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Solid compositions of triglycerides and uses thereof

a technology of triglyceride and solid composition, which is applied in the field of solid composition of triglyceride, can solve the problems of gastrin-related stomach spasm and emesis, difficulty in handling, carrying, and dispense, and difficulty in administering liquid dosage forms,

Inactive Publication Date: 2020-03-05
ULTRAGENYX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Several problems are associated with the liquid dosage form due to its physical and physiological properties.
First, the liquid dosage forms, such as oil, are difficult to be administered due to low miscibility with food or drinks.
Second, the oil formulations are difficult to be handled, carried, and dispensed.
Furthermore, upon administration, the oil composition is hydrolyzed and released rapidly in the stomach leading to gastric upset, gastric retention, and likely gastrin-related stomach spasm and emesis.
In addition, the oil formulations can cause diarrhea by reforming oil droplets and causing a mineral-oil like excess lubrication.
Upon repetitive administration of the oil, some patients experience gastric stress which causes vomiting and / or diarrhea.
Thus, the tolerability in the oil form can be a dose-limiting toxicity or lead to adverse effects, and the reduced administrable dose would negatively impact the treatment effect for a fatty acid oxidation disorder or deficiency (FAOD); adult polyglucosan body disease; a mitochondrial fat oxidation defect; a glycogen storage disease; a mitochondrial myopathy; glucose transporter type 1 (GLUT1) deficiency syndrome, or other related diseases.

Method used

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  • Solid compositions of triglycerides and uses thereof
  • Solid compositions of triglycerides and uses thereof
  • Solid compositions of triglycerides and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0132]Table 5 shows the high purity of exemplary triheptanoin oil samples and solid samples comprising triheptanoin oil in accordance with the present invention.

[0133]Further, the stability of an exemplary solid composition (solid sample 2 in Table 5) comprising triheptanoin oil was tested. Measurements were conducted after storage at 25° C. / 60% RH (relative humidity) in double LDPE (low density polyethylene) bags in a 60 cc induction sealed HDPE (high density polyethylene) bottle and results are shown in Table 6. Measurements were also conducted after storage at 40° C. / 75% RH in double LDPE bags in a 60 cc induction sealed HDPE bottle and results are shown in Table 7.

TABLE 5Initial Purity Test ResultsParameterSpecificationOIL Sample 1OIL Sample 2SOLID Sample 1SOLID Sample 2SOLID Sample 3ImpuritiesGlycerol≤1.0%NDNDNDNDNDMonoheptanoate≤0.5%NDNDNDNDNDDiheptanoate≤1.5%1.2%0.7%1.1%1.1%1.1%Hexano-≤1.0%0.4%0.4%0.4%0.4%0.4%DiheptanoateIndividualUnidentified≤0.5%RRT 0.91: 0.06%RRT 1.26: 0.2...

example 2

[0134]Single dose study of each arm with full pharmacokinetics (PK) profile through 48 hours post dose was performed to determined when metabolites return to baseline (one week washout between each arm) as well as if acute release of gastrin and cholesystokinin (CCK) hormones cause spasmodic stomach contractions. Blood samples were collected from each arm 0-90 min plus anytime outside this window if gastric distress observed.

[0135]More specifically, animals (n=3 / sex) were fasted prior to dose and fed 4 hrs post dose. Blood samples for PK analysis of triheptanoin and metabolites were collected pre-dose through 48 hrs post dose. As seen in the multiple dose study (Example 3), there were no major differences between males and females thus data was combined for all metabolites.

[0136]In FIGS. 1-21, animals were administered a single oral gavage dose level of a triheptanoin oil sample (i.e., the oil) or exemplary solid samples comprising triheptanoin oil in accordance with the present inv...

example 3

[0148]Multiple dose study was performed on the oil, the Powder and the Powder-ER as used in Example 2 and the results are shown below.

[0149]Powder Arm:[0150]Day 1: Animal #6501 vomited ˜1 hour post dose[0151]Day 3: Animal #6502 vomited[0152]Day 3: Animal #6510 gastric distressed observed

[0153]Oil Arm:[0154]Day 1: Animal 46501 vomited ˜3 hours post dose[0155]Day 1: Animal 46516 vomited ˜3 hours post dose[0156]Day 5: Animal #6509 gastric distressed observed

[0157]Powder ER Arm:[0158]No vomiting or gastric distress observed

[0159]Heptanoic Acid Across Dose Groups

[0160]Overall, results as expected, the triheptanoin releases heptanoic acid. Referring to FIG. 22, triheptanoin was metabolized primarily in liver to C7 fatty acids and ketone bodies which distribute via circulation to other tissues to provide an energy source. There were no triheptanoin values in oil arm. All triheptanoin oil was converted to C7.

[0161]Trace amounts of triheptanoin were observed in powder arm. The powder matrix ...

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Abstract

The present invention includes solid compositions of triglycerides with one or more fatty acids, such as triheptanoin and glycerol phenylbutyrate, and therapeutic use thereof. The solid compositions can be prepared by spray-drying or other processes.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a Continuation of U.S. application Ser. No. 14 / 419,601, filed on Feb. 4, 2015, which is a U.S. National Stage Application of International Application No. PCT / US2014 / 065693, filed on Nov. 14, 2014, which claims the benefit of U.S. Provisional Patent Application No. 61 / 904,369 filed Nov. 14, 2013, the contents of each of which are herein incorporated by reference in their entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to solid compositions of triglycerides with one or more fatty acids, such as triheptanoin and glycerol phenylbutyrate, and the therapeutic use thereof.BACKGROUND OF THE INVENTION[0003]Current dosage form of the triglycerides drug, e.g., triheptanoin, is a liquid with the consistency of oil. Several problems are associated with the liquid dosage form due to its physical and physiological properties. First, the liquid dosage forms, such as oil, are difficult to be administ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/23A61K31/20A61K9/14A61K9/16
CPCA61K31/23A61K9/146A61K31/20A61K9/143A61K9/1611A61K9/1652A61P21/02A61P25/08A61P3/00A61P9/10Y02A50/30A61K9/16A61K9/1664A61K31/201A61K31/202
Inventor KLOPP, JOHNMORRIS, GABRIELLEKAKKIS, EMILJUNGLES, STEVEN
Owner ULTRAGENYX PHARMA INC
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