Lyophilized pharmaceutical compositions for naked DNA gene therapy
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Publication Number
US-11554179-B2
Publication Date
2023-01-17
Expiration Date
Abstract
The present invention provides a novel lyophilized pharmaceutical composition that maintains the stability of a DNA plasmid while forming a uniform and elegant cake during lyophilization. The novel lyophilization formulation further allows uniform reconstitution of the DNA plasmid in a pharmaceutically acceptable solution, enabling complete recover of the active ingredients, minimizing partial loss of potency and allowing administration of the active ingredients in an accurate and consistent manner. Additionally provided herein include methods of making the lyophilized pharmaceutical composition and methods of administering the composition for treatment of various diseases.
Core Innovation
The invention relates to a lyophilized pharmaceutical composition comprising plasmid DNA or a lyophilized “naked” DNA gene therapy product comprising plasmid DNA. The composition is obtained by lyophilizing a liquid composition that contains DNA of a first plasmid selected from VM202, pTx-HGF-X7, pTx-IGF-1Ec, pTx-IGF-1Ea, pTx-IGF-1X6, pTx-IGF-1X10, and pCK-SDF-1α, together with potassium phosphate buffer, mannitol, sucrose, and NaCl.
A central aspect is maintaining plasmid DNA predominantly in a supercoiled form rather than converting to open circular or linear forms. In particular embodiments, at least 95% of the plasmid DNA in the liquid composition is supercoiled, and at least 90% remains supercoiled after storage at 25°C for 7 days following reconstitution of the lyophilized pharmaceutical composition. Stability and conformation are assessed after reconstitution and storage.
Further embodiments define specific formulation parameters and presentation as a unit dose in a vial. The liquid composition may comprise 10 mM potassium phosphate buffer of pH 8.0, mannitol at 2% (w/v), sucrose at 1.0% (w/v), and NaCl at 0.45% (w/v), with DNA of a first plasmid at 0.5 mg/ml, and the vial contains 2.5 mg of plasmid DNA in total. Reconstitution by dissolving in water is described to produce a reconstituted composition, and light absorbance at 450 nm is used as a quantitative quality indicator.
Claims Coverage
The independent claims cover three inventive features centered on lyophilized plasmid DNA compositions prepared from a defined liquid formulation, with quantitative requirements for supercoiled content, reconstituted composition quality, and unit-dose vial content.
Lyophilized composition with defined liquid formulation
A lyophilized pharmaceutical composition comprising plasmid DNA obtained by lyophilizing a liquid composition comprising DNA of a first plasmid selected from VM202, pTx-HGF-X7, pTx-IGF-1Ec, pTx-IGF-1Ea, pTx-IGF-1X6, pTx-IGF-1X10, and pCK-SDF-1α; potassium phosphate buffer with pH 7.0 to 9.0; mannitol at 2% to 3% (w/v); sucrose at about 1.0% (w/v); and NaCl at 0.1% to 0.6% (w/v).
Predominantly supercoiled formulation with short-term storage retention
A lyophilized pharmaceutical composition comprising plasmid DNA obtained by lyophilizing a liquid composition comprising DNA of a first plasmid at 0.5 mg/ml selected from VM202, pTx-HGF-X7, pTx-IGF-1Ec, pTx-IGF-1Ea, pTx-IGF-1X6, pTx-IGF-1X10, and pCK-SDF-1α; 10 mM potassium phosphate buffer of pH 8.0; mannitol at 2% (w/v); sucrose at 1.0% (w/v); and NaCl at 0.45% (w/v), wherein at least 95% of the plasmid DNA in the liquid composition is supercoiled and at least 90% remains supercoiled after storage at 25°C for 7 days following reconstitution.
Unit dose vial with specified total plasmid DNA
A lyophilized pharmaceutical composition comprising plasmid DNA in a unit dose obtained by lyophilizing a liquid composition comprising DNA of a first plasmid at 0.5 mg/ml selected from VM202, pTx-HGF-X7, pTx-IGF-1Ec, pTx-IGF-1Ea, pTx-IGF-1X6, pTx-IGF-1X10, and pCK-SDF-1α; 10 mM potassium phosphate buffer of pH 8.0; mannitol at 2% (w/v); sucrose at 1.0% (w/v); and NaCl at 0.45% (w/v), wherein the lyophilized pharmaceutical composition is in a vial and the vial contains 2.5 mg of plasmid DNA in total.
Overall, the claims define lyophilized pharmaceutical compositions of plasmid DNA prepared from a specified liquid formulation using selected named plasmids and defined excipient and buffer components, and they require predominantly supercoiled plasmid DNA with retention after reconstitution and storage. The unit-dose claim further specifies a vial containing 2.5 mg total plasmid DNA.
Stated Advantages
Maintains plasmid DNA in a supercoiled form through lyophilization and reconstitution, with quantified retention requirements after storage.
Provides quantitative quality acceptance criteria for the reconstituted composition using light absorbance at 450 nm.
Documented Applications
Disease-treatment use of the lyophilized “naked” DNA gene therapy product with intramuscular administration described in the document.
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