Uridine triacetate amorphous formulation and its use
An amorphous uridine triacetate formulation with hypromellose acetate succinate and copovidone addresses bioavailability and stability issues, enabling effective treatment of energy deficiency disorders and fluoropyrimidine toxicity through enhanced oral delivery and mitochondrial energy modulation.
Patent Information
- Application Number
- JP2025502869
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2022-07-26
- Filing Date
- 2023-07-26
- Publication Date
- 2025-08-01
AI Technical Summary
The low oral bioavailability and stability issues of uridine triacetate, particularly at high doses required for therapeutic indications, hinder its effective delivery and treatment of energy deficiency disorders and fluoropyrimidine toxicity.
A composition of amorphous uridine triacetate formulated with hypromellose acetate succinate and optionally copovidone, produced through spray drying or hot melt extrusion, enhances stability and bioavailability, allowing high loading and improved oral delivery.
The amorphous formulation achieves enhanced stability, bioavailability, and effective delivery of uridine triacetate, particularly in energy deficiency disorders and fluoropyrimidine chemotherapy, by maintaining high plasma concentrations and targeting mitochondrial energy production.
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Abstract
Description
Background Art
[0001] Pyrimidine nucleoside uridine has several potential clinical uses, including the treatment of fluoropyrimidine toxicity and mitochondrial energy deficiency disorders. The barrier to the therapeutic use of uridine itself is poor oral bioavailability, which has been measured at approximately 7% - 10% in both humans and mice. Uridine triacetate, an ester prodrug of uridine, in its crystalline form improves oral bioavailability to approximately 50%. However, due to the need for relatively high doses (up to 5 - 10 grams / dose) of uridine triacetate for its therapeutic use in some disorders, further improvement in bioavailability is important to reduce the amount of drug required (and the corresponding cost), and particularly for therapeutic indications that benefit from high peak plasma uridine concentrations (Cmax). Such therapeutic indications include, but are not limited to, other energy deficiency disorders such as mitochondrial diseases and Huntington's disease, Down syndrome dementia, age-related dementia, and neuromuscular degeneration (sarcopenia), and vulnerability to secondary injury after acute brain injury (e.g., traumatic brain injury, concussion, ischemic or hemorrhagic stroke, asphyxia, etc.).
[0002] One important factor in regulating the rate and extent of plasma uridine delivery after oral administration of uridine triacetate is the dissolution rate of the crystals of this compound. The solubility of uridine triacetate in water is limited (approximately 10 milligrams per milliliter).
[0003] Due to the need for relatively high doses of uridine triacetate, a high ratio of uridine triacetate to formulation excipients is important, but a high ratio of uridine triacetate to excipients can result in poor stability, including crystal formation over time, and can cause both functional and regulatory problems. Additionally, the excipients must be safe in amounts compatible with the required amount of uridine triacetate.
Summary of the Invention
[0004] The present invention provides a composition comprising uridine triacetate formulated as an amorphous (non-crystalline) dispersion in one or more excipients, wherein the amount of amorphous uridine triacetate is from about 50 weight percent to about 60 weight percent of the composition, and one of the one or more excipients is hypromellose acetate succinate - MG, and the amount of hypromellose acetate succinate - MG is from about 37 weight percent to about 40 weight percent of the composition.
[0005] The present invention provides a method of delivering exogenous uridine to a mammalian subject in need thereof, the method comprising administering to the subject an effective amount of the composition. The methods of the present invention are useful for the treatment of mammalian subjects having a uridine deficiency state or an energy insufficiency disorder, or mammalian subjects undergoing fluoropyrimidine chemotherapy, and the exogenous uridine modulates the toxicity or efficacy, or both the toxicity and efficacy, of fluoropyrimidine chemotherapy. Detailed Description of the Invention
[0006] In one embodiment of the composition according to the present invention, one of the one or more excipients is copovidone. When the composition comprises copovidone, it is advantageous for the amount of copovidone to be about 12 weight percent of the composition, such as about 12.5 weight percent.
[0007] In a preferred embodiment of the composition according to the present invention, the amount of amorphous uridine triacetate is about 60 weight percent of the composition and the amount of hypromellose acetate succinate - MG is about 40 weight percent of the composition. In another preferred embodiment, the amount of amorphous uridine triacetate is about 50 weight percent of the composition and the one or more excipients comprise about 37.5 weight percent of the composition of hypromellose acetate succinate - MG and about 12.5 weight percent of the composition of copovidone.
[0008] The amorphous dispersion composition according to the present invention enables a high loading of uridine triacetate, appropriate stability during storage, and improved oral bioavailability compared to an equimolar dose of crystalline uridine triacetate particles. Further, the composition according to the present invention has an improved taste and texture compared to the coated granules of crystalline uridine triacetate currently on the market. The composition according to the present invention can optionally be mixed with a soft food such as applesauce, pudding, or yogurt within about 30 minutes before ingestion.
[0009] Generally, amorphous formulations are used when the pharmaceutical active ingredient (API) is very soluble, and thus a small amount of the API is made more soluble and is therefore biologically available. Amorphous formulations are generally not used with moderately soluble APIs such as uridine triacetate. The amorphous formulation of uridine triacetate enables the practical oral delivery of a large amount of the API. In the expressions “amorphous formulation” and “amorphous dispersion” of uridine triacetate, the term “amorphous” refers to the fact that uridine triacetate is non-crystalline.
[0010] The amorphous dispersion is produced by one of two basic methods: spray drying and hot melt extrusion. In spray drying, the drug and excipients (generally including polymers) are dissolved in a volatile solvent. The solution is sprayed as a fine mist, the solvent is evaporated by heat or vacuum, and the remaining fine particles are recovered. In hot melt extrusion, the drug and excipients are melted together, mixed, extruded, and cooled to yield a solid material, which can be milled to form particles of an appropriate size. According to the present invention, the particles can be milled to any conventional size. For example, it is convenient for the particles to have a D50 of about 200 microns.
[0011] The amorphous dispersed particles are optionally further formulated into aggregates and coated with a taste masking or release modulating excipient. The particles can also be incorporated into suspensions, capsules, or tablets that include minitablets small enough to pass through a gastrostomy or nasogastric tube, or are administered via an oral dosing syringe.
[0012] Uridine triacetate readily crystallizes under aqueous conditions. Thus, it was unexpected that heat melt extrusion compositions such as Formulation 1 (60% API / 40% HPMCAS-MG) and Formulation 2 (50% API / 37.5% HPMCAS-MG / 12.5% copovidone) were successfully created, showed stability, and were able to overcome the challenge of targeting very high drug loads (≥50% uridine triacetate) of APIs that tend to revert to a crystalline form, especially in the presence of moisture.
[0013] In the field of heat melt extrusion, it is common to add surfactants or plasticizers. Nevertheless, it has been found that the heat melt extrusion of the formulations according to the invention does not require the addition of surfactants or plasticizers (Examples 1 and 2). Without wishing to be bound by theory, it appears that uridine triacetate itself may act as a plasticizer.
[0014] The compositions of the present disclosure are beneficial in disorders or diseases where the delivery of exogenous uridine is beneficial, such disorders or diseases include uridine deficiency states (e.g., hereditary orotic aciduria, or biallelic CAD deficiency), modulation of the toxicity and / or efficacy of fluoropyrimidine chemotherapy, and various energy deficiency states, particularly energy deficiency states associated with either genetic or acquired mitochondrial dysfunction. The compositions of the present disclosure are particularly intended to optimize the treatment of energy deficiency disorders, which include: 1. Primary mitochondrial disorders (PMD) having a pathogenic mutation in either mitochondrial DNA or nuclear DNA that impairs mitochondrial energy production, 2. Chronic neurodegenerative diseases characterized by pathogenic defects in mitochondrial function, including but not limited to Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and dementia in Down syndrome. 3. Neuromuscular dysfunction or neuromuscular atrophy characterized by pathogenic mitochondrial dysfunction, including sarcopenia (associated with aging or early onset, exacerbated by chronic kidney disease, COPD, or heart failure), cachexia, disuse atrophy, and circulatory insufficiency (e.g., peripheral arterial disease or intermittent claudication). 4. Acute brain injuries, including but not limited to traumatic brain injury, stroke (both ischemic and hemorrhagic), birth asphyxia, cardiac arrest, drowning, and carbon monoxide poisoning. 5. Acute or chronic myocardial ischemia, left ventricular heart failure, and right ventricular heart failure (e.g., due to pulmonary hypertension).
[0015] A common feature of these energy deficiency disorders along with the success of treatment using the compositions of the present disclosure is the presence of genetic or acquired mitochondrial dysfunction that results in impairment of mitochondrial storage (or reserve) energy capacity, which is the ability to rapidly increase cellular energy production in response to demand, an important property since although ATP is not stored, it must be continuously generated by mitochondrial oxidative phosphorylation and glycolysis. The gap between energy production and utilization is a major determinant of cellular dysfunction and death across a wide variety of diseases and conditions exemplified by those listed above.
[0016] In the treatment of energy deficiency disorders, the primary pharmacokinetic and pharmacodynamic goal is to deliver sufficient uridine into cells to increase intracellular (particularly mitochondrial) uridine nucleotides, especially within the mitochondrial inner membrane space (IMS). Without being bound to a specific mechanism of action, one contribution of exogenous uridine to improving mitochondrial bioenergetic capacity is the activation of mitochondrial ATP-sensitive potassium channels in the inner mitochondrial membrane by an increase in the concentration of uridine diphosphate (UDP) in the mitochondrial membrane space (IMS). UTP (uridine triphosphate) and UDP are in equilibrium with the ratio of ATP to ADP via the enzyme nucleoside diphosphate kinase across the inner and outer mitochondrial membranes within the IMS. The ATP / ADP ratio, and thus the UTP / UDP ratio, acts as an indicator of the cellular bioenergetic state and an increase in ADP and UDP in the IMS occurs when mitochondrial ATP synthesis is impaired or cytoplasmic energy utilization increases to an extent that exceeds the replenishment rate by oxidative phosphorylation or glycolysis. The increase in total IMS uridine nucleotides with exogenous uridine delivered by uridine triacetate in the compositions of the present disclosure allows for a more rapid and extensive increase in UDP in the IMS when cellular bioenergetic capacity is decreased. Activation of mitochondrial ATP-sensitive potassium channels by UDP prevents disruption of optimal mitochondrial structure during acute energy disorders, particularly attenuating osmotic swelling of the IMS width and concomitant shrinkage of the mitochondrial matrix, the internal compartment of the mitochondria. The IMS width is a decisive determinant of the fuel oxidation rate and efficiency of the transfer of biologically available energy from ATP within the mitochondria to creatine phosphate in the cytosol, which allows for a more rapid equilibration of the potential for phosphorylation (energy) throughout the cell.The efficient function of mitochondrial creatine kinase (CK) enables the retention of ATP + ADP in mitochondria while transporting the generated creatine phosphate (CrP) from creatine to the cytosolic site where ATP is locally regenerated from CrP. This efficient function depends on maintaining the width of the IMS of approximately 90 angstroms such that the enzyme physically cross-links the inner and outer mitochondrial membranes. By promoting the maintenance of the IMS width, the compositions of the present disclosure reduce the decline in stored energy capacity in energy deficiency disorders, reduce cellular dysfunction, and improve health and survival. The energy state dependence of UDP production in the IMS enables the chronic treatment of energy deficiency disorders without the adverse effects of other classes of agents, which can open ATP-sensitive channels, even when cellular energy is abundant, resulting in inappropriate swelling of the mitochondrial matrix and narrowing below the optimal distance of the IMS width, which can impair oxidative phosphorylation. Thus, the compositions of the present disclosure have unique advantages over other regulators of mitochondrial ATP-sensitive potassium channel activity, particularly for the chronic treatment of energy deficiency disorders.
[0017] The optimal single dose of the compositions of the present disclosure for the treatment of energy deficiency disorders in human patients comprises 30 - 120 mg / kg of uridine triacetate (as well as polymers and other excipients), more specifically 60 - 100 mg / kg of uridine triacetate (e.g., as the active agent in a composition of 100 - 167 mg / kg containing 60% uridine triacetate in Example 1 below, or as a composition of 120 - 200 mg / kg containing 50% uridine triacetate in Example 2 below). It is administered orally 1 - 4 times per day, generally with 2 doses per day divided over approximately 8 - 12 hours.
[0018] In the case of treating disorders related to the central nervous system, the pharmacokinetic goal is to saturate uridine transport across the blood-brain barrier (mainly via endothelial pyrimidine transporters of the ENT family) and achieve peak plasma uridine concentrations above 100 micromolar. Optimal treatment of peripheral organs can be achieved with lower concentrations of plasma uridine than are required for treatment of the brain, since most other tissues have a restrictive epithelial barrier comparable to the blood-brain barrier.
[0019] Abbreviations and Definitions: HPMCAS means hypromellose acetate succinate (also known as hydroxypropyl methylcellulose acetate succinate). KF refers to the Karl Fischer method for determining water content. RH means relative humidity. CAD is an enzyme complex that catalyzes the rate-determining steps in pyrimidine nucleotide biosynthesis, carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase. Uridine triacetate is also known as 2’,3’,5’-tri-O-acetyluridine, or triacetyluridine.
[0020] The present invention will be better understood by reference to the following examples, which illustrate but do not limit the invention described herein.
Examples
[0021] Example 1: Amorphous solid dispersion consisting of 60% uridine triacetate and 40% hypromellose acetate succinate-MG An amorphous solid dispersion (ASD) consisting of 60% uridine triacetate (w / w) as the active pharmaceutical ingredient (API) and 40% hypromellose acetate succinate - MG (HPMCAS - MG) polymer was prepared by mixing uridine triacetate and hypromellose acetate succinate - MG in the ratios described in Table 1, and subsequently melt - extruding through a twin - screw extruder under heating. The cooled extrudate was milled to a D50 of approximately 200 microns.
[0022]
Table 1
[0023] Example 2: An amorphous solid dispersion consisting of 50% uridine triacetate and 37.5% hypromellose acetate succinate - MG and 12.5% copovidone An amorphous solid dispersion (ASD) consisting of 50% uridine triacetate (w / w) as the active pharmaceutical ingredient (API), 37.5% hypromellose acetate succinate - MG (HPMCAS - MG), and 12.5% copovidone was prepared by mixing uridine triacetate, hypromellose acetate succinate - MG, and copovidone polymers in the ratios described in Table 2, and subsequently melt - extruding through a twin - screw extruder under heating. The cooled extrudate was milled to a D50 of approximately 200 microns.
[0024]
Table 2
[0025] Example 3: Stability of ASD Formulation 1 and ASD Formulation 2 under long - term (25°C / 60%RH) and accelerated (40°C / 75%RH) conditions Formulation 1 (60% API) was stable for 12 weeks under long - term conditions (Table 3: 25°C / 60%RH) and accelerated conditions (Table 4: 40°C / 75%RH) without an increase in impurities or crystallinity as detected by HPLC and optical microscopy, respectively.
[0026] Formulation 2 (50% API) was stable for 12 weeks under long-term conditions (Table 5: 25°C / 60% RH) and accelerated conditions (Table 6: 40°C / 75% RH) without an increase in impurities or crystallinity as detected by HPLC and optical microscopy, respectively.
[0027]
Table 3
[0028]
Table 4
[0029]
Table 5
[0030]
Table 6
[0031] Example 4: Treatment of Primary Mitochondrial Disease A 10-year-old male patient was diagnosed with primary mitochondrial disease by the identification of pathogenic mutations known to impair mitochondrial oxidative phosphorylation (by whole exome sequencing and comparison to a database of known pathogenic genetic variants) in combination with symptoms consistent with PMD (in this case, including recurrent epileptic seizures, developmental delay, proximal renal tubular acidosis requiring bicarbonate supplementation, and exercise intolerance with early onset of fatigue during exercise).
[0032] Treatment with the compositions of the present disclosure is initiated at a dose of 60 mg of uridine triacetate per kg of body weight and administered twice daily, before breakfast and before dinner. Within about one week, the seizure frequency decreases by more than 50%, and the daily bicarbonate requirement to compensate for excessive urinary excretion due to proximal renal tubular acidosis is reduced from 200 milliequivalents per day to less than 25 milliequivalents per day. The treatment goal is to maintain plasma bicarbonate above 20 mEq / liter. After a few more weeks, endurance during exercise is improved as measured by timed walking distance and standard clinical measures of subjective fatigue.
[0033] Increasing the dose of uridine triacetate to 100 mg / kg per administration and administering it twice daily further reduces the seizure frequency.
Claims
**Claim 1** A composition comprising amorphous uridine triacetate dispersed in one or more excipients, wherein the amount of the amorphous uridine triacetate is about 50 weight percent to about 60 weight percent of the composition, wherein one of the one or more excipients is hypromellose acetate succinate - MG, and wherein the amount of the hypromellose acetate succinate - MG is about 37 weight percent to about 40 weight percent of the composition. **Claim 2** The composition according to claim 1, wherein one of the one or more excipients is copovidone. **Claim 3** The composition according to claim 2, wherein the amount of the copovidone is about 12 weight percent of the composition. **Claim 4** The composition according to claim 1, wherein the amount of the amorphous uridine triacetate is about 60 weight percent of the composition and the amount of the hypromellose acetate succinate - MG is about 40 weight percent of the composition. **Claim 5** The composition according to claim 1, wherein the amount of the amorphous uridine triacetate is about 50 weight percent of the composition and the one or more excipients comprise hypromellose acetate succinate - MG in an amount of about 37.5 weight percent of the composition and copovidone in an amount of about 12.5 weight percent of the composition. **Claim 6** The composition according to any one of claims 1 - 5, produced by heat - melt extrusion. **Claim 7** The composition according to claim 6, wherein the composition comprises particles having a D50 of about 200 microns. **Claim 8** The composition according to any one of claims 1 - 5, wherein the composition does not contain a plasticizer other than the amorphous uridine triacetate. **Claim 9** A method of delivering exogenous uridine to a mammalian subject in need thereof, the method comprising administering to the mammalian subject an effective amount of the composition according to any one of claims 1 - 5. **Claim 10** The method according to claim 9, wherein the mammalian subject has a uridine deficiency or an energy deficiency disorder or is undergoing fluoropyrimidine chemotherapy, and wherein the exogenous uridine modulates the toxicity or efficacy or both the toxicity and efficacy of the fluoropyrimidine chemotherapy. **Claim 11** A method for treating a mammalian subject having an energy deficiency disorder, the method comprising administering to the mammalian subject an effective amount of the composition according to any one of claims 1 to 5 for treating the mammalian subject.
12. The method according to claim 11, wherein the energy deficiency disorder is selected from the group consisting of primary mitochondrial diseases; chronic neurodegenerative diseases characterized by pathogenic defects in mitochondrial function; neuromuscular dysfunction or neuromuscular atrophy characterized by pathogenic mitochondrial dysfunction; acute brain injury; and heart diseases selected from the group consisting of myocardial ischemia and ventricular heart failure.
13. The method according to claim 12, wherein the chronic neurodegenerative disease characterized by a pathogenic defect in mitochondrial function is selected from the group consisting of Huntington's disease, Alzheimer's dementia, Parkinson's disease, amyotrophic lateral sclerosis, and Down syndrome dementia.
14. The method according to claim 12, wherein the neuromuscular dysfunction or neuromuscular atrophy characterized by pathogenic mitochondrial dysfunction is selected from the group consisting of sarcopenia, cachexia, disuse muscle atrophy, and circulatory insufficiency.
15. The method according to claim 12, wherein the acute brain injury is selected from the group consisting of traumatic brain injury, stroke, acute brain injury caused by birth asphyxia, acute brain injury caused by cardiac arrest, acute brain injury caused by drowning, and acute brain injury caused by carbon monoxide poisoning.
16. The method according to claim 11, wherein the mammalian subject is a human subject, the composition is administered in one or more doses, and each dose contains 30 to 120 milligrams of uridine triacetate per kilogram of body weight of the human subject.
17. The method according to claim 16, wherein the dose contains 60 to 100 milligrams of uridine triacetate per kilogram of body weight of the human subject.
18. The method according to claim 16 or claim 17, wherein the composition is administered orally.
19. The method according to any one of claims 16 to 18, wherein one to four daily doses of the composition are administered to the subject.
20. The method according to claim 19, wherein two daily doses of the composition are administered to the subject, and each dose after the second dose in the treatment process is administered 8 to 12 hours after the previous administration.