lec 3 (minko) - drug product design

dosage form

• drug + non-medical agents (pharmaceutical ingredients) come together to form drug

• drug substances are rarely administered alone but rather as part of formulation in combo with one or more non-medical agents

• dosage form = combination of a drug with there non-medical agents referred as pharmaceutical ingredients

why we need dosage forms?

• for the safe and convenient delivery of an accurate dosage

• for the protection of a drug from destructive influences of atmospheric oxygen or humidity

• for the protection of a drug from the destructive influences of gastric acid after oral admin

• to conceal bad taste or odor

• to provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle (e.g. suspensions)

• to provide clear liquid dosage forms of substances (syrups, solutions)

• to provide controlled release drug delivery

• to provide optimal drug action through diff. admin sites

drug and drug product stability

• chemical

  • each active ingredient retains chemical integrity and labeled potency within specified limits

• physical

  • the original physical properties, including appearance, palatability, uniformity, dissolution and suspend-ability are retained

• microbiologic

  • sterility or resistance to microbial growth = retained according to the specified requirements. antimicrobal agents taht are present retain effectiveness within specified limits.

• therapeutic

  • therapeutic effect remains unchanged

• toxicologic

  • NO significant increase in toxicity

• stability = extent to which a product retains, within specific limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture

drug stability: mechanisms of degradation

• hydrolysis

  • process in which drug molecules interact with water molecules to yield breakdown products of different chemical constiutions

• oxidation

  • process in which a substance combines with oxygen to form oxides

• chemical instability of medicinal agents may take many forms since modern drugs are of such diverse chemical constiutions

• chemically the most frequently encountered destructive processes = hydrolysis and oxidation

stability testing: kinetic study

• half life = time required to decrease the conc. of an active component in the drug form by 50%

• kinetic study begins by measuring the conc. of the drug being examined at given time intervals under a specific set of conditions:

  • temperature

  • pH

  • ionic strength

  • light intensity

  • drug concentrations

• the measurement of the drug concentration at various time intervals reveals the stability or instability of the drug under the specified conditions with the passage of time

• from this starting point, each of the OG conditions may be varied based on individual basis to determine the influence that such changes make on drug’s stability

• from experimental data, half life can be determined

pharmaceutic ingredients

• solvents = to dissolve drug substance

• flavors and sweeteners = to make product more palatable

• colorants = to enhance product appeal

• preservatives = to prevent microbial growth

• stabilizers = such as antioxidants and chelating agents to prevent drug decomposition

• diluents and fillers = to increase the bulk of formulation

• binders = to increase the adhesion of powdered drug and pharmaceutic substances

• anti-adherents or lubricants = to assist the smooth tableting process

• disintegrating agents = to promote tablet break-up after admin

• to prep. a drug substance into final dosage form, pharmaceutic ingredients are required

sterilization and preservation

• physical methods

  • autoclaving for 20 minutes at 15 PSI and 120 degrees C

  • dry heat at 180 degrees C for 1 hour

  • bacterial filtration

• chemical method

  • use of preservatives

• although some types of pharmaceutical products like ophthalmic and injectable preparations are sterilized by physical methods during manufacturing, many of them additionally require an antimicrobial preservative to maintain their aseptic conditions throughout the period of their storage and use

dissolution and drug absorption

• dissolution = process by which a drug particle assimilates into the fluid at the absorption site

• for instance, drug administered orally in tablet or capsule CANNOT be absorbed until the drug particles are dissolved by the fluids at some point within the GI tract → drug will be dissolved in the stomach (acidic conditions) or intestines (low acidic, neutral or basic conditions) depending on the pH-dependent solubility of the drug

• pH of GI tract

  • duodenum pH = 5-7

  • stomach pH = 1-3

  • ascending colon pH = 7-8

  • jejunum pH = 6.5

bioavailability and bioequivalence

• bioavailability = rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action

• bioequivalence = comparison of bioavailability of different formulations, drug products, or batches of the same drug product

blood concentration-time curve

• bioavailability of drug is presented by concentration-time curve of the administered drug in an appropriate tissue system e.g. plasma

• rise and fall of the concentration of the drug in the blood plasma over time determines the course of action of most drugs

• if drug is given orally, 3 phases can be distinguished

  • absorption phase → leads to peak in plasma concentration

  • redistribution phase → plasma concentration falls rapidly as the drug is taken up by various tissues

  • elimination phase → slower phase of decline as drug is metabolized or excreted

parameters for assessment and comparison of bioavailability

• when the drug is first administered (time zero), the blood concentration of the drug should also be zero

• as drug passes into stomach and/or intestine, it is released from dosage form, dissolved, and absorbed

• blood sample reveal increasing concentrations of drug until max (peak) concentration is reached → blood level of the drug progressively decreases and if no additional dose is given → eventually falls to zero

• following parameters are usually used for describing and comparison of bioavaliability

  • Cmax = peak concentration

  • Tmax = time of peak concentration

  • AUC = area under the curve

excretion of drugs

• urine (kidney)

• feces

• bile

• lungs

• sweat, saliva, milk

• excretion of drugs and their metabolites terminates their activity/presence in body

• drugs may be eliminated by various routes with kidney playing dominant role by eliminating drugs via urine

• drug excretion with feces = also important especially for drugs that are poorly absorbed and remain in GI tract after oral admin

• exit through bile is significant only when the drugs reabsorption from GI tract is minimal

• lungs provide the route of elimination for many volatile drugs through expired breath

• sweat glands, saliva, and milk play only minor roles in drug elim; should be noted that if a drug gains access to the milk of a mother during lactation it could easily exert its effects in the nursing infant

novel dosage forms and drug delivery technologies

new drug delivery system development is largely based on:

• promoting the therapeutic effects of a drug

• minimizing its toxic effects by:

  • increasing the amount and persistence of a drug in the vicinity of a “target” cell

  • reducing the drug exposure of “nontarget” cells

new drug delivery systems: mechanisms

novel drug delivery systems can include those based on physical mechanisms and biochemical mechanisms

• physical mechanisms (controlled drug delivery systems) include:

  • osmosis

  • diffusion

  • erosion

  • dissolution

  • electrotransport

• biochemical mechanisms include:

  • monoclonal antibodies

  • gene therapy and vector systems

  • polymer drug abducts

  • etc.

novel drug compositions

• composition of newer drug delivery systems can be quite variable ranging from naturally derived substances such as gelatin and sugars → more complex polymers

• therapeutic efficacy of selected products can be enhanced and toxicity can be decreased by incorporating novel polymer technology

  • for example, degradable bonds can be used to attach an active drug to a synthetic or naturally occuring polymer → upon delivery to the target site and in the presence of certain enzymes or through hydrolysis the product can be cleaved releasing the active drug at a specific site of action

cancer vaccines

• cancer treatment by vaccines include 3 main steps

  • immunization (limiting step)

  • activation of immune system (dendritic cells, T-lymphocytes and natural killer cells)

  • killing of cancer cells

• treated cancer cells, cancer cell-dendritic cell conjugates or cancer specific peptides might be used as tumor antigens

cell based cancer vaccines

• form of immunotherapy used to treat cancer by stimulating the immune system to recognize and attack cancer cells

• immunization using pt’s own cancer cells or tumor antigens

  • involves using the pt’s own dendritic cells (a type of immune cell that helps initiate the immune response)

  • dendritic cells are extracted from the pt’s blood → dendritic cells exposed to tumor-specific antigens → re-injected into pt

• the dendritic cells present the tumor antigens to T cells which activate T cells and natural killer cell → immune response against cancer which kills the cancer cells

cell free cancer vaccines

• do NOT involve the use of whole cells but instead focus on using tumor derive components such as proteins, peptides, or nucleic acids to stimulate the immune system

• use tumor specific peptides to formulate vaccine → peptides taken up by dendritic cells → activates T cells and natural killing cell → kills cancer cells