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Formulations comprising a nucleic acid in a high concentration

A nucleic acid and preparation technology, applied in the field of defibrillated glycosides, DNA and RNA vaccines, and can solve problems such as incompatibility

Pending Publication Date: 2020-05-08
JAZZ PHARMA IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The treatment regimen may not be compatible with other disease indications in which defibrotide may exhibit a therapeutic effect when administered as an outpatient

Method used

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  • Formulations comprising a nucleic acid in a high concentration
  • Formulations comprising a nucleic acid in a high concentration
  • Formulations comprising a nucleic acid in a high concentration

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] It is shown in Example 1 that increasing defibrotide concentration increases both viscosity and osmolarity. For pharmaceutical formulations for parenteral administration, low viscosity and / or isotonicity are important. To identify buffers or excipients that may reduce the viscosity and / or osmolarity of defibrotide formulations, a 200 mg / mL defibrotide formulation was performed on various buffers and excipients, including GRAS excipients. Wide plank screening.

[0140] As shown in Table 1 below, test formulations were prepared to target 200 mg / mL.

[0141] Table 1 : Defibrotide formulations using various buffers and excipients

[0142]

[0143]

[0144] Table 2: Solution Viscosity and Osmolality of Defibrotide in Gly-Gly-Containing Buffers as a Function of Product Concentration Compared to Sodium Citrate

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151] as in Tables 1 and 2 and Figure 1B , 1C As shown in the figure in and 2A, ...

Embodiment 6

[0178] 6.6 Example 6 - Pharmacokinetics of Nucleic Acid Formulations Using Various Routes of Administration

[0179] 6.6.1 Example 6.1 - Intravenous (IV) infusion, IV bolus injection, subcutaneous (SC) injection and intramuscular injection of defibrotide (IM) injection

[0180] When administered to male Gottingen pigs at doses via a single 2-hour intravenous (IV) infusion, IV bolus injection, subcutaneous (SC) injection, intramuscular (IM) injection, or oral (PO) gavage The pharmacokinetics (PK) of various defibrotide preparations were compared. Additionally, the bioavailability of various extravascular routes of administration was determined relative to IV infusion.

[0181] The male Gottingen pig or minipig is the industry standard for exploring subcutaneous delivery and is an accepted model for studying subcutaneous formulations and delivery options of defibrotide. As listed in Table 5 for treatment groups, each animal received a single administration of defibrotide...

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Abstract

Low-viscosity, high concentration nucleic acid compositions that can be administered by multiple parenteral routes may allow for less frequent dosing than nucleic acid products currently on the market. In particular, low-viscosity defibrotide formulations for subcutaneous, intramuscular, and intraperitoneal administration are more convenient to the patient and / or are administered outside of the hospital setting. Formulations of the invention may be used for the treatment of numerous conditions including for example, treatment of peripheral arteriopathies, treatment of acute renal insufficiency, treatment of acute myocardial ischemia, and treatment and prevention of sinusoidal obstruction syndrome or VOD.

Description

[0001] 1. Cross-references to related applications [0002] This application claims the benefit of priority to US Provisional Application No. 62 / 540,657, filed August 3, 2017, the contents of which are hereby incorporated by reference in their entirety. [0003] 2. Background technology [0004] Defibrotide is a nucleic acid salt, a complex mixture of random sequences, mainly single-stranded polydeoxyribonucleotides derived from animal mucosal DNA. It has a protective effect on vascular endothelial cells, especially those of small blood vessels, and has antithrombotic, anti-inflammatory and anti-ischemic properties. [0005] Sodium salt of defibrotide (Gentium S.r.L., Villa Guardia, Italy) and is currently approved for the treatment of hepatic veno-occlusive disease (VOD) (also known as sinusoidal obstruction syndrome (SOS)) following hematopoietic stem cell transplantation (HSCT) ) adult and pediatric patients with renal or pulmonary dysfunction. It is administered to pati...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K8/44A61K47/18A61K31/7088A61K9/08
CPCA61K9/0019A61K47/183A61K9/08A61K31/7105A61K48/00A61K31/711A61P9/00A61P9/04A61P9/10A61P7/02A61P35/00A61P31/00A61K31/7088
Inventor M.迪米特罗瓦W.J.本内特Q.王
Owner JAZZ PHARMA IRELAND LTD
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