IE 2: Hormones

Why is it so difficult to administer insulin by the oral route?

• It Is degraded by enzymes in the GI tract

What are biopharmaceuticals known as?

• Biopharmaceuticals, known as the application of biomolecules as therapeutic products, are defined as recombinant proteins and nucleic acids

What is pharmaceutical biotechnology a process of?

• Pharmaceutical biotechnology is a process of translation and integration of biological and life science discoveries to produce biologics and therapeutic products

What are biopharmaceuticals genetically engineered as?

• Cell based products

What are categories of biopharmaceuticals?

• Recombinant clotting factors; recombinant thrombolytics, anticoagulants and other blood-related products; recombinant hormones; recombinant growth factors; recombinant interferons, interleukins and tumor necrosis factor; vaccines; monoclonal antibody-based products; and other recombinant products
  

What are biologicals vs small molecule drugs?

• Biologics

  • Produced by living cell cultures

  • High molecular weight

  • Complex, heterogenous structure

  • Strongly process-dependent

  • Not entirely characterizable

  • Unstable

  • Immunogenic

• Small molecules

  • Produced by chemical processes

  • Low molecular weight

  • Well defined structure

  • Mostly process independent

  • Completely characterizable

  • Stable

  • Non-immunogenic

What are hormones?

• A chemical or polypeptide protein released by a cell or a gland that
  modifies the function and metabolism of other cells in the body

What are examples of hormones?

• Insulin, human growth hormone, and follicle-stimulating hormone

Where do endocrine and exocrine glands secrete products to?

• Endocrine glands secrete products directly into the bloodstream

• Exocrine glands secrete hormones through ducts

How do hormones function by?

• Binding to receptors on the cell surface or inside the cell

How can hormones be classified as?

• Peptide (insulin) or nonpeptide (progesterone, estrogen) hormones

Where are peptide hormones purified from? What could extracted protein hormones be?

• Purified from animal sources

• Extracted protein hormones could:

  • Include other animal proteins

  • Be contaminated with infectious agents (ex: spongiform virus and the prion protein)

• Purified from human sources

How can small peptides be made?

• Chemically synthesized

Most protein hormones are produced as what?

• Recombinant protein

Many hormones are available in what form? What is an example of the first one?

• Recombinant form

• Insulin was the first recombinant protein hormone in 1982

  • Methionyl hGH was approved later in 1985

What is insulin extracted from? What later led to human insulin?

• Extracted from animals

• rDNA tech and improved purification methods have led to the production of pure >98% human insulin

What type of protein is insulin? What is it’s purpose and how is it secreted?

• A small protein (51 AA)

• It is a major metabolism regulating hormone secreted by B cells of the pancreas

What is human insulin brand?

• Humulin, Novolin, Afrezza

What is insulin lispro?

• Humalog, Liprolog, Admelog

What is insulin aspart?

• NovoRapid, NovoLog

What is insulin Glulisine?

• Apidra

What is insulin glargine?

• Toujeo, Lantus, Basaglar

What is insulin detemir?

• Levemir

What is insulin degludec?

• Tresiba

Which insulin preparations have rapid onset and short duration?

• Insulin aspart

• Insulin lispro

• Insulin glulisine

• Insulin (Agrezza) (oral inhalation)

• Insulin regular

What insulin preparation has intermediate onset and duration?

• Isophane insulin (NPH)

What insulin preparation has prolonged duration?

• Insulin degludec

• Insulin detemir

• Insulin glargine

Where is insulin absorption from?

• 20% from the interstitium

• 80% from the microvascular endothelium

What is the brand of insulin lispro?

• Humalog

• Admelog

• Liprolog

What is the brand of insulin aspart?

• Fiasp

What is the brand of insulin glulisine?

• Apidra

What is the brand of Inhaled Insulin?

• Afrezza

What are the ultra-rapid initiatives for insulin?

• Inhaled insulin

• Insulin pumps

  • Insulin patch pumps

What can affect the chemical stability of insulin formulations?

• Hydrolytic transformation of amide to acid groups

  • Transformation of Asn at the terminal 21 position of the A-chain to aspartic acid

  • The deamidation of the AsnB3 of the B chain

• Formation of HMWP

  • Covalent dimers of insulin linked at the A21Asn and B29Lys positions

What can affect the physical stability of insulin formulations?

• Noncovalent aggregation of insulin

  • Formation of insulin fibrils (destabilization of hexamers leads to an increase in the population of monomers)

• Insulin suspensions are the most susceptible to changes in physical stability

  • Clumping of the insulin microcrystalline particles

  • Adherence of the aggregates to the inner wall of the glass storage container (frosting)

What are injection devices in insulin?

• Insulin syringes

• Needles

• Insulin pen devices

What type of delivery is insulin?

• Noninvasive

How should insulin be stored?

• Stored in a cool place that avoids sunlight

What is resuspension of insulin?

• Insulin suspensions should be resuspended by gentle back-and-forth mixing and rolling of the vial between the palms to obtain a uniform, milky suspension

How to do dosing for insulin?

• A new needle and syringe for each injection

What is human growth hormone extracted from?

• Extracted from cadavers and from patients undergoing hypophysectomy

  • Possible contamination of the pituitary derived hGH preparations by the prion

When was hGH identified and when has recombinant hGh products been available? Recombinant hGH products have been produced in what?

• Identified in the 1950s

• Recombinant hGH available since 1985

• Produced in bacteria, yeast, mammalian cells

What regulates Growth hormone?

• Somatostatin inhibits growth hormone

• GHRH releases GH

What is Lonapegsomatotropin?

• Long acting prodrug

What is the clinical use of Human Growth Hormone?

• Growth Hormone Deficiency

• Idiopathic Short Stature

• Turner Syndrome

• Prader-Willi syndrome

• Small for gestational age

• CKD

• Noonan syndrome

• SHOX

• Growth hormone deficient adults

What are safety concerns with human growth hormone?

• SE (benign intracranial HTN, glucose intolerance, and the rate development of anti-hGH antibodies)

• Cause an increase in secondary malignancies in childhood cancer survivors

• Could potentially unmask undiagnosed central adrenal insufficiency

• May increase requirement corticoteroid in those already diagnosed with adrenal insufficiency

• Fluid retention

• Sudden death

• Illicit use

What is FSH controlled by?

• Hypothalamic releasing factor GnRH

What does FSH stimulate?

• Follicular development and estrogen synthesis by granulosa cells of the ovary

What does FSH increase number of? How does FSH affect males?

• Oocytes retrievable for in vitro fertilization or intracytoplasmic sperm injection

• FSH plays role in spermatogenesis, testicular growth + enhances synthesis of androgen binding proteins

Where is FSH derived from? What is a disadvantage in terms of donors and impurity?

• Derived from urine in postmenopausal women

• Too many donors needed for single batch

  • May contain impurities such as LH

What is done to fix impurity in FSH?

• Recombinant DNA tech makes FSH drug products with high purity nd similar to natural FSH

What is Urofollitropin from and indication?

• HUMAN URINE

• Assisted reproductive tech, ovulation induction

Where are Follitropin formulations from?

• Recombinant DNA