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What is the difference between pharmaceutical research and development, and product development?

Pharmaceutical research and development is to do with converting a synthesised chemical compound into candidate drugs for development.
Product development involves converting candidate drugs into dosage forms for registration and sale

1

Drug companies need a "pipeline" of NCEs, what does this mean?

Pipeline of new chemical entities
I.e some drugs going into phase 1 some going into phase 2 some at drug dis discovery stage
Should always be looking for a pipeline that shows 10% growth, so that you don't lose money
If you don't have one, go to other companies to help you do it.
Drug company must frequently bring new discoveries to market to be successful

2

Are clinical trials done in healthy or unhealthy humans? I.e do they have the disease?

In HEALTHY humans
Don't want to make the person worse

3

What is a generic drug?

A drug which is BIOEQUIVALENT to a leading brand name
I.e it pharmacodynamic and pharmacokinetic properties are the same!
Same crystalline form
Same dose, route of administration,
Same safety and efficacy as innovator brand

4

Do bioequivalent drugs cost a lot to make?

No! Lower than innovators
No investing in R&D needed
Testing and manufacturing costs low, just need small group of people to test on

5

When can Generic businesses kick in?

When a leading brand loses it's Patent
Makes leading brands profits lower
Pharma R&D have introduced life cycle management to increase their patent protection, where they try to squeeze out every last penny by making the drug in several diff formulations

6

What is the Hatch Waxmans litigation (legal) act?

This is where Generic drugs are granted a 180-day period of exclusivity to the market, this increases the economic incentive for generic companies to be "FIRST to FILE" when a big companies Patent runs out and be first to get to market.
I.e NO other generic companies can enter the market during the 180 day period
It provides incentive for generic companies to challenge a patent validity and 'design around' patents to find an alternative

8

How should the 180-day exclusivity work?

Generic company launches generic drug
They are first to file, so have a 180-day period of exclusivity
During this period the company earns a return on investment
The company COULD invalidate the PATENT of the company that has the new drug on the market (the BRAND), and therefore come to Market a few years EARLY (before 10 year patent ends)
After the 180 day exclusivity period other generic company's jump in, decrease the sales of the first filer.

9

What is a "war chest"?

Kind of like PROFIT a GENERIC company makes during it's 180 day "first to file" exclusive period of sales.
GENERIC Drug company needs this war chest for future development, just like big companies do when they release a blockbuster

10

The search for a blockbuster being the Heart  of R&D drug companies strategy needs to change. WHY?

Due to advances in pharmacoGENOMICs and PERSONALISED medicines
So they don't have as bigger market as shaping drugs design to specific people, focussing on specific ailments/ therapies
Future blockbuster drugs aren't forthcoming

11

How can a drug company extend their patent by 6 months?

By testing their product in children between 10-17 years old.

Eg. Pfizer did this, extended their patent for Lipitor by releasing paediatric data and launching chewable version of the tablets for children by the end of their patent: so extended it for 6 months.

12

What is the innovation cycle?

Each drug product has it's own life cycle
It's to do with sales;
Introduction, development (large increase), maturity (peaks, becomes worthless here, if you're going to sell company sell it here!), decline OR revitalisation(could get another 5 years sales if you tweak a few things!)

13

What is consolidation?

Where drug companies merge together to succeed
Eg; Astra Zeneca (Astra AB/ Zeneca PLC)

14

Those nominated as candidate drugs, 1 in 5- 1 in 10 reach registration and sale,
For drugs marketed, only 3 in 10 are likely to achieve a fair return on investment.
How can we help to ensure product success?

Early phase candidate drug selection and product design is critical.
Aim: to ensure the compound has desired safety, selectivity, efficacy (potency/duration),
and properties of solubility, stability ( we want shelf life to last for at least 2 years) and bioavailability

15

Medicinal chemistry and drug discovery:
Investigates pharmacological properties:
Potency
Selectivity
Duration of action (everything we've been doing in 244)
Safety and toxicology

Formulation science and product development:
Pharmaceutical properties:
Solubiltiy
Thermal stability
Crystalline nature
Hygroscopicity (ability to absorb water)

18

What is a BLOCKBUSTER?

A drug that makes OVER 1 BILLION dollars A year!!

19

Pre 1990's, what kind of methods could we get Lead compounds from?

Serendipity- coming across drugs by mistake
Rational design- building on structures of known compounds
Natural products- base drug on these e.g Taxol, cyclosporin
Herbal remedies

20

Post 1990s, how could we get lead compounds ?

Hight throughput screening
Combinatorial chemistry
Lots of drug companies use these method
Obtain leads efficiently
Relatively easy to achieve invitro potency (in a tube)

21

In these modern methods, introducing oral activity is unpredictable

Molecular weights are Increasing
Lipophilicity is increasing
Solubility is increasing

All making oral bioavailability worse

22

What is done with automated High Throughput screening?

It assays Small samples (1 microliter)
Can analyse thousands of samples a day using WELL micro plates 
Used to measure pharmacological activity, binding in the wells emits a colour from a Fluorophore
But can also be used to assess metabolism, other pharmacokinetics and toxicity

23

Automated high throughput screening speeds up drug discovery through finding a 'hit and a lead' what does this mean?

where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds.

24

A chemical lead from HTS then is used to generate specific compounds with the OPTIMAL desired characteristics. How?

By testing a range of selected compounds in vitro and in vivo (tests for pharmacology effect and toxicity)
Then go on to preformulation and biopharmaceutical studies. This highlights the most relevant physiochemical and biopharmaceutical properties of potential candidate drugs. Tells us which candidate drugs to select to carry forward

25

HTS uses a black box approach, what does this mean?

Black-box testing is a method of software testing that examines the functionality of an application (e.g. what the software does) without peering into its internal structures or workings. This is a problem as pharma companies tend to leave something's in the dark.
For e.g for fluticasone you have to wait a whole year before you can formulate it, it just sits in storage, drug companies don't know why you do this, they just do it (Novartis wait 2 years)
If the company looked into WHY they have to wait this long, then They could probably find a solution and speed things up (this is a limitation of HTS) 

26

Why is causal understanding of functionality required?

Need to understand mechanisms and categories of circumstances which influence functionality
It will increase out predictive understanding, it will generate success
Technologies can subsequently flourish and be optimised and streamlined to save time!

27

What is preformulation?

It is the PHYSICOCHEMICAL characterisation of the properties of compounds
Takes place before the candidate to be explored is nominated
It is very important as whatever you do at preformulation stage may effect success of your product

28

When does the preformulation stage occur?

Preformulation testing is the FIRST step in rational development of dosage forms of a drug substance
(Remember rational means based on logic/ reasoning)
The objective: to generate information useful to the person formulating the drug about its stability and bioavailable dosage forms

It's all about ensuring the right formulation is made 

29

What is the ultimate aim of preformulation?

To produce a mathematical model for drug behaviour when it's been formulated
Also to provide an initial working model of behaviour of dosage forms in vitro and in vivo

30

In order to optimise the dosage form, what do we need a clear understanding of?

Stability and solubility of the API
How to inhibit decomposition and increase shelf life of the product

Shelf life should be at least 2 years

31

What is the very critical decision to make just before formulating the drug(part of preformulation)?

As you won't have made much of the compound At this this stage, there is limited arount of compound available to carry forward.
CRITICAL decision:
WHICH compound, the SALT or POLYMORPHIC is going to proceed into development?!

If this decision is wrong, and at a later stage it's decided the other was needed, it will really slow down the time to market :(
Therefore in order to get the decision right, upon candidate selection a more detailed preformulation study is undertaken

32

Can you name a few PHYSICOCHEMICAL tests that need to be carried out as part of preformulation studies?

Spectroscopy (NMR, IR, Mass)
HPLC
pKa
Log P
Initial Solution solubility/ solution stability
Crystallinity investigations 
Initial Solid stability
Hygroscopicity if a drug takes up water an increases it volume you could cause death :(

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