Patent Application
20240009157
The present subject matter is directed to pharmaceutical compositions comprising 3,5-diiodothyropropionic acid, or a salt thereof, and one or more pharmaceutically acceptable excipients. The present subject matter is further directed to methods of treating Allan-Herndon-Dudley syndrome comprising administering compositions comprising 3,5-diiodothyropropionic acid, or salt thereof, and one or more pharmaceutically acceptable excipients to a subject in need thereof.
Allan-Herndon-Dudley Syndrome (“AHDS”) is an X-linked recessive developmental disorder causing intellectual disability and movement issues in males. Specifically, patients with AHDS have a mutant SLC16A2 gene resulting in a malformed monocarboxylate transporter 8 (“MCT8”) protein. Symptoms of AHDS are caused by a lack of cellular uptake of the thyroid hormone triiodothyronine (“T3”), which is normally transported across the cell membrane by MCT8. This MCT8 deficiency leads to a lack of T3 in tissues that need T3 to function properly contributing to an accumulation of T3 in the blood serum. The other thyroid hormone thyroxine (“T4”) usually remains at normal serum levels in AHDS patients but may also be slightly reduced from a normal level. Thyroid stimulating hormone (“TSH”) is normal to slightly elevated in AHDS patients.
Currently, no treatment for AHDS has been approved by the United States Food and Drug Administration. Clinical trials have been completed for the drug, triiodothyroacetic acid (“TRIAC”), for use in the treatment of AHDS. However, TRIAC shares a close structural similarity to T3, which makes it difficult to accurately assess T3 serum levels. Further, TRIAC has been shown to significantly reduce T4 serum levels.
3,5-diiodothyropropionic acid (“DITPA”) is another thyroid hormone analog that has been studied for treatment of AHDS. However, as mentioned above, DITPA has not been approved for use in the treatment of AHDS. This lack of approval may be due to a lack of effective dosing regimens, stable and effective compositions and extensive pharmacological assessments. While WO/2012/171065, published Dec. 20, 2012, attempts to establish DITPA dosing regimens for AHDS patients, this publication offers only theoretical examples.
Thus, there is a need in the art for stable and effective compositions containing DITPA.
The present subject matter is directed to pharmaceutical compositions comprising 3,5-diiodo-thyropropionic acid (“DITPA”) and one or more pharmaceutically acceptable excipients.
The present subject matter is further directed to methods of treating Allan-Herndon-Dudley syndrome (“AHDS”) or one or more symptoms of AHDS comprising administering compositions comprising DITPA and one or more pharmaceutically acceptable excipients to a subject in need thereof.
The Applicant has discovered compositions of 3,5-diiodothyropropionic acid (“DITPA”) that are surprisingly stable, and surprisingly effective for the treatment of Allan-Herndon-Dudley Syndrome (“AHDS”).
In one embodiment, the present subject matter is directed to pharmaceutical compositions comprising DITPA, or a salt thereof, and one or more pharmaceutically acceptable excipients.
In a preferred embodiment, DITPA, or a salt thereof, may present in the pharmaceutical compositions of the present subject matter at a concentration from about 0.001% to about 10% w/w or w/v.
In a preferred embodiment, the one or more pharmaceutically acceptable excipients may be present in the pharmaceutical compositions of the present subject matter at a concentration from about 90% to about 99.999% w/w or w/v.
Pharmaceutically acceptable excipients suitable for use in the present formulations include, but are not limited to, disintegrants, binders, fillers, plasticizers, lubricants, permeation enhancers, surfactants, sweeteners, sweetness enhancers, flavoring agents and pH adjusting agents.
The term “disintegrants” as used herein refers to pharmaceutically acceptable excipients that facilitate the disintegration of the tablet once the tablet contacts water or other liquids.
Disintegrants suitable for use in the present formulations include, but are not limited to, natural starches, such as maize starch, potato starch etc., directly compressible starches such as starch 1500, modified starches such as carboxymethyl starches, sodium hydroxymethyl starches and sodium starch glycolate and starch derivatives such as amylose, cross-linked polyvinylpyrrolidones such as crospovidones, modified celluloses such as cross-linked sodium carboxymethyl celluloses, sodium hydroxymethyl cellulose, calcium hydroxymethyl cellulose, low-substituted hydroxypropyl cellulose, alginic acid, sodium alginate, microcrystalline cellulose, methacrylic acid-divinylbenzene copolymer salts and combinations thereof.
Binders suitable for use in the present formulations include, but are not limited to, polyethylene glycols, soluble hydroxyalkyl celluloses, polyvinylpyrrolidone, gelatins, natural gums and combinations thereof.
Fillers suitable for use in the present formulations include, but are not limited to, dibasic calcium phosphate, calcium phosphate tribasic, calcium sulfate and dicalcium sulfate, lactose, sucrose, amylose, dextrose, mannitol, inositol and combinations thereof.
Plasticizers suitable for use in the present formulations include, but are not limited to, microcrystalline cellulose, triethyl citrate, poly-hexanediol, acetylated monoglyceride, glyceryl triacetate, castor oil, and combinations thereof.
Lubricants suitable for use in the present formulations include, but are not limited to, magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl behenate, micronized polyoxyethylene glycol, talc, and combinations thereof.
Permeation enhancers suitable for use in the present formulations include, but are not limited to, precipitated silicas, maltodextrins, P-cyclodextrins menthol, limonene, carvone, methyl chitosan, polysorbates, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, cetylpyridium chloride, edetate disodium dihydrate, sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate, dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glyceryl monostearate, citric acid, peppermint oil and combinations thereof. Surfactants suitable for use in the present formulations include, but are not limited to, sorbitan esters, docusate sodium, sodium lauryl sulphate, cetriride and combinations thereof.
Sweeteners suitable for use in the present formulations include, but are not limited to, aspartame, saccharine, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, dextrose, mannitol, glycerin, xylitol, and combinations thereof.
Sweetness enhancers suitable for use in the present formulations include, but are not limited to, ammonium salt forms of crude and refined glycyrrhizic acid.
Flavoring agents suitable for use in the present formulations include, but are not limited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil and combinations thereof.
pH adjusting agents suitable for use in the present formulations include, but are not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate, sodium acetate and combinations thereof. In another preferred embodiment, the pharmaceutical compositions of the present formulations do not contain a preservative.
Pharmaceutical compositions of the present formulations may be formulated in any dosage form including but not limited to aerosol including metered, powder and spray, chewable bar, bead, capsule including coated, film coated, gel coated, liquid filled and coated pellets, cellular sheet, chewable gel, concentrate, elixir, emulsion, film including soluble, film for solution and film for suspension, gel including metered gel, globule, granule including granule for solution, granule for suspension, chewing gum, inhalant, injectable including foam, liposomal, emulsion, lipid complex, powder, lyophilized powder and liposomal suspension, liquid, lozenge, ointment, patch, electrically controlled patch, pellet, implantable pellet, pill, powder, powder, metered powder, solution, metered solution, solution concentrate, gel forming solution/solution drops, spray, metered spray, suspension, suspension, syrup, tablet, chewable tablet, coated tablet, coated particles in a tablet, film coated tablet, tablet for solution, tablet for suspension, orally disintegrating tablet, soluble tablet, sugar coated tablet, dispersible tablet, tablet with sensor, tape, troche and wafer and extended release and delayed release forms thereof.
In a preferred embodiment, the pharmaceutical compositions of the present formulations are in tablet form. In a more preferred embodiment, the pharmaceutical compositions of the present formulations are in a dispersible tablet form. In an even more preferred embodiment, the pharmaceutical compositions of the present formulations are in a water-dispersible tablet form. In a most preferred embodiment, the pharmaceutical compositions of the present formulations are in a water-dispersible tablet form wherein the tablet is scored such that the tablet is dividable into four equal parts.
In a preferred embodiment, when the pharmaceutical compositions of the present formulations are in a water-dispersible tablet form the tablet dispersion time is about 70 seconds or less, more preferably about 60 seconds or less and even more preferably about 40 seconds or less, when the tablet is placed in at least one teaspoon of water.
In another embodiment, the present subject matter is directed to a method of treating Allan-Herndon-Dudley syndrome (“AHDS”) comprising administering compositions comprising DITPA, or a salt thereof, and one or more pharmaceutically acceptable excipients to a subject in need thereof. In another embodiment, the present subject matter is directed to a method of treating one or more symptoms of AHDS comprising administering compositions comprising DITPA, or a salt thereof and one or more pharmaceutically acceptable excipients to a subject in need thereof.
In a preferred embodiment, the compositions of the present subject matter are administered to a subject in need thereof once a day, more preferably twice a day and most preferably three times a day. Each administration may be one or more full tablets, or a portion of a tablet, such as ½ or ¼ of a whole tablet.
In another preferred embodiment, the compositions of the present subject matter are administered at a dosage of from about 0.1 to about 10 milligrams per kilogram of body weight of the subject per day (“mg/kg/day”), more preferably from about 1 to about 5 mg/kg/day and most preferably at about 2.5 mg/kg/day.
In a preferred embodiment, DITPA is administered to a subject that is less than 18 years old. In another preferred embodiment, DITPA is administered to a pregnant mother of a subject in need thereof.
In a preferred embodiment, the pharmaceutical compositions of the present subject matter are administered orally to the subject.
As used herein the term “pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable in an oral application.
As used herein, all numerical values relating to amounts, weights, and the like, are defined as “about” each particular value, that is, plus or minus 10%. For example, the phrase “10% w/w” is to be understood as “9% to 11% w/w.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.
As used herein “% w/w” refers to the weight percent by weight of the total formulation. As used herein “% w/v” refers to the weight percent by volume of the total formulation. As used herein the term “effective amount” refers to the amount necessary to treat a subject in need thereof.
As used herein the term “treatment” or “treating” refers to alleviating or ameliorating AHDS or symptoms of AHDS.
As used herein, the term “stable” includes, but is not limited to, physical and chemical stability. Pharmaceutically acceptable salts of that can be used in accordance with the current subject matter include but are not limited to hydrochloride, dihydrate hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, mesylate, maleate, gentisinate, fumarate, tannate, sulphate, tosylate, esylate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
Throughout the application, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.
The disclosed embodiments are simply exemplary embodiments of the inventive concepts disclosed herein and should not be considered as limiting unless the claims expressly state otherwise.
The following examples are intended to illustrate the present subject matter and to teach one of ordinary skill in the art how to use the formulations of the subject matter. They are not intended to be limiting in any way.
A water-dispersible tablet of the present subject matter, such as, for example, a tablet as in Example 1 (Table 1) above, typically completely dissolves in water, with mixing, in about 60 seconds or less. The resulting dispersion is then immediately orally administered to an infant.
The dispersion is imbibed by the infant and generally is well tolerated.
3,5-diiodothyropropionic acid (“DITPA”) was administered to a pediatric patient suffering from Allan-Herndon-Dudley Syndrome at a daily dosage of 1 mg/kg/day divided over three administration spaced 8 hours apart for 2 weeks. Following the first 2 weeks, the daily dosage was increased to 2 mg/kg/day for 2 additional weeks. Following the 2 additional weeks, T3 serum levels were assessed. The patient was found to have T3 serum levels more than 15% below normal. The patient was then administered DITPA at a daily dosage of 1.5 mg/kg/day for 28 days at which time T3 serum levels were reassessed. Upon reassessment T3 serum levels were normal.
The dosing regimen allows successfully identified proper dosing for the pediatric patient to maintain normal T3 serum levels.
DITPA was administered to a pediatric patient suffering from Allan-Herndon-Dudley Syndrome at a daily dosage of 1 mg/kg/day divided over three administration spaced 8 hours apart for 2 weeks. Following the first 2 weeks, the daily dosage was increased to 2 mg/kg/day for 2 additional weeks. Following the 2 additional weeks, T3 serum levels were assessed. The patient was found to have T3 serum levels more than 15% above normal. The patient was then administered DITPA at a daily dosage of 2.5 mg/kg/day for 28 days at which time T3 serum levels were reassessed. Upon reassessment T3 serum levels were normal.
The dosing regimen allows successfully identified proper dosing for the pediatric patient to maintain normal T3 serum levels.
DITPA was administered to a pediatric patient suffering from Allan-Herndon-Dudley Syndrome at a daily dosage of 1 mg/kg/day divided over three administration spaced 8 hours apart for 2 weeks. Following the first 2 weeks, the daily dosage was increased to 2 mg/kg/day for 2 additional weeks. Following the 2 additional weeks, T3 serum levels were assessed. The patient was found to have T3 serum levels more than 15% below normal. The patient was then administered DITPA at a daily dosage of 1.5 mg/kg/day for 28 days at which time T3 serum levels were reassessed. Upon reassessment T3 serum levels were again found to be more than 15% below normal. The patient was then administered DITPA at a daily dosage of 1.0 mg/kg/day for 28 days at which time T3 serum levels were reassessed. Upon reassessment T3 serum levels were found to be normal.
The dosing regimen allows successfully identified proper dosing for the pediatric patient to maintain normal T3 serum levels.
One child who started DITPA while having a G-tube, gained weight and the g-tube was removed. We designed a proposed Phase 3 study to be robust with endpoints intended to determine the clinical benefit of DITPA versus surrogate endpoints.
Below are the specific endpoints of the planned Phase 3 study and associated rationales:
Disease Models & Mechanisms. 9, 1339-1348.
Endocrinology. 156: 3889-3894.
Endo. 150(9): 4450-4458.
Our primary endpoint was chosen to ensure high probability of NDA success based on following factors:
The drug product is a tablet for suspension (i.e., dispersible tablet) designed to rapidly disintegrate in a small amount of aqueous media prior to administration. Each tablet strength may be quadrisectally scored to allow for administration of dosing of half or quarter tablets. This allows, for example with a 4 mg tablet, doses as low as 1 mg increments. A summary of the exemplary drug product attributes is presented in Table 2.
One intended commercial product will be a tablet for suspension (dispersible tablet) that is quadrisectally scored to allow partitioning of the tablet into halves or fourths, to allow a 4 mg tablet to be broken easily into 1 mg increments for dosing.
Two product strengths (4 and 10 mg) could be developed that will allow flexible dosing across the anticipated dose ranges for study PRZ-MCT8-101 and for commercial use. These two tablets, quadrisectally scored, provide easy dose portions of 1 mg, 2 mg, 2.5 mg, 4 mg, 5 mg, and 10 mg. Of course, multiple portions can be combined to provide additional dosage amounts, such as combining a 1 mg portion with a 2 mg portion to provide a 3 mg dose, or combining a 5 mg portion with a 2 mg portion to provide a 7 mg dose.
Qualification of the scored tablet will be characterized in accordance with FDA Guidance for Industry: Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (March 2013) and the specific studies outlined in EOP2/Pre-phase 3 FDA meeting package.
The drug product may be a tablet for suspension (dispersible tablet) quadrisectally scored so that it can be split into halves or fourths. See, for example,
The drug product components and composition are summarized in Table 3 below. All excipients are well-established for oral products and are at levels well below the respective maximum potencies listed in FDA's Inactive Ingredients (IIG) database. Therefore, there are no novel excipients involved in the manufacture of the drug product.
The primary container closure system will be blister packaging. Based on drug substance and drug product (i.e., capsules) from Titan studies, the drug is stable at ambient temperature and light. While the drug does not appear to have hygroscopicity, the formulation itself will be evaluated accordingly to assess for any need for moisture mitigation.
One exemplary manufacturing process consists of compounding and blending SRW101 and excipients stepwise in a tote bin blender to form a common 10 kg blend (commercial batch size). From the common blend, the 4 and 10 mg tablets may be compressed using, for example, an IMA Comprima tablet press.
Exemplary lots will be manufactured at full scale (10 kg) using the intended commercial manufacturing process. The 4 and 10 mg product strengths will be manufactured from the same 10 kg blend.
The exemplary drug product specification is provided in Table 4. The specification will be developed in accordance with ICH-Q6A. All non-compendial methods (i.e., in-house HPLC for assay, degradation products, and dissolution sample testing) would be fully validated prior to the release of the clinical drug product lots. All compendial methods will be qualified prior to the release of clinical drug product lots. The degradation product method will be validated to be stability indicating with forced degradation studies (i.e., heat, light, acid, base, and oxidation).
The limits for degradation products will be qualified for safety in accordance with ICH-Q3B Impurities in New Drug Products.
E. coli
In addition to dispersion of the tablet in water, studies will be performed to evaluate and ensure the adequate dispersion (physical tests) of divisible portions of the tablet in other vehicles (i.e., formula milk and apple sauce).
The tablet is intended to be hand split in halves or quarters by breaking along the scored lines cut into the surface of the tablet. See
The drug product manufactured with the reprocessed drug substance batch and NDA Registration Lot will be placed in stability studies under long-term, intermediate, and accelerated environmental conditions as outlined in Table 19.6 and in accordance with ICH-Q1A(R2). Drug product maintained under intermediate conditions will be tested at every time point versus at time of out-of-specification (OOS) results during testing of drug substance under accelerated stability conditions.
Photostability studies will also be performed in accordance with ICH-Q1B. 6-month stability data will be developed for all three stability conditions (i.e., long-term, intermediate, and accelerated conditions) along with photostability data.
It is to be understood that the DITPA formulations and regimen for treating AHDS or a symptom of AHDS are not limited to the specific embodiments described above but encompass any and all embodiments within the scope of the generic language of the following claims enabled by the embodiments described herein, or otherwise shown in the drawings or described above in terms sufficient to enable one of ordinary skill in the art to make and use the claimed subject matter.
This application claims the benefit of U.S. Provisional Patent Application No. 63/388,241, filed on Jul. 11, 2022, the content of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63388241 | Jul 2022 | US |
