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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

(52 cards)

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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

Study These Flashcards
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

Study These Flashcards
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

Study These Flashcards
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

Study These Flashcards
A

Liposomes, niosomes and other vesicular adjuvants

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

25
Factor to consider concerning parenteral vaccination
>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
Factor to take into consideration for mucosal vaccines
>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
Types of mucosal vaccinations
>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
What the examples of oral mucosal vaccines
-Fleas from cows infected with cowpox -Sabin oral polio vaccines -Typhoid fever Cholera
29
How does oral mucosal vaccines work
Recognised by microfold (M-cells) in the peyer's patch of the intestines and by DC
30
What is the formulation ingredients for Pfizers covid-vaccine
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
What are the ingredient for Az/oxford vaccine formulation
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
What the the storage requirements for covid vaccines
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
What are the advantages of nasal drug delivery
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
Describe the nasal cavity
``` 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
What is the function of the vestibular region and were is it located
Located at the opening of the nasal cavity and filters airborne particles Particles filtration: > 10 µm filtered by vibrissae at nostrils 5
36
Describe the respiratory regions
Make up 77% of the nasal cavity Has mucociliary to remove particles (5-10um) Made of pseudostratified columnar secretory epithelium
37
What is the olfactory region of the nasal cavity
Make 10% of the nasal cavity Composed of non-ciliated pseudostratified columnar epithelial with 6-10m olfactory sensory neurons Used to smell
38
What are Turinates
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
What is the delivery sites for nasal drug formulations.
``` -Have large surface area for absorptions Two potential deposition sites 1.anterior nares (nostrils) - longer residence time - low permeability ``` 2. 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
Describe muco-ciliary clearance
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
Types of local nasal delivery formulation
Drops, sprays, powders, washes, semisolids, sticks Single dose or mutli-dose +/- device Non-irritating +/- no A/Es on mucosa or cilial function
42
Consideration when formulating nasal preparations
Critical processes - Deposition - Clearance - Absorption
43
How does systemic nasal delivery work
Mimic parenteral delivery | Fast onser of action
43
How does systemic nasal delivery work
Mimic parenteral delivery Fast onset of action -Pain relief: morphine, ketamine, enkephalin -Erectile dysfunction: Apomorhine
44
Advantages of nasal systemic delivery
``` Surface area Permeability Avoid 1st pass Low enzymatic activity Self administration Patent extension ```
45
Disadvantages of nasal systemic delivery
``` Limited Dose Size Low absorption of high MW hydrophilic drugs Tissue irritation Low reproducibility Mucociliary clearance ```
46
Barriers of drug absorption in nasal delivery
Mucus Rapid mucociliary clearance of administered formulation Permeation across epithelial cells Metabolism (enzymatic degradation in the vestibule and /or crossing epithelium
47
How the barriers of nasal drug delivery overcome
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
What are the novel technologies used to overcome
``` Mucolytics Absorption enhancers Viscocity enhancers Mucoadhesives (sol, dry powder, colloidal) >Reduce MCC >Reduce clearance >Increase local drug concentration >Protect drug from dilution ```
49
Absorption enhancers
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
Chitosan and positively charged polymers
>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
What are some licenced therapies for nasal delivery
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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