Pharmaceutical Drugs

Alexis Aberle

CBE 555

Spring 2008

                                             

How are medicines made?

Previously, from plants and animals

Currently, from chemical processes

‘Preclinical’ development stage lasts 3-4 years

Different stages depending on number of volunteers needed and amount of testing

Sodium starch glycolate?

Yes, it’s true! Medicine contains additivesAnything besides the active ingredient are called ‘excipients’

They help hold a dose of the active pharmaceutical ingredient (API) together

Keeps it stable for a longer shelf lifeMasks an unpleasant taste or texture Helps ensure the correct amount of API makes it to the right place in the body at the right time

Food and beverage additives are used as excipients

They have already been approved for human consumption

Diluents or fillers

Help bulk up the size of a capsule so it’s convenient to take and sensible to make

Can also serve as a ‘glue’ to hold all the ingredients in the recipe together

Examples are lactose, magnesium stearate, dibasic calcium phosphate, cornstarch

For alcohol or water-based liquids, gelatin or polyethylene glycol are used as thickening agents

Glidants or granulating agents

Chemicals that generate a free-flowing granular material

Similar to salt or sugar, unlike flourEnsures API stays uniform throughout the powder formulationMakes the formulation capable of sliding into the gelatin capsules or into dies so that it can be made into capsules on machinery

Granules that dissolve at different rates important for time-release

Antiadherant or Lubricant

Talc, silica

Helps prevent the pressed tablets from sticking to the punch faces of the tableting machines

Coatings

Extends shelf lifePrevents photodegradationProtects from moistureMakes medicine taste better and larger pills easier to swallowEnables drug information to be printedUsed to be sugarsNow, synthetic polymer or polysaccharide coating with plasticizers

Triethyl citrate and pigments added

Coatings cont’d.

Helps to control the release or location in gastrointestinal tract where the drug is released

Maybe a coating is designed to stay together in acidic stomach but dissolves quickly in the neutral pH of the intestines for better absorption

Disintegrants

Reagents that expand and dissolve when wet, enabling a tablet to break downWithout them, the medicine might go through intestinal tract without being absorbed, thereby not workingBinders are used, such as cornstarch and modified celluloseSodium starch glycolate and polyvinylpyrrolidone

Sweeteners and flavorings

Improves the taste, or texture, in the mouth

More important for chewable tablets or liquids

Antacids or cough syrups

“Fun Flavorings” are used in children’s medicines

How do Drugs Work?

A common antibiotic: penicillinHistory:

Discovered by Alexander FlemingPenicillin is derived from a toxin produced by penicillium notatum, a fungusIt had killed the bacteria Staphylococcus in a laboratory experiment

Penicillin disrupts the cell walls of bacteria, killing them Others interfere with the ability of microorganisms to manufacture essential proteins

Blocking Enzymes

Chloresterol-lowering drug: inhibit action of a liver enzyme, HMG-CoA reductase, manufacturer of cholesterolWhen the enzyme is blocked, drugs foil the process and cholesterol levels are reduced, mainly the LDL, or “bad cholesterol” that is the main cause of heart disease

“Lock and Key” Mechanism

A ligand is a protein which is the “key”

This fits into cell receptors, the “locks”

Eg, insulin binding to receptors in cells, allowing sugar in the

blood to penetrate into the cell

Osteoporosis drug Evista

Receptor Blocking

Won’t allow ligands to bind to the cell receptors

Eg, an active ingredient that prevents a hormone from binding to receptors in the heart, called beta-blockers, an important class of cardiac drugs

Cell Transport Alteration

Prozac

Prevents or stops brain cells from collecting and processing used molecules of serotonin, a chemical in the brain

When levels of serotonin are increased, more are available to brain cells

Alleviates depression

Synthesis and PurificationApproximately 8 and a half years to study and test a drug before it may be approved to the publicNew research starts with understanding of how the body functions, normally and abnormally Assays, or test tube experiments, compounds are added to enzymes, cell cultures, or cellular substances grown in a labSome will indicate ways that compound’s structure is changed to give light to how something might workComputers can show what the receptor site looks like and how a compound could be made to block an enzyme from attaching thereMicroorganisms are grown in “fermentation broth” to test if it has desirable effect

Animal Testing

As few as possible are usedAt least two different species because one may react differently from anotherUsed to measure how much of a drug is absorbed into the blood, how it is broken down in the body, toxicity of the drug, break down products (metabolites), and how quickly the drug and its metabolites are excreted from the body2 weeks to 3 months: Short term A few weeks to several years: Long term

Institutional Review Boards (IRB)

Used to keep the rights and welfare of people volunteering in clinical trials before and during their participation

Makes sure people are fully informed and have given their written consent

Monitored by FDA to protect and ensure safety of volunteers in research

No less than 5 experts and varying backgrounds

Must have concerns in relevant areas

Drug Development: Phase I

Introduction of an investigational new drug into humansUsually in healthy volunteer subjectsGoal: to determine the metabolic and pharmacologic actions of the drug in humans, side effects, and effectivenessEvaluate drug metabolism, structure-activity relationships, and mechanism of action in humansUsually 20 to 80 volunteersIf determined unsafe, the study may be stopped

Phase II

Studies are done to get data on effectiveness of the drug for an indication with the symptoms in patients

Helps in understanding short-term side effects and risks associated

Well-controlled, closely monitored

Several hundred people

Phase III

Controlled and uncontrolled trialsAfter Phase II effectiveness has been establishedGoal: to obtain additional information about effectiveness and safety to evaluate overall benefit-risk relationship of the drugProvide information to apply to general populationSeveral hundred to several thousand people

Accelerated Development/Review

Speeds development of drugs if they show promise over existing therapy for serious illnesses for which there is no therapyUsed under two circumstances:

When approval is based on evidence of a product’s effectWhen FDA determines safe use of a product depends on restricting its use

Manufacturers must continue testing after this process to show the drug would provide a benefitIf not, FDA can withdraw drug from the market

Treatment INDTreatment Investigational New DrugsUsed to make promising new drugs accessible to ill patients as early as possible in development phaseFDA permits use if:

Preliminary evidence of effectivenessIntended to treat life-threatening diseaseIf no other similar drug or therapy available to treat the diseaseClinical trials must be almost finished

Life-threatening disease defined as a stage of a disease in which there is likelihood that death will occur in matter of monthsAvailable before general marketing, typically during Phase 3FDA can obtain additional data on drug’s safety and effectiveness

Parallel Track

Mechanism to permit wider availability of experimental agents

Developed by US Public Health Service in response to AIDS

Patients with AIDS can get IND shown in early studies that are promising if their condition prevents them from participating in controlled trials

Prescription Drugs

In 2006: global spending topped $600 billion

Worldwide rose 7% to $602 billion (IMS Health)United States: accounts for the majority of these sales at $252 billion, up 5.7%

China, Russia, South Korea and Mexico grew 81%

In 2004 the US accounted for 45% worldwide and Europe 25%

In US, companies spend $19 billion on advertising

Top Ten CompaniesCompany Sales ($M) Growth (%)Pfizer 45 1.8

GlaxoSmithKline 37 9.7

Sanofi-Aventis 36 5.7

Novartis 29 4.6

Hoffman-La Roche 27 4.2

AstraZeneca 26 4.1

Johnson&Johnson 23 3.7

Merck & Co. 23 3.6

Wyeth 16 2.5

Eli Lily and Company 15 2.4

Generic Drugs

Definition:A generic drug is one which is produced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredientMust contain the same active ingredientsAssumed to be in same dose, strength, route of administration, safety, efficacy, and intended useOnly available when patent protections have expired

Patents last between 7-12 years

India leading manufacturer

Generic vs Prescription Drugs?

FDA requires generic drugs to be as safe and effective as brand namesBecause of trademarks, generic drugs are not allowed to be the same color, shape, etc. as brand namesGenerics industry: $35 billionCost to discover and test a drug: $800 millionGeneric drugs much, much cheaper!

Generics producible:

Patent expired

Generic company finds the patents are in valid for the brand name company

For drugs that never had patents

In countries that do not have patents

Generic Exclusivity

FDA offers a 180 day exclusivity period when only one company may make the generic drugOnly used when argued that a patent is invalidIs a reward for the generic company because they are willing to risk liability in court Company does not have to make the drug but can file an application to keep other companies from producing the drugName brand companies often license a subsidiary to make the drug generically under the original patentAuthorized generics: generics sold under the license from the patent holder

They are not under the 180 day trial period

Process for Approval of Generic Drugs

Drug Price Competition and Patent Restoration Act of 1984, or Hatch-Waxman Act

Set out abbreviated process for generics to get FDA approvalAllows generic companies to get approval and do testing before patents expireSpecifies a process for resolution of patent disputes between generic and name-brand firms

Before a patent expires, companies can apply to FDA for permission to make and sell the drug

If multiple companies produce the drug, the price drops further

FDA estimates 50% of generic drug production is by name-brand companies

Generic drugs are called by their chemical name

Generics must also be approved

Abbreviated New Drug Application (ANDA)Application for a US generic drug approvalProvides for review and approval of a generic drugCalled ‘abbreviated’ because they do not have to include preclinical (animal) and clinical (human) data for the safety and effectivenessInstead, generic companies must demonstrate that their product is bioequivalent, or performs the same way as the name brand drug

A measure of bioequivalence is to time how long it takes for the drug to reach the bloodstream in 24 to 36 volunteers

– Gives rate of absorption (bioavailability) and can be compared to that from the name brand drug

» Established by Hatch-Waxman Act

Patent Protection

Brand-name companies try to avoid patent expirations by creating reformulations of key products that use a different delivery system in an effort to switch to a product with a longer patentPfizer campaign to promote Lipitor: an effort of advertising benefits over generic to patients and prescribers to keep them purchasing their product Companies now carry an average of 10 patents for each drug

A decade ago, it was only 2

Proportions of Total Expenditures on Prescription Drugs (Panel A) and of Total Prescriptions Dispensed (Panel B) Accounted for by Brand-Name Drugs and by Generic Drugs. Data are from IMS

Health, National Prescription Audit Plans, National Sales Perspective, June 2007.

Generic Drug Pricing

Change in the Average Relative Price of a Drug as the Number of Generic Versions Increases.

The average relative price is the average price of a generic version divided by the price of the brand-name drug. Data are from an FDA analysis of retail sales data from IMS Health.

Questions?

References

www.wikipedia.com

www.medicinenet.com

www.ftc.gov/bcp/pubs/consumer/health/hea06.shtm

www.Johnshopkinshealthalerts.com/reports/prescription_drugs/1552-1.html

www.Medicalnewstoday.com

http://pubs.acs.org/isubscribe/journals/cen/86/i01/html/8601sci3.html

http://www.fda.gov/cder/handbook/develop.htm