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Formulations of L-ornithine phenylacetate

A technology of phenylacetate and ornithine, applied in the field of L-ornithine phenylacetate preparations, can solve problems such as exhaustion, sudden deterioration of symptoms and the like

Pending Publication Date: 2021-11-05
OCERA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, such patients are at risk of a sudden exacerbation that can lead to acute-on-chronic liver failure on a chronic basis

Method used

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  • Formulations of L-ornithine phenylacetate
  • Formulations of L-ornithine phenylacetate
  • Formulations of L-ornithine phenylacetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Embodiment 1——preparation of coating controlled release preparation

[0110] Three controlled release oral pharmaceutical formulations of L-ornithine phenylacetate (Formulations 3, 5 and 6) were prepared. Formulations 3 and 6 contained sugar spheres ("Suglets") onto which a mixture of L-ornithine phenylacetate and hydroxypropylmethylcellulose (HPMC) in aqueous solution was sprayed and layered to an approximate weight percent of 35%. After drying, these spray-layered beads or pellets were further coated with a solution of ethylcellulose ("ETHOCEL™") in an organic solvent. By adjusting the amount of ethylcellulose coating applied, the release profile of the pellets can be tailored to produce the desired release profile. This distribution can be measured in vitro, for example by dissolution results, or by in vivo techniques, where the pharmacokinetic distribution of the drug in plasma (or other biological location, such as urine) is assessed. Formulation 3 is describe...

Embodiment 2

[0112] Example 2 - Pharmacokinetic studies in dogs

[0113]A pharmacokinetic study of a controlled-release oral formulation of L-ornithine phenylacetate was performed in dogs. Two groups (three each) of 6 dogs were used in the study. Controlled release formulations (formulations 3, 5 and 6 described in Example 1) were administered orally at a dose of 200 mg / kg. An immediate release formulation of L-ornithine phenylacetate in water was administered orally at a dose of 50 mg / kg. The AUC and plasma Cmax for the analyte L-ornithine and the phenylacetate metabolites phenylacetylglutamine (PAGN) and phenylacetic acid (PAA) are shown in image 3 middle. All controlled release formulations produced comparable PAGN and ORN pharmacokinetics, and the controlled release formulations had equal plasma Cmax to AUC ratios for PAA and PAGN.

[0114] The in vivo PK data of the metabolite PAA and the in vivo surrogate PD data of the metabolite PAGN in animal models were collected and shown...

Embodiment 3

[0115] Example 3 - Preparation of Large Pellets of Coated Controlled Release Formulation

[0116] Three controlled release oral pharmaceutical formulations of L-ornithine phenylacetate (Formulations A, B and C) were prepared following similar procedures as described in Example 1. Sugar spheres with an average diameter between 500 and 600 μm were used as cores. A mixture of L-ornithine phenylacetate and hydroxypropylmethylcellulose (HPMC) in water was then sprayed and layered onto the sugar spheres. In each case, the excipient talc was also used in forming the layered core pellets.

[0117] After drying, these layered core pellets were further coated with a slow release polymer selected from ethylcellulose or Eudragit NM 30D. The components of Formulations A, B and C are summarized in Table 1 below. The final pellets in Formulations A, B and C contained 15%, 30% or about 41% ER coating relative to the total weight of the pellets, respectively. The average diameter of the ...

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Abstract

Some embodiments of the present application are directed to oral formulations of L- ornithine phenylacetate and methods of preparing the same. These oral formulations offer altemative administration route than the standard intravenous administration of L-ornithine phenylacetate for treating hyperammonemia in patients having various acute and chronic liver diseases and disorders, for example, acute liver failure, liver cirrhosis, liver decompensation, portal hypertension, hepatic encephalopathy, or patients with urea cycle disorders.

Description

[0001] This application is a divisional application of the No. 201680036045.1 invention patent application filed on April 19, 2016 with the invention name "L-ornithine phenylacetate preparation". The invention patent application No. 201680036045.1 corresponds to the international application PCT / US2016 / 028298, the said international application entered the Chinese national phase on December 19, 2017. [0002] Incorporation by reference of the priority application [0003] This application claims U.S. Provisional Patent Application No. 62 / 150,238, filed April 20, 2015, U.S. Provisional Patent Application No. 62 / 150,676, filed Apr. 21, 2015, U.S. Provisional Patent Application No. 62 / 150,676, filed Apr. 28, 2015 62 / 211,619, U.S. Provisional Patent Application No. 62 / 255,300, filed November 13, 2015, and U.S. Provisional Patent Application No. 62 / 276,754, filed January 8, 2016; the entire contents of all of these applications are at This is expressly incorporated into this specif...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K31/198A61P1/16A61P3/00A61P7/00A61P9/12A61P25/00
CPCA61K31/198A61K9/0053A61P7/00A61P1/16A61P3/00A61P25/00A61P9/12A61K31/222A61K2300/00A61K9/5026A61K9/5047A61K9/5089
Inventor K·鲁特曼M·科芬J·伯恩斯坦G·古德森L·王
Owner OCERA THERAPEUTICS INC
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