Deformulation and Formulation of Multi-Component, Controlled Substance, Sustained Release Product for ANDA Submission and Commercialization

Benefits of Case:

• Deformulation and Formulation of 3 different strengths of a combination sustained release generic oral solid dosage form
• Progress client to ANDA submission with acceptable dosage forms

Background and Challenge:

The Client wanted a sustained release product deformulated and reformulated. The drug product contained two APIs which were both class II controlled substances in 3 different strengths. The new formulation could not infringe upon existing formulation patents covering a variety of methods to stabilize the drugs in the solid dose form. 

CoreRx® Development Strategy:

Tailor multidisciplinary team of formulation development, analytical chemistry and manufacturing to identify possible approaches for formulation development.

• Execute experiments to understand the formulation of the Reference Listed Drug (RLD), and explore possible formulations
• Review patent literature on the protected technologies used to stabilize the drug substance in the dosage form and determine which formulation approaches that permitted “freedom to operate”
• Identify a stable formulation and manufacture batches to support an ANDA filing 

The Objectives:

• Rapidly determine the qualitative and quantitative formulation of the RLD
• Identify approaches for a stable formulation with “freedom to operate”
• Complete formulation work without disruption to the proposed ANDA submission schedule 

Value for the Client:

CoreRx staff identified a stable formulation that met the client’s needs for planned ANDA submission and intellectual property requirements within 3 months. 

Results from CoreRx Combined Experience and Expertise:

CoreRx quickly assembled a team with expertise in formulations, analytical chemistry, organic chemistry, patents, and manufacturing to perform a thorough analysis of the RLD and determine a new sustained release formulation without infringing on existing patents. To quickly evaluate potential solutions to the stability problem, numerous experiments evaluating alternative formulation and packaging approaches were designed and performed. Once formulations were narrowed down, stability batches were made to identify the formula that would solve the stability problem and allow the development of the ANDA to meet the client’s previously established schedule.

Multi-layer, Dual Active Ingredient Re-formulation

Project: The client had a modified release, multi-layer, dual active pharmaceutical ingredient drug product which needed re-formulation into either a multi-layer or mono-layer tablet. There was substantial intellectual property regarding stabilization of one of the drug molecules, as well as various formulation patents which had to be circumvented. The project was seen as a potential “blockbuster” drug (a drug generating more than $1 billion of revenue for its owner each year). 

Assignment: Facing decreasing investor resources from the early phase of the project it was imperative that CoreRx, Inc. develop the drug product into various forms quickly and efficiently (for clinical trials) to ensure investors the project was on the right path to enhance future capital investment into the project from both private and public domain. 

Results: Within one year CoreRx™ formulated various prototypes in tri-layer, bi-layer and mono-layer tablet form, each with characteristic release profile in an attempt to “mimic” phase I in-vivo clinical release of each of the active pharmaceutical ingredients. These prototype formulations and processes were manufactured into an “experimental design” matrix to over-lay the phase I clinical data. The product is currently in Phase III development.

Reformulation to Achieve Acceptable Stability Profile for NDA Submission and Commercialization

Benefits of Case:

• Reformulation of unstable Phase III dose form
• Progress client to NDA submission with an acceptable dose form

Background and Challenge:

The Client had progressed into a clinical program with a sustained release combination drug formulation in which one of the drug substances exhibited an unacceptable long term stability profile, and the inert placebo layer consisted of a commercially unacceptable process. Alternate formulations had to be rapidly developed. Additionally, the new formulation could not infringe upon existing formulation patents covering a variety of methods to stabilize the drug in the solid dose form.

CoreRx® Development Strategy:

• Tailor multidisciplinary team of formulation development, organic chemistry and manufacturing to identify possible approaches for formulation development,
• Review patent literature on the protected technologies used to stabilize the drug substance in the dosage form and determine which formulation approaches that permitted “freedom to operate”,
• Execute experiments to understand the degradation pathway and sustained release profile for the drug substance, and explore possible formulation and/or packaging approaches for stabilization,
• Identify a stable formula and manufacture batches to support an NDA filing.

Value for the Client:

CoreRx staff identified a stable formulation that met the client’s needs for planned NDA submission and intellectual property requirements

Results from CoreRx Combined Experience and Expertise:

CoreRx quickly assembled a team with expertise in formulations, organic chemistry, patents, and manufacturing to perform a thorough analysis of technologies that could potentially solve the formula stability problem without infringing on existing patents. To quickly evaluate potential solutions to the stability problem, numerous experiments evaluating alternative formulation and packaging approaches were designed and performed. Once formulations were narrowed down, stability batches were made to identify the formula that would solve the stability problem and allow the development of the NDA to meet the client’s previously established schedule.