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Pharmaceutical formulation and quality assurance > Vaccines, nasal drug delivery and Gene delivery > Flashcards

Vaccines, nasal drug delivery and Gene delivery Flashcards

1
Q

what kinds of vaccines already exist and when were they invented?

A

Live and virulent <1800

Live and attenuated 1870<

Recombinant after 1982

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2
Q

What are the two types of immune responses

A

Adaptive Immune response

Innate immune response

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3
Q

What is the innate response

A

It is conducted by myeloid cells
It is the first line of defence
Cellular rapids

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4
Q

Cells involved in innate immunity include:

A

Dendritic cells
Macrophages, mast cells. natural killer cells. basophils, complement protein, eosinophils, Neutrophils, T-cells and Natural killer T-cells.

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5
Q

What is the Adaptive immune response and what cells are involved

A

Specialised immune, immuneological memory, humoral and is slow.

B cells, antibodies, CD4 T-cell and CD8 T-cells

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6
Q

Describe as a summary the immune response

A

The pathogen antigen binds to APC’s recognition receptors.

The APC will digest it, break it down and presents fragments of it on to T-cells and B-cells which activates the Adaptive immune system

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7
Q

What are the current convectional vaccines

A

Live attenuated : live microbial agent that is mutated to reduce the ability to grow in human cells

  • Not safe for immunocompromised patient
  • Bacillus Calmette-Guerin, measles, mumps, yellow fever and rubella (MMR)

Inactivated: Microorganism or viruses treated with heat or chemical (CH2O).

  • Inactivated vaccine are less infective but are safer
  • Polio, Hep A, cholera, influenzas

Toxoids: Inactivated toxins that cause disease (Tetnus and diphtheria).
-Can be as vaccines or to improve immunogenicity of other vaccines (haemophilus influenza)

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8
Q

List some more conventional vaccines

A

Subunit vaccines: uses small part of the organism - gene from genome.

Recombinant DNA tech helps the development of these vaccines.

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9
Q

Characteristic of subunit vaccines

A 
Unable to revert to pathogenic form
Decreased toxicity
Reproducible production
Improved antigen specificity
Immune response is though short lived 
Several booster doses are needed
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10
Q

What are the types of covid-19 vaccines available

A

Live attenuates, inactivated, Replicating viral vector, non-replicating viral vector, DNA vaccines, RNA Vaccine and subunit vaccines

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11
Q

How can subunit vaccine efficacy be increased?

A

use of adjuvants: used in combo with specific antigen to produce robust immune response

Aluminium salts eg Aluminium hydroxide, phosphate, potassium phosphate and aluminium.

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12
Q

How does adjuvants aid immunisation?

A

Induces a polarised immune response (Th-2 biased immunity- strongly humoral).

High levels IgG1 antibodies and cytokines such as IL-4

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13
Q

Which adjuvants are used for which vaccines?

A

Aluminium salts: Various diseases

MF59: Influenzas

AS03: Influenzas

AS04: HPV, HBV

virosome: Influenza and HAV

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14
Q

What are the types of Adjuvant mediated immunity

A 
Danger model
Signal 0
Recombinant signal 2
Emulsion
Depot effect
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15
Q

What is the danger model for an adjuvant

A

Parenteral delivery -> cells rupture releasing intracellular contents, mitochondria, uric acid and heat shock proteins Alarmins.

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16
Q

Describe the Signal 0

A

Binding of Alarmins and PAMP to pathogen binding receptors on cells such as TLR, antibody Fc receptors.

Leads to activation of the cells and causes proinflammtory cytokines, chemokines and co-stimulatory (CD80/CD86) molecules to activate T-cells

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17
Q

Describe recombinant signal 2

A

Adjuvant activate macrophage and B-cells to induce CD80 AND CD86- upregulate the expression on the dendritic cells.

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18
Q

Emulsion or particles in the adjuvant mediated immunity

A

Vesicular structures carry antigen either by entrapment or adsorption. Vesicles are naturally occurring and appropriately sized to be endocytosed by cells (composition and size critical)

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19
Q

Depot effect in Adjuvant Mediated Immunity

A

Localisation of antigen (with or without adjuvant) at the injection site and not in the lymphoid organs (although increased presentation of antigen in the lymphoid organs may be a direct consequence of the depot-effect and is often the desired effect) [route of injection, viscosity, particle size]

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20
Q

what are the characteristic of an ideal adjuvant

A

> Must contain sufficient PAMPs to alert immune system without hyper-stimulation
Cause some tissue damage to release Alarmins
Stays associated with antigen until uptake
Free antigens, peptides and genes rapidly degraded or cleared

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21
Q

Typical adjuvants forming a depot

A
  • Chemical \precipitates (Aluminium salts) (? Uric acid/danger signal)
  • Oil-in-Water / Water-in-Oil (IFA, Montanide MF59) [MF59: 0.5% Tween 80, 0.5% Span 85, 4.3% Squalene, Water for injection, 10nM Sodium citrate] – direct effect on Cytokine levels
  • Protein precipitates (IC31)
22
Q

Typical adjuvants activating DCs

A

> CpGs, IC31 (TLR9), MPL (TLR4), TLR-2, 3,4,5,6,8 ligands
Peptidoglycan (nods), QS21, Saponin
Heat-shock proteins

23
Q

Typical adjuvants targeting DCs

A

> Liposome
Virosome and virosome like particles
Microparticles (polymers)
ISCOMs (Th1 & Th2) /Iscomatrix (Th2) [Immune stimulating complexes, 40nm, saponins (Quil A), lipids, cholesterol and antigen; chol binds to saponin forming 12 nm rings that are fixed together by lipids to form spherical NPs. Hydrophobic and amphipathic antigens preferred. Increased antigen presentation to B cells and uptake by APC inducing a potent humoural and cellular response]
IC31 [11-mer antibacterial peptide (KLKL(5)KLK) and a synthetic oligodeoxynucleotide (ODN1a) which is a Toll-like receptor 9 agonist without containing cytosine phosphate guanine (CpG) motifs –humoural response]

24
Q

what are Nano-enabled Vaccine Formulations

A

Liposomes, niosomes and other vesicular adjuvants

Enhancing protection and APC uptake of antigen
Can include immunomodulating molecules in liposomes prepared with dimethyldioctadecylammonium

25
Q

Factor to consider concerning parenteral vaccination

A

> Needle-phobia especially in children making vaccination unnecessarily stressful
Needle stick injuries (300,000 injuries annually in US)
Re-use of needles (developing countries-cost)
Need for sterility
Need for cold transport
Need for trained healthcare professionals
IgG and IgM produced circulate in the blood
-Thus no mucosal antigen produced
-Most infections start at a mucosal surface

26
Q

Factor to take into consideration for mucosal vaccines

A

> Improved patient compliance
No need for sterility
No need for cold transport
No need for trained healthcare professionals
MALT (mucosal associated lymphoid tissue)
IgA secreted at mucosal surfaces and IgM produced circulate in the blood
-Most infections start at a mucosal surface

27
Q

Types of mucosal vaccinations

A

> Oral: Antibody response in SI (proximal segment), ascending colon, mammary and salivary glands
Rectal: Antibody response –small in SI and proximal colon
Nasal or tonsilar: Antibody response in upper airway mucosa, regional secretions such saliva, nasal secretions (no gut response)
Vaginal but also nasal: strong IgG antibody response in human cervicovaginal mucosa
-Menstrual status can affect intensity of immune response in genital secretions

28
Q

What the examples of oral mucosal vaccines

A

-Fleas from cows infected with cowpox
-Sabin oral polio vaccines
-Typhoid fever
Cholera

29
Q

How does oral mucosal vaccines work

A

Recognised by microfold (M-cells) in the peyer’s patch of the intestines and by DC

30
Q

What is the formulation ingredients for Pfizers covid-vaccine

A

Active: ModRNA encoding viral pike glycoprotein

Lipids: Ionisable Lipid: ALC-0315: (4-hydroxybutyl) azanediyl)bis (hexane-6,1-diyl)bis(2-hexyldecanoate)
Peg Lipid: ALC-0159: 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide
DSPC: 1,2-Distearoyl-snglycero-3-phosphocholine
Cholesterol

Salts: Potassium chloride, monobasic potassium phosphate,
Sodium chloride, potassium dihydrogen phosphate

Others: Dihydrate sucrose, water for injection

31
Q

What are the ingredient for Az/oxford vaccine formulation

A

Active: Non-replicating chimpanzee AdV5 expressing spike protein

Excipients:
>Polysorbate 80 (0.1mM) [Non-ionic surfactant/emulsifier]
>Sodium Chloride (35mM)
>Magnesium chloride (1mM) [Stabiliser heat, Immune response booster]
>Histidine (10mM) (pKa 6.1)
>Sucrose (7.5% w/v)
>Ethanol (0.002 mg/0.5mL dose) [Not enough to cause noticeable effects – Deemed negligible by Muslim scholars (comparable amount of ethanol in natural foods or bread)]

32
Q

What the the storage requirements for covid vaccines

A

Pfizer RNA vaccine : -70oC and stable for 5 days at 2-8oC

Moderna RNA vaccine: -20oC and stable for 30 days at 2-8oC

33
Q

What are the advantages of nasal drug delivery

A
  1. Rapid onset of action (e.g. migraine)
  2. Avoidance of GIT or 1st pass metabolism
  3. Preferred to parenteral or rectal
  4. Lower costs
  5. Chronic disorders
  6. Delivery of peptides, proteins
  7. Vaccination esp for resp tract infections as influenza or TB
  8. CNS access: reach local receptors
  9. Delivery across the BBB
34
Q

Describe the nasal cavity

A 
It is around 160cm2 and is made of 3 sections:
>Nasal vestibule and atrium
>Respiratory region
  -Inferior turbinate
  -Middle turbinate
  -Superior turbinate 
>Olfactory regions
35
Q

What is the function of the vestibular region and were is it located

A

Located at the opening of the nasal cavity and filters airborne particles

Particles filtration:
> 10 µm filtered by vibrissae at nostrils
5

36
Q

Describe the respiratory regions

A

Make up 77% of the nasal cavity
Has mucociliary to remove particles (5-10um)
Made of pseudostratified columnar secretory epithelium

37
Q

What is the olfactory region of the nasal cavity

A

Make 10% of the nasal cavity
Composed of non-ciliated pseudostratified columnar epithelial with 6-10m olfactory sensory neurons

Used to smell

38
Q

What are Turinates

A

They are thin bony structure that line the mucosa and protrude into the nasal airways

Maxillo-turbinate: Cover respiratory epithelium

  • Warm, humidify and cleans inhaled air
  • Removes H20 from exhaled air

Ethmo-turbinates

  • Cover olfactory epithelium
  • High SA for neurons
  • Associated with cribriform plate
  • olfactory receptor nerves synapse with the mitral olfactory nerve cells through the cribriform plate
39
Q

What is the delivery sites for nasal drug formulations.

A 
-Have large surface area for absorptions 
  Two potential deposition sites
1.anterior nares (nostrils)
- longer residence time
- low permeability
  1. posterior turbinates
    - high permeability
    - shorter residence time

Two delivery routes

  1. volatile substances via olfactory receptors
    - essential oils
    - odours
  2. potential non-invasive route for CNS delivery circumventing the BBB
40
Q

Describe muco-ciliary clearance

A

Maintain integrity of muco-ciliary system by removing trapped

Ciliary activity is the driving force: 1000 strokes /min

Mucous flow rate of 7mm per min

41
Q

Types of local nasal delivery formulation

A

Drops, sprays, powders, washes, semisolids, sticks
Single dose or mutli-dose +/- device
Non-irritating +/- no A/Es on mucosa or cilial function

42
Q

Consideration when formulating nasal preparations

A

Critical processes

  • Deposition
  • Clearance
  • Absorption
43
Q

How does systemic nasal delivery work

A

Mimic parenteral delivery

Fast onser of action

43
Q

How does systemic nasal delivery work

A

Mimic parenteral delivery
Fast onset of action
-Pain relief: morphine, ketamine, enkephalin
-Erectile dysfunction: Apomorhine

44
Q

Advantages of nasal systemic delivery

A 
Surface area
Permeability
Avoid 1st pass
Low enzymatic activity
Self administration
Patent extension
45
Q

Disadvantages of nasal systemic delivery

A 
Limited Dose Size
Low absorption of high MW hydrophilic drugs
Tissue irritation
Low reproducibility
Mucociliary clearance
46
Q

Barriers of drug absorption in nasal delivery

A

Mucus
Rapid mucociliary clearance of administered formulation
Permeation across epithelial cells
Metabolism (enzymatic degradation in the vestibule and /or crossing epithelium

47
Q

How the barriers of nasal drug delivery overcome

A

Inhibit mucociliary clearance/manipulate contact time (viscosity enhancers)
Enhance permeation using absorption/penetration enhancers
E.g. chitosan derivatives able to reversibly open the TJ
Enzyme inhibitors

48
Q

What are the novel technologies used to overcome

A 
Mucolytics
Absorption enhancers
Viscocity enhancers
Mucoadhesives (sol, dry powder, colloidal)
>Reduce MCC
>Reduce clearance
>Increase local drug concentration
>Protect drug from dilution
49
Q

Absorption enhancers

A

Insulin + dimethyl-b-cyclodextrin = 100% bioavailability

  • More effective when combined with a mucoadhesive
  • Bile salts, surfactants, fatty acids (phospholipids and lysophospholipids) improved transcellular transport of drugs but result in membrane damage
50
Q

Chitosan and positively charged polymers

A

> Chitosan glutamate (250 KDa, 80% deacetylation)
Sheep: Insulin peak plasma level increased from 34 to 191ml U-1 and a 7-fold increase in AUC
Humans: 9-15% bioavailability of SC Insulin

51
Q

What are some licenced therapies for nasal delivery

A

PecFent: Pain relief which contain fentanyl (Higher than plasma level than oral)
>Highly lipophilic
>In a pectin based gel in which the drug diffuses out of. = sustained release

Pharmaceutical formulation and quality assurance (14 decks)

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