Big Questions - Accelerating Proof of Concept

Big Questions

The “Big Questions” must be answered in order to accelerate proof of concept.  Improved Pharma focuses on quickly answering these questions and then using this information to reduce the time to reach the Proof of Concept, Phase II clinical trial.  Our goal is to go from structure on paper to the start of a Phase 2 clinical trial in 30 months or less.

The Big Questions are:

1.What is the structure of the compound?

2.What is the likely dose?

3.What is the route of administration and desired dosage form?

4.What is the indication?

5.How difficult is it to synthesize?

6.How soluble is the compound/formulation?

7.What is the toxicology of the compound? What is the NOAEL?

8.How well is the compound absorbed? What is the BCS class of the compound?

9.What are the solid state properties of the compound/formulation?

10.How chemically stable is the compound/formulation?

11.How physically stable is the compound/formulation?

12.How well will the powder flow?

13.What is the design, composition, and manufacturing procedure of the formulation?

14.Is moisture an issue?

15.What is the maximum dose in humans?

16.What doses should be used for the Phase 2 clinical trial?

Questions 1 through 5 can typically be answered based on the drug discovery research that has already been carried out.

Questions 6 through 8 are typically determined by preformulation studies and toxicology studies.  An important aspect of these early studies is getting the formulation for toxicology correct. To do this it is necessary to answer one of the central questions, question 9 – What are the solid state properties of the compound?  This requires a rapid screen for the best solid form.  Improved Pharma tries to make sure this screen is carried out in 20 weeks or less and includes a polymorph, salt and possibly a cocrystal screen and a screen for sub-micron particles.  This screen is carried out in parallel with the large scale synthesis of the drug.  At the end of this 20 week period a solid form is selected and synthesized as the last step in the scale–up of the synthesis.  In most cases this solid form can be directly used for the toxicological formulation and then later for the first in human studies.  If possible, the solid form is filled directly into capsules.  Alternatively, powder in a bottle is used.

Questions 10 through 12 are answered in the course of the synthesis of the large scale batch and by stability experiments carried out both during and immediately after the solid form is selected (question 9).

Questions 13 and 14 are answered next.  After the form has been selected and its properties are known a formulation is developed.  This formulation needs to be stable and have good bioavailability.  The simplest possible formulation will be used.

The last two questions involve dose.  The first in human trial will used the NOAEL from the toxicology studies to provide information in determining the maximum dose for humans.  This dose along with therapeutic considerations will be used to arrive at the dose(s) for the phase 2 clinical trial.  Dosage forms will be manufactured containing the required doses.

The overall goal of Improved Pharma is to enable its clients to be able to begin a Phase 2 clinical trial in 30 months.  Improved Pharma utilizes its subcontractors along with the FPOC program to accelerate the development process.

Solubility and Poorly Soluble Compounds

To accelerate proof of concept it is particularly important to optimize solubility.  Improved Pharma has extensive experience with poorly soluble materials. Improved Pharma will usually use amorphous dispersions, cocrystals, or salts to improve solubility.

Stability

During the solid form screening, extensive stability studies under accelerated and forced degradation studies are performed. These studies focus on both chemical and physical stability of the solid form. Improved Pharma has a strategy using a minimum of experiments to obtain information on the stability of clinical supplies. These stability studies are used to select the form for manufacture into clinical supplies.

API Synthesis

Improved Pharma's external partners/subcontractors have outstanding experience and capability in synthesizing APIs. Typically, these collaborators synthesize enough API during the exploratory phase to allow form screening and selection of the best form for IND and POC (Phase 2) clinical supplies.

Preclinical Studies

Preclinical studies are performed at one of Improved Pharma's third party providers. Because of their importance, only the best providers are included in Improved Pharma's network. The preclinical studies are carried out on the most soluble, stable solid form to insure maximum exposure of the animals.

FPOC

FPOC is a template-based software tool that provides instantaneous feedback on the progress of a project. This allows fast, informed decision making.  FPOC also contains a stability prediction module that facilitates decision making in cases where development is difficult due to stability problems. FPOC is currently under development.

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Powerful methods of analysis including IVIVC

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Informatics system to insure quality documents

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Strong IP assigned to client

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Quality by Design for formulations

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Rapid assessment of the risk of stability problems

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Fast screening for the right solid form....