Modern Drug Discovery

1.Drug Discovery

• Pharmaceutical patents provide inventors with exclusive rights for 17 years to produce and sell their "branded drug."
• Generic drugs offer cheaper alternatives due to absence of patent restrictions.
• Cheaper competition, government/activist pressure, and intellectual property piracy are threats to drug companies
• These issues could reduce the incentive for companies to invest in discovering new drugs.
• Drug formulation initially used plant extracts during its early beginning.
• Drugs shifted from formulation with plant sources to chemical synthesis .
• The field of chemistry and biology saw rapid progress from the 1920s-1980s.
• Many novel drugs came to market, during this period, effective in treating conditions and diseases.
• Focus has recently expanded to drugs based on proteins.
• Understanding DNA is a key part of protein based therapeutic development

Modern Drug Discovery

• The modern drug discovery path is long, expensive, difficult and often unproductive.
• Big pharmaceutical companies conduct drug development helped in research by universities.
• Smaller companies can sell drug rights to bigger pharma who have more resources for clinical trials.
• Drug discovery interactions exist between investors, industry academics, patent laws, regulatory exclusives, and marketing.

Drug Discovery Stages

• Includes hitting on a screen, and medicinal chemistry.
• Hits should be optimized to increase the drug's affinity, selectivity, half-life and oral bioavailability.
• Final product: patent on potential drug
• Phase I, II, and III clinical trials are also required, which are very expensive.

Drug Discoveries

• Active ingredients can be found using traditional medicine.
• Classical Pharmacology tests involve the screening of small molecule libraries in intact cells or organisms.
• Reverse Pharmacology libraries of large molecules that sequence the human genome to clone genes rapidly for synthesis.
• Isolating a substance in crystal form can allow recognition and identification of a chemical substance.

Modelling a Molecule

X-ray Crystallography

• William Bragg discovered narrow beams of light would pass unobstructed when x-rays pass through a crystalline solid.
• A beam of x-rays strikes the crystal, creating a diffraction pattern.
• The pattern is recorded at intensity at various angles, leading to development of an electron density map.
• Serially adjusting the angle allows for accurate assessment of emergent intensity and angle.
• X-ray crystallography calculates the position of the atoms in the crystal which scattered the beam.
• The three dimensional structure can be mapped for molecules inside crystal.

Computer Modelling Challenges

• Depends on the availability of real crystal of the receptor protein with well-defined facets and sharp edges.
• Rotates these chemical structures on the screen and visualize the interactions between a pair of compounds, knowing their composition.
• Models can be broken down into primitives (points, polygons, and vector) for 3D objects in n-dimensional space.
• The coordinates form to represent it and transformed using mathematical operations.

2. Pharmaceutical Formulation

• Pharmaceutical formulation uses chemical substances with an active ingredient to produce a final product.
• Formulation develops and prepares stable drugs that patients can accept.
• Inert components can be combined with the drug as long as no harm is caused.
• Factors to consider include particle size, pH, polymorphism, and the drug's bioactivity.
• Pre-formulation involves characterizing a drug's physical, chemical, and mechanical attributes.
• Protein preformulation is the solution behavior under stress (freeze/thaw, shear stress, temperature).
• An oral drug involves incorporating it into a capsule or tablet.
• An excipient is any substance in a dosage form other than the drug itself.
• Excipient selection depends on administration route, dosage form, active ingredients, and other factors.
• Excipients stabilize the medication, bulk it up if its solid, enhance efficacy, and help manufacture it.
• Excipients facilitate handling, ensure powder flow, prevent denaturation, and aid in vitro stability.

Routes of Medication Administration

• Buccal route entails keeping meds held inside the cheek.
• Inhalable administration involves breathing the medication using a mask or tube.
• Nasal: spraying medication into the nose.
• Ophthalmic: putting the medication into the eye as drops/gels/ointments.
• Oral: swallowing liquids/lozenges/tablets/capsules.
• Otic: placing medications in the ear using drops.
• Sublingual: keeping meds held under the tongue.

Through the skin

• Infused: Slow IV injection.
• Intramuscular: Syringe injected into muscle.
• Intrathecal: Injection into spine.
• Intravenous : Injection into IV line or vein
• Subcutaneous: Injection under the skin.
• Topical: Application to the skin.
• Transdermal: Putting patch on the skin.
• Enteral medications are delivered to the intestines or stomach using a G-tube or J-tube.
• Rectal medications are inserted into the rectum.

Properties of Drugs (ADPME)

• Absorption rates depend on a drug's permeability, lipophilicity, and solubility
• Knowing solubility at a wide range of pH levels is paramount.
• Partition effect: ability to dissolve in fats indicates ability to permeate cell membranes.
• Permeability: measure of passive diffusion through the intestinal wall; dictates absorption.
• Solubility and lipophilicity are big contributors to drug distribution.
• Some drugs bind effectively to albumin when it is acidic.
• Protein binding can greatly increase a drug's half-life because the bound drugs will need to metabolize.
• Drug metabolism mainly occurs in the liver; changing fat-soluble to water-soluble, so that it can be eliminated.
• Excretion is the removal of drugs by the kidneys after liver metabolism changes it to a water-soluble form.
• The pH level of urine has influence on kidney excretion with acids promoting the secretion of toxins.
• Some drugs can be unchanged as they pass through the liver and are excreted in bile.

Dosage Form Design

• Coatings of some drugs ensures they disintegrate in small intestines to pH 5.5-7.
• Half-life: needed time for a drug to be metabolized and eliminated at ½ of its original.
• A short half-life requires dosing 3-4 times/day, whereas a long half-life needs 1-2 dosages.

Formulation Types

• Enteral: ingested orally
• Parenteral: administered in the body via other routes (like injection): fluids and lyophilized.

Excipients

• Excipients can be anything that appears in the dosage form besides the drug.
• Compendial manufacturers do not have to provide justification due to detailed published information.
• Non-compendial manufacturers use information from testing, justification, and validation.
• Multipurpose excipients can have 2+ jobs dependent on their concentration.
• Excipients come in many purity levels and various pricing.
• Excipients should be non-toxic, promote stability, and compatible with drug properties.

Formulation

• Formulation develops the right API and excipients to elicit the right amount of drug to the site targeted.
• Bioavailability and amount in the bloodstream are two big components for formulation developers.

Medication Administration

• Enteral medications are delivered to the intestines or mouth.
• Parenteral involves introducing into the body with alternative ways (injection): liquid and lyophilized.

Formulation Production

• Tablets and capsules can be made with direct blending, wet/dry blending, grinding, or compaction.
• Direct compression: API (active ingredient) is active and compressible.
• Wet granulations: API is not compressible.

Technique Selection

• Excipients can increase flowability when the drug does not flow by itself.
• Moisture sensitive or degrading actives = wet/dry blending or rolling compaction.
• Lower active amounts= granulating will ensure evenness.
• Compression sensitive actives = blending.

Chemical Production Techniques

• Active with excipients and water mixed to create granules (wet granulation).
• Dry granulation if active can degrade with water.
• Compression degrades some actives and can encapsulate them into blends with no tablets.
• Disintegrates added for tablets to be broken faster.
• Comminution achieves parameters by grinding size of particles.
• Surfactants promote poorly soluble actives.
• Active and polymers of crystalline active form solids by stabilization.

Degradation Issues

• Breakage during hydrolysis happens in water.
• Silica or clay can protect dose via water elimination.
• Scavenger and antioxidants slow down process.
• Purging bottlenecks and package headspaces is key.

Stability Issues

• Chemical and physical events with fillers, binders, etc.
• Hygroscopic substance can absorb water to form hard plugs.
• Capsule shells can give off 16% water to add to breakage.
• Cross-linking is less of a major issue in tablets.
• Sugar and granulating must stay dry to stay stable.

Stability Testing Procedures

• ICH (International conference of Harmonisation) recommends the following: testing 40°C / 75% RH after 4-12 weeks .
• Also testing at 30°C / 60% RH as data is acceptable.
• Testing at room temp for two years is a must.

Stability Testing

• Gaining capsule/tablet weight indicates moisture/degradation when hydrolyzing.
• Weight loss indicates too much desiccant is being used in packaging.
• Drug release can lead to active sublimation, or a break in time.

Scale Up

• Steps after testing for formulators include scaling product to 10 to 100kg batches.
• Solids at scale can cause issues from the scaled up processes.
• Liquids have few scale-up problems.

Pilot Batches

• Tablet manufacturing falls under two categories after many processes: Granulated or Directly compressible.

Processing

• Blending via oscillating is achieved through milling, twin shells, or blends.
• Rotary press and coating for films/sugars
• Direct compression provides simpler manufacturing.
• All processes require strict control and equipment specifications.

Process Validation

• The creation of product is documented as assured specification of quality.
• Installation, performance, function, and condition are all steps of validation.
• Product should be fit for its intention to design high-quality drugs with good manufacturing practices.

Regulations

• Productions need written procedures to ensure products have labeled properties.
• It needs to be consistent to eliminate any variable impacting consistency or characteristics.

Controls

• Raw to finished product should match scientific specifications approved by the control unit.
• Check specifications and take action for acceptable limitations.

Active Pharmaceutical Ingredient (API)

• The active ingredient has the therapeutic impact.

Must specify the following

• Manufacturing: Is there chemical synthesis, extraction, or fermentation?
• Starting Material: Where it can be purchased or manufactured in house.
• Storage and handling conditions if processing could pose a risk to manufacturing process.

Good Manufacturing Practice (GMP)

• A series of guidelines must be followed to maintain quality.

GMP

• Hygiene, Traceability, Complaints, Facilities, Personnel, and Quality Management are key.

Manufacturing Equipment

• Active ingredient in manufacturing process, with materials not altering structure and functionality.
• Qualities match intended scale and be food safe.
• All locations need a defined processing line.

General Controls

• Scientific verification of sampling, specifications, and test procedures.
• The action needs to be taken for any limit.
• List all potential impurities.
• Changes needs to be checked by unit.

Standards for Manufacturing

• Reference compound effects used for bioactivity.
• Material should be high purity or from a purified origin.

Validation

• Document the equipment (cleaning and process).
• Use historical range for manufacturing or development.
• Batches tested to remain consistent.

Manufacturing Process, Control, and Instructions

• Instructions should have formulas to maintain consistency.
• Batch records also should apply to safety, control, maintenance, and cleaning.
• Follow documentation of instructions.
• Packaging provides protection and identifies function.
• It requires containment and environment with materials.