ahmedabad

Author for correspondence

R M Bhavyasree

Department of Pharmaceutics,

Karnataka College of Pharmacy,

Thirumenahalli, Bangalore 560064,

E Mail:

Year: 2019, Volume: 9, Issue: 1, Page no. 3-9,
Views: 980, Downloads: 37
Licensing Information:
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0.

The standard strategy for the treatment of hypothyroidism is the daily administration of Levothyroxine(LT4). However, Liothyronine (LT3) has shown a similar effect as that of Levothyroxine and has been used as a treatment for hypothyroidism. Tablets available are a good candidate for treatment. Different formulation of Liothyronine such as oral solution, capsules, subcutaneous preparation, Metal complexes, Intravenous injection, Intraperitoneal injection, regenerative tissue approach and others approach for treatment has been described in this article. This article provides a better understanding of these formulations which can help researchers to develop a better dosage form of the same drug.

<p>The standard strategy for the treatment of hypothyroidism is the daily administration of Levothyroxine(LT4). However, Liothyronine (LT3) has shown a similar effect as that of Levothyroxine and has been used as a treatment for hypothyroidism. Tablets available are a good candidate for treatment. Different formulation of Liothyronine such as oral solution, capsules, subcutaneous preparation, Metal complexes, Intravenous injection, Intraperitoneal injection, regenerative tissue approach and others approach for treatment has been described in this article. This article provides a better understanding of these formulations which can help researchers to develop a better dosage form of the same drug.</p>
Hypothyroidism, Liothyronine, Levothyroxine, Different formulations.
  • 1


Thyroid gland plays a key role in controlling human metabolic functions through the action of thyroxine (T4) and triiodothyronine(T3). The most common thyroid abnormality is hypothyroidism or underactive thyroid disease. In this condition, life-long thyroid hormone replacement is required. This therapy is available either as oral preparations or as intramuscular or intravenous injections. In most people, oral treatment provides a satisfactory form of replacement. However, in around 20% of patients with hypothyroidism, oral replacement is either completely or partially ineffective because of poor or no hormone absorption following oral administration. It is very difficult to treat such people and they end up taking painful intramuscular or even intravenous injections on an almost daily basis for the rest of their lives. This is an extremely uncomfortable and challenging scenario.1


The thyroid gland is a highly vascularized butterfly-shaped organ located in the lower part of the neck inferior to the larynx. It consists of two lobes present on either side of the trachea connected by an isthmus. On the posterior surface of the lobe are small, round masses of embedded tissue known as parathyroid glands. T4 and T3 are two major hormones produced and secreted by the thyroid gland. The production and release of thyroid hormones are regulated by the hypothalamus and pituitary glands.(Fig.1) The hypothalamus secretes thyrotropin-releasing hormone (TRH) that stimulates the pituitary gland, which in turn secretes thyroid-stimulating hormone (TSH). The TSH then signals thyroid follicular cells present in the thyroid gland to produce and secrete thyroid hormones. To produce T4 and T3, the thyroid follicular cells require iodine that is readily available in the everyday diet.2

Hypothyroidism is the most widely recognized issue of the endocrine system wherein the thyroid organ does not create enough thyroid hormone.3 Hypothyroidism is divided into primary and secondary, where the primary cause is a failure of thyroid function and secondary is due to adequate thyroid-stimulating hormone (TSH) secretion from the pituitary gland or thyrotrophinreleasing hormone (TRH) from the hypothalamus.4 In the United Kingdom, the yearly occurrence of essential hypothyroidism in ladies is 3.5 per 1000 and in men 0.6 per 1000. Presently a day doctors are including liothyronine(engineered S.T3) to give better indication control, however, this has not been affirmed by studies.5


Levothyroxine is one of the most normally recommended drugs. The primarily manufactured levothyroxine was presented in 1958. The utilization of sodium levothyroxine expects to keep TSH levels inside the points of confinement of typicality. The patients taking levothyroxine have, be that as it may, demonstrated that somewhere in the range of 40% and 48% are either over-treated or under-treated. Its clinical viability was confirmed through long periods of clinical use. There is a high level of vulnerability about the utilization of this medicament, which has been expected to:

a) The shelf life of the product.

b) Consistency of formulation over time within a given “brand”.

c) Bioequivalence research between brands.

d) Degradation of levothyroxine with exposure to light, moisture, oxygen, and carbohydrate Excipients.

e) Significant changes in formulation occurring over time as firms attempted to improve product stability.6

It is commonly available in its sodium salt form. The molecular weight, degree of ionization at physiological pH, and partition coefficient (log P) have to be optimal for clinically relevant plasma concentrations to be reached. The sodium salt of T4(Fig.2) is a weekly acidic drug with 50 % ionization when pH equals pKa. Hence the drug is only approximately 1 % ionized at blood pH (7.4). Other physicochemical properties of the drug relevant for respiratory and transdermal delivery are as follows: pKa of ionized form = 8.72, log P (neutral form) = 3.21, log P (ionized form) = 0.35, intrinsic solubility = 42.8 μg/ml, solubility in experimental buffer (HBSS) = 10μM at pH 7.4 and molecular weight = 798.86 (anhydrous).1

Liothyronine(Fig.3) is a L-Triiodothyronine which is in synthetic form. Its molecular formula is C15 H12 I3 NO4 . It is best used for short-term suppression of TSH.3,3’,5-triiodo-L-thyronine is an iodothyronine compound having iodo substituents at the 3-, 3’- and 5-positions. Its metabolic activity is about 3 to 5 times that of L-thyroxine.

It is available in sodium salt form. The sodium salt is used in the treatment of hypothyroidism.

LT3 are Soluble in dilute alkalies with the formation of a brownish, water-soluble, sodium salt. Insoluble in propylene glycol and molecular weight =650.97g/mol.7

Nonparental/Enternal instead of parental/ Enternal


Administration of LT3 through the mouth can be utilized to restore TH signaling in laboratory animals that have been made hypothyroid. Adding LT3 to the drinking water or to the diet avoids the administration of a single dose of LT3 and has been shown to restore thyroid status in thyroidectomizedrodents. However, the dose consistency was inevitable due to the dilution due to drinking water. A liquid preparation for oral administration of liothyronine is available. In this PK profile was not shown, thus further improvement in dosing flexibility and PK properties of oral administration of LT3 is required. For these orodispersiblefilms(ODFs) have been developed but PK profile has not been generated as ODF disintegrated in less than 45s but the prospect of fine customization of LT4 and LT3 dosages is exciting. Furthermore, it is believed that the utilization of different ODFs could effectively modify the PK properties of orally administered LT3.8

Some alternative approach to modify LT3 PK properties when given orally is to delay its absorption which can be done by using formulation of slow-release this can only happen when slow-release LT3 tablets containing hydrophilic swellable matrix system made with hydroxy propyl cellulose, CMC, Calcium phosphate, and magnesium stearate have been utilized to prepare tablet(US patent #5,324,522). Also, a combination of salts and matrices like mannitol, magnesium stearate, calcium phosphate, and polypropylene can be used(US patent #5,324,522). When tested in vitro and in vivo, the result showed that slow release of LT3 in intestine decreases the peak serum level and prolonged the time i.eCmax.9

However, in preparation for LT3 containing MCC and magnesium stearate shows no sustainedrelease.10 Another approach has been made utilizing chewable gum with ion-exchange resins that can form multi-particulate drug resin complex which can potentially provide an enhanced drug release profile and PK profiles in human, however clinical trials has yet to be performed.

To meet the challenges of formulating sustained or slow release delivery of LT3 derivatives can be utilized. Such derivatives include sulphation of phenolic hydroxyl group of T3 but this enhances the solubility of LT3 in water and loss to the environment. But sulphatases found in the liver can reactivate T3-S via desulfation and prevent its loss to the environment11. Another approach of derivatization includes the formation of a metal complex of L-T3, [Zn(T3)(H2O)]n, known as poly-zinc-liothyronine(PZL) and was loaded into coated gelatin capsules for delivery to the duodenum where the sustained release of LT3 from PZL occurs. Capsules of PZL given orally restore T3-dependent biological effects while exhibiting a reduced and delayed serum T3 peak after dosing, thus providing a longer period of relatively stable serum T3 levels when compared with capsules of L-T3. However this delivery relies upon 3 distinct steps: (a) Mucoadhesion of PZL to an area of the gastrointestinal tract, (b) Controlled ligandexchange (e.g., hydrolysis) of T3 from PZL, followed by (c)Drug absorption of the LT3(Fig.4). Pharmacokinetics data of PZL has been described for a single and multiple-dose regimen by12, A novel strategy using the Inkjet printing method has been utilized for the delivery of T4 and T3 in hypothyroidism patients. In this method, T4 and T3 are printed on the same substrate but using two different cartridges containing blue and black color ink. This novel approach can revolutionaries the way of personalized medicine. Other data have been depicted in.13

Rectal :

The rectum is one of the best routes for the administration of any drug as it is highly vascularized, resulting in higher absorption. Pharmacokinetics properties have been established for LT4 which shows Tmax of 14h but AUC is found to be 3 times smaller thus indicating incomplete absorption.14 Unfortunately, no such formulation has been developed for LT3.

Transdermal preparation :

Transdermal patches prepared by the incorporation of a microemulsion of LT4 to the film prepared have shown good retention of LT4 in the skin of the rabbit even after 24hr. T4 concentration in the skin varies slightly with different concentrations of microemulsion administered through film. Also, slow release was observed with enhanced bioavailability. However permeating power needs to be enhanced further.15

Parenteral Preparation

Subcutaneous preparation :

It was found that the subcutaneous approach of delivering Levothyroxine might be an effective inpatient who doesn’t respond to oral therapy. However, splitting of a dose of 10ml can be done to 5ml twice a day instead of 10ml at once a daily. However, it is painful but also can be self-administered. However, some drawbacks like compliances, pseudomalabsorption and malabsorption with different types of patients were observed.16

Also, a liquid preparation of the subcutaneous injection of LT3 has shown relatively fast absorption than the oral form in rodents followed by a peak of LT3. The peak can be minimized by splitting the dose into multiple injections every 24h, the problem arises as the half-life of only 2 hr peak of LT3 will inevitably remain.11 Theoretically, it can be predicted that oily suspension of LT3 can delay the release and thus provide a sustained therapeutic effect. Although osmotic pump and pellets are considered as gold standard which is designed in such a way that can be implanted subcutaneously releasing a fixed amount of LT3 daily. Titan pharmaceutical has utilized similar technology for the development of subcutaneous formulation (Proneura) for the slow release of LT3 which consists of a rod-shaped solid mixture of LT3 and ethyl-vinyl acetate which can be placed subcutaneously in the arm and can be removed at the end of therapy. Preliminary studies have been performed in thyroidectomized rats and beagles dogs. Also, Medincell (Pharmaceutical company) utilizes the biocompatible polymer and formulated aqueous depot subcutaneous injection(Bepo) consisting of PEG(polyethylene glycol) linked with poly-D-lactic acid which creates depot for after placing in an aqueous environment which is later released from matrix by diffusion. However, preliminary studies are not available but believed to be released for days, weeks or months.8

Intravenous and Intraperitoneal preparation :

Both routes were used for the administration of LT3 in form of Liquid solution but the major peak of LT3 was observed in serum.8

Other approaches

Regenerative approaches of Functional thyroid from Embryonic Stem Cells(ESC) :

Generated Functional thyroid follicles by the recombinant technology from murine ESC based on transient overexpression of two transcription factors(NKX2-1 and PAX8) by the addition of Doxycycline followed by recombinant human thyroid-stimulating hormone(rhTSH)treatment. When transplanted in mice, the ESC-derived cells generated functional thyroid tissue able to produce thyroid hormone in hypo or athyroid animals. This study can further change the way of medication for a patient with hypothyroidism.17

Tissue targeting approach of LT3:

LT3 delivery has been progressed in recent years by different methods of targeting tissues. One example is chemically engineered glucagon and T3 to provide a synergistic effect that can be used to treat hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance and obesity in metabolically disordered mice.18

Lamellar nanostructures produced by the complexation of dodecanoic(C12) acid with Poly ethylene imine(PEI) used for the loading of LT3 which can target specific tissue. PEI-C12 was doped with coenzyme Q10 and hormone T3.19


LT3 is commercially available in the form of Sodium salt in a different dosage form. However, till this date tablet form is one of the best formulation available due to its rapid absorption and bioavailability as depicted in table 1. The different slow-release formulation has been developed but not marketed due to a lack of pharmacokinetic properties. PZL capsules have shown the promising effect to treat hypothyroidism with thyromimetics effect butare still in clinical trials.Sub-cutaneous preparation has shown very sustained release but due to splitting of dose and its half-life of 2 h has made it uncomfortable for use. The regenerative approach of tissue can be taken as the best strategy for hypothyroidism treatment as it has shown very good results for elevating the level of thyroxine but is very long-term therapy in an animal model. Clinical trials have to be conducted for the same if have to be developed for human use. This review article provides a better understanding of formulation approaches for hypothyroidism.


Authors declare no conflict of interest 





Supporting File

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