RU2846767C2 - Long-term resorbable subcutaneous sustained-release implant of pre-concentrated pharmacologically active substance in polymer for treatment of hypothyroidism and method for making said implant - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to health care. Disclosed is a subcutaneous biodegradable implant for the treatment of hypothyroidism, comprising from 100 mcg to 3000 mcg of triiodothyronine (T3), from 100 mcg to 3000 mcg of thyroxine (T4) or a combination thereof in the form of particles uniformly distributed in a biodegradable and bioabsorbable polymeric matrix, wherein said matrix contains from 1% to 20% of a biodegradable polymer in relation to the weight of the drug. What is also disclosed is a method for making the implant.

EFFECT: group of inventions provides an effective, constant and long-term serum drug level for treating hypothyroidism.

5 cl, 4 dwg

Description

Scope of invention

[01] The present invention application has priority over application BR 1020210060832, is directed to the healthcare sector and includes a long-acting subcutaneous implant with sustained release of a pre-concentrated pharmacologically active substance in a polymer for the treatment of hypothyroidism.

Basics of invention

[02] Hypothyroidism is an endocrine disorder characterized by a deficiency in the endogenous production of thyroid hormones or, less commonly, by inadequate action of these hormones on target tissues. Thyroid hormones act on nearly all nucleus-containing cells in the body and are essential for normal growth, as well as for regulating the function and metabolism of all organs.

[03] The production and regulation of thyroid hormones is carried out using a negative feedback system. Thyrotropin, the hypothalamic stimulating hormone (HRT), is produced in the hypothalamus and stimulates the synthesis and release of thyroid-stimulating hormone (TSH). The release of TSH stimulates the thyroid gland to synthesize and release the hormones triiodothyronine (T3) and levothyroxine (T4). Increased concentrations of T3 and T4 inhibit the synthesis and secretion of HRT and TSH. This negative feedback system ensures precise control of TSH levels in the body.

[04] Decreased thyroid hormone production leading to hypothyroidism may be caused by decreased action of thyroid stimulating hormone (TSH) or by decreased stimulation of the thyroid gland due to decreased thyrotropin-releasing hormone (HRT).

[05] Hypothyroidism can be classified according to three criteria: onset, level of endocrine dysfunction, and severity of the pathology. Onset refers to the onset of the disease in a patient, regardless of whether it was congenital or acquired during life.

[06] The level of endocrine dysfunction in hypothyroidism can be divided into two categories: primary and central. Primary hypothyroidism, which accounts for more than 99% of cases, is characterized by dysfunction of the thyroid gland, while central hypothyroidism, which is quite rare, is divided into secondary and tertiary, caused by dysfunction of the pituitary gland or hypothalamus, respectively.

[07] Primary hypothyroidism can be caused by a variety of reasons, with iodine deficiency being the most common cause worldwide. The thyroid gland requires iodine to synthesize T3 and T4, and if the body lacks iodine, the production of these hormones is impaired. In areas where iodine deficiency is controlled in the population, the most common cause of hypothyroidism is chronic autoimmune thyroid disease, the most common of which is Hashimoto's thyroiditis. Hashimoto's thyroiditis causes the destruction of thyroid tissue as a result of the activation of the immune system against thyroid cells. Primary hypothyroidism can also be caused by medications or be congenital. However, primary hypothyroidism can also result from medical treatments such as cancer or from the complete or partial removal of the thyroid gland, called a thyroidectomy.

[08] Based on the severity of the disease, primary hypothyroidism can be divided into reported or subclinical hypothyroidism. The classification is based on the measurement of TSH, free thyroxine (T4L), and free triiodothyronine (T3L) hormone levels, when there is reproducibility of the results over a period of 4 to 6 weeks. When the TSH value is high and the T4L and T3L values are low, the diagnosis is primary hypothyroidism. When there is no pituitary or hypothalamic disease that could correspond to secondary or tertiary hypothyroidism, respectively, and the TSH value is higher than the control value, while the T4L and T3L levels are normal, the classification is subclinical hypothyroidism. Subclinical hypothyroidism may be a sign of an ongoing autoimmune disease or may be a consequence of recovery from some disease or substance abuse.

[09] Regarding central hypothyroidism, the secondary type is more common, while the tertiary type is rare. The most common cause of central hypothyroidism is a pituitary adenoma. Low levels of TSH, T4L, and T3L may indicate central hypothyroidism.

[10] Hypothyroidism causes symptoms that can easily be confused with other clinical conditions, especially in postpartum women or elderly patients. Among the most common symptoms are fatigue, weight gain, cold intolerance, dry skin, hair loss, constipation, memory problems, and depression.

[11] Certain populations are at increased risk of developing hypothyroidism, including postpartum women, people with a family history of autoimmune thyroid disease, patients who have had surgery or radiation to the head, neck, or thyroid gland itself, people with other autoimmune endocrine conditions such as type 1 diabetes, adrenal insufficiency, or ovarian insufficiency, people with other non-endocrine autoimmune diseases such as vitiligo, celiac disease, multiple sclerosis or pernicious anemia, primary pulmonary hypertension, Down syndrome, and Turner syndrome. Additionally, there is a higher prevalence of hypothyroidism in the elderly population compared to other age groups.

[12] In countries where the population has adequate iodine intake, hypothyroidism reaches 1-2% of the general population, and in people over 85 years of age, this figure rises to approximately 7%. In Europe, the prevalence of reported hypothyroidism ranges from 0.2% to 5.3%, and in the United States, this figure ranges from 0.3% to 3.7%, depending on the laboratory cutoffs accepted for diagnosing the disease. Hypothyroidism is approximately 10 times more common in women than in men. A study of 1,220 women in the city of Rio de Janeiro reported an incidence of hypothyroidism in 12.3% of participants.

[13] Diagnosis and proper treatment are crucial to ensure the quality of life of patients with hypothyroidism. The main goal of hypothyroidism treatment is to achieve a euthyroid state, in which circulating levels of TSH and thyroid hormones are normal without recurrence of adverse symptoms and clinical signs of the disease. The thyroid gland secretes approximately 85 mcg of thyroxine (T4) and 6.5 mcg of triiodothyronine (T3) daily for an adult male. This amount of T3 accounts for only 20% of the T3 used in the body daily, and the remaining 80% (26 mcg) is obtained from the peripheral conversion of T4 to T3. The biologically active hormone that effectively binds to thyroid hormone receptors and acts on peripheral tissues is T3. T4 hormone is its precursor and must be converted to T3 through the process of deiodination. This process occurs in most tissues, the main ones being the liver and kidneys.

[14] Treatment of hypothyroidism is carried out with drugs to correct the endogenous deficiency of thyroid hormones in cases of declared and central hypothyroidism. For patients with pictures of subclinical hypothyroidism, this comes from medical behavior to compliance or lack of compliance with treatment with hormone replacement therapy. Conventional treatment is carried out by replacing thyroxine (T4), despite the fact that the bioactive hormone that effectively binds to receptors and acts on peripheral tissues is triiodothyronine (T3). And T4 replacement begins with the assumption that peripheral conversion of T4 to T3 is sufficient to meet the T3 needs of the target tissues. The dosage used is approximately 1.7 μg T4/kg/day for healthy adult patients, which can be reduced to 1 μg T4/kg for elderly patients. However, the optimal dosage should be analyzed on a case-by-case basis based on the patient's clinical symptoms and the results of their follow-up examinations, taking into account normal TSH reference values.

[15] Although T4 replacement therapy is the most widely used in clinical practice, there is a proportion of patients who do not respond adequately to this treatment. One reason is the lack of continuity of treatment, caused by poor treatment regimen and patient compliance. Administration of T4, which has a long half-life, should allow the body to accumulate this hormone bound to its carrier proteins and ensure that there is always enough T4 for deionization to T3, the hormone that is effectively biologically active. Thus, T4 replacement will provide a sufficient load hormone for the continuous action of T3 in tissues. However, if the medication is not taken regularly, T4 replenishment is impaired, and the signs and symptoms of hypothyroidism will worsen.

[16] Another important factor in treatment is the fact that its effectiveness depends on the deiodination of T4 to T3 in peripheral tissues. It is known that the intracellular concentration of the deiodinase enzyme responsible for the conversion to T3 is not the same in all tissues. However, if a patient's body has any problems that disrupt this conversion, they may suffer the consequences of a deficiency of this hormone in the body. Therefore, for some patients with hypothyroidism, it is necessary to use T3 in combination with T4 for effective treatment.

[17] Many studies support the use of treatment methods that combine T3 and T4 administration to patients, especially in patients who have TSH values within the T4 replacement range but still have many adverse disease symptoms.

[18] The article titled "Effect of Combination Therapy with Thyroxine (T4) and 3,5,3'-Triiodothyronine versus T4 Monotherapy in Patients with Hypothyroidism, a Double-Blind, Randomized Crossover Study" reported a randomized, double-blind, crossover study of 59 patients with reported hypothyroidism due to autoimmune thyroiditis who had been receiving stable and sufficient thyroxine (T4) treatment for at least 6 months. Patients were randomly divided into two groups, receiving either one tablet containing 20 mcg T3 instead of the usual dose of 50 mcg T4 or one tablet of 50 mcg T4 for 12 weeks. This period was followed by a 12-week crossover period. At the end of treatment, 49% of patients preferred combination therapy with T3 and T4, while 35% had no preference for either, and only 15% of patients preferred T4 monotherapy.

Another study compared T4 monotherapy with T3 monotherapy. The article, "Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover study of liothyronine and levothyroxine," reported on a randomized, double-blind, crossover study of 14 patients with primary hypothyroidism who were already receiving T4 treatment. Patients were randomly divided into two groups: one received 2.5, 10, or 16 mcg T3, and the other received 5, 10, or 33 mcg T4, both three times daily for 6 weeks. By the end of treatment, the T3 group had lost an average of 1.8±1.9 kg more weight than the T4 group. A 10.9±10.0% decrease in total cholesterol, a 13.3±12.1% decrease in low-density (non-HDL) cholesterol, and an 18.3±28.6% decrease in apolipoprotein B were also observed in the T3-treated group compared with the T4-treated group. Thus, it was possible to observe that T3 treatment, compared with T4, resulted in greater weight loss and favorable changes in patients' lipid profiles without significant side effects. The results of T3 monotherapy suggest that this treatment can be used in patients with hypothyroidism associated with comorbidities such as cardiovascular disease, diabetes, dyslipidemia, and/or obesity.

[19] There is even a derivative of the T3 (triiodothyronine) molecule known as triiodothyronine sulfate (T3S). Two characteristics associated with the pharmacokinetics of T3S (triiodothyronine sulfate) have generated interest in its use in hypothyroidism. This substance is biologically inactive but is converted to T3 (triiodothyronine) by sulfatase enzymes found in various tissues and gut microbiota. Degradation and inactivation of T3S (triiodothyronine sulfate) occurs through its conversion to diiodothyronine sulfate by deiodinase-1, an enzyme with activity directly regulated by T3 (triiodothyronine). Soon, high levels of T3 (triiodothyronine sulfate) accelerate the inactivation of T3S (triiodothyronine sulfate). This mechanism allows for more precise control of T3 (triiodothyronine) levels, as it protects against excess hormone by stimulating its degradation by deiodinase-1. Conversely, T3S (triiodothyronine sulfate) can function as a reservoir, converting to T3 (triiodothyronine) as needed in cases of hormone deficiency.

[20] The article "Steady-state serum T3 concentrations over 48 hours after a single oral dose of 3,5,3'-triiodothyronine sulfate (T3S)" demonstrated that after a single oral dose, T3S (triiodothyronine sulfate) is converted to T3 (triiodothyronine), resulting in an increase in serum T3 (triiodothyronine) levels. This increase in hormone levels peaks 2-4 hours after administration, and a progressive return to baseline levels is observed within 8-24 hours. These results indicate that T3S (triiodothyronine sulfate) can be used in combination with LT4 (free thyroxine) for the treatment of hypothyroidism.

[21] To investigate the efficacy and safety of this combination treatment (T4L+T3S) in hypothyroidism over a long period of time (75 days), Santini et al. (2009) conducted a study entitled “Treatment of hypothyroid patients with L-thyroxine (L-T4) plus triiodothyronine sulfate (T3S), a Phase II, open-label, single-center, parallel-group study of therapeutic efficacy and tolerability.” The study demonstrated that the proposed therapy allows for the maintenance of normal serum T3 (triiodothyronine) levels and the restoration of the physiological T4L (free thyroxine) / T3L (free triiodothyronine) ratio. In addition, there were no reports of adverse effects in patients during the study.

[22] T3 monotherapy or T3+T4 or T3S+T4 combination therapy for hypothyroidism has the disadvantage that it must be administered several times a day to achieve optimal results, especially because T3 has a short half-life. The optimal treatment proposed by some authors would be a combination of T4 with T3, with the latter in an extended-release regimen and absorbed slowly to avoid multiple dosing. Increasing the number of tablets and the number of times a day the patient must take the medication significantly reduces compliance, which is the main disadvantage noted in articles reporting the use of these treatments in clinical practice.

[23] According to the World Health Organization, adherence to treatment is determined by the interaction between the healthcare system and staff, socioeconomic factors, patient-related factors, treatment-related factors, and disease-related factors. Adherence to treatment is one of the main factors associated with the success or failure of drug therapy. Often, the therapeutic outcome is not as positive as expected due to patient behavior; for various reasons, the patient does not fully comply with treatment, and the drug does not produce the expected effect.

[24] Chronic diseases such as hypothyroidism require patients to take at least one medication, often more than once a day for an extended period of time, to manage the disease. Increasing the number of medications a patient takes per day reduces treatment adherence by approximately 20%, and medications used in multiple doses, as in the case of T4+T3 or T4+T3S combination therapy, also reduce adherence compared to a single dose.

[25] The oral route of administration traditionally used to treat hypothyroidism has a major drawback, namely poor therapeutic adherence. The most effective way to improve patient adherence to treatment is to simplify drug dosages. For many chronic diseases, such as hypothyroidism, the development of extended-release drugs has made it possible to simplify dosages.

[26] Besides poor treatment adherence, another disadvantage of oral medication use for the treatment of hypothyroidism is the ease of misuse of prescribed medications, the increased risk of sub- or supraphysiological doses, increased sensitivity of patients to the side effects of the drug or still suffering from the side effects of not taking the drug, which compromises their overall condition during treatment.

[27] Thus, a third option can be found known as implants or bioabsorbable granules of triiodothyronine (T3), triiodothyronine (T3C) sulfate, thyroxine (T4), a combination of T3 and T4, or a combination of T3C and T4 for the treatment of hypothyroidism. Such implants demonstrate a sustained release of the drug over a long period of time to treat the disease, make the treatment independent of the patient's medication and improve its clinical symptoms.

[28] The terms "implant" or "granule" refer to this pharmaceutical form, which is already established in official collections of standards for drugs and pharmaceutical substances. They are characterized by the fact that solid and sterile preparations of suitable size and shape for parenteral implantation and release of the active substance(s) over a prolonged period of time.

[29] The terms "extended release," "slow release," or "sustained release" refer to a form of drug release through an implant that occurs continuously and gradually over an extended period of time and does not result in an immediate and concentrated release of the drug into the body. [30] Biodegradable polymers or bioeffective polymers refer to a polymer that degrades in vivo and that its erosion over time occurs simultaneously with and/or subsequently to the release of the therapeutic agent. A biodegradable polymer may be a homopolymer, a copolymer, or a polymer that compresses more than two polymer units. In some cases, a biodegradable polymer may include a blend of two or more homopolymers or copolymers.

[31] Biodegradable implants or bio-effective implants can be understood as implants that have some mechanism that leads to a gradual reduction in their mass over a long period of release. The forces involved in this mass reduction can be either from cellular interactions or from shear forces on the implant surface. In addition, erosion and gradual dissolution of its components are possible. The terms also refer to complete degradation and absorption by the body, which occurs at the site where the implants were applied, eliminating the need for removal of the implants at the end of treatment.

State of the art (Background of the invention)

[32] Citing patent records directed to absorbable implants, document US 4957119 (Contraceptive Implant) mentions an implant made of a polymeric material that can release a contraceptive agent for a relatively long time when applied subcutaneously or locally. The implant consists of an ethylene/vinyl acetate copolymer core material that functions as a matrix for the contraceptive substance, an ethylene/vinyl acetate membrane surrounding the core material, and a contact layer at the interface between the core material and the membrane that prevents separation of the core material from the membrane.

[33] Although it requires an absorbable implant, US 4957119 uses different active substances, is produced by extrusion, and has a very long release period of the active substance (at least 1 year), which is different from the absorbable subcutaneous implant of the present invention.

[34] The second registration number US 9980850 (Biodegradable contractile implant and methods of use) describes a bioreservoir implant and methods of use in the form of a controlled-release bioreservoir pellet for subcutaneous implantation. The bioreservoir pellet provides sustained release of the contraceptive over an extended period of time. The bioerosion products are water-soluble, bioabsorbable, or both, eliminating the need for surgical removal of the implant.

[35] As in the first mentioned previous entry, this entry US 9980850 similarly uses different active substances, the release period of the active substance is very long (6 months to 4 years), and the preferred method of manufacturing the granules is the hot melt process.

[36] Considering the shortcomings and previously existing problems in the conventional treatment of hypothyroidism, the present invention aims to be a tool that helps these patients control hypothyroidism and improve its clinical pictures, and can be used in both patients with declared hypothyroidism and patients with subclinical hypothyroidism depending on the medical behavior.

[37] The proposed treatment does not depend on the patient's memory and adherence to the correct use of the medication, and thanks to the prolonged release and lower dosage of the active substance, it is possible to reduce the adverse symptoms that may be observed with oral administration of this drug, and to avoid the metabolism of this drug in the liver, since it enters the bloodstream directly through the implants. In addition, after the expiration of the implants, there is no need to remove them, only re-install new ones to maintain treatment.

Description of the drawings

[38] For a better understanding of the present invention, the following drawings are attached:

Figure 1 - Representation of the chemical structure of the substances triiodothyronine (T3), triiodothyronine sulfate (T3C) and thyroxine (T4);

Figure 2 - Dimensional design of a bioabsorbable implant with triiodothyronine (T3), triiodothyronine sulfate (T3C), thyroxine (T4), a combination of T3 and T4, or a combination of T3C and T4 for the treatment of hypothyroidism;

Figure 3 - Dimensional design of a non-bioabsorbable implant with triiodothyronine (T3), triiodothyronine sulfate (T3C), thyroxine (T4), a combination of T3 and T4, or a combination of T3C and T4 for the treatment of hypothyroidism;

Figure 4 - Table presenting the equivalence between doses used in oral T4 treatment and combined oral T4 and T3 subcutaneous implant treatment.

Detailed description of the invention

[39] The present patent application provides a biodegradable implant containing triiodothyronine (T3), triiodothyronine sulfate (T3C), thyroxine (T4), a combination of T3 and T4, or a combination of T3C and T4 for the treatment of hypothyroidism in a polymer matrix. The implant is administered subcutaneously and has a continuous release of the active substance over an extended period of time. This release is aimed at providing an effective, constant, and prolonged serum level of the drug for the treatment of hypothyroidism.

[40] "Active substance," "active," or "drug" refers to a drug for the treatment of hypothyroidism, which may be: triiodothyronine (T3) alone, triiodothyronine sulfate (T3C) alone, thyroxine (T4) alone, a combination of T3 and T4, or a combination of T3C and T4. The chemical structures are shown in Figure 1.

[41] The implant of the present invention may have in its constitution only an agent for treating hypothyroidism, but is preferably formed by particles of active triiodothyronine (T3), triiodothyronine sulfate (T3C), thyroxine (T4), a combination of T3 and T4, or a combination of homogeneously dispersed T3C and T4 in a bioresorbable polymer matrix. This polymer matrix may be formed by a polymer or a mixture of polymers. The amount of active substance present in the implant may vary from 100 to 3000 μg T3, from 100 to 3000 μg T3, from 100 to 3000 μg T4, a combination of T3 and T4, or a combination of T3 and T4; and its composition consists of 1-20% of a biodegradable polymer in proportion to its weight.

[42] The biodegradable polymer used may be: poly(D-lactide), poly(L-lactide), racemic polylactate, poly(glycolic acid), polycaprolactone, methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), poly(ethylene oxide) (PEO), polyethylene glycol, starch, natural and synthetic gum and wax.

[43] Implants can be of any size, shape or structure that facilitates their fabrication and subcutaneous administration, however, to achieve a more constant and uniform release of the active, it is necessary to use geometric shapes that maintain their surface area over time.

[44] Thus, the implant developed and demonstrated in this appendix has a cylindrical shape (1) in the form of a rod with straight or rounded ends, with a length of 2 to 25 mm and a diameter of 1 to 6 mm. A schematic drawing of an example of the size of the implant (1) is shown in Figure 2.

[45] The manufacture of an implant of triiodothyronine (T3), triiodothyronine sulfate (T3S), thyroxine (T4), a combination of T3 and T4, or a combination of T3S and T4 for the treatment of hypothyroidism can be accomplished by adding 100 to 3000 μg T3, 100 to 3000 μg T3S, 100 to 3000 μg T4, a combination of T3 and T4, or T3S. The proportional relationship between T3S and T4 in a solution of the selected biodegradable polymer matrix is 1-20% to the weight of the drug to form a homogeneous mixture. If the polymer solvent is not also a solvent for the drug, it will be dispersed in the form of particles or a suspension, and a mixer can be used to make the solution homogeneous. This solution is then dried and then molded to the shape (1) of the implant or other desired shape.

[46] Another possible method for preparing an implant with triiodothyronine (T3), triiodothyronine sulfate (T3C), thyroxine (T4), a combination of T3 and T4, or a combination of T3C and T4 for the treatment of hypothyroidism consists of a mixture of 100 to 3000 μg T3, 100 to 3000 μg T3S, 100 to 3000 μg T4, a combination of T3 and T4, or a combination of T3S and T4 in each implant and 1 to 20% of a selected biodegradable polymer matrix relative to the weight of the drug in its dry powder forms. The drug and polymer matrix are added to a suitable container and the mixture is homogenized.

[47] The active ingredient mixture for the implant can be formed under pressure or heat, so as not to compromise the effectiveness of the drug or destroy the polymer material. Implant forming methods include injection molding, thermoforming, compression molding, or extrusion molding.

[48] For the present invention, the technique chosen was compression molding. In this method, a mixture of active ingredients in powder form is added to a mold, and a mechanical force is applied underneath the mixture, causing the particles to compress and thus forming an implant in the mold (1). The implant is then filled and sterilized with a hypothyroidism treatment agent. Sterilization can be accomplished by heat (approximately 90°C) or gamma rays.

[49] The implant may have a coated polymer membrane with a thickness of 0.1 to 0.7 mm. The polymer used for the coating must be bioabsorbable and ensure the passage of the active substance. The coating of the implant is preferably achieved by immersing the implant in a polymer solution. The coating may cover the entire surface of the implant, including the edges, only its longitudinal surface with uncoated edges, or only the edges of the implant without coating its length. Polymers that can be used for the coating include poly(lactic-co-glycolic acid) (PLGA) and D,L-lactic acid copolymers.

[50] Another option for an implant for the treatment of hypothyroidism is non-biodegradable implants. Non-biodegradable or non-biodegradable implants (2) (Fig. 3) have a central core (2.1) formed by a polymer matrix in a percentage of 1 to 20% relative to the weight of the drug, in this case from 100 to 3000 μg T3, from 100 to 3000 μg T4, a combination of T3 and T4, and the core is surrounded by a non-degradable polymer membrane (2.2), which controls the rate of release of the drug.

[51] The polymer membrane surrounding the implant can be made of silicone, urethane, acrylates and their copolymers, polyvinylidene fluoride copolymers, polyethylene vinyl acetate-ethylene vinyl l, or dimethylpolysiloxane. This membrane has a thickness of 0.2 to 1 mm and is cast using in-house equipment. After the membrane is molded from the polymer material, the active mixture is inserted, forming the central core (2.1) of the implant (2). The polymers used in the polymer matrix and mixture utilize the same compounds and process as the bioabsorbable implant.

[52] The drug release in this system occurs through diffusion at a relatively constant rate, and the drug release rate can be changed through the thickness or material of this membrane. In this system, the implant must be removed at the end of treatment.

[53] The claimed technological innovations provide different treatment options for hypothyroidism defined according to medical criteria: (a) monotherapy with triiodothyronine (T3) implants; (b) monotherapy with triiodothyronine sulfate (T3S) implants; (c) monotherapy with thyroxine (T4) implants; (d) combination therapy with T3 implant and oral T4; (e) combination therapy with T3 implant and T4 implant; (f) combination therapy with T3 and T4 on one implant; (f) monotherapy with T3 and T4 on the same implant; (g) combination therapy with T3c implant and oral T4; (h) combination therapy with T3c implant and T4 implant; (i) combination therapy with T3s and T4 in one implant.

[54] The dosage of triiodothyronine (T3) implant for the treatment of hypothyroidism is calculated based on the initially used oral thyroxine (T4) dose. The oral T4 dosage initially used by the patient is reduced by 40%, and the treatment is associated with T3 implantation with a dose equivalent to 20% of the adjusted oral T4 dose. Table 1, presented in Figure 4, shows the equivalence between: the doses used in oral T4 treatment and the combined oral T4 and T3 subcutaneous implant treatment.

[55] On the other hand, in the case of using triiodothyronine (T3) linked to thyroxine (T4) or triiodothyronine (T3S) linked to thyroxine (T4) sulfate, all in the form of implants, a T4/T3 or T4/T3S ratio of 80:20 can be used initially, following the physiological pattern of thyroid hormone production, or a ratio determined by the physician to be most appropriate.

[56] Regardless of the chosen therapeutic regimen, in order to determine the individual treatment for each patient, the specialist must take into account the stage of hypothyroidism, the assessment of the clinical picture and subsequent monitoring of TSH, T3L and T4L levels. In this way, concentration standards and optimal approaches can be determined for each individual.

[57] During treatment, the dosage can be adjusted by installing additional implants if necessary. Furthermore, in case of rejection or any adverse reactions after implant placement, the implant can be removed within the first few days of treatment.

[58] The use of the implant proposed herein is safe and effective in the treatment of hypothyroidism, since the therapy does not depend on the patient's will or discipline regarding the action of the drug, which, as a result, ensures the maintenance of the dosage and regularity of treatment. The use of these implants in therapeutic behavior prevents the discontinuation of treatment without medical assistance and ensures the correct treatment, as well as its effectiveness. Furthermore, the invention prevents the patient from misusing the drug, using more than the doctor's recommended amount, and becoming more susceptible to unwanted side effects and worsening of his clinical picture.

[59] An implant containing triiodothyronine (T3), triiodothyronine sulfate (T3S), thyroxine (T4), a combination of T3 and T4, or a combination of T3S and T4 for the treatment of hypothyroidism avoids the "peaks and troughs" of oral administration. The mechanism of action of the implant in the body allows for a more continuous release of the active substance over a long period of time. Daily release of a sufficient amount of the drug ensures the maintenance of effective serum drug levels, maintenance of TSH levels in the blood within the normal range, improvement in the patient's quality of life, and improved treatment compliance.

[60] Combination therapy with thyroxine (T4) orally or by subcutaneous implantation and triiodothyronine (T3) implantation and combination therapy with thyroxine (T4) orally or by subcutaneous implantation and triiodothyronine sulfate (T3S) implantation is an innovation in the treatment traditionally used for patients with hypothyroidism. It represents an alternative for those patients who do not respond adequately to T4 monotherapy, since its conversion to T3 in peripheral tissues is crucial for improving the patient's symptoms and clinical picture, however, it is known that the intracellular concentration of the deiodinase enzyme, which makes the conversion to T3, is not the same in all tissues.

[61] Furthermore, combination therapy provides excellent results for all patients undergoing treatment for hypothyroidism, as it binds the bioactive hormone T3 to T4. T3 is released in low and constant doses, providing a molecule that already has a direct effect on tissue. T4, on the other hand, allows the body to accumulate this hormone bound to its carrier proteins, thereby ensuring that there is always enough T4 for deionization to T3.

[62] Another benefit of using T3 is that it promotes weight loss and produces favorable results in the lipid profiles of patients, being an option for the treatment of cases of hypothyroidism associated with comorbidities such as cardiovascular disease, diabetes, dyslipidemia and/or obesity.

[63] Triiodothyronine (T3), triiodothyronine sulfate (T3S), thyroxine (T4), a combination of T3 and T4, or a combination of T3S and T4 implants may also be used in cases of subclinical hypothyroidism, following the same line of treatment as for the reported hypothyroidism, if the physician deems it necessary to perform medical intervention.

[64] Another advantage of this invention's implants is the release of the drug directly into the bloodstream, which limits side effects, makes its action much more effective, and prevents first-pass metabolism of the drug. Simplifying the dosage and reducing the frequency of administration contributes to greater adherence to treatment.

Claims (5)

1. A subcutaneous biodegradable implant for the treatment of hypothyroidism, containing from 100 to 3000 mcg of triiodothyronine (T3), from 100 to 3000 mcg of thyroxine (T4) or a combination thereof in the form of particles uniformly distributed in a biodegradable and bioabsorbable polymer matrix, wherein said matrix contains from 1 to 20% of a biodegradable polymer relative to the weight of the drug. 2. The implant according to claim 1, characterized in that the biodegradable polymer used is poly(D-lactide), poly(L-lactide), racemic polylactate, poly(glycolic acid), polycaprolactone, methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), poly(ethylene oxide) (PEO), polyethyleneglycol, starch, natural and synthetic gum and wax. 3. An implant according to paragraphs 1 and 2, characterized by a cylindrical shape (1) in the form of a rod with straight or rounded ends with a length of 2 to 25 mm and a diameter of 1 to 6 mm. 4. The implant according to paragraphs 1, 2 and 3, characterized in that it is provided with a polymer shell with a thickness of 0.1 to 0.7 mm with a complete coating of the implant, including its edges, or with a coating of only its longitudinal surface, not including its edges, or with a coating of only its edges without coating along its entire length, wherein poly(lactic-co-glycolic acid) (PLGA) and D.L-lactic acid copolymers are used for the shell. 5. A method for manufacturing an implant according to paragraphs 1, 2 and 3, characterized in that it begins with the addition of 100 to 3000 mcg of triiodothyronine (T3), 100 to 3000 mcg of thyroxine (T4) or a combination thereof to a solution of a biodegradable polymer matrix in a proportion of 1 to 20% relative to the weight of the drug to form a homogeneous mixture, after which drying and subsequent molding into the shape (1) of the implant occurs.