Verona Pharma Plc

Peter Lionel Spargo

Edward James French

Phillip A Haywood

Julian Scott Northen

John Mykytiuk

Kevin Stephen Turner

Phillip Andrew Haywood

Philip A Haywood

The present invention relates to a process for producing a sterile liquid pharmaceutical composition suitable for administration by inhalation comprising ensifentrine particles, wherein the process comprises: (a) heating ensifentrine particles at a temperature of from 100° C. to 220° C. to obtain sterile ensifentrine particles; and (b) combining the sterile ensifentrine particles with a sterile liquid vehicle to produce the sterile liquid pharmaceutical composition suitable for administration by inhalation. A process for producing an ampule comprising the sterile liquid pharmaceutical composition is also described.

Formulation production process

The disclosure relates to a particulate composition comprising ensifentrine, wherein the particulate composition further comprises: from greater than 0.00 wt % to 0.60 wt % of 1,3-bis(2-(2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]isoquinolin-3(4H)-yl)ethyl)urea (BMIQU) relative to the total weight of ensifentrine; and from 0.00 wt % to 0.50 wt % of a biuret impurity of formula (A) relative to the total weight of ensifentrine. Further disclosed herein are liquid pharmaceutical compositions comprising the particulate composition, and a process for producing the particulate composition are also described.

Particulate composition

The present invention relates to a pharmaceutically acceptable acid addition salt of: (i) 9,10-dimethoxy-2-(2,4,6-tri-methylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554); and (ii) ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid.

Salt of a pyrimido[6,1-A]isoquinolin-4-one compound

The present invention relates to a liquid pharmaceutical composition suitable for administration by inhalation which comprises a diluent and a suspension of particles of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554) or a pharmaceutically acceptable salt thereof. Also described is a liquid pharmaceutical composition according to the invention for use in the treatment of the human or animal body.

Liquid inhalation formulation comprising RPL554

The present invention relates to a novel nitrile derivative of a pyrimido[6,1-a]isoquinolin-4-one compound of formula (A). The invention further relates to a process for producing a compound of formula (A). The invention also relates to a process which comprises reducing a compound of formula (A). Compounds of the invention are useful in the production of compounds such as RPL554. 

Compound and process

The present invention relates to a pharmaceutically acceptable acid addition salt of: (i) 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554); and (ii) ethane-1,2-disulfonic acid, ethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid.

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Canterbury, United Kingdom

Peter Lionel Spargo