Microneedle devices for controlling thyroid hormone levels

Abstract

A microneedle device, preferably a controlled-release device, for delivering liothyronine (LT3 or a salt thereof) to a patient with hypothyroidism and / or who is not pregnant is described. The microneedle device contains LT3 or a salt thereof in an amount effective to maintain normal and stable levels of free and / or total T3 in serum. The microneedle device includes at least two components: a multidimensional array of microneedles and a substrate to which the bases of the microneedles are fixed or integrated. The microneedles contain LT3 or a salt thereof and a biodegradable and / or biosoluble polymer (e.g., polyvinylpyrrolidone) for the controlled release of LT3 or a salt thereof. Methods of making and using the microneedle device are also described.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 028,268, filed May 21, 2020, which is incorporated herein by reference in its entirety.

[0002] Field of the Invention The present invention is in the field of drug delivery devices, particularly microneedle devices for the transdermal delivery of thyroid hormones, triiodothyronine (liothyronine), and thyroxine (levothyroxine) to patients with hypothyroidism.

Background Art

[0003] Background of the Invention Hypothyroidism affects over 10 million Americans and hundreds of millions of people worldwide (Jonklaas et al., Thyroid 2014, 24:1670 - 1751). Thyroid hormone replacement therapy has been used as a treatment strategy for hypothyroidism for over a century (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50 - 56). For most of the 20th century, natural thyroid preparations (thyroid extract, desiccated thyroid, or thyroglobulin) containing thyroxine (T4) and triiodothyronine (T3) dominated the market (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50 - 56).

[0004] T4 is the primary secretory prohormone of the thyroid gland, providing the rationale for levothyroxine (LT4) (a synthetic form of T4), the standard treatment for thyroid hormone replacement therapy (Jonklaas et al., Thyroid 2014, 24:1670-1751; McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56). Outside the thyroid gland, one iodine atom is removed from T4, thereby converting T4 to the active hormone T3 by enzymes called deiodenase (types I and II). The thyroid gland also secretes T3, but in smaller amounts than T4. Whether LT4 treatment restores thyroid hormone signaling in all tissues remains controversial. There is growing evidence of persistent signs and symptoms of hypothyroidism during LT4 treatment at doses that normalize serum thyroid-stimulating hormone (TSH). Studies in the United States and Europe have shown that patients receiving LT4 have approximately 10% lower serum T3 levels (Gullo et al., PLoS One. 2011;6:e22552; Peterson et al., J. Clin. Endocrinol. Metab. 2016, 101(12):4964-4973; Conceicao et al., Thyroid 2018, 28(11), 1425-1433; McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56). Recent evidence suggests that this 10% difference in serum T3 levels may have significant clinical implications. Approximately 10–20% of patients treated with LT4 therapy still experience symptoms of hypothyroidism and, estimated, report decreased well-being despite appropriate LT4 treatment (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56; Peterson et al., J. Clin. Endocrinol. Metab. 2016, 101(12):4964-4973; Conceicao et al., Thyroid 2018, 28(11), 1425-1433).Furthermore, thyroid hormone-dependent markers (e.g., serum cholesterol and basal metabolic rate) may remain abnormal in LT4-treated patients with normal serum TSH levels (McAninch et al., J. Clin. Endocrinol. Metab. 2018, 103, 4533-4542). This evidence supports the need for new treatment options for hypothyroidism (Jonklaas et al., Thyroid 2021, 31(2), 156-182).

[0005] Instead, liothyronine (LT3) (a synthetic form of T3) is used in the treatment of hypothyroidism (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56; Bakhteyar et al., International Journal of Pharmaceutical Compounding 2017, 21(5), 418-425). However, oral LT3 has limited clinical application because it has a shorter half-life (a few hours to 2 days) compared to oral LT4 (approximately 7 days), exhibits rapid clearance, and shows absorption that results in large fluctuations in serum T3 levels (Saravanan et al., Exp. Clin. Endocrinol. Diabetes 2014, 115:261-267; Bakhteyar et al., International Journal of Pharmaceutical Compounding 2017, 21(5), 418-425; Jonklaas 2015). This is a major problem because endogenous serum T3 levels are stable, strictly regulated, and fluctuate by less than 10% on a daily basis (Abdalla and Bianco, Clin. Endocrinol. 2014, 81:633-641; Conceicao et al., Thyroid 2018, 28(11), 1425-1433). Furthermore, even patients showing minimal elevations in thyroid hormone levels have a significantly increased risk of cardiovascular events and hip fractures (Biondi et al., Cardiologia 1999, 44:443-449; Sawin et al., New Engl. J. Med. 1994, 331:1249-1252; Bauer et al., Ann. Intern. Med. 2001, 134:561-568; Conceicao et al., Thyroid 2018, 28(11), 1425-1433). An improved method for delivering LT3 to achieve stable levels of serum free T3 and / or total T3, while avoiding problems such as the short half-life of oral LT3, remains an unmet need in the treatment of hypothyroidism. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] McAninch and Bianco, Ann. Intern. Med. (2016) 164:50~56 [Non-Patent Document 2] Bakhteyar et al., International Journal of Pharmaceutical Compounding (2017) 21(5) 418~425 [Overview of the project] [Means for solving the problem]

[0007] Therefore, the object of the present invention is to provide a transdermal delivery system for improved treatment of hypothyroidism.

[0008] Summary of the Invention A microneedle device for sustained, controlled transdermal delivery of liothyronine (LT3) or a combination of LT3 and levothyroxine (LT4) to patients with hypothyroidism is described. The microneedle device contains LT3 or an alkali salt thereof to generate an effective amount of serum T3 in a non-pregnant patient with hypothyroidism to maintain normal and stable levels of serum total T3 and / or free T3; normalize TSH levels; and / or maintain a normal free T4:free T3 ratio. Preferably, the microneedle device is a controlled-release device.

[0009] The above microneedle device comprises at least two components: at least one, more preferably, microneedles, and a substrate to which the bases of the microneedles are fixed or integrated. In some embodiments, the microneedles are biodegradable and contain LT3 or a salt thereof (e.g., an alkali salt thereof). In these embodiments, the microneedles contain a biodegradable and / or soluble polymer (e.g., polyvinylpyrrolidone). The above microneedle device is provided as a multidimensional array, in contrast to a microneedle device having a single microneedle or a row of microneedles.

[0010] In some embodiments, the microneedle device comprises, rather than a microneedle, LT3 or a salt thereof (e.g., an alkali salt thereof), and further comprises at least one reservoir that is selectively fluid-connected to the base end of the microneedle, either integrally or separately until the moment of use. Preferably, if the microneedle device comprises a reservoir that is not a microneedle, at least one microneedle comprises at least one hollow path positioned between the base end and the tip, or between the base end and the tip. In these embodiments, LT3 or a salt thereof (e.g., an alkali salt thereof) is formulated such that the formulation has a viscosity suitable for flowing through a microneedle having a gauge size between 26 gauge and 31 gauge (including both values), between 26 gauge and 32 gauge (including both values), between 26 gauge and 33 gauge (including both values), or between 26 gauge and 34 gauge (including both values).

[0011] Methods for fabricating and using the above-described microneedle device are also described. The preferred patient population is individuals with hypothyroidism who are not pregnant. In embodiments of the present invention, for example, the following items are provided. (Item 1) A microneedle device, wherein the device is a) A plurality of microneedles, each having a proximal end and a tip; b) A substrate to which the proximal end of the microneedle is fixed or integrated; and c) When administered transdermally to patients with hypothyroidism: (i) Stable serum levels of free or total T3, preferably total T3, T4, preferably free T4, or both. (ii) Normal serum free T3:free T4 ratio, (iii) Normal serum total T3:free T4 ratio, (iv) Normal serum levels of thyroid-stimulating hormone (TSH), or (v) Combinations of (i), (ii), (iii), and (iv); To maintain this, an effective amount of liothyronine (LT3) or a salt thereof, This includes, where the patient is not a pregnant woman or a woman planning to become pregnant, and the microneedle device. (Item 2) The amount of LT3 or a salt thereof maintains a stable level of serum free T3 or total T3 in the microneedle device according to item 1. (Item 3) The microneedle device described in item 1 or 2 is a controlled-release device, an immediate-release device, or both. (Item 4) The microneedle device is a controlled-release device, as described in any one of items 1 to 3. (Item 5) The microneedle is a microneedle device according to any one of items 1 to 4, comprising LT3 or a salt thereof. (Item 6) The microneedle is a microneedle device according to item 5, comprising LT4 or a salt thereof. (Item 7) A microneedle device according to any one of items 1 to 6, wherein at least one of the microneedles comprises a biodegradable and / or biosoluble compound. (Item 8) The biodegradable and / or biosoluble compound comprises a polymer, a low molecular weight GRAS organic, or a combination thereof, as described in item 7 of the microneedle device. (Item 9) The biodegradable and / or biosoluble compound comprises a polymer, as described in item 7 or 8, for the microneedle device. (Item 10) The microneedle device according to item 8 or 9, wherein the polymer comprises polyvinylpyrrolidone, polyvinyl alcohol, polysaccharides (e.g., hyaluronic acid, chitosan, cellulose, alginate); poly(esters) (e.g., poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), poly(caprolactone)); poly(orthoesters); polylysine; poly(ethyleneimine); poly(acrylic acid); poly(urethane); poly(anhydride); poly(trimethylene carbonate); poly(ethyleneimine), poly(β-aminoesters), and copolymers thereof. (Item 11) The aforementioned patient with hypothyroidism is, in some cases, obese, according to items 1-10. A microneedle device as described in item 1. (Item 12) A microneedle device according to any one of items 1 to 11, further comprising a chemical permeability enhancer (CPE). (Item 13) The microneedle device according to item 12, wherein the CPE is anionic, cationic, zwitterionic, or nonionic. (Item 14) The microneedle device according to any one of items 6 to 13, wherein the LT4 or a salt thereof is in the same microneedle as the LT3 or a salt thereof, or in a microneedle different from the LT3 or a salt thereof. (Item 15) A microneedle device as described in any one of items 1 to 14, further comprising another therapeutic, prophylactic, or diagnostic agent. (Item 16) The drug is selected from the group consisting of peptides, proteins, carbohydrates, nucleic acids, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof, as described in item 15 for the microneedle device. (Item 17) The therapeutic agent is selected from the group consisting of LT4, thyroid hormone analogs such as LT4 or LT3 N-methyl, LT4 or LT3 N-ethyl, LT4 or LT3 N-triphenyl, LT4 or LT3 N-propyl, LT4 or LT3 N-isopropyl, LT4 or LT3 N-tert-butyl, 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxyacetic acid (GC-I), 3,5-diiodotyropropionic acid (DITPA), tetraiodotyroacetic acid (TETRAC), and triiodotyroacetic acid (TRIAC), or salts thereof, and is a non-peptide hormone; antibiotics; steroids; neuroactive agents; anesthetics; and sedatives, as described in item 15 or 16. (Item 18) The microneedle device according to item 15, wherein the diagnostic agent is selected from the group consisting of radioisotopes; radiopaque agents; metals; gases; and labels including chromatographic labels, fluorescent labels, or enzymatic labels. (Item 19) The microneedle device according to any one of items 1 to 18, wherein the length of the microneedle is between 10 μm and 1 mm (including the values ​​at both ends). (Item 20) The microneedle is a microneedle device according to any one of items 1 to 19, which provides an insertion depth of approximately 100 μm to less than 700 μm. (Item 21) A microneedle device as described in any one of items 1 to 20, including a three-dimensional array of needles. (Item 22) A microneedle device according to any one of items 1 to 21, further comprising an adhesive for securing the microneedle device during delivery. (Item 23) The substrate is flexible, as described in any one of items 1 to 22, for the microneedle device. (Item 24) A method for transdermally delivering LT3 or a salt thereof to a patient with hypothyroidism, wherein the method is: A step of providing a microneedle device as described in any one of items 1 to 23, A method that includes. (Item 25) The method according to item 24, further comprising the step of placing the microneedle device on the skin of the patient having hypothyroidism. (Item 26) The patient is a human patient or an animal, as described in item 24 or 25. [Brief explanation of the drawing]

[0012] [Figure 1] Figures 1A-1C are cross-sectional views of microneedle devices. The microneedle device in Figure 1A includes a reservoir and is suitable for transdermal drug delivery. The microneedle devices in Figures 1A and 1B include a deformable reservoir, where delivery is actuated by applying pressure to directly compress the reservoir manually (e.g., with a finger or thumb) (Figure 1B) or indirectly compress it (Figure 1C).

[0013] [Figure 2]Figure 2 is a cross-sectional view of another microneedle device, where delivery is actuated by manually applying pressure to compress the reservoir via a plunger.

[0014] [Figure 3] Figure 3 is a cross-sectional view of another microneedle device, where delivery is actuated by pushing in a plunger, which releases a compression spring that compresses the reservoir.

[0015] [Figure 4] Figures 4A and 4B are cross-sectional views of a microneedle device having a reservoir with multiple chambers.

[0016] [Figure 5] Figure 5 is a cross-sectional view of a microneedle device incorporating an osmotic pump to push drug contents from the reservoir mentioned above.

[0017] [Figure 6] Figures 6A–6C are cross-sectional views of a microneedle device having a microneedle containing a biodegradable and / or biodissolvable polymer and a drug to be delivered to a patient (e.g., LT3, or LT3 and LT4, or a salt thereof). In Figure 6A, the device includes a base and a bubble between the microneedle and the substrate. In Figure 6B, the device includes a junction between the microneedle and the substrate. In Figure 6C, the device includes a base between the microneedle and the substrate. [Modes for carrying out the invention]

[0018] Detailed description of the invention I. Definition In the context of a given compound, an "analog" refers to another compound that is structurally similar, functionally similar, or both to a particular compound. Structural similarity can be determined using any criterion known in the art (e.g., Tanimoto coefficients, which provide a quantitative measure of similarity between two compounds based on their molecular descriptors). Preferably, the molecular descriptors are 2D properties (e.g., fingerprint, topological index, and maximum common substructure) or 3D properties (e.g., overall shape) and molecular force fields. The Tanimoto coefficients range from 0 to 1 (inclusive of both ends) for dissimilar and identical pairs of molecules, respectively. A compound may be considered an analog of a given compound if it has a specified Tanimoto coefficient between 0.5 and 1.0 (inclusive of both ends), preferably between 0.7 and 1.0 (inclusive of both ends), and most preferably between 0.85 and 1.0 (inclusive of both ends). A compound is functionally similar to a particular compound if it induces the same pharmacological, physiological, or both effects as that particular compound.

[0019] The terms “effective dose” or “therapeutically effective dose,” as used herein, mean a sufficient amount of the drug being administered (e.g., LT3 or a salt thereof (e.g., its alkali salt) that is expected to alleviate to some extent one or more of the symptoms of the disease or condition being prevented (i.e., the amount necessary to maintain normal, stable serum total T3, free T3, free T3:free T4 ratio, total T3:free T4 ratio, and / or normalize serum TSH levels). The term “therapeutically effective dose” includes an “effective dose” of LT3 that achieves, for example, the desired pharmacological effect without excessive adverse side effects; or maintains stable serum levels of total T3, free T3, free T3:free T4 ratio, total T3:free T4 ratio, and / or normalizes serum TSH levels. Adverse side effects of overtreatment include osteoporosis, cardiac arrhythmias, hair loss, frequent bowel movements (bowel movements). Possible adverse effects of undertreatment include menstrual irregularities and psychosis (frequency of administration). Possible adverse effects of undertreatment include higher cholesterol levels, lower well-being, weight gain, menstrual irregularities, and a low basal metabolic rate that can lead to depression. It is understood that the “effective dose” or “therapeutically effective dose” may vary among subjects in some administrations due to variations in the metabolism of the administered compound, the age, weight, and general condition of the subject, the condition being prevented, the severity of the condition being prevented, and the judgment of the prescribing physician. It is also understood that the “effective dose” in long-release dosing formulations may differ from the “effective dose” in immediate-release formulations based on pharmacokinetic and pharmacodynamic considerations.

[0020] The terms "triiodothyronine" (T3), its synthetic form, and the drug name "liothyronine" (LT3) are used interchangeably. Similarly, "thyroxine" (T4), its synthetic form, and the drug name "levothyroxine" (LT4) are used interchangeably.

[0021] "GRAS" is an acronym for "Generally Recognized as Safe." Under Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act in question), any substance intentionally added to food is a food additive, and is subject to pre-market review and approval by the FDA unless the substance is generally considered to be adequately demonstrated to be safe under the conditions of its intended use by qualified experts, or unless the use of the substance is otherwise excluded from the definition of a food additive. Under Sections 201(s) and 409 of the relevant legislation, and under the FDA's implementing rules in Code 170.3 and Code 170.30, the use of a food substance may be GRAS (Generally Recognized as Safe) if it is either through a scientific procedure or, in the case of a substance used in food prior to 1958, through experience based on common use in food under Code 170.30(b). A scientifically recognized safety requires the same amount and quality of scientific evidence as required to obtain approval for the substance as a food additive. A scientifically recognized safety is based on the application of generally available and accepted scientific data, information, or methods (which are usually publicly available), and on the application of scientific principles, which may be confirmed by the application of unpublished chemical data, information, or methods. A database of compounds that meet the requirements defined by Code can be found in Title 21: Food and Drugs, Part 184.

[0022] Hypothyroidism can be defined as a deficiency in serum levels of endogenously produced thyroid hormones (Jonklaas et al., Thyroid 2014, 24:1670-1751). Hypothyroidism can also occur when an individual has low T4 levels and high TSH levels as a result of a dysfunctional thyroid. For example, TSH levels above 10 mIU / L accompanied by T4 levels below normal levels is clear evidence of hypothyroidism (Garber et al., Endocr. Pract. 2012, 18(6), 988-1028). Total T3, free T4, free T3, and TSH levels can be determined from serum of patients currently undergoing or who have previously undergone microneedle device treatment via standard analytical methods (e.g., enzyme-linked immunosolvent assay and radioimmunoassay) (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56; Conceicao et al., Thyroid 2018, 28(11), 1425-1433).

[0023] "Stable," in the case of serum levels of free or total T3 and / or free T4, refers to the level of one or both of these thyroid hormones that does not deviate by more than ±10% from the reference value within 1, 2, 3, 4, 5, or 24 hours after administration. Both total T3 and free T3 may be measured. For example, the reference value may be (i) free T3 in serum when T3 levels are used, (ii) total T3 in serum when T3 levels are used, (iii) free T4 in serum when T4 levels are used, or (iv) a value within the range of what is considered a normal level of TSH when serum TSH levels are used.

[0024] The appropriate medical ranges for TSH, T3, and T4 considered normal depend on where (Quest Diagnostics, LabCorp, Mayo Clinic, Abbott Architect, Beckman Coulter Unicel, Roche Cobas, Siemens Advia Centaur, etc.) and method (immunoassay or equilibrium dialysis / mass spectrometry) in which they are measured, as shown in the table below. [Table 1]

[0025] Table 2 in Barth et al., Annals of Clinical Biochemistry 2018, 55(1), 107-112 also provides the range of free T4 in pmol / L units.

[0026] "Transcutaneous" means delivery that crosses or enters the epidermis, dermis, or both, where the components of the delivery device (e.g., microneedle device) (e.g., microneedle) refer to delivery that penetrates the epidermis, dermis, or both, but does not reach the subcutaneous connective tissue beneath the patient's skin.

[0027] II. Microneedle Devices The above microneedle device preferably comprises at least two components: at least one, more preferably, a microneedle and a substrate to which the base of the microneedle is fixed or integrated. The above microneedle device preferably contains an effective amount of LT3 or a salt thereof (e.g., its alkali salt) to maintain normal and stable levels of total T3 or free T3 in serum; normalize serum TSH levels; and / or maintain a normal serum free T3:free T4 ratio, or to maintain a normal serum total T3:free T4 ratio, in patients who are not pregnant and suffering from hypothyroidism. In some forms, the above microneedle device contains LT3 or both LT3 and LT4, or a salt thereof. The above LT3 and LT4, or a salt thereof (e.g., its alkali salt), may be in the same reservoir or microneedle, or in different reservoirs or microneedles of the same microneedle device.

[0028] The above microneedle device may be a controlled-release device, an immediate-release device, or both. Preferably, the microneedle device is a controlled-release device. Preferably, the amount of LT3 or its salt (e.g., its alkali salt) is effective in maintaining a stable level of serum free T3 or total T3. Maintaining a stable level of serum free T3 may be important because these levels are typically kept to fluctuate by less than 10% throughout a given day (Gullo et al., PLoS One. 2011;6:e22552; Peterson et al., J. Clin. Endocrinol. Metab. 2016, 101(12):4964-4973; Conceicao et al., Thyroid 2018, 28(11), 1425-1433).

[0029] Furthermore, maintaining a normal serum free (or total) T3:free T4 ratio may be an important consideration in thyroid hormone delivery because higher serum levels of T4 can impair systemic T3 production by downregulating the deiodinase pathway (McAninch and Bianco, Ann. Intern. Med. 2016, 164:50-56). In a study of approximately 3800 healthy individuals, the serum free T3:free T4 ratio was approximately 0.32 (0.27-0.37, 95% CI) (Gullo et al., PLoS One. 2011;6:e22552). In another population study of approximately 9,700 healthy individuals, the free T3:free T4 ratio was 0.41±0.09, and the total T3:free T4 ratio was 149.6±40.7 (Peterson et al., J. Clin. Endocrinol. Metab. 2016, 101(12):4964-4973). Therefore, in some forms, based on studies reported in Peterson et al., J. Clin. Endocrinol. Metab. 2016, 101(12):4964-4973 and Gullo et al., PLoS One. 2011;6:e22552, the above LT3 is effective in maintaining serum free T3:free T4 ratios of approximately 0.32, 0.41±0.09, between approximately 0.27 and 0.37, between 0.27 and 0.42 (including values ​​at both ends), between approximately 0.30 and 0.42, or between 0.37 and 0.42 (including values ​​at both ends).

[0030] In some forms, the above microneedles are biodegradable and / or soluble and contain a drug to be delivered to the patient (e.g., LT3 or a salt thereof (e.g., its alkali salt)).

[0031] As a controlled-release microneedle device, the microneedle comprises LT3 or both LT3 and LT4, or a salt thereof, as well as a biodegradable and / or soluble polymer (e.g., polyvinylpyrrolidone). The LT3 and LT4 may also be provided in their salt forms (e.g., alkali salts).

[0032] As a controlled-release microneedle device, the microneedle releases LT3 or both LT3 and LT4 or a salt thereof, so that administration (e.g., application of the microneedle device) can be performed every 8 hours, daily, every other day, twice a week, weekly, once every 28 to 31 days, or up to every 3 months, depending on the indication.

[0033] As a controlled-release microneedle device, the microneedle comprises (i) LT3 or both LT3 and LT4, or a salt thereof, and a biodegradable and / or soluble polymer (e.g., polyvinylpyrrolidone), such that administration (e.g., application of the microneedle device) can be performed depending on the indication, every 8 hours, daily, every other day, twice a week, weekly, once every 28 to 31 days, or up to once every 3 months; and (ii) the microneedle releases LT3 or both LT3 and LT4, or a salt thereof.

[0034] Preferably, the above emission follows a zero-order emission dynamic in which burst emission is minimized or absent.

[0035] In some embodiments, the microneedle device further comprises, preferably, at least one reservoir connected (selectively fluid-connected) to the proximal end of at least one of the microneedles, either integrally or separately until the moment of use. In these embodiments, the reservoir contains the drug (e.g., LT3, or LT3 and LT4, and / or salts thereof).

[0036] Preferably, the microneedles are provided as a multidimensional array, in contrast to a microneedle device having a single microneedle or a row of microneedles. The microneedle device may be adapted to be a single-use disposable device or may be adapted to be fully or partially reusable.

[0037] drugs Preferably, LT3 is delivered by the microneedle device described above. The LT3 may be provided in its salt form (e.g., alkali salt). Other drugs to be delivered may also be provided in their salt form. The amount of LT3 or its salt may be selected by those skilled in the art based, for example, on the desired effect of LT3 or its salt at a planned release level and the period over which LT3 or its salt should be released. In some forms, the LT3 or its salt in the microneedle device is present in an amount that provides an effective amount of LT3 or its salt to a subject in need. For example, for an average adult weighing 70 kg, the effective amount may be LT3 / day between 2.5 μg and 45 μg (including both extreme values), LT3 / day between 5 μg and 20 μg (including both extreme values), or LT3 / day between 5 μg and 10 μg (including both extreme values). When the above microneedles act as reservoirs for LT3, or LT3 and LT4, or their salts, the daily amount may depend on the presence of biodegradable and / or soluble polymers, low molecular weight generally safe (GRAS) organic substances, the release kinetics of LT3 and / or LT4, their salts, or a combination thereof. "Low molecular weight" refers to compounds having molecular weights between 200 Da and 2,500 Da (including both extreme values), preferably nonpolymeric compounds.

[0038] Furthermore, other drugs may be delivered together with LT3 or a salt thereof using these microneedle devices. As used herein, the term “drug” refers to a compound that, when administered in vivo, for example to an animal (including mammals such as humans), has therapeutic, prophylactic, or diagnostic properties. The therapeutic, diagnostic, and / or prophylactic agents may be peptides, proteins, carbohydrates, nucleic acids, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof. Examples of appropriate therapeutic and / or prophylactic active agents include LT4, thyroid hormone analogs such as LT4 or LT3 N-methyl, LT4 or LT3 N-ethyl, LT4 or LT3 N-triphenyl, LT4 or LT3 N-propyl, LT4 or LT3 N-isopropyl, LT4 or LT3 N-tert-butyl, 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxyacetic acid (GC-I), 3,5-diiodotyropropionic acid (DITPA), tetraiodotyroacetic acid (TETRAC), and triiodotyroacetic acid (TRIAC), non-peptide hormones including sovethyrom, eprotirome, MB07811 / VK2809, MGL-3196, T2, T1AM, TA1, or salts thereof; antibiotics; steroids; neuroactive agents; anesthetics; and sedatives. Examples of suitable diagnostic agents include radioisotopes; radiopaque agents; metals; gases; and labels including chromatographic, fluorescent, or enzymatic labels.

[0039] Microneedles Solid microneedles In some forms, the microneedles are solid. “Solid” in this context means that the microneedles do not contain annular holes or channels from their base to their tip. In these forms, the microneedles can act as reservoirs for the drug being delivered to the patient (e.g., LT3, or LT3 and LT4, or salts thereof). Preferably, in these forms, the microneedles are made from biodegradable and / or biosoluble compounds (e.g., polymers), low molecular weight GRAS organic materials, or combinations thereof. In these forms, the microneedles may contain GRAS inactive excipients or additives. These excipients may enhance the incorporation of the drug into the microneedles, control the rate of degradation of the microneedles, affect the drug release kinetics, or be a combination thereof.

[0040] Preferably, when the microneedles act as a reservoir for a drug being delivered to a patient (e.g., LT3, or LT3 and LT4, or a salt thereof), the microneedle device may be applied to the skin, the substrate may be separated from the microneedles, and the microneedles may remain embedded in the skin for controlled release of the drug (e.g., LT3, or LT3 and LT4, or a salt thereof). Thus, the microneedle device may include means to facilitate the separation of the substrate from the microneedles. The means may be a junction, a bubble, or a combination thereof between the microneedles and the substrate.

[0041] Hollow microneedles The microneedles may be hollow; that is, each includes at least one substantially annular hole or channel having a diameter large enough to allow a pathway for a drug-containing fluid and / or solid substance through the microneedle. The hollow shafts may be linear, i.e., extending upward from the needle base to the needle tip, or they may take more complex paths, for example, extending upward from the needle base but thus connecting to one or more “portholes” or “slits” on the side of the needle rather than an opening at the needle tip. If the microneedle device includes hollow microneedles, the microneedle device may also include means for stopping the delivery of the drug (e.g., LT3, or LT3 and LT4, or a salt thereof). The microneedle device may also include velocity control means, which may be used to regulate the speed or degree at which a substance flows through the microneedle. In some forms, the velocity control means is located within the microneedle.

[0042] The above microneedles may be constructed from biodegradable and / or biosoluble materials, or non-biodegradable materials. Non-biodegradable materials include metals, ceramics, semiconductors, non-biodegradable organic compounds (e.g., non-biodegradable polymers), and composites. Some specific non-biodegradable materials include pharmaceutical-grade stainless steel, gold, titanium, nickel, iron, tin, chromium, copper, palladium, platinum, alloys of these or other metals, silicon, silicon dioxide, and polymers with a carbon backbone (e.g., polystyrene and polyolefins). "Composite" is a technical term referring to a substance comprising two or more different materials associated with each other through physical non-covalent interactions. Thus, composites may include metal alloys, as well as mixtures of non-metallic materials. Typical biodegradable and / or biosoluble materials include low molecular weight GRAS organic compounds and polymers. Examples of the polymers mentioned above include polyvinylpyrrolidone, polyvinyl alcohol, polymers of hydroxy acids (e.g., polylactide, polyglycolide, polylactide-co-glycolide, and copolymers thereof with PEG), polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone). Typical non-biodegradable polymers include polycarbonate, polyester, and polyacrylamide. Other soluble substances include sugars.

[0043] The above-mentioned microneedles should possess mechanical strength to remain intact while inserted into a biological barrier, while remaining in place for several days, and, where applicable, while being removed.

[0044] In a preferred embodiment, the microneedles are formed from a biodegradable and / or biosoluble compound (e.g., a biodegradable and / or biosoluble polymer). These microneedles must remain intact for at least a sufficient length of time for them to be inserted into a patient.

[0045] The above microneedles should be sterilizable using standard methods such as ethylene oxide or gamma irradiation.

[0046] The microneedles described above may have a straight or tapered shaft. In a preferred embodiment, the diameter of the microneedle is greatest at the proximal end and tapers to a point at the distal end from the proximal end. The microneedles may be manufactured to have a shaft that includes both a straight (non-tapered) portion and a tapered portion. The needles may not have a tapered end at all; that is, they may simply be cylindrical with a blunt or flat tip. Hollow microneedles having a substantially uniform diameter but not tapering to a point are referred to herein as “microtubes.” Microneedles may also include grooves on their sides to direct the drug from the reservoir in the substrate to the tissue at the insertion point. As used herein, the term “microneedle” includes both microtubes and tapered needles unless otherwise specified.

[0047] The microneedles may be oriented perpendicularly or at an angle to the substrate. Preferably, the microneedles are oriented perpendicularly to the substrate so that a higher density of microneedles per unit area of ​​the substrate can be provided. The array of microneedles may include a mixture of microneedle orientation, height, or other parameters.

[0048] The above microneedles may be formed from shafts having a vertically circular cross-section, or the cross-section may be non-circular. For example, the cross-section of the above microneedles may be polygonal (e.g., star-shaped, quadrilateral, triangular), rectangular, or another shape. The above shafts may have zero, one, or more holes. The cross-sectional diameter is typically between about 1 μm and 500 μm, preferably between 10 and 100 μm. The outer diameter is typically between about 10 μm and 100 μm, and the inner diameter is typically between about 3 μm and 80 μm.

[0049] In one configuration, the cross-sectional diameter is designed to leave a residual hole of less than approximately 0.2 μm (after microneedle insertion and withdrawal) to avoid creating a hole that would allow bacteria to enter the penetration wound. The actual microneedle diameter is typically in the range of a few microns, because the hole typically shrinks after the aforementioned microneedle is withdrawn. Larger diameters and longer microneedles are acceptable as long as they can penetrate the biological barrier to the desired depth.

[0050] The length of the above-mentioned microneedles is typically between approximately 10 μm and 1 mm (e.g., between 100 μm and 700 μm, between 100 μm and 600 μm, between 100 μm and 500 μm, or between 150 μm and 350 μm). The length is selected to suit the specific application, taking into account both the inserted and uninserted portions. The array of microneedles may include, for example, a mixture of microneedles having various lengths, outer diameters, inner diameters, cross-sectional shapes, and spacings between the microneedles. In percutaneous applications, the "insertion depth" of the microneedles is preferably between approximately 100 μm and less than 700 μm, or between approximately 100 μm and less than 600 μm, so that the insertion of the microneedles into the skin does not penetrate to the dermis and thereby avoid contact with nerves that may cause pain. In such applications, the actual length of the microneedles is typically longer. This is because the portion of the microneedle distal to the tip does not need to be inserted into the skin; the length that is not inserted depends on the specific device design and configuration. The actual (overall) height or length of the microneedle should be equal to the insertion depth plus the length that is not inserted.

[0051] The above microneedles typically have gauge sizes between 26 gauge and 31 gauge (including both ends), between 26 gauge and 32 gauge (including both ends), between 26 gauge and 33 gauge (including both ends), or between 26 gauge and 34 gauge (including both ends). Examples of gauge sizes include 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, and 31 gauge.

[0052] Base material The substrate for the above-described microneedle device can be constructed from a variety of materials (including metals, ceramics, semiconductors, organic materials, polymers, and composites). The substrate includes a base to which the microneedles are bonded or integrally formed. The substrate can be adapted to fit Luer lock syringes or other conventionally used drug delivery devices that currently use subcutaneous needles as a barrier penetration method.

[0053] In some forms of the microneedle device described above, the substrate, like other components, is formed from a flexible material to allow the microneedle device to conform to the contour of the biological barrier (e.g., skin) to which it is applied. Flexible microneedle devices can facilitate more consistent penetration of some biological barriers because penetration can be limited by asymmetry at the application surface. For example, the surface of human skin is not flat due to skin texture (i.e., fine wrinkles) and hair. However, for some biological barriers, a rigid substrate may be preferred.

[0054] Reserva The reservoir is selectively connected to the microneedle pores so that the contents of the reservoir can flow out of the reservoir and through the microneedle tips into the target tissue. Typically, the reservoir is bonded to or integrated with the substrate either integrally (as in a one-part device) or at the moment of drug delivery (similar to a Luer-lock type device). The reservoir provides adequate leak-free storage of the drug composition before delivery. The reservoir should keep the drug composition free from contaminants and degradation enhancers. For example, the reservoir should be light-shielded if the drug composition contains photosensitive substances and should include oxygen barrier material to minimize exposure of oxidation-sensitive drugs. The reservoir should also retain volatile substances inside to prevent, for example, water from evaporating and drying out the drug composition, rendering it undeliverable.

[0055] The drug reservoir described above may be substantially rigid or easily deformable. The reservoir may be formed from one or more polymers, metals, ceramics, or combinations thereof. In a preferred embodiment, the reservoir may contain a volume enclosed by one or more walls, or contain a porous material (e.g., a sponge, which may, for example, hold the liquid drug until the material is compressed).

[0056] In a preferred embodiment, the reservoir is formed from an elastic material (e.g., an elastomer polymer or rubber). For example, the reservoir may be a balloon-like pouch that stretches (in an extended state) when filled with the drug composition of the fluid to be delivered.

[0057] The reservoir of a single microneedle device may include a plurality of compartments separated from each other and / or from a portion of the microneedles in an array. The microneedle device may be provided, for example, for delivering different drugs through different needles, or for delivering the same or different drugs at different rates or in different times (Figure 4A). Alternatively, the contents of different compartments may be brought together by removing, for example, punctures or by other means, the barriers between the compartments so that the materials can mix. In a preferred embodiment, one compartment may contain a saline solution or another delivery vehicle, while another compartment contains a lyophilized drug (Figure 4B). In a preferred embodiment, the reservoir is a standard or Luer-lock syringe adapted to be connected to a microneedle array.

[0058] III. Preparation Method The above-mentioned microneedles and substrates are manufactured by methods known to those skilled in the art. Examples include microfabrication processes that involve creating small mechanical structures in silicon, metals, polymers, and other materials. Three-dimensional arrays of hollow microneedles may be manufactured, for example, using a combination of dry etching processes; micromolding and selective sidewall electroplating in polymers as defined by lithography; or direct microfabrication techniques using epoxy mold transfer. These methods are described, for example, in U.S. Patent Application No. 09 / 095,221 filed June 10, 1998; U.S. Patent Application No. 09 / 316,229 filed May 21, 1999; and Henry et al., "Micromachined Needles for the Transdermal Delivery of Drugs," Micro Electro Mechanical Systems, Heidelberg, Germany, pp. 494-98 (Jan. 26-29, 1998).

[0059] Non-limiting examples of fabricating three-dimensional arrays of solid microneedles are described in Li et al., Nat. Biomed. Eng. 2019, 3, 220-229. The above method generally involves applying a substrate to an array of separable microneedles capable of controllingly releasing a drug (e.g., LT3, or LT3 and LT4) over a desired time. The substrate may, after formation, include an array of pedestals positioned at the base of each microneedle to elevate the microneedles on the base of the substrate.

[0060] In short, a suitable mold (e.g., a polydimethylsiloxane mold) can be used to template the microneedles to fabricate the microneedle device. The microneedles can be arranged in a desired array, with a desired spacing between centers and area. The microneedles may have straight shafts, tapered shafts, or a combination thereof.

[0061] The fabrication of a microneedle device may involve the step of pouring one or more solutions into a mold. Preferably, at least one solution contains the drug (e.g., LT3, or LT3 and LT4, or a salt thereof) and the biodegradable and / or biosoluble compound (e.g., a biodegradable and / or biosoluble polymer, e.g., polyvinylpyrrolidone). The concentration of the solution may be selected so that the biodegradable and / or biosoluble compound exerts primary control over its drug release rate.

[0062] If necessary, a second casting solution containing a polymer (e.g., polyvinyl alcohol) and, optionally, another compound (e.g., sucrose) in a solvent such as deionized water may be applied to the mold surface to form some or all of the substrate. During this casting, bubbles may be trapped between the microneedles and the base of the substrate. The bubble size may be controlled by adjusting the volume of the second casting solution. After drying (e.g., in a chemical hood), the mold may be further placed in a desiccator at room temperature for complete drying, if necessary. The formed microneedle device may be carefully peeled from the mold and safely stored (e.g., in a desiccator) for later use.

[0063] IV.How to use The preferred patient population for the above microneedle device includes non-pregnant patients with hypothyroidism. It is not advisable to administer LT3 to pregnant women because T3 does not cross the placenta at appropriate doses. The placenta expresses large amounts of deiodinase, which inactivates T3 (Jonklaas et al., Thyroid 2014, 24:1670-1751). The fetal thyroid does not begin producing sufficient thyroid hormones until approximately 18-20 weeks of gestation. As a result, the fetus becomes dependent on maternal thyroid hormones in early pregnancy. Insufficient thyroid hormone availability can lead to delayed growth and development, and in its most severe form, a clinical syndrome known as cretinism. However, it should be noted that LT4 in the above microneedle device is acceptable to pregnant women, given that LT4 crosses the placenta.

[0064] The above microneedle device is applied to the skin of patients who need to maintain normal levels of serum TSH, serum free or total T3, and / or serum free (or total) T3:free T4 ratio. Preferably, the above microneedle device contains LT3 or a salt thereof. Preferably, the above patients have hypothyroidism. Than et al., Small Methods 2017, 1, 1700269 described percutaneous delivery of an anti-obesity compound (containing LT3) to convert white adipose tissue to brown adipose tissue as a strategy to treat obesity. However, the patient population and / or test mouse model described in Than et al., Small Methods 2017, 1, 1700269 is simply obese and not hypothyroid.

[0065] LT3 or its salts in the above-described microneedle device may be administered in single or multiple doses. LT3 or its salts may also be formulated for administration as immediate-release or controlled-release formulations. Certain factors may influence the dose required to effectively treat or improve hypothyroidism (including, but not limited to, the severity of the disease or disorder, prior prevention, the subject's overall health and / or age, and other pre-existing conditions). It is also recognized that the effective dose of the formulation used for treatment may increase or decrease over the course of a particular treatment. Dose changes may result and be evident from assay results.

[0066] In some forms, the reservoir of the above microneedle device contains LT3 or a salt thereof, which is formulated alone in a pharmaceutically acceptable excipient and delivered to patients in need.

[0067] In other forms, the reservoir of the microneedle device contains LT3 or a salt thereof, formulated alone in a pharmaceutically acceptable excipient, and is administered in combination with LT4 or a salt thereof in combination therapy. In these forms, LT3 or a salt thereof is used for supplementation in patients taking LT4 or a salt thereof. In this “combination therapy” regimen, LT4 or a salt thereof may be administered orally, transdermally, or both. When LT4 or a salt thereof is administered orally, it may be in the form of an oral solution, tablet, or pill. When LT4 or a salt thereof is administered transdermally, it may be administered via the same microneedle device containing LT3 or a salt thereof, or, if necessary, via a different microneedle device that does not contain LT3 or a salt thereof. When LT3 and LT4, or their salts, are administered via the same microneedle device, LT3 and LT4, or their salts, may be in the same reservoir or in different reservoirs of the same microneedle device.

[0068] Other additives and excipients The above microneedle device may also contain other additives and / or excipients.

[0069] These additives and / or excipients may be incorporated into the microneedles described above. Preferably, these are GRAS organic compounds. Typical GRAS organic compounds are nonionic. These include polysaccharides (e.g., cellulose); low molecular weight GRAS compounds (e.g., ascorbyl alkanate, sorbitan alkanoate, triglycerol alkanoate, sucrose alkanoate, glycocholic acid, retinyl acetate, and α-tocopherol acetate); or combinations thereof. The alkanoates mentioned above include hydrophobic C1-C linked via unstable linkages (e.g., ester, carbamate, thioester, and amide bonds) to ascorbyl, sorbitan, triglycerol, or sucrose molecules. 22 Alkyl compounds (e.g., acetyl, ethyl, propyl, butyl, pentyl, caprylyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, or behenyl) may be included. For example, ascorbyl alkanates may be ascorbyl palmitate, ascorbyl decanoate, ascorbyl laurate, ascorbyl caprylate, ascorbyl myristate, ascorbyl oleate, or any combination thereof. Sorbitan alkanoates may be sorbitan monostearate, sorbitan decanoate, sorbitan laurate, sorbitan caprylate, sorbitan myristate, sorbitan oleate, or any combination thereof. Triglycerol monoalkanoates may include triglycerol monopalmitate, triglycerol monodecanoate, triglycerol monolaurate, triglycerol monocaprylate, triglycerol monomyristate, triglycerol monostearate, triglycerol monooleate, or any combination thereof. Sucrose alkanoates may include sucrose palmitate, sucrose decanoate, sucrose laurate, sucrose caprylate, sucrose myristate, sucrose oleate, or any combination thereof.

[0070] In some forms, the above-mentioned additives and / or excipients may be incorporated into formulations containing LT3 or a salt thereof. In some forms, these other substances are in a separate reservoir from the one containing LT3 or a salt thereof. Typical materials include chemical permeation enhancers (CPEs), diluents, buffers, dispersants or viscosity modifiers, and stabilizers. Preferably, these additives and excipients do not cause problems such as skin irritation, discomfort, and / or sensitization.

[0071] Representative classes of CPEs include, but are not limited to, fatty acids, terpenes, fatty alcohols, medium-chain glycerides, surfactants, steroidal detergents, pyrrolidines, sulfoxides, laurocaprums, amides, amines, quaternary ammonium compounds, silicones, alkanoates, acylcarnitines, lauroyl-DL-carnitines, alkanoylcholines, N-acetylated amino acids, esters, salts, bile salts, sodium salts, nitrogen-containing rings, derivatives thereof, and combinations thereof. The above CPEs may be anionic, cationic, zwitterionic, or nonionic. Examples of anionic CPEs include, but are not limited to, sodium lauryl sulfate, sodium decyl sulfate, sodium octyl sulfate, N-lauryl sarcosinate, and sodium caprate. Cationic CPEs include, but are not limited to, cetyltrimethylammonium bromide, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonio chloride, and deodecyl pridinium chloride. Zwitterionic CPEs include, but are not limited to, decyldimethylammoniopropanesulfonate and palmityldimethylammoniopropanesulfonate. Fatty acids include, but are not limited to, butyric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidonic acid, oleic acid, linoleic acid, and linolenic acid, their salts, their derivatives, and combinations thereof. In some forms, fatty acids can be modified as esters, such as glycerides, monoglycerides, diglycerides, or triglycerides.Bile acids or bile salts (including conjugated or unconjugated bile acids CPE) may include, but are not limited to, cholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, taurodeoxycholic acid, ursodeoxycholic acid, tauroursodeoxycholic acid, chenodeoxycholic acid, derivatives thereof, salts thereof, and combinations thereof. In some forms, CPE may include metal chelating agents (e.g., EDTA or EGTA), surfactants (e.g., sodium dodecyl sulfate), polyethylene ethers or esters, polyethylene glycol-12 lauryl ether, salicylate polysorbate 80, nonylphenoxypolyoxyethylene, dioctyl sodium sulfosuccinate, saponins, palmitoyl carnitine, lauroyl-l-carnitine, dodecyl maltoside, acylcarnitine, alkanoyl cjolline, and combinations thereof. Other CPEs may include, but are not limited to, 3-nitrobenzoates, zoonula occulden toxins, fatty acid esters of lactates, glycyrrhizinates, hydroxyl β-cyclodextrins, N-acetylated amino acids (e.g., sodium N-[8-(2-hydroxybenzoyl)amino]caprylate and chitosan), their salts, their derivatives, and combinations thereof. An exemplary CPE is 1 wt% palmityldimethylammoniopropanesulfonate (PPS). CPEs are also described in Whitehead et al., J. Control. Release, 128 (2008) 128-133 and Whitehead et al., Pharm. Res., 25 (2008) 1782-1788 (the entire contents of these are incorporated herein by reference).

[0072] The term “diluent” refers to a compound that is used to dilute a formulation, preferably one containing LT3 or a salt thereof, before delivery, and which is preferably compatible with the epidermis and / or dermis.

[0073] The terms “dispersant” and / or “viscosity modulating agent” and / or “thickening agent” refer to substances that control the diffusion and uniformity of the formulation in the reservoir, preferably via a liquid medium. Examples of dispersants / diffusion-controlling substances include hydrophilic polymers, electrolytes, and TWEEN. (登録商標) 60 or TWEEN (登録商標) 80, PEG, polyvinylpyrrolidone (PVP; PLASDONE (登録商標) (also commercially known as), and carbohydrate-based dispersants, e.g., hydroxypropylcellulose (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcellulose (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), modified celluloses, polyvinyl alcohol (PVA), vinylpyrrolidone / vinyl acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer (also known as tyroxapol) with ethylene oxide and formaldehyde, polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone Examples include, but are not limited to, K30, polyvinylpyrrolidone / vinyl acetate copolymer (S-630), and polyethylene glycol.

[0074] Formulations containing LT3 or a salt thereof in the above reservoir may have a viscosity suitable for flowing through microneedles having gauge sizes between 26 gauge and 31 gauge (including both ends), between 26 gauge and 32 gauge (including both ends), between 26 gauge and 33 gauge (including both ends), or between 26 gauge and 34 gauge (including both ends).

[0075] The term “stabilizer” preferably refers to any buffer, acid, and preservative compound that is compatible with the epidermal and dermal environment. Examples of stabilizers include compounds that improve the compatibility between excipients and reservoirs or microneedles, improve the stability of formulation components, or improve formulation stability. [Examples]

[0076] V. Exemplary Microneedle Devices Examples Exemplary forms of the microneedle device described above are shown in Figures 1A-1C. The microneedle device 10 includes a substrate 12 from which a three-dimensional array of microneedles 14 protrudes. As shown, the annular holes of the microneedles 14 extend through the substrate 12. The microneedle device 10 also includes a reservoir 16 fixed to the substrate 12 via a sealing mechanism 18. Figure 1A shows how the reservoir can be directly accessed by application to the skin, for example, for simple transdermal delivery of a drug. The microneedle device in Figure 1B includes a deformable bubble reservoir 16. Its contents can be discharged at the application site using manual compression. Figure 1C shows a reservoir 16 separate from means 19 for discharging the contents of the reservoir 16 at the administration site. The discharge means 19 may simply be a flexible bag. The discharge means 19 may also include a vacuum so that it expands when discharged, generating pressure against the reservoir, or the discharge means may be elastic so that it deforms (not shown) when it is discharged from one position. Alternatively, the reservoir 16 may be formed from an elastic material that deforms when discharged.

[0077] The sealing mechanism 18 may be, for example, an adhesive material or a gasket. The sealing mechanism 18 may further function as a shatterable barrier or a rate-controlling film covering the surface of the substrate, or may include these. In this embodiment, nothing can be released until the seal or peel-off strip covering is removed.

[0078] Another embodiment of the microneedle device described above is shown in Figure 2. The microneedle device 20 includes a substrate 12 from which a three-dimensional array of microneedles 14 protrudes. The microneedle device 20 also includes a plunger 22 which is slidably fixed to the upper surface of the substrate 12 by a plunger guide frame 24 using a constraint such as a Luer lock interface 23. The substrate 12 can be coupled to or detached from a syringe 26 via a connector such as a Luer lock type attachment 23. The plunger 22, guide frame 24, and connector 23 are connected to form or include a reservoir 16. The Luer lock type attachment may instead be used to fix the microneedle device to a means (e.g., a pump) for controlling the flow or transport through the microneedle device.

[0079] A more preferred embodiment of the microneedle device described above is shown in Figure 3. As with the microneedle device in Figure 2, the microneedle device 30 includes a substrate 12, a microneedle 14, a plunger 22, a plunger guide frame 24, and a reservoir 16. The microneedle device 30 further includes a plunger housing 32, which is coupled to or integrally formed with the plunger guide frame 24. A compressed spring or other extension-based mechanism 34 is positioned between the plunger housing 32 and the plunger 22. The microneedle device 30 further includes a spring-holding / release mechanism 36, which holds the plunger upward (compressing the spring) until it is triggered to compress the reservoir 16.

[0080] Adhesion characteristics In some forms, the microneedle device includes an adhesive substance to fix the microneedle device to the skin, temporarily fixing the microneedles while they are inserted into the skin to deliver the drug. The adhesive is typically applied to the substrate (between the microneedles at their base) or to an adhesive collar or tab adjacent to the microneedles.

[0081] Care must be taken to ensure that no adhesive clogs the holes of the hollow microneedles. For example, the adhesive may be applied in a liquid solution by overflowing the top of the substrate beneath the tips of the microneedles (e.g., from the sides of the microneedle array), or by using a three-dimensional printing process. The solvent is then evaporated from the adhesive solution, which may cause the adhesive to precipitate or gel, resulting in a sticky surface. An alternative method to keep the adhesive from being present on the tips is to select a hydrophobic or hydrophilic building material to control surface wetting to the microneedle tips.

[0082] Start of delivery In some forms, the delivery of the drug from the reservoir is initiated by applying force (e.g., by pressing the top of the reservoir) to cause the contents of the reservoir (i.e., the drug-containing composition) to flow out through the microneedle (an active or dynamic process). For example, the user may apply pressure directly with their finger to a deformable reservoir "bubble" (Figures 1A-1C), a plunger mechanism (Figure 2), or a Luer-lock type syringe. This subsequently causes the drug composition to be pushed out of the reservoir. The plunger may also be adapted to operate by the application of a constant, reproducible force (e.g., a spring (e.g., under compression) (Figure 3) or an elastic band (e.g., in a stretched state)).

[0083] A variation of this configuration utilizes a balloon-like reservoir in an extended state to provide force. Then, when an opening is formed within the balloon reservoir, its contents are pushed out of the reservoir as the balloon contracts to its relaxed state. This contraction is selectively induced to provide driving force for delivery.

[0084] In some embodiments, the force breaks a shatterable barrier between the contents of the reservoir and the entrance of the microneedle. Typical barriers include thin foil, polymer, or laminant film. In other embodiments, the tip of the microneedle is blocked until immediately before use. The blocking material may be, for example, a peelable adhesive or gel film. These prevent the opening at the tip of the microneedle from clogging when the film is removed from the microneedle device.

[0085] Delivery may also be initiated by opening a mechanical gate or valve sandwiched between the reservoir outlet and the microneedle inlet. For example, a thin film or plate may be slid or peeled off from the back of the substrate.

[0086] In an alternative form, delivery is initiated by altering the physical or chemical properties of the drug composition and / or barrier material. For example, the barrier may be a porous membrane having porosity that can be selectively altered to allow flow, or the drug composition may be selected to change from a solid or semi-solid state to a fluid state (for example, as the temperature rises from ambient temperature to body temperature). Such drug compositions may be prepared, for example, by combining the drug with a biodegradable polymer material.

[0087] Another form of the microneedle device described above is shown in Figure 4A. Figure 4A shows a microneedle device 40 in which microneedles 14 bonded to a substrate 12 are bonded to a number of compartments 16a, 16b, 16c, and 16d. Each compartment may contain or function as a reservoir. Material can be discharged from each compartment through all or a portion of the microneedles 14.

[0088] Figure 4B shows a microneedle device 50 in which a microneedle 14 is coupled to a substrate 12, which is coupled to a reservoir 58 containing, for example, a lyophilized drug 54. The reservoir 58 is coupled to a shatterable barrier 52, which is coupled to another reservoir 56 containing, for example, saline solution. When the barrier 52 is shattered, the two reservoirs 54 and 56 become fluidly connected to each other, and their contents can mix.

[0089] Delivery can also be initiated by activating an osmotic pump, for example, as described in U.S. Patent No. 4,320,758 (Eckenhoff). The pump is adapted to the substrate of the microneedle device. For example, the reservoir / osmotic pump includes an inner flexible bag that holds the drug load, an intermediate layer of osmotically effective solute composition (e.g., an inorganic salt) enclosing the bag, and an outer shape-retaining membrane enclosing both the layer of osmotically effective solute composition that is at least partially permeable to water and enclosing the bag. During operation, the bag filled with the fluid drug composition is exposed to an aqueous environment, and as a result, water is absorbed from the environment by the osmotically effective solute, through the membrane, into the space between the inner flexible bag and the membrane. Because the bag is flexible and the membrane is rigid, the absorbed water compresses the bag inward, thereby transferring the drug from the microneedle.

[0090] Figure 5 shows a microneedle device 60 in which a microneedle 14 is coupled to a substrate 12 which is coupled to a drug reservoir 62. This reservoir is at least partially surrounded by a flexible, impermeable membrane 64. The drug reservoir is connected to another reservoir 66 containing, for example, an inorganic salt. The two reservoirs 62 and 66 are separated by an impermeable membrane 64, which is impermeable to the contents of both reservoirs 62 and 66. Reservoir 66 is also connected to another reservoir 68 containing, for example, an aqueous solution in which an organic salt is at least partially soluble. The two reservoirs 66 and 68 are separated by a rigid, semipermeable membrane 70, which is partially or completely impermeable to the salt in reservoir 66 and partially or completely permeable to the solution in reservoir 68. There are also fill ports or vents 72, as needed, that are in contact with the reservoir 68, through which substances can be added to or removed from the reservoir 68. Using this microneedle device 60, water can be drawn from the reservoir 68 through the semipermeable membrane 70 to the reservoir 66 due to osmosis caused by the presence of salt in the reservoir 66. The flow of water increases the volume of the reservoir 66 and thereby decreases the volume of the reservoir 62, which causes substances to be discharged from the reservoir 62 through the microneedles 14.

[0091] In an alternative form, delivery is initiated by opening a pathway between the reservoir and the tip of the microneedle, or by unblocking the opening of the tip, thereby simply allowing the drug to be delivered by diffusion (i.e., a passive process).

[0092] Other illustrative forms of the microneedle device described above are shown in Figures 6A-6C. Referring to Figure 6A, the microneedle device 70 includes a substrate 74 (which may be the same as the substrate 12 described earlier), from which a three-dimensional array of microneedles 71 protrudes. The microneedle device 70 also includes a base 73 on the substrate and a bubble 72 between the base 73 and the microneedles 71. In Figure 6B, the base 73 and bubble 72 are absent, resulting in a joint 75, which is formed at the interface between the substrate 74 and the microneedles 71. In Figure 6C, the bubble 72 is absent, and the microneedles rest on a base 73 supported by the substrate 74. The base may facilitate the complete insertion of the microneedles into the skin or other surface. The base may be made of the same or different material as the substrate. In some embodiments, the base is made of the same material as the substrate. Although shown as straight, the base may be tapered in these devices. In a tapered structure, the side surface in contact with the substrate may be wider than the side surface in contact with the microneedle.

[0093] Feedback about delivery In some embodiments, the microneedle device includes feedback means so that the user can (1) determine whether delivery has started; and / or (2) confirm that the reservoir is empty, i.e., delivery is complete. Typical feedback means include sound, color (change) indicator, or change in the shape of a deformable reservoir. In another embodiment, the feedback of completion of delivery is simply that the reservoir is pressed flat against the back of the substrate and cannot be further deformed.

[0094] Feedback on microneedle penetration into tissue Users of the above-mentioned microneedle device can typically determine, through visual or tactile means, whether the microneedles are properly inserted into the skin or other tissue, that is, whether the substrate is pressed essentially flat against the tissue surface. For example, if a pool of liquid drug composition appears near the microneedle device, the user may determine that the microneedles are not fully inserted, which suggests that the microneedle device needs to be reapplied. The liquid drug composition may contain colorants to enhance visual feedback.

[0095] In more complex forms, electrical or chemical measurements are adapted to provide the above feedback. For example, permeability may be determined by measuring changes in electrical resistance or pH in the skin or other tissue. Alternatively, electrical resistance between needles may be measured. In some forms, the microneedle device includes a disposable cartridge containing the microneedles. In these microneedle devices, an LED (e.g., green / red light) or liquid crystal display may be provided in conjunction with the reusable portion of the microneedle device.

[0096] Controlling delivery speed The microneedle device described above must have the ability to transport drugs across or into tissue at a useful rate. For example, the microneedle device must have the ability to deliver drugs at a rate sufficient to be therapeutically useful. The delivery rate of the drug composition can be controlled by changing one or more of several design variables. For example, the amount of material flowing through the needles can be controlled by manipulating the effective hydrodynamic conductivity (volumetric through-capacity) of a device array, for example by using more or fewer microneedles, by increasing or decreasing the number or diameter of holes in the microneedles, or by filling at least some of the holes in the microneedles with a diffusion-limiting material. However, it is preferable to simplify the manufacturing process by limiting the needle design to two or three "sizes" of the microneedle array to accommodate, for example, small, medium, and large volumetric flow rates, thereby allowing the delivery rate to be controlled by other means.

[0097] Other means for controlling the delivery rate include varying the driving force applied to the drug composition in the reservoir. For example, in a passive diffusion system, the drug concentration in the reservoir may be increased to increase the rate of mass transfer. In an active system, for example, the pressure applied to the reservoir may be varied, for example, by varying the spring constant or the number of springs or elastic bands.

[0098] In either an active or passive system, the barrier material may be selected to provide a specific diffusion rate for drug molecules to be delivered through the barrier at the needle inlet.

[0099] Other forms of controlling drug release include encapsulating the drug (e.g., LT3 or a salt thereof) within a microneedle containing a biodegradable and / or biosoluble compound (e.g., a biodegradable and / or biosoluble polymer). During the decomposition or hydrolysis of the substance, the drug is slowly released into the body over time after the microneedle device has been attached to the patient's skin. Suitable biodegradable and / or biosoluble polymers may include, but are not limited to, polyvinylpyrrolidone, polyvinyl alcohol, polysaccharides (e.g., hyaluronic acid, chitosan, cellulose, alginate); poly(esters) (e.g., poly(lactic acid), poly(glycolic acid), poly(lactide-co-glycolide), poly(caprolactone)); poly(orthoesters); polylysine; poly(ethyleneimine); poly(acrylic acid); poly(urethane); poly(anhydride); poly(trimethylene carbonate); poly(ethyleneimine), poly(β-aminoesters), and copolymers of these and / or other polymers.

[0100] The above-mentioned drugs (e.g., LT3 or a salt thereof) may also be provided in a controlled-release formulation in at least one of the above-mentioned reservoirs that are not microneedles. In these forms, the formulation in the reservoir may be a hydrogel containing the above-mentioned drug; or the formulation may contain nanoparticles and / or fine particles containing the above-mentioned drug (e.g., LT3 or a salt thereof). Materials that may be used to form a suitable hydrogel include polymers, e.g., polysaccharides (e.g., hyaluronic acid, chitosan, cellulose, alginate); poly(2-hydroxyethyl methacrylate) (pHEMA); poly(ethylene glycol) (PEG); poly(vinyl alcohol) (PVA); PEG-polyester copolymer; poly(N-isopropylacrylamide) (pNIPAAm); poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide); and gelatin. Materials that may be used to form suitable nanoparticles and / or fine particles include alginates, carbohydrates such as cellulose; polyhydroxyalkanoates; polyamides; polyphosphazenes; polypropyl fumarates; polyethers; polyacetals; polycyanoacrylates; biodegradable polyurethanes; polycarbonates; polyanhydrides; poly(orthoesters); and other biodegradable polyesters.

[0101] Multi-cartridge microneedle device Modifications of disposable, single-use microneedle devices utilize a reusable induction device (e.g., a plunger) in combination with a cartridge containing one or more, preferably multiple, single-use microneedle devices. For example, the cartridge may be a circular disk having an array of 10 or 12 microneedles connected to a single-dose reservoir. The cartridge can be loaded into or removed from the induction device. The induction device may be designed, for example, to move a new dose to a delivery position, compress the reservoir to deliver the drug, and then remove and immobilize the used array. This type of reusable induction device may also include a power source (e.g., a battery) used to operate a built-in measuring device, for example, for measuring interstitial fluid analytes or for electrical verification of needle penetration into the skin, as described earlier in this document.

[0102] Microneedle device packaging In some post-manufacturing forms of the above microneedle device, it is packaged for storage, transport, and sale before use. The above packaging should prevent contamination and damage. The above packaging should also prevent premature induction or release of any drugs or vehicle contents from the above reservoir.

[0103] It is particularly important that the microneedle device is provided with a removable protective cover or cushion that protects the microneedles from damage. The protective cover may also function to prevent premature leakage of drug substances from the microneedles. In a preferred form, an adhesive or gel film is used to selectively secure the cover that encloses the microneedles. In an alternative form, the film may be antiseptic and, after removal, act as a wipe to prepare the skin surface before insertion of the microneedles.

[0104] The above packaging may also be adapted to serve as a container for the safe disposal of used microneedle devices. In a preferred embodiment, a single-use microneedle device or material is provided that shears the needle from the substrate or clogs the microneedle to prevent undesirable reuse of the microneedle device. In one embodiment, the inner back surface of the reservoir is provided with an adhesive substance. When the reservoir is pressed against the back surface of the substrate after delivery of the contents of the reservoir, the adhesive substance is pushed into the opening of the microneedle, clogging the opening. In one embodiment of this microneedle device, the adhesive substance dries and hardens so that the substance cannot be easily removed.

[0105] Those skilled in the art can recognize or confirm many equivalents to specific embodiments of the inventions described herein by conventional experimentation alone. Such equivalents are intended to be covered by the following claims.

Claims

1. A microneedle device, wherein the device is a) A plurality of microneedles, each having a base end and a tip end; b) A substrate to which the proximal end of the microneedle is fixed or integrated; and c) When administered transdermally to patients with hypothyroidism: (i) Stable serum levels of free or total T3, T4, or both, (ii) Normal serum free T3:free T4 ratio, (iii) Normal serum total T3:free T4 ratio, (iv) Normal serum levels of thyroid-stimulating hormone (TSH), or (v)(i), (ii), (iii), and (iv) combinations; To maintain this, an effective amount of liothyronine (LT3) or a salt thereof, This includes, where the patient is not a pregnant woman or a woman planning to become pregnant, and the microneedle device.

2. The microneedle device according to claim 1, wherein the amount of LT3 or a salt thereof maintains a stable level of serum free T3 or total T3.

3. The microneedle device according to claim 1 or 2, wherein the microneedle device is a controlled release device, an immediate release device, or both.

4. The microneedle device according to any one of claims 1 to 3, wherein the microneedle comprises LT3 or a salt thereof.

5. The microneedle device according to claim 4, wherein the microneedle comprises LT4 or a salt thereof.

6. The microneedle device according to claim 5, wherein the LT4 or a salt thereof is in the same microneedle as the LT3 or a salt thereof, or in a microneedle different from the LT3 or a salt thereof.

7. The microneedle device according to any one of claims 1 to 6, wherein at least one of the microneedles comprises a biodegradable and / or biosoluble compound, and the biodegradable and / or biosoluble compound comprises a polymer, a low molecular weight GRAS organic substance, or a combination thereof.

8. The microneedle device according to claim 7, wherein the biodegradable and / or biosoluble compound comprises a polymer, the polymer comprising polyvinylpyrrolidone, polyvinyl alcohol, polysaccharide; poly(ester); poly(orthoester); polylysine; poly(ethyleneimine); poly(acrylic acid); poly(urethane); poly(anhydride); poly(trimethylene carbonate); poly(ethyleneimine), poly(β-aminoester), and copolymers thereof.

9. The microneedle device according to any one of claims 1 to 8, wherein the patient having hypothyroidism is obese.

10. The microneedle device according to any one of claims 1 to 9, further comprising a chemical permeability enhancer (CPE), wherein the CPE is anionic, cationic, zwitterionic, or nonionic.

11. The microneedle device according to any one of claims 1 to 10, further comprising another therapeutic, prophylactic, or diagnostic agent selected from the group consisting of peptides, proteins, carbohydrates, nucleic acids, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof.

12. The microneedle device according to claim 11, wherein the therapeutic agent is selected from the group consisting of non-peptide hormones including analogs of thyroid hormones selected from LT4, LT4 or LT3 N-methyl, LT4 or LT3 N-ethyl, LT4 or LT3 N-triphenyl, LT4 or LT3 N-propyl, LT4 or LT3 N-isopropyl, LT4 or LT3 N-tertbutyl, 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxyacetic acid (GC-I), 3,5-diiodotyropropionic acid (DITPA), tetraiodotyroacetic acid (TETRAC), and triiodotyroacetic acid (TRIAC), or salts thereof; antibiotics; steroids; neuroactive agents; anesthetics; and sedatives.

13. The microneedle device according to claim 11, wherein the diagnostic agent is selected from the group consisting of radioisotopes; radiopaque agents; metals; gases; and labels including chromatographic labels, fluorescent labels, or enzymatic labels.

14. The microneedle device according to any one of claims 1 to 13, wherein the length of the microneedle is between 10 μm and 1 mm (including the values ​​at both ends).

15. The microneedle device according to any one of claims 1 to 14, wherein the microneedle provides an insertion depth of 100 μm to less than 700 μm.

16. A microneedle device according to any one of claims 1 to 15, comprising a three-dimensional array of needles.

17. The microneedle device according to any one of claims 1 to 16, further comprising an adhesive for fixing the microneedle device during delivery.

18. The microneedle device according to any one of claims 1 to 17, wherein the substrate is flexible.

19. A microneedle device according to any one of claims 1 to 18 for transdermal delivery of LT3 or a salt thereof to a patient having hypothyroidism.

20. The microneedle device according to claim 19, characterized in that it is placed on the skin of the patient having hypothyroidism.

21. The microneedle device according to claim 19 or 20, wherein the patient is a human patient or an animal.

22. It is a microneedle device, a) A plurality of biodegradable microneedles, each having a proximal end and a tip; b) A substrate to which the proximal end of the microneedle is fixed or integrated; and c) In patients with hypothyroidism, an effective amount of liothyronine (LT3) or its salt in a sustained-release formulation released transcutaneously to maintain therapeutically effective serum levels of free or total T3. Microneedle devices, including [the specified element].

23. The microneedle device according to claim 22, configured to provide a sustained controlled release of an amount of LT3 or a salt thereof to maintain a stable level of serum free or total T3 in a patient with hypothyroidism.

24. The microneedle device according to claim 22, configured to provide a sustained controlled release of an amount of LT3 or a salt thereof to maintain a stable level of serum free T3 or total T3 in a patient with hypothyroidism.

25. The microneedle device according to claim 22, comprising a reservoir configured to provide controlled sustained release of LT3.

26. The microneedle device according to claim 22, wherein the microneedle comprises LT3 or a salt thereof that is released from the microneedle after administration to a patient having hypothyroidism.

27. The microneedle device according to claim 26, wherein the microneedle further comprises levothyroxine (LT4) or a salt thereof.

28. The microneedle device according to claim 22, wherein the microneedle comprises a biodegradable polymer.

29. The microneedle device according to claim 22, further comprising LT4 released transdermally.

30. The microneedle device according to claim 28, wherein the polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polysaccharide, poly(ester), poly(orthoester), polylysine, poly(ethyleneimine), poly(acrylic acid), poly(urethane), poly(anhydride), poly(trimethylene carbonate), poly(ethyleneimine), poly(β-aminoester), and copolymers thereof.

31. The microneedle device according to claim 22, wherein the amount of LT3 is effective for treating obese patients with hypothyroidism.

32. The microneedle device according to claim 22, further comprising a chemical permeability enhancer (CPE).

33. The microneedle device according to claim 32, wherein the CPE is anionic, cationic, zwitterionic, or nonionic.

34. The microneedle device according to claim 27, wherein the microneedle comprises LT3 and LT4, and the LT4 or a salt thereof is either in the same microneedle as the LT3 or a salt thereof, or in a different microneedle than the LT3 or a salt thereof.

35. The microneedle device according to claim 22, further comprising a therapeutic agent, preventive agent, or diagnostic agent other than LT3.

36. The microneedle device according to claim 35, wherein the therapeutic agent, prophylactic agent, or diagnostic agent is selected from the group consisting of peptides, proteins, carbohydrates, nucleic acids, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof.

37. The microneedle device according to claim 22, comprising a therapeutic agent selected from the group consisting of LT4 or LT3 N-methyl, LT4 or LT3 N-ethyl, LT4 or LT3 N-triphenyl, LT4 or LT3 N-propyl, LT4 or LT3 N-isopropyl, LT4 or LT3 N-tertbutyl, 3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)-phenoxyacetic acid (GC-I), 3,5-diiodotyropropionic acid (DITPA), tetraiodotyroacetic acid (TETRAC), and triiodotyroacetic acid (TRIAC), or salts thereof.

38. The microneedle device according to claim 35, wherein the diagnostic agent is selected from the group consisting of radioisotopes, radiopaque agents, chromatographic labels, fluorescent labels, and enzymatic labels.

39. The microneedle device according to claim 22, wherein the microneedle has a length between 10 μm and 1 mm (including the values ​​at both ends).

40. The microneedle device according to claim 22, wherein the microneedle provides an insertion depth of 100 μm to 700 μm.

41. The microneedle device according to claim 22, further comprising an adhesive for fixing the microneedle device during delivery.

42. The microneedle device according to claim 22, wherein the substrate is flexible.

43. A microneedle device according to claim 22 for transdermal delivery of LT3 or a salt thereof to a patient having hypothyroidism.

44. The microneedle device according to claim 43, characterized in that it is placed on the skin of a patient having hypothyroidism.

45. The microneedle device according to claim 43, wherein the patient is a human patient or an animal.

46. The microneedle device according to claim 22, configured to produce an improved serum free T3:free T4 ratio in a patient with hypothyroidism.

47. The microneedle device according to claim 22, configured to produce improved serum levels of thyroid-stimulating hormone (TSH) in a patient with hypothyroidism.

48. The microneedle device according to any one of claims 1 to 47, configured to release LT3 or a salt thereof transcutaneously for at least 8 hours in a patient having hypothyroidism to maintain a therapeutically effective serum level of free or total T3.

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