Hormones

biopharmaceuticals

• Recombinant products and nucleic acids ← genetically engineered as cell-based products (made in an organism)

• genetically engineered as cell-based products

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

biologics

• produced by living cell cultures

• high MW

• complex, heterogenous structure

• strongly process-dependent

• not entirely characterizable

• unstable

• immunogenic

• ex. insulin

small molecule drugs

• produced by chemical processes

• low MW

• well-defined structure

• mostly process dependent

• completely characterizable

• stable

• nonimmunogenic

• ex. Piroxicam

hormones

• chemical or polypeptide protein released by a cell or a gland that

  modifies the function and metabolism of other cells in the body

endocrine vs exocrine glands

• endocrine

  • secrete into blood

• exocrine

  • secretion through ducts

hormones function by

binding to receptors on the cell surface or inside the cell

hormones classified as

peptide (e.g., insulin) or nonpeptide (e.g., progesterone, estrogen) hormones

peptide hormones

• purified from animal sources or human sources

• If from animals → can have animal proteins or be contaminated

• Smaller peptides can be chemically synthesized → most protein hormones are recombinant

non-peptide / recombinant / synthetic hormones

• — is the first recombinant hormone

insulin

why difficult to administer insulin by oral route?

degraded by enzymes in GI tract

insulin

• produce —% pure insulin

• structure

• Produce >98% pure insulin

• Structure:

  • Small 51 AA protein secreted by beta cells in pancreas (has A and B chain)

insulin association

• insulin monomer becomes dimer w/ increased concentration

• dimer becomes hexamer w/ addtion of zinc (bind)

• w/ phenolic preservative, becomes longer acting

insulin analogs

• ultra rapid (monomers)

• rapid (monomers)

• short acting (monomers)

• intermediate acting (dimers)

• long acting (hexamers)

insulin analogs

• ultra rapid

Insulin apart (Fiasp)

Insulin lispro (Lyumjev)

Insulin oral inhaled (Afrezza)

→ shortest; no buffer/preservative

insulin analogs

• rapid

Insulin aspart (Novolog)

Insulin lispro (Humalog, Admelog, Liprolog)

Insulin glulisine (Apidra)

insulin analogs

• short acting

Insulin regular

(Humalin R, Novolin R)

insulin analogs

• intermediate acting

Insulin NPH (Humalin N, Novolin N)

insulin analogs

• long acting

Insulin glargine (Lantus; Basaglar; Toujeo; Semglee, Rezvoglar)

Insulin degludec (Tresiba)

rapid onset and short DOA insulin preparations

• insulin aspart

• insulin lispro

• insulin glulisine

• insulin (afrezza) — oral inhalation

• insulin regular

intermediate onset and duration

isophane insulin (NPH)

prolonged duration

• insulin degludec

• insulin detemir

• insulin efsitora alfa

• insulin glargine

• insulin icodec

solution products

• regular insulin

• insulin lispro (Humalog, Admelog, Liprolog)

• insulin aspart (Fiasp)

• insulin glulisine (Apidra)

only inhaled insulin

Afrezza (ultra-rapid)

preparation for ultra-rapid insulin

2 types of pumps (traditional and patch)

basal insulin suspension preparations

insulin NPH

• modifying protein: protamine

• all cloudy appearance

basal insulin solution preparation

• insulin glargine (Lantus, Basaglar, Toujeo)

• insulin degludec (Tresiba)

2 new products of basal insulin solution preparation

• Insulin Efsitora alfa (Onswik)

  • time to peak: 3 - 4 days

• Insulin Icodec (Awiqli FlexTouch)

  • time to peak: 15 hrs

dosing frequency: once weekly due to phenol and benzyl alcohol

pharmaceutical concerns

• chemical stability

• Hydrolysis of amide to acids

  • Asparagine to aspartic acid 

  • Deamidation of Asn in B chain

• Formation of high MW proteins

  • Covalent dimers formed by insuli

pharmaceutical concerns

• physical stability

• Noncovalent aggregation

  • Destabilized hexamers = more monomers

• Suspensions are MORE susceptible to changes in physical stability

  • Clumping + aggregates adhering to the storage container

clinical aspects of insulin formulation

• Insulin syringes (should match the strength of the insulin that is to be administered)

• stored in cool place that avoids sunlight

• Resuspension is required for suspension formulations d/t to aggregation/clumping

  • Mix back and forth by rolling vial between the palms to make it uniform and milky looking

• new needle and syringe for each injection

• extememporaeous mixing

human growth hormone (hGH)

• structure

• Produced in bacteria, yeast, mammalian cells

• Just know the diff. between the structures of hGH and insulin if you look

• AA = 191

• 4 helixes

hGH

• function

• GH receptor is a monomer → when bound, dimerizes and becomes active

hGH

• regulation

• Endogenous GHRH excreted by hypothalamus to stimulate pituitary

• Pituitary excretes GH to liver, adipose, muscle and bone

  • Somatostatin from hypothalamus DECREASES GH release by negative feedback look

  • IGF-I will stimulate positive feedback

rGH products

• produced in E.coli

• genotropin

• norditropin

• nutropin AQ

• humatrope

• zomaction

• omnitrope

rGH product

• produced in mammalian cells

Serostim (AIDS wasting)

LonaPEGsoatropin

• long acting prodrug

• contains PEG and linker

• weekly dosing compared to daily somatropin due to longer DOA

FSH

• function

• release controlled by hypothalamic releasing factor GnRH

• females: stimulates follicular development and estrogen synthesis

• males:

  • plays a role in spermatogenesis

  • promotes testicular growth and enhances the synthesis of androgen-binding proteins

• increases the number of oocyte

FSH

• structure

has alpha and beta subunit

formulations of FSH

• follitropin alfa

• follitropin beta

• folliptropin delta