Drug Development and Biopharmaceutics

• Pharmaceutics is the study of the physical, chemical, and biological factors influencing the:
  • Formulation
  • Manufacture
  • Stability
  • Effectiveness of pharmaceutical dosage forms

Biopharmaceutics

• Biopharmaceutics considers the interrelationship of:
  • Physio-chemical properties of the drug/dosage form
  • Route of administration
  • Rate and extent of systemic drug absorption (bioavailability)

Pharmacokinetics

• Pharmacokinetics involves the kinetics of ADME and their corresponding pharmacologic, therapeutic, or toxic response in animals or humans.

Bioavailability

• Bioavailability describes the rate and extent a drug is absorbed from the dosage form.
• Bioequivalent products have the same bioavailability of a drug from different drug products.

Drug Discovery

• New drugs can be discovered from natural sources or created in the lab through high throughput screening and rational drug design.
• Vinca rosea yielded Vinblastine and Vincristine, used to treat cancers such as acute leukemia and lymphocytic leukemia.
• Hormonal substances (thyroid extract, insulin, pituitary hormone) from endocrine glands of cattle, sheep, and swine are life-saving drugs.

Genetic Engineering

• Recombinant DNA examples are human insulin, human growth hormone, Hep B vaccine, epoetin alpha, and interferon.
• Monoclonal antibody (MoAB) are also created through genetic engineering
• Gene Therapy was first used to treat adenosine deaminase deficiency (abnormal functioning of the immune system).

Pre-Clinical Trials

• Assesses physio-chemical properties like drug solubility, partition coefficient, dissolution rate, and physical/chemical form.
• Models used include In Vitro, In Vivo, and In Silico
• Biological Properties assessed are Pharmacology, ADME, and Toxicology

IND (Investigational New Drug Application)

• INDs are a request to the FDA to test a new drug/biological product on humans, also known as experimental drugs/investigational agents.

Clinical Protocols

• Institutional Review Board reviews/approves studies involving human subjects.
• Subject inclusion/exclusion relates to age, sex, smoking, health status, and factors necessary in a given investigation.
• Informed consent requires the sponsor to certify each participant is informed.
• Types of studies are:
  • Controlled (Placebo/Positive control)
  • Blinded(Single/Double Blind)
  • Open Label

Human Clinical Trials

• Phase I uses healthy subjects or patients to establish dose range and route of administration.
• Phase IIa uses specialized errors and restricted population, with short/medium range dose ranging pilot studies in diseased men/women.
  • Efficacy
  • Pharmacodynamic
  • Effective dosage range
• Phase IIb uses specialized errors, restricted population, short/medium range:
  • Definitive dose response
  • Controlled
  • Minimum and maximum doses
  • Pivotal studies
• Phase III uses less specialized investigators, a general population, and long-term duration.

Phase III goals

• Controlled studies
• Confirmation of efficacy
• Safety profile
• Regulatory information
• Assessment of risk/benefit

NDA (New Drug Application)

• NDAs requests the FDA to market a new drug, giving data to support safety/effectiveness.
• NDA must demonstrate:
  • Safe and effective for intended use
  • Benefits outweigh risks
  • Justify drug label
  • Manufacturing methods and controls are adequate
• Biological Licensing Application (BLA) is for vaccines, biologics, & antibiotics.
• Developing a new drug takes 14 years and costs $2 billion.

Topical Dosage and Delivery Systems

• Main barrier of drug transport through the skin is the stratum corneum.
• Two routes of drug transport are:
  • Transfollicular
  • Transdermal
• Penetration enhancers increase percutaneous absorption by reversibly changing the physicochemical nature of the stratum corneum to reduce diffusional resistance.
• Factors affecting percutaneous absorption: physio-chemical
  • Drug Concentration (increase drug conc. increases PA)
  • Skin/Drug/Vehicle interactions (influences PA)
  • Drug solubility and molecular weight
  • Degree of ionization
  • Vehicles/Solvents (Penetration enhancers)
• Factors affecting percutaneous absorption: physiological
  • Degree of skin hydration
  • Skin temperature
  • Skin age and regional sites
  • Species variation
  • Traumatic/Pathological injuries to the skin
  • Cutaneous drug metabolism

Percutaneous Adsorption Models

• In Vitro for transdermal delivery systems
• In-= Vivo for dermatological formulations
• J = DKdCd* / H where:
  • J = Flux of drug across skin
  • D = Drug diffusion through skin
  • Kd = Drug partitioning into skin
  • Cd = Drug concentration
  • H = Skin thickness

Iontophoresis

• Iontophoresis delivers charged drugs across the skin by potential gradient, for peptides, proteins, and hydrophilic molecules.

Phonophoresis

• Phonophoresis (Sonophoresis) moves drugs under the influence of ultrasonic perturbation, like Hydrocortisone, Lidocaine, and Salicylic acid.
• Ultrasound (Phonophoresis) changes skin permeability through thermal and mechanical mechanisms.
• Transdermal drug delivery advantages include avoiding GI absorption difficulties, avoiding first-pass effect, and better patient compliance.

Transdermal drug delivery disadvantages

• Unsuitable for drugs that irritate/sensitize skin
• Only potent drugs are suitable due to stratum corneum barrier properties.

Ointments

• Ointments are semisolid preparations intended for external application.
• Ointment base types are hydrocarbon, absorption, water-removable, and water-soluble.
• Hydrocarbon bases are emollient, occlusive, non-water washable, hydrophobic, and greasy like Petrolatum, Yellow Ointment (simple), and Mineral Oil (liquid petroleum).
• Absorption bases are emollient, occlusive, absorb water, anhydrous, or greasy, and permit the incorporation of aqueous solutions, forming water-in-oil emulsions.
• Water-Removable Bases are water-washable, non-greasy, can be diluted in water, and non-occlusive, they are oil-in-water emulsions capable of being washed from skin.
• Water-Soluble Bases are anhydrous, water-soluble and washable, non-greasy, non-occlusive, or lipid-free, like PEG 400, 1500, 4000, or 6000 and Polyethylene glycol ointment USP.
• Top prescribed topicals include Elocon (momentason) and Lotrisone (clotrimazole or betamethasone)
• Ointment preparations include Incorporation with mortar and pestle or spatula with ointment slab.
• Fusion is used to prepare cream & incorporation by mixing base and drug.

Creams

• Creams are viscous liquid/semisolid emulsions, typically oil-in-water type, used as emollients/medicated skin applications.
• Pastes are for external skin application, contain a higher percentage of solid material, and are thicker/stiffer than ointments.
• Pastes are preferred over ointments for acute lesions with crusting/oozing tendencies.
• Lotions are liquid suspensions/dispersions intended for external application, with labels saying "For external use only" and "shake well."
• Liniments are alcoholic or oleaginous solutions/emulsions intended for external skin application by rubbing, with labels saying "For external use only” and “shake well".
• Gels are translucent, non-greasy semi-solids for external skin application. These include:
  • Single-Phase with dispersed macromolecules
  • Two-Phase Gels with floccules of distinct particles.

Ophthalmic

• Ophthalmic non-blinking state contains 30 uL (microliters)
• Ophthalmic blinked state contains 10uL
• 1 drop equals 50uL

Pharmaceutical Requirements for Ophthalmic drugs

• Sterility
• Preservation with EDTA
• Isotonicity (Isotonic)
• Buffering for greater comfort
• Viscosity for thickening
• Ocular Bioavailability is influenced by physicochemical factors like protein binding, drug metabolism, and lacrimal drainage.
• Tears contain lysozyme to metabolically degrade drugs.
• The cornea is a membrane barrier with lipophilic/hydrophilic layers.
• Ophthalmic drugs are packaged in small glass bottles with separate glass/plastic droppers.

Contact Lenses

• Hard lenses provide crisp vision and durability (7-10mm).
• Soft lenses are hydrophilic transparent plastic (HEMA) with crosslinking agents for a hydrogel network (13-15mm).
• Rigid Gas Permeable lenses combine hard and soft lens advantages, constructed of oxygen-permeable hydrophobic material.
• Care involves saline, sodium chloride, benzalkonium chloride, wetting or combination solutions

Modified Release Dosage and Delivery Systems

• Pilopine HS Gel contains Pilocarpine (Alcon), and uses Carbopol 940 polymer to form the gel.
• OCUSERT is a flexible ophthalmic insert which has a drug-containing core surrounded on each side by a hydrophobic ethylene/vinyl acetate copolymer membrane.
  • The drug diffuses at a constant rate.
  • The PILOCARPINE inserts is placed in the conjunctival sac and releases medication for 7 days to treat GLAUCOMA.
• Lacrisert (Merck) contains water-soluble hydroxypropyl cellulose in a rod shape.
  • Placed into the inferior cul-de-sac once or twice daily to treat dry eye.
  • Slowly dissolves, thickening the precorneal tear film.

Rectal/Vaginal Dosage Forms and Delivery Systems

• Rectal Physiology:
  • 15 cm long, terminates G.I.
  • Contains 2mL aqueous fluid, pH 7.4
  • Easily irritated, reduces bioavailability.
  • Has lipoidal membrane without villi
  • Blood supply and implications for first-pass
• Rectal Absorption occurs through:
  • Suppository Fatty Base (incorporates water-soluble drug)
  • Epithelial Water
  • Lipoidal Membrane
  • Absorption Fluid

Rectal vs. Other Administrations

• Sodium Sulfadimidine is better taken orally, has little effect rectally.
• Aspirin has similar bioavailability regardless of administration
• Methylprednisolone Acetate (MPA) has an AUC (rectal) / AUC (oral) = 0.14
  • Retention time < 2 hours results in no detectable plasma levels
• Lidocaine:
  • High clearance and large 1st pass effect
  • Oral bioavailability is 33%, rectal is 67%
  • 50% of the 1st-pass effect is circumvented

Rectal Delivery Conclusions

• Difficult to predict relative bioavailability
• Bioavailability depends on drug
• Suppository vehicle may have an effect or none
• Retention time is important
• First-pass effect may be circumvented
• Suppositories are solid dosage forms made for insertion into body orifices for local/systemic effects.
• Pessaries are rectally/vaginally inserted
• Rectal Suppositories have 32 mm length, a cylindrical bullet/torpedo shape (2g)
• Advantages are direct application to treat local problems, good for nausea, vomiting, and lower dosage for issues.
• Disadvantages are poor patient compliance, leaking, and insertion problems.
• Relieves constipation, pain, irritation, itching, and inflammation associated with hemorrhoids.

Rectal delivery Factors

• Physiological factors are colonic content, colonic pH and lack of buffering capacity
• Physio-chemical factors are lipid-water solubility, particle size, or nature of the suppository base.

Vaginal Suppositories

• Vaginal Suppositories are globular, oval or con shaped (5g).
• Used for contraceptives, antiseptics in vaginal hygiene, or combat vaginitis. Bougies (urethrally) are urethral suppositories with 2-6mm diameter, 140 mm length, and a slender/pencil shape used as antibacterials, can be used to provide local anesthetics for urethral examination

Suppository Bases

• Fatty or oleaginous bases (MELTING):
  • Cocoa butter, triglyceride, with a melting point of 30-36 degrees C

Fatty or oleaginous bases

• Polymorphic
  • A-crystals at low melting point
  • B-crystals at higher melting point.
• Witepsol is a synthetic triglycerides
• Beeswax is used as a stiffening agent.
• Water soluble/miscible bases (DISSOLVING):
  • Glycerinated gelatin (moistened with water before insertion)
  • Polyethylene glycols (dissolves in body fluids, no fridge needed)
  • Polyoxyl 40 stearate is a hydrophilic base, acts as dispersing agent.
• MOLDING is a type of preparation using suppository molds with stainless steel, Al, or plastics.
  • Lubricate the mold
  • Calibrate the mold
  • Determination of amount of base required
  • Preparing and pouring the melt
• COMPRESSION is a preparation technique for heat liable drugs
• HAND ROLLING AND SHAPING is a preparation technique in these steps:
  • The base is melted in a water bath in a porcelain casserole.
  • The drug is incorporated in the molten base while stirring.
  • The mixture is cooled until it is congealing while stirring
  • The mixture is poured in the mold, and kept stirring while pouring
  • The filled mold is cooled to freeze or solidify suppositories. Scrape off excess material from the top
  • The suppository is separated and dislodged
  • The suppository is wrapped in metallic foil
  • The suppository is stored at room temperature
• Vaginal Tablets are more widely used than vaginal suppositories, prepared by tablet compression (mix and compress into tablets)
• Vaginal Capsules contain gelatin, filled with medication
• Rectal capsules in pediatrics are for children unwilling to take meds orally

Bioadhesive vaginal tablets

• Bioadhesive vaginal tablets controllably release topical and systemic drugs
• Vaginal Suppositories: containing:
• Progesterone Suppositories:
  • Progesterone (micronized powder)
  • PEG 400
  • PEG 8000
• Progestasert contains 38 mg of progesterone suspended in silicone oil, and barium sulfate, and gives 60-65 ug/day of Progesterone for 1 year
• Vaginal Insert (Cervidil vaginal insert) is administered to skilled personnel to induce labor
• Vaginal Ring (Estring) is made of estradiol vaginal ring with barium sulfate, and gives 75 ug/day of estradiol for 90 days
• Antifibrinolytic agents can be added to Intrauterine Progesterone Drug Delivery system to prevent excessive bleeding.

Explore key concepts in drug development, including biopharmaceutics, formulation, and preclinical trials. This quiz covers ADME properties, clinical trial phases, and regulatory submissions to the FDA. Test your knowledge of pharmaceutics and drug development strategies.