Injectable sustained release pharmaceutical formulations of levothyroxine and methods for preparing same

Abstract

The present invention relates to a stable injectable sustained release formulation based on poly(D,L-lactide-co-glycolide) microparticles containing levothyroxine.The present invention also relates to a method for preparing the microparticles and their use for controlling hypothyroidism in adults, congenital hypothyroidism in infants, and acquired hypothyroidism in children.

Description

[Technical field]

[0001] The present invention relates to stable, injectable, sustained release formulations of levothyroxine or a pharma-ceutically acceptable salt, derivative, or metabolite thereof, methods for making the formulations, and uses of the formulations to control hypothyroidism. [Background technology]

[0002] Levothyroxine is a hormone that was first isolated in crystalline form in 1915. Its structural formula was discovered in 1926 and first synthesized in 1927. The thyroid gland produces hormones that regulate the metabolism of the organism. There are several disorders that can lead to an overactive thyroid gland (hyperthyroidism) or an underactive thyroid gland (hypothyroidism), the best known being Hashimoto's disease, Graves' disease, goiter, and nodular goiter. Common symptoms of hypothyroidism include fatigue, weight gain, cold intolerance, slow heart rate, dry skin, and constipation. Levothyroxine is an oral drug that is usually used to treat thyroid hormone deficiencies such as hypothyroidism and thyroid tumors, and is used to treat or prevent goiter, often with lifelong treatment on levothyroxine. For a severe type of thyroid hormone deficiency known as myxedema coma, levothyroxine is given intravenously with an initial loading dose, followed by a daily intravenous maintenance dose until levothyroxine levels are controlled. Intravenous preparations were used as early as the 1960s.

[0003] Currently approved oral and injectable formulations of levothyroxine require daily dosing, but there are no approved oral or injectable pharmaceutical forms of levothyroxine (extended release formulations) that maintain pharmacological action for a long period of time and require less frequent dosing. Given that hypothyroidism and other thyroid disorders are long-lasting in most patients, who often take medications as a lifelong treatment, and that the medication must be taken on an empty stomach, free of other medications, supplements, or food, for at least 30 minutes, a less frequent dosing would ensure greater patient compliance and contribute to improved quality of life. An injectable extended release formulation would eliminate the need for daily dosing and even fasting.

[0004] There have been attempts in the past to create injectable formulations with sustained release. For example, CN1127634, published in 1996, disclosed an injectable (intramuscular) controlled release formulation of estriol, estradiol valearate, testosterone propionate, and thyroid-T3 and T4-powder microparticles that was said to control the release of the drugs for 30 to 90 days. Polylactic acid (PLA) was used to form microparticles of levothyroxine. However, the inventors did not publish any actual release data that deviated from the model formulation, and no formulation has been approved to date.

[0005] In a study published in Biopharma. Drug. Dispos. 32:380-388, 2011, levothyroxine microparticles were prepared for topical and transdermal delivery. They were prepared in various polymer matrices, namely poly D,L lactide (PLA), poly (lactic-co-glycolic acid) (PLGA), poly (N-isopropylacrylamide) (PNIPAM), and ethylcellulose (EC). The release rates (in vitro) showed that levothyroxine exhibited a rapid release regardless of the polymer, with more than 60% of the drug released within the first hour. These preparations are clearly not suitable for use in injectable sustained release formulations aimed at release up to 2 months (at least a less rapid release is required), as the high initial rate of release leads to undesirable side effects such as restlessness, irritability, and nervousness, or serious side effects such as chest pain, palpitations, dyspnea, and heart failure.

[0006] There is a need for an injectable sustained-release formulation of levothyroxine that provides reduced initial onset, controlled release, reduced toxicity, extended systemic half-life, reduced dosing frequency, increased patient compliance, and potential reductions in overall health care costs. Summary of the Invention

[0007] In accordance with the present invention, there is provided a sustained release pharmaceutical formulation comprising levothyroxine, or a pharma- ceutically acceptable salt, derivative, or metabolite thereof, and microparticles of poly(D,L-lactide-co-glycolide) polymer, having a theoretical levothyroxine loading of at least 1.5% w / w, which overcomes the deficiencies of the prior art and provides a relatively low initial rapid release of levothyroxine, and a sustained release rate over an extended period of time.

[0008] The theoretical drug loading (TDL) is calculated using the equation: TIFF2024536419000001.tif12170

[0009] Another object of the present invention is to provide a stable parenteral pharmaceutical formulation containing levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof as an active ingredient, which is toxicologically safe.

[0010] It is a further object of the present invention to provide an injectable controlled release formulation comprising levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof, which exhibits good syringeability, injectability, no needle clogging or obstruction, good drainage, sterility, and resuspension.

[0011] A further advantage of the present invention is that the levothyroxine formulations improve patient compliance with medication and may replace existing treatment regimens that require frequent (daily) oral or injection administration.

[0012] The present invention provides a pharmaceutical formulation for intramuscular or subcutaneous administration at one or multiple injection sites, which contains levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite as an active ingredient and can exert a pharmacological action for at least one week up to two months after a single administration. The formulation may be administered monthly to bimonthly, preferably monthly or bimonthly.

[0013] The present invention further includes sterile, injectable, controlled release formulations comprising levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof in the form of a ready-to-use solution, a ready-to-use suspension, and a suspension / solution formed upon reconstitution with an appropriate diluent immediately prior to administration (injection).

[0014] A further aspect of the present invention provides a rapid, simple, cost-effective method for preparing a stable injectable pharmaceutical formulation comprising levothyroxine or a pharma-ceutically acceptable salt, derivative, or metabolite thereof.

[0015] Other objects and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The following terms are used in the present invention with the following meanings.

[0017] "Microparticles" or "microspheres" are particles that contain a polymer that acts as a matrix or binder for the particle. The microparticles can contain an active compound dispersed or dissolved in the polymer matrix and are biodegradable and biocompatible.

[0018] A "biodegradable substance" is a substance that breaks down through bodily processes into products that the body can readily dispose of and that must not accumulate in the body.

[0019] "Biocompatible" means non-toxic, pharma- ceutical acceptable, non-carcinogenic, and does not induce significant inflammation in body tissue. "Weight percent" means the percentage of weight per total weight of the microparticles.

[0020] "Sustained release formulation": a pharmaceutical dosage form that provides sustained release of a pharmacologic active ingredient for a sustained period of days to months following a single administration.

[0021] "PLGA" is poly(lactic acid-co-glycolic acid).

[0022] Because different chains of synthetic polymers have different lengths and different numbers of side chains, there is no single number for the molecular weight of a synthetic polymer, so there is a distribution of molecular weights and so an "average molecular weight" of the polymer is generally calculated.

[0023] The terms "active agent," "API," "active compound," and "drug" are used interchangeably and refer to the pharmacologically active compound of the present invention that is levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof. The term levothyroxine is used interchangeably throughout the present specification with the same meaning.

[0024] "Erosion" is defined as the physical dissolution of a polymer as a result of its degradation.

[0025] MeOH: Methanol DCM: dichloromethane The "extraction factor g" is: Defined as TIFF2024536419000002.tif12170.

[0026] As previously mentioned, it is an object of the present invention to provide an injectable, sustained release formulation of levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof to overcome the problems of existing thyroid treatments and provide an even, sustained release rate over an extended period of time.

[0027] The formulation comprises levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof, preferably levothyroxine or a hydrated or anhydrous pharma- ceutically acceptable salt thereof. When the formulation comprises a pharma- ceutically acceptable salt, the salt is selected from sodium, potassium, etc., preferably sodium.

[0028] Another object of the present invention is to provide a method for preparing the levothyroxine microparticles of the invented formulation, since levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite is generally hydrophobic or amphiphilic and is usually insoluble in the solvents used to form the polymer solution, making it difficult to incorporate levothyroxine into the matrix polymer.

[0029] It is a further object of the present invention to provide an injectable sustained release formulation of levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof having a drug loading suitable to meet maximum dosing requirements.

[0030] Yet a further object of the present invention is to provide an injectable sustained release formulation of levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite thereof, which when injected subcutaneously or intramuscularly, exhibits release over an extended period, preferably over a period ranging from 1 week to 2 months, more preferably over a period ranging from 1 to 2 months, while exhibiting an initial rapid release that is not eliminated before the release begins (lag phase) or is eliminated only for a short period of time, and is low compared to typical values. In microspheres, the lag phase is generally up to 10 days, and the initial rapid release is less than 40% of the total levothyroxine.

[0031] In one embodiment, the levothyroxine microparticles of the injectable sustained release formulation are prepared by a single emulsion process. According to this process, the PLGA polymer is dissolved in a suitable solvent, including but not limited to dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, hexafluoroisopropanol, chloroform, or acetone, or a combination thereof, to form a PLGA polymer solution. The levothyroxine is dissolved in a suitable solvent to form a levothyroxine solution, including methanol for the sodium salt form of levothyroxine. The dispersed (oil) phase is prepared by mixing the PLGA polymer solution with the levothyroxine solution, resulting in a co-solvent system in which both PLGA and levothyroxine can be dissolved.

[0032] In accordance with the present invention, there is also provided a method for preparing a sustained release pharmaceutical formulation for intramuscular or subcutaneous administration comprising levothyroxine or a pharma- ceutically acceptable salt, derivative, or metabolite as an active ingredient.

[0033] The levothyroxine in the formulations of the present invention is preferably levothyroxine or a pharma- ceutically acceptable salt, more preferably hydrated or anhydrous levothyroxine sodium.

[0034] The formulation of the present invention comprises a pharma- ceutical active ingredient, a vehicle, other pharma- ceutical acceptable additives, and a pH adjusting agent. The order of mixing the components of the formulation is interchangeable.

[0035] A typical preferred method for preparing the microparticles comprises the following steps: - dissolving PLGA (poly(D,L-lactide-co-glycolide)) polymer in DCM with stirring; - dissolving levothyroxine in MeO and mixing with a polymer solution to form a dispersed phase (DP); - dissolving poly(vinyl alcohol) in water for injection at 80°C and cooling the solution to 25°C to form a continuous phase (CP); - mixing the dispersed phase and the continuous phase and emulsifying using a high shear rotor-stator continuous flow disperser (i.e., an in-line homogenizer) or an overhead stirrer to form a suspension; - emulsifying the DP in the CP by vigorous stirring; - subjecting the suspension to solvent extraction and evaporation by stirring under air flow and at a controlled temperature between 5 and 25°C to ensure removal of the organic solvent and solidification of the particles; After 3 hours, the microparticles are collected on a glass filter dryer, washed with excess water at room temperature, and left to dry under reduced pressure for 24 hours. Includes.

[0036] In a preferred embodiment, PLGA is dissolved in dichloromethane with stirring. Levothyroxine sodium is dissolved in methanol (with stirring) and then added to the polymer solution with stirring to form a dispersed phase. The dispersed phase is kept at a controlled temperature between 5°C and 25°C, preferably 5-10°C.

[0037] The formed mixture of levothyroxine sodium and the PLGA polymer (oil phase or dispersed phase) is subsequently emulsified in an aqueous or continuous phase containing an aqueous surfactant solution, preferably an aqueous solution of polyvinyl alcohol (PVA). In a preferred embodiment, the mixture of levothyroxine sodium and the PLGA polymer is emulsified in the aqueous PVA solution.

[0038] Emulsification is preferably performed using a high shear rotor-stator continuous flow disperser (such as an in-line homogenizer) or an overhead stirrer. The emulsion is then transferred to a receiving vessel and placed under controlled conditions of temperature, air flow, and agitation to remove the organic solvent. The suspension is thermostatically regulated at a temperature below 20°C, more preferably 5-10°C, for 3 to 4 hours. After removal of the organic solvent, a suspension of microparticles is formed and filtered through a glass filter drier to collect the microparticles of the desired size. The microparticles are then washed with excess water at room temperature on the glass filter drier and allowed to dry under reduced pressure for 24 hours. The method of the present invention provides microparticles having a particle size distribution of 10-200 microns as measured by laser light diffraction.

[0039] The solubility of API in MeOH at 20° C. was determined as follows: Approximately 50 mg of levothyroxine sodium was weighed into a vial. Methanol was added in small portions until the solution became clear. The solubility was determined to be 3.41% mass of LVX / mass of MeOH.

[0040] Next, the solubility of PLGA in DCM / MeOH mixtures was measured at 20°C. A 5% solution of PLGA polymer (PURASORB PDLG5002A) in DCM was prepared. Methanol was added in small portions until precipitation of the polymer was observed. The minimum acceptable DCM / MeOH ratio for a 5% solution of PLGA in DCM was determined to be 10 / 3.

[0041] Approximately 0.25g of polymer and various amounts of LVX corresponding to theoretical drug loading values ​​of 1%, 2%, 3%, and 4% were weighed into four vials. A 10 / 3 ratio of DCM / MeOH mixture (to ensure the polymer is always dissolved) was added in small portions to each vial. The respective PLGA (PURASORB PDLG5002A) concentrations, LVX content %, and LVX solubility were evaluated and are shown in the table below. Evaluation of maximum theoretical drug loading values. TIFF2024536419000003.tif117170

[0042] From the results, Levothyroxine is soluble when the ratio of LVX / (DCM+MeOH) is below 0.1%; The theoretical drug loading, higher than 3%, indicates that the PLGA concentration must be lower than 3%, which is too low for the formulation of microparticles.

[0043] The results of the solubility test led to the selection of the theoretical drug loading. The PLGA (PURASORB PDLG5002A) concentration was set at 5% in DCM (3.8% in DCM+MeOH mixture). The theoretical drug loading value of the formulation ranges between 1.5 and 3%. Such theoretical drug contents of at least 1.5%, preferably 1.5% to 3.0%, and more preferably 2% to 3%, and g-factors of 1 to 1.5 lead to microparticles with at least one month of release and low initial lag phase according to the present invention. Levothyroxine microparticles with lower theoretical drug loading do not release for a sufficient time. Also, PLGA polymers with higher MW and lactide to glycolide ratio result in release profiles that are considered too slow for the purposes of the present invention.

[0044] Preferably, levothyroxine is dissolved in methanol, where the weight of levothyroxine relative to the weight of MeOH is about 3.41%.Moreover, PLGA is particularly preferably dissolved in DCM, where the percentage of levothyroxine relative to the total weight of DCM plus MeOH is less than 0.1%.

[0045] PLGA is a linear aliphatic copolymer obtained in various ratios between its constituent monomers, lactic acid (LA) and glycolic acid (GA). It can be synthesized with any ratio of LA and GA, with a wide range of molecular weights (Mw) from less than 10,000 up to 200,000 g / mol, and in fully amorphous or highly crystalline forms. The amorphous form proves more suitable for drug release since it also provides more dispersion of the cargo in the polymer matrix. The release and degradation rates are highly influenced by Mw and LA / GA ratio. Overall, polymers with higher Mw acquire more structural integrity through crosslinking and exhibit longer release characteristics. PLGA with higher GA content is more hydrophilic and allows higher water permeability, resulting in faster degradation rates while at the same time exhibiting a higher degree of crystallinity.

[0046] Currently, PLGA polymers are commercially available from a variety of suppliers and can be easily customized to any customer's requirements. Exemplary commercially available PLGA polymers that can be used in the present invention are Resomer®, Medisorb®, Expansorb®, and Purasorb® PDLG. These polymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid, and with a variety of polymer chain end groups.

[0047] The inventors of the present invention have found that the degradation rate of PLA used in the prior art injectable sustained release formulations of levothyroxine is slow, leading to very slow drug release. Surprisingly, it has now been found that the PLGA polymers suitable for the presently claimed injectable sustained release formulations of levothyroxine have lactide to glycolide ratios of 80:20 to 20:80, more preferably 75:25 to 25:75, and most preferably 75:25 to 50:50. Particularly preferred PLGA polymers are those having lactide to glycolide ratios of 50:50 and 75:25. The average molecular weight (M) of the PLGA polymer is 100%. w) is preferably in the range of from 5 kDa to 200 kDa, more preferably between 15 and 120 kDa. Particularly preferred PLGA polymers are those having average molecular weights of 18 kDa and 115 kDa.

[0048] The injectable sustained release formulation of the present invention is disclosed to comprise microparticles comprising levothyroxine or a levothyroxine salt, preferably a sodium salt, and a polymer, preferably PLGA. The levothyroxine or levothyroxine sodium may be present in a concentration of 1.0-5.0% by weight, more preferably 1.5-3.0% by weight, while the PLGA concentration may range between 99.0 and 95.0% by weight, preferably between 97.0 and 98.5% by weight. Most preferably, the levothyroxine is present in a concentration of 2.5% and the PLGA in a concentration of 97.5%.

[0049] PLGA molecular weights were determined using gel permeation chromatography (GPC) polystyrene (PS) calibration standards (M w The retention time values ​​are determined by comparison with the MW values ​​of the CoAs in the standard solutions (range 3-200 kDa). According to the method, calibration standards and samples are dissolved in THF and analyzed using two GPC columns with identical characteristics connected in series. The retention time values ​​are combined with the MW values ​​of the CoAs in the standard solutions to obtain the retention time vs. log(M w ) is used to generate a calibration curve that plots retention time versus log(M). The retention times of the samples are converted to molecular weights based on the calibration curve. The calibration curve is calculated by the GPC software as retention time versus log(M). w ) is a cubic expression of

[0050] The in vitro release of drug from the microparticles of the present invention was studied in phosphate buffered saline solutions at various pH values. The microparticles of the formulation were suspended in a release medium of phosphate buffered saline and incubated at 37° C. in a water bath system. Samples were taken at regular time intervals and the amount of released drug was measured by HPLC.

[0051] The microparticles of the present invention are reconstituted to form a suspension before injection. The suspension comprises the microparticles and a vehicle (diluent), which may be aqueous or non-aqueous. The suspension may also comprise one or more solubilizing or wetting agents, one or more flocculating or suspending agents, one or more antibacterial preservatives, one or more antioxidants, one or more buffering agents, one or more pH adjusting agents, one or more tonicity adjusting agents, and one or more chelating agents.

[0052] Examples of suitable solubilizers include diethylene glycol monostearate, diethylene glycol monolaurate, glycerin monostearate, polyoxyethylene sorbitol beeswax, polyethylene lauryl ether, polyoxyethylene leuryl ether, polyoxyethylene monostearate, polyoxyethylene alkylphenol, polyethylene sorbitan monooleate, polyethylene sorbitan monolaurate, polyoxyethylene lauryl ether, potassium oleate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, sodium lauryl sulfate, sodium oleate, triethanolamine oleate, etc. Poloxamer and Lutrol® F108 are particularly preferred as solubilizers or wetting agents. Sodium carboxymethylcellulose and hydroxypropylmethylcellulose are particularly preferred as flocculants or suspending agents.

[0053] Examples of antioxidants that may be present include sodium acetone bisulfate, ascorbate, α-tocopherol, sodium bisulfate, butylated hydroxyanisole, butylated hydroxytoluene, cysteine, cysteinate HCL, sodium dithionite, gentisic acid, gentisic acid athanolamine, sodium glutamate, sodium formaldehyde sulfoxylate, potassium pyrosulfite, sodium pyrosulfite, monothioglycerol, propyl gallate, sodium sulfite, α-tocopherol, sodium thioglycolate, etc. Butyl hydroxyl anisole and / or bisulfite are particularly preferred as antioxidants.

[0054] In the preparation of non-aqueous injectable controlled release suspensions prepared for use, buffers are optionally used. Examples of suitable buffers include sodium phosphate, potassium phosphate, sodium hydroxide, sodium succinate, disodium succinate, sulfuric acid, sodium tartrate, tartaric acid, and tromethamine. Sodium phosphate is particularly preferred as a buffering agent.

[0055] One or more pH adjusting agents may also be present to adjust the pH of the suspension to about 6 to about 8, preferably about 7. The pH adjusting agent may be either an acid or a base. Examples of pH adjusting agents suitable for use in the present invention include acetic acid, calcium carbonate, hydrochloric acid, magnesium oxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like. Sodium hydroxide and hydrochloric acid are particularly preferred as pH adjusting agents.

[0056] The preparation of suspension can optionally use one or more tonicity adjusting agents.Suitable examples of tonicity adjusting agents include magnesium sulfate, maltose, mannitol, polyethylene glycol, polylactic acid, polysorbate, potassium chloride, povidone, sodium chloride, sodium cholesteryl sulfate, sodium succinate, sodium sulfate, sorbitol, sucrose, and trehalose.Sodium chloride is particularly preferred as tonicity adjusting agent.

[0057] The suspension may optionally contain one or more chelating agents. Examples of suitable chelating agents include calcium disodium ethylenediaminetetraacetic acid (EDTA), disodium EDTA, sodium EDTA, and diethylenetriaminepentaacetic acid (DTPA). Citric acid, tartaric acid, and amino acids such as lysine and arginine can also act as chelating agents. Disodium EDTA is particularly preferred as a chelating agent.

[0058] The sustained release formulation of the present invention can be used to control hypothyroidism in adults, congenital hypothyroidism in infants, and acquired hypothyroidism in children.The formulation can further be used as a replacement or replacement treatment for congenital or acquired hypothyroidism of any etiology, except for transient hypothyroidism in the convalescent stage of subacute thyroiditis.Specific indications include primary (thyroid), secondary (pituitary), and tertiary (hypothalamic) hypothyroidism, as well as subclinical hypothyroidism.Primary hypothyroidism may result from lack of functioning, primary atrophy, and partial or total congenital deficiency of the thyroid gland, or from the effects of surgery, radiation, or drugs, with or without the presence of goiter. In another embodiment, the formulations may be used in the treatment or prevention of various types of euthyroid goiter, such as thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), multinodular goiter, and as an adjunct to surgery and radioactive iodine therapy in the treatment of thyrotropin-dependent well-differentiated thyroid cancer.

[0059] The formulation is preferably reconstituted with a suitable diluent and then administered by subcutaneous or intramuscular injection. More specifically, the formulation may be provided as a kit, in which the diluent is packed in a prefilled syringe and the microparticles are in a vial. Just before use, the contents of the prefilled syringe (diluent) and the vial (powder) are mixed to prepare the suspension that is injected into the patient. Alternatively, a dual-chamber syringe may be used, in which the microparticles are provided in one chamber of the syringe, and the diluent is stored in the other chamber of the prefilled syringe, and just before injection, the contents of each chamber are mixed to form the suspension that is injected into the patient.

[0060] Suitable diluents include inactive ingredients such as sodium carboxymethylcellulose, mannitol, sodium chloride, sodium hydroxide, polysorbate, acetic acid, sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate, and the like.

[0061] Preferably, the formulation is administered once every one or two months. EXAMPLES

[0062] Example 1 (Comparative Example) Microparticles were prepared using three PLGA polymers, namely, PURASORB PDLG 5002A, with a molecular weight of 18 kDa, and RESOMER RG 504H, with a molecular weight of 60 kDa, both with a lactide to glycolide ratio of 50:50, and PURASORB PDLG 7510, with a molecular weight of 115 kDa and a lactide to glycolide ratio of 75:25, by the method exemplified in the above description.

[0063] They were characterized in terms of drug loading, particle size distribution and in vitro release and the results are shown in the table below. PSD (particle size distribution) and in vitro release rate of formulations LVX_1.2, LVX_1.3, and LVX_1.4 TIFF2024536419000004.tif35170

[0064] Formulations LVX_1.2 and LVX_1.3 are characterized by a sigmoidal profile with a lag phase of about 10 and 20 days, respectively, followed by a main release phase up to about the 25th and 40th days, respectively.

[0065] The results show the effect of polymer MW on the PSD and release profile of levothyroxine microparticles: higher MW (formulation LVX_1.3) resulted in larger microparticles (higher viscosity during dispersion at the emulsification stage) and, consequently, a slower release profile (lower surface area per unit volume leads to slower water penetration and matrix degradation).

[0066] For formulation LVX_1.4, the higher lactide to glycolide ratio (75:25 compared to 50:50 for the other two formulations) in addition to the higher MW resulted in a release profile that was deemed too slow for the purposes of this invention. The lactide to glycolide ratio affected the degradation rate of the microparticles and therefore the release rate.

[0067] Example 2 Two formulations (LVX_1.5 and LVX_1.6) were prepared based on LVX_1.2 and one formulation (LVX_1.12) based on LVX_1.3, resulting in changes in theoretical drug loading and g-factor. Both parameters are increased towards higher drug loading (from theoretical drug loading 1.5% to 2.0 and 3.0% and g-factor 1 to 1.5). Theoretical drug loading ratio (TDL), PSD, and in vitro release rate of formulations LVX_1.5, LVX_1.6, and LVX_1.12 TIFF2024536419000005.tif44170

[0068] The increase in theoretical drug loading and g-factor values ​​resulted in higher actual drug loading. In addition to this, the release time of both formulations (LVX_1.5 and LVX_1.6) was longer compared to the LVX_1.2 formulation. More specifically, the 50% release time shifted from 14 days (LVX_1.2) to 20-22 days (LVX_1.5 and LVX_1.6) and the 100% release time shifted from 25 days to 35 days, respectively. The shift towards longer release characteristics was justified by the increase in core drug loading. Similar initial steepness was obtained, suggesting that g-values ​​applied in the range of 1.0-1.5 would result in similar ratios of surface and subsurface drug content to total drug content.

[0069] Similar to what was seen for the low MW polymer PLGA, increased drug loading leads to a longer release profile for the higher MW, and also appears to correlate with an initial steep increase (compare LVX_1.3 with LVX_1.12).

[0070] Formulation trials conducted with lower MW (18 kDa) and higher MW PLGA of approximately 55 kDa show release times ranging from 25 to 35 days, or up to 60 days, respectively. Formulations with higher MW polymers also show a lower initial steepness.

Claims

1. 1. A sustained-release pharmaceutical formulation for intramuscular or subcutaneous administration once a month to once every two months comprising levothyroxine or a pharmaceutically acceptable salt thereof and microparticles of poly(D,L-lactide-co-glycolide) polymer having a 50:50 lactide to glycolide ratio and a weight average molecular weight in the range of 15 to 120 kDa, the formulation having a theoretical levothyroxine loading of 2% w / w to 3% w / w.

2. 10. The pharmaceutical formulation of claim 1, wherein the polymer has a weight average molecular weight in the range of 18 kDa to 115 kDa.

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the microparticles have a particle size of from 10 to 200 microns as measured by laser light diffraction.

4. 3. The pharmaceutical formulation of claim 1 or 2, which is reconstituted with a diluent prior to intramuscular or subcutaneous administration.

5. 5. The pharmaceutical formulation of claim 4, wherein the diluent comprises one or more of sodium carboxymethylcellulose, mannitol, sodium chloride, sodium hydroxide, polysorbate, acetic acid, sodium dihydrogen phosphate monohydrate, disodium phosphate heptahydrate.

6. 3. The pharmaceutical formulation of claim 1 or 2, which is administered monthly or bimonthly.

7. 10. The pharmaceutical formulation of claim 1, which is administered intramuscularly or subcutaneously using a kit with a dual-chamber syringe or a syringe pre-filled with diluent and microparticles present in a separate vial.

8. 3. The pharmaceutical formulation of claim 1 or 2, comprising hydrated or anhydrous levothyroxine sodium.

9. 10. A method for preparing microparticles according to claim 1 or 2 having a theoretical levothyroxine loading of 2% w / w to 3% w / w for monthly or bimonthly intramuscular or subcutaneous administration, comprising the steps of: - dissolving a PLGA polymer with a lactide to glycolide ratio of 50:50 and a weight average molecular weight in the range of 15 to 120 kDa in DCM with stirring; - dissolving levothyroxine in MeOH and mixing with a polymer solution to form a dispersed phase (DP); - dissolving poly(vinyl alcohol) in water for injection at 80°C and cooling the solution to 25°C to form a continuous phase (CP); - mixing the dispersed and continuous phases and emulsifying them using a high shear rotor-stator continuous flow disperser (i.e., in-line homogenizer) or an overhead stirrer to form a suspension; - emulsifying the DP in the CP by vigorous stirring; - subjecting the suspension to solvent extraction and evaporation by stirring under a controlled temperature of between 5 and 25°C and air flow to ensure removal of the organic solvent and solidification of the particles; After 3 hours, the microparticles are collected on a glass filter dryer, washed with excess water at room temperature and left to dry under reduced pressure for 24 hours. A method comprising:

10. 10. The method of claim 9, wherein the dispersed phase is maintained at a temperature of from 5°C to 25°C.

11. 10. The method of claim 9, wherein the dispersed phase is maintained at a temperature of from 5°C to 10°C.

12. 10. The method of claim 9, wherein the weight of levothyroxine relative to the weight of MeOH is less than 3.41%.

13. 10. The method of claim 9, wherein the percentage of levothyroxine relative to the total weight of DCM plus MeOH is less than 0.1%.