1.Areas where new development tools could accelerate progress
Download
1 / 30

1.Areas where new development tools could accelerate progress -- Formulation -- Glycosylation - PowerPoint PPT Presentation

1.Areas where new development tools could accelerate progress -- Formulation -- Glycosylation 2.Potentially important future areas of medical development -- Nanotechnology -- Tissue Engineering Other variables process 1 solvent 2 3 4 Impact of TransForm Technology Traditional

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha

Download Presentation

1.Areas where new development tools could accelerate progress -- Formulation -- Glycosylation

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


1.Areas where new development tools could accelerate progress

-- Formulation

-- Glycosylation

2.Potentially important future areas of medical development

-- Nanotechnology

-- Tissue Engineering


Other variables

process

1

solvent

2

3

4

Impact of TransForm Technology

Traditional

TransForm

# of F & F experiments

  • 200-20,000+

  • 10-20

Ability to explore F&F space more effectively and efficiently

Timing

  • 2 – 4 Weeks

  • 1 – 2 Months

Informatics;

data mining,

learning

  • Deep & iterative

  • Minimal


Case Study: Ritonavir

  • 1.5 years after launch, converted into unanticipated form II polymorph

  • 50% less soluble

  • Abbott compelled to recall & reformulate

MPT 122 °C

MPT 125 °C

MPT 80 °C

MPT 97 °C

MPT 116 °C

Form I

Form II

Form III

Form IV

Form V

  • Within weeks at TransForm, using < 2g:

    • Both known forms identified & characterized

    • Found three novel, previously unreported forms

    • Novel, robust methods to make each form

Morissette et al. PNAS100, 2180 (2003).


New Tools

  • Imaging

  • Informatics

  • Genomics

  • Proteomics

  • 5. Glycomics


3

B

N

R

A G C T A G C

-

-

C

H

O

S

O

-

C

H

O

S

O

-

C

H

O

S

O

-

O

O

C

2

3

2

3

2

3

3

O

O

O

O

O

O

O

O

-

C

O

O

-

C

O

O

O

O

O

O

O

H

O

H

O

H

O

H

O

H

O

H

O

H

O

H

O

O

-

-

-

-

-

N

S

O

-

O

S

O

N

H

S

O

-

N

H

S

O

S

O

O

O

O

O

S

3

3

3

3

3

3

3

“Cracking the Code” of Sugars is

Analogous to the Sequencing of DNA

  • The sequencing of DNA has laid the foundation for biotechnology revolution

  • Like DNA and proteins, sugars play a central role in regulating basic biological activity, disease mechanisms, and drug action

  • Sugars exist as sequences of building blocks similar to DNA, but there has been a lack of adequate sequencing tools

  • Understanding of sugars is critical for polysaccharide drugs (e.g. Lovenox) and glycosylated proteins (e.g. Epogen)


Inherent complexity of sugars has prevented comprehensive understanding

  • Structural complexity and information density

  • Lack of amplification

  • Heterogeneity

The Problem:

Lack of technology to and tools to sequence sugars has made it difficult to characterize and engineer sugars, and decipher their role in biology.


ESI-MS

NMR

Linkage information

Mass signatures

of groups

MALDI

-MS

Mass of chain

– chain length

Quantitative building block information

CE

Multiple Enzymes

Integration of Data

Convergence on unique solution to complex sequences

Sequencing Complex Polysaccharides [1999] Science 286: 537-542.Momenta Pharmaceuticals


Future areas of medical development

1.Nanotechnology

2.Tissue Engineering


Prototype Device

Silicon Nitride or Dioxide

Silicon

Active Substance

Cathode

Anode


Implantable Drug Delivery System

Battery-powered,

telemetry-controlled

implant

Design based on

pacemaker and ICD

microelectronics


Reservoir Opening Mechanism


Pre-Clinical Studies Demonstrate in vivo Release

  • Experimental Protocol

  • Implant microchips subcutaneously in rats

  • Release radioactive mannitol (388 ng/well non-metabolized sugar)

  • Collect urine and analyze for radioactive content

  • as an indicator of drug release


hydrophilic block

DNA

cationic block

polyplex

polymer-DNA complex

Polymer Therapeutics : Nanosized medicines

polymer-protein

conjugate

polymeric drug

or sequestrant

protein

Mw = 5 - 40,000 Da

~20nm

40-60 nm

5-15 nm

targeting residue

hydrophilic block

drug

linker

hydrophiobic block

drug

polymer-drug

conjugates

polymeric micelle

60-100 nm


  • 1.How do you assess safety?

  • 2.How do you characterize nanomedicines

  • --Biological

  • --Physical/chemical

  • 3. What animal models are appropriate?


Annual Tissue LossEnd Stage Organ Failure (U.S.)

  • Over $500 billion in health care costs

  • 40 to 90 million hospital days

  • 8 million surgical procedures


Bone

Joint replacement 558,000

Bone graft275,000

Internal fixation480,000

Facial reconstruction30,000

Cartilage

Patella319,400

Meniscus250,000

Arthritis (Knee)149,900

Arthritis (Hip)219,300

Small Joints179,000

Tendon33,000

Ligament90,000

Skin

Burns, Sores, 3,650,000

Ulcers1,100,000

Heart754,000

Blood Vessels606,000

Liver205,000

Pancreas728,000

Incidence of Organ and Tissue Deficiencies


Biodegradable Polymer Scaffold

In Vivo Implantation

New

Bone

Cartilage

Liver

Intestine

Ureter

In vitro Tissue Culture

Cells

Osteoblasts

Chondrocytes

Hepatocytes

Enterocytes

Urothelial Cells


Cartilage Tissue Engineering

BEFORE cell seeding

AFTER 2 weeks in culture


System

  • Modified PGA Tubes

  • 8 Weeks SMC Culture, then EC

  • Bio-Reactors – Pulsatile Radial Stress


MediumReservoir

Flow Direction

4 Bioreactors,

Assembled in parallel

20 cm

Pulsatile Pump

Compliance Chamber

Magnetic Stirplate


Characteristics

  • 50% Collagen

  • Rupture Strengths > 2000 mg Hg

  • Suture Retention – Strengths up to 90g

  • Demonstrates Contractile Responses to Serotonin, endothelin-1, and Prostaglandin F2α


Human Embryonic Endothelial Cells Form Functional Blood-Carrying Microvessels

PECAM1

CD34


  • How should safety be assessed?

  • What are appropriate markers?

  • How do you determine appropriate function?

  • What are appropriate animal models?


  • Login