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RED - Pharmaceutics > Protein Formulations > Flashcards

Protein Formulations Flashcards

1
Q

What are the problems with protein delivery?

A
  • They are large hydrophilic molecules; issues with absorption (lipophilic desirable)
  • Extra-vascular access difficult
  • Poor stability (degradation)
  • Purity/characterisation of recombinant products
  • Complex pharmacoglogical action
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2
Q

How do low molecular weight drugs reach their site of action?

A

Diffusion and partition

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3
Q

What factors determine biodistribution of macromolecules?

A
  • Ability of macromolecules to be transported across endothelium
  • Differences in relative blood flow to different tissues
  • Elimination by kidneys/metabolism
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4
Q

What is the cut-off for glomerular filtration for proteins and why is this beneficial?

A
  • 60kDa for proteins

- Serum albumin is 65kDa (essential)

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5
Q

What is the cut-off for glomerular filtration for dextrans/polysaccharides?

A

40kDa

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6
Q

Where are the receptors located for the removal of old serum proteins/unwanted macromolecules released by dying cells?

A

Receptors in liver on parenchymal cells, and macrophages

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7
Q

How does the Asialoglycoprotein receptor (ASGPR) recognise proteins for disposal?

A
  • Many proteins are glycoproteins (have CHO residues)
  • Terminal sugar residue is sialic acid
  • Sugars beneath e.g. D-galactose are recognised by specific receptors such as the ASGPR; protein is ‘exposed’ and marked for removal
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8
Q

What materials does the ASGP receptor clear?

A
  • Hormones
  • Carrier molecules
  • Protease inhibitors
  • Immunological
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9
Q

What hormones does the ASGP receptor clear?

A
  • Erythropoietin
  • Follicle stimulating hormone (FSH)
  • Interferon
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10
Q

What carrier molecules does the ASGP receptor clear?

A
  • Thyroglobulin (iodine)
  • Caeruloplasmin (Cu)
  • Transferrin (fe)
  • Transcobolamin (vitamin B12)
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11
Q

What protease inhibitors does the ASGP receptor clear?

A
  • α-1 antitrypsin

- α-2 macroglobulin

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12
Q

What other clearance receptor besides ASGPR exist?

A
  • N-acetylgalactosamine/mannose receptor on macrophages

- Fucose receptor on liver parenchymal cells

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13
Q

How proteins such as albumin/LDL with no sugar residues cleared?

A

They age by becoming acetylated and are then cleared by a receptor recognising acetylated proteins

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14
Q

What occurs after proteins bind to clearance receptors?

A
  • Proteins are endocytosed, sent to lysosomes

- Low pH of lysosome degrades protein and chops it up

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15
Q

How are clearance receptors beneficial for drug delivery?

A

Protein drugs can be cleared from circulation by normal homeostatic mechanisms; specific receptors could be used to target drugs to the liver.

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16
Q

What sizes are protein/peptide drugs and what is their bioavailibility?

A
  • Large, hydrophilic molecules 0.5 - 100 kDa

-

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17
Q

How does the half-life of protein drugs compare with small MW drugs?

A

Much less; from 15 seconds for angiotensin, oxytocin 2 mins and vasopressin 4 mins.

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18
Q

Why are protein drugs fairly physically unstable/what causes this?

A
  • Can easily lose their native 3D structure (secondary, tertiary, quaternary denaturation)
  • Unfolding/denaturation as a result of: hydrophobic conditions/surfactants, pH/solvent/temperature, dehydration/lyphilsation
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19
Q

What are the issues concerning adsorption to interfaces with protein drugs?

A
  • Polar and non-polar residues (surfactant-like)
  • Adsorbed at surfaces e.g:
    > Air-water: foaming
    > Air-solid: insulin binds to many surfaces; delivery pumps/glass/plastic syringes, plastic tubing/containers.
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20
Q

How does aggregation of protein drugs come about and what may this lead to?

A
  • Denatured/unfolded proteins may interact

- Aggregation becomes precipitation at a macroscopic level

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21
Q

Give examples of protein drugs suffering chemical instability

A
  • Deamidation; asparagine and glutamine residues hydrolysed to form carboxylic acid
  • Oxidation; methionine, cysteine (can cause disulfide bond breakage)
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22
Q

How can protein drugs become unstable with oxidation?

A
  • Oxygen in air
  • Mechanism via oxygen radical
  • Catalysed by transition metals (Fe and Cu)
  • Mediated by antioxidants e.g. Ascorbate
  • PEG can result in peroxide formation
  • Photo-oxidation
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23
Q

What barrier with biological stability do protein drugs face?

A
  • Protein drugs hydrolysed to AAs and small peptide by GIT
  • Gastric acid; denaturation, pepsin enzyme (phe, tyr)
  • Small intestine; trypsin, chymotrypsin, carboxypeptidases, aminopeptidases (pancreas)
  • Colon; substantial microbial enzymes
24
Q

Give examples of peptides stable to biodegredation by the GIT.

A
  • Cyclosporin (11 residues, cyclic); immunosuppressant
  • TRH (thryotrophin releasing hormone); stimulates release of thyrotropin (thyroid-stimulating hormone/TSH) and prolactin from the anterior pituitary.
25
Q

What are the preformulation aspects for protein drugs?

A
  • Selection of candidate drug (protein)
  • Determination of properties
  • Chemical/biological alteration, Select pH, salts, solvents, surfactants, Liquid or dried formulation,
  • Stable, active formulation
26
Q

What needs to be considered with preformulation in regards to appropriate conditions?

A
  • Physical state
  • pH (affects ionisation of groups e.g. COOH/NH2)
  • ionic strength
  • temperature
27
Q

How does freeze-drying affect stability?

A

Enhances stability (lyophilisation)

28
Q

How does the addition of salts affect protein formulation?

A

Decrease denaturation via binding to the protein (also metal ions); stabilises structure

29
Q

How do polyalcohols (e.g. glycerol) affect protein formulation?

A

They stabilise the protein via selective solvation (dissolution); of hydrophobic/hydrophilic groups

30
Q

How do surfactants affect protein formulation?

A

They prevent adsorption of proteins at surfaces and aggregation (also phospholipids, fatty acids, other proteins); preventing interacting and keeping protein in solution.

31
Q

What chemical modifications are available for proteins and how they do help?

A
  • Adding synthetic polymers - PEG (polyoxyethylene); increases solubility - more ‘membrane friendly’
  • Lipids covalently bound to protein
32
Q

What does primary sequence alteration ential for protein formulation?

A

Specific amino acids can be changes; improving physical and chemical stability

33
Q

What are the issues with parenteral administration with protein drugs?

A
  • Repeated administration required (short term)
  • Patient compliance
  • Stability of dosage form
    e. g. Insuin
34
Q

Why are non-parenteral routes preferred and how are proteins not suited?

A
  • Highly desirable (especially oral)

- Proteins have v. low absorption/bioavailability apart from a few select peptides

35
Q

Which peptides can be administered non-parenterally and why?

A
  • Cyclosporin
  • TRH
  • Captopril
    »> Short chain hydrophobic moieties (unusual)
36
Q

What are the advantages of parenteral delivery?

A

Site-specific delivery:

  • Pharmacokinetic advantages
  • Improvement of therapeutic index
  • Protection from unwanted drug disposition
  • Extravascular access
37
Q

What are the parenteral methods of site-specific delivery?

A
  • Particulate systems; attach to polymer etc. (lipid membranes, coating proteins)
    »> Problems with RES (reticuloendothelial); particles can’t cross vascular endothelium
  • Soluble carriers; but have transport/stability problems (polymer of sorts)
38
Q

What types of implantable system are there for protein drugs?

A
  • Polymer gel matrix (biodegradable)
  • Polymer fibre system
  • Osmotic mini-pumps (respond to osmotic conditions)
  • Tablet-type implants
  • Automatic feedback systems
39
Q

How do implantables deliver protein drugs and for how long do they last?

A
  • Via the intramuscular/subcutaneous route

- Drug release for periods of up to one year

40
Q

What are some examples of implantable protein delivery systems?

A
  • Zoladex (LHRH analogue); injectable biodegradable polymer matrix > 1 month
  • Levonorgestrel; polymer fibre system > 6 months
41
Q

How is Zoladex/Goserelin administered and form does it take?

A
  • Into the upper abdominal wall via S.C.
  • A sterile white/cream in a coloured cylinder 1mm in diameter & 5mm long, preloaded into a special single-use syringe
  • Continuous release for 28 days for palliative treatment of advanced prostate carcinoma
42
Q

How do peptidase inhibitors affect protein drug formulation?

A
  • Improve stability/oral bioavailibility

E.g. amistatin promotes absorption of enkephalins

43
Q

How is saturation/bypassing of intestinal peptidases achieved?

A
  • Increase dosage or load with another peptide
  • Enteric coating e.g. acid-resistant acrylic resin (stomach)
  • Use of azo polymers
44
Q

How do penetration enhancers work? What are their disadvantages?

A
  • Improvement of passive absorption either transcellular or paracellular
  • Problems with irritation/tissue damage
45
Q

List 3 penetration enhancers for insulin.

A
  • Ionic/non-ionic detergents
  • Bile salt surfactants
  • EDTA and other chelating agents (coordinate bonds to metal ions)
46
Q

How can reduction of hepatic first pass clearance/biliary excretion be achieved?

A
  • Saturation of specific enzymes

- Promotion of lymphatic uptake

47
Q

How does cyclosporin bioactivity change when given in an olive-oil based formulation? Why is it so?

A
  • From 1% to 20-50%

- Reduction of hepatic first pass clearance through promotion of lymphatic uptake

48
Q

What factors influence non-passive/paracellular transport for protein drugs and what does it affect?

A
  • Carrier-mediated for di- and tri- peptides
  • Endocytic/transcytotic for proteins
  • M-cell (Peyer’s patch, small intestine; can’t take up enough for effective dose though)
  • Role of P-glycoprotein efflux pump
  • Transport across tight junctions (paracellular; widen junctions?)

> > > Affects oral bioavailability of peptides/proteins.

49
Q

How can oral bioavailibility of peptides/proteins be improved?

A
  • Peptidase inhibitors
  • Saturation/bypassing of intestinal peptidases
  • Penetration enhancers
  • Reduction of hepatic first pass clearance
  • Non-passive and paracellular transport
50
Q

What factors must be considered with the pharmacological action of peptides?

A
  • Dose-response relationships non-standard
  • Multi-faceted cascade processes
  • Hormone/paracrine/autocrine actions (short and long distance, local vs. systemic)
  • Differences in biological action in male/female:
    > How much?
    > How often?
    > Where to?
51
Q

How do the actions of LHRH change with zero-order kinetics and pulsatile delivery? What does this suggest?

A
  • Zero-order; antagonist
  • Pulsatile; agonist

Zero order controlled release not always optimal; pulsatile/complex delivery kinetics beneficial sometimes.

52
Q

What factors are considered when designing non-zero order delivery systems to achieve optimal pattern?

A
  • Trigger (marker of disease state)

- Recognition of trigger by system

53
Q

What are the issues with delivery insulin subcutaneously?

A
  • Fails to mimic endogenous insulin secretion

- Non-compliance

54
Q

How is insulin delivered to the lungs?

A
  • Spray-dried insulin powder with stabilisers in blister
  • Blister loaded at teh base of the inhaler and punctured by actuation
  • Fluidization/deaggregation in aerosolisation chamber by compressed air
  • Patient inhales particle cloud through slow deep breath
55
Q

How do the pharmacokinetics/dynamics of inhaled insulin compare with insulin SC?

A
  • Serum concentrations peak earlier and decay more rapidly
  • Onset of action quicker and duration of action prolonged compared to rapid-acting insulin analogues
  • Patients can inhlae insulin just 10 minutes before meal but still require bedtime SC injection
56
Q

What are the potential non-respiratory adverse effects of inhaled insulin and how do they come about?

A
  • Hypoglycaemia (frequency + severity similar to SC injections)
  • Increase in insulin antibodies (no clinical effects so far but long-term?)

Bioavailibility of inhaled insulin; 15-30% (unabsorbed dose = side effects)

57
Q

What are the potential respiratory adverse effects of inhaled insulin?

A
  • Cough, increased sputum
  • Decrease in lung function in some patients (recommend patients undergo lung function tests and periodically thereafter)

RED - Pharmaceutics (1 decks)

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