Pharmaceutical formulation for intraduodenal administration comprising melevodopa and carbidopa
Inventors
INACIO, Ricardo • Saunders, Mark • MEHTA, Bhanvi • MUEHLHOELZL-ODOERFER, Kathrin • FONT, Isabel Sole • Caivano, Grazia
Assignees
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Publication Number
US-11844860-B2
Publication Date
2023-12-19
Expiration Date
Abstract
A pharmaceutical formulation for intraduodenal administration comprising melevodopa and carbidopa as active ingredients and one or more excipients. Once dispersed in an aqueous medium, melevodopa is completely dissolved, and carbidopa is present as nanoparticles.
Core Innovation
The invention relates to an aqueous pharmaceutical formulation for intraduodenal administration for severe Parkinson’s disease comprising melevodopa and carbidopa. The formulation includes one or more excipients and uses an aqueous vehicle in which melevodopa is completely dissolved while carbidopa is present as nanoparticles. The melevodopa and carbidopa are provided in a ratio of 1:5 by weight and the nanoparticle volume diameter is within 100 to 1000 nm.
Carbidopa nanoparticles are formed using routes that include micro-jet reactor precipitation and wet bead milling, together with excipients that act as stabilization agents and wetting agents. The micro-jet reactor precipitation is described with carbidopa in an acidic aqueous solution of HCl contacting a basic aqueous anti-solvent such as NaOH, followed by removal of the aqueous medium. The nanoparticles include reported drug loading values in the range of about 65% to about 90% and are characterized by particle size, DLS, PdI, and precipitation stability.
The invention further addresses solid and storage embodiments, including powder and lyophilized forms with cryoprotectants such as mannitol and trehalose for reconstitution in water. Stability and viscosity considerations include oxygen-exclusion storage in sealed containers. The document also describes reduced-volume administration and dispersion/homogeneity after storage, supported by turbidity/homogeneity and sedimentation analysis, along with analytical characterization including HPLC-UV and XRPD.
Claims Coverage
The claim set defines one aqueous intraduodenal formulation with three key inventive features: melevodopa completely dissolved, carbidopa present as nanoparticles, and a specified 1:5 by weight ratio, with a defined nanoparticle volume diameter range. Dependent claims refine the formulation with quantitative concentration ranges, narrower nanoparticle size ranges, specific excipient roles, and additional formulation forms and preparation or particle-surface refinements.
Intraduodenal aqueous formulation with dissolved melevodopa and nanoparticle carbidopa
An aqueous pharmaceutical formulation for intraduodenal administration, comprising carbidopa and melevodopa as active ingredients in a ratio of 1:5 by weight, and one or more excipients, wherein said melevodopa is completely dissolved, and said carbidopa is present as nanoparticles having a volume diameter of 100 to 1000 nm.
Quantified active concentrations for melevodopa and carbidopa
A pharmaceutical formulation defined by specific concentration ranges of melevodopa and carbidopa, including 50 to 150 mg/ml for melevodopa and 5 to 30 mg/ml for carbidopa.
Narrower carbidopa nanoparticle volume diameter window
A pharmaceutical formulation containing nanoparticles whose volume diameter is within 200 to 900 nm.
Dried powder formulation with reconstitution in water
A pharmaceutical formulation is provided as a dried powder that is reconstituted in water prior to use.
Micro-jet-controlled precipitation route for carbidopa nanoparticles from acidic HCl to basic anti-solvent
A formulation in which carbidopa nanoparticles are prepared by dissolving carbidopa with excipients in an acidic HCl aqueous solution, forming the nanoparticles by controlled precipitation into a basic aqueous anti-solvent using micro jet reactor technology, and then removing the aqueous medium.
Excipients adsorbed on the surface of carbidopa nanoparticles
A pharmaceutical formulation where at least one excipient is adsorbed onto the surface of carbidopa nanoparticles to coat them.
Overall, the claim set covers an aqueous intraduodenal formulation with completely dissolved melevodopa and carbidopa nanoparticles at a 1:5 weight ratio, with a defined nanoparticle volume diameter range. Dependent claims further narrow nanoparticle size and concentration ranges, add dried powder reconstitution embodiments, and specify nanoparticle preparation via micro-jet-controlled precipitation from acidic HCl into a basic anti-solvent and/or surface coating by excipient adsorption.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Intraduodenal administration for severe Parkinson’s disease.
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