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Biopharmaceutical Technology > DDS: Nasal > Flashcards

DDS: Nasal Flashcards

1
Q

What are the examples of conditions affecting the nose or paranasal sinuses that the nasal route is used for?

A

allergic or infectious rhinitis and sinusitis

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2
Q

Why is there potential for systemic DD in the nasal route?

A
  • rich vasculature of nasal mucosa; porous, thin epithelial membrane
  • minimal degradation of proteins/peptides; avoid first-pass metabolism

potential for nose-to-brain delivery

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3
Q

For nasal route;

A) What is used to increase retention

B) what is used to increase permeability?

A

A)

  • mucoadhesive polymers

B)

  • permeation enhancers
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4
Q

What is NALT?

A

nasal associated lymphoid tissue

  • vaccines: both humoral and cell-mediated immune responses
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5
Q

Outline the anatomy of the nasal route

A
  • Outermost nasal vestibule (15 mm) connects nostrils to nasal valve
  • Nasal cavity (60 mm; 20 mL volume) contains 3 folds or turbinates – increase surface area
  • Mucous membrane with columnar (cilia for mucociliary clearance), goblet and basal cells
  • Rich blood flow
  • Nasal secretion of adult pH 5.5- 6.5 (becomes alkaline in conditions such as acute rhinitis, acute sinusitis)
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6
Q

What are advantages of nasal delivery?

A
  • Surface area of 150 cm2 – microvilli
  • Highly vascular and porous basement membrane
  • Avoids first pass
  • Easily accessible
  • Pulsatile delivery possible
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7
Q

What are the disadvantages of nasal delivery?

A
  • Mucocilliary clearance
  • High enzymatic activity
  • Volume: 100-150 μL per nostril
  • Bioavailability decreases with MW > 1000 Da
  • Ciliated epithelium easily damaged
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8
Q

For Nasal delivery

A) Where are nasally administered drugs deposited?

B) What are the three mechanisms that inhaled droplets by which solid particles are deposited?

C) Where is the site of deposition for standard nasal spray?

D) Drugs can either be absorbed through the ….. or ….

E) What is the nasal mucosa permeability for polar molecules? Give examples

A

A)

  • Nasally administered drugs deposited on respiratory epithelium

B)

  1. inertial impaction
  2. gravitational sedimentation
  3. Brownian diffusion

C)

  • Anterior part of nose

D)

  • Drug can either be absorbed through epithelium and reach the systemic circulation or be cleared via the nasopharynx and gastrointestinal tract by the mucociliary clearance system

E)

nasal mucosa permeability for polar molecules is low

  • BA = 10% for small molecules like calcitonin
  • BA = 1% for small peptides like insulin
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9
Q

What are THREE common mechanisms of epithelial cell transport?

A
  1. Transcellular (lipoidal route through cells by concentration dependent passive diffusion, active transporter-mediated or vesicular transport)
  2. Paracellular (through tight junctions between cells)
  3. Transcytosis mediated by vesicle carriers
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10
Q

What are some biological factors affecting nasal drug absorption?

A
  • Nasal blood flow
  • Mucociliary clearance
  • Enzymatic degradation
  • Tranpsorters and efflux
  • Physical condition of mucosa
  • Site of deposition within nasal cavity
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11
Q

What are some physiochemical factors affecting nasal drug absorption?

A
  • Molecular weight and size
  • Lipophilicity
  • Partition coefficient
  • Dissociation coefficient
  • Solubility and dissolution rate
  • Stability
  • Polymorphism and morphology
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12
Q

What are some formulation factors affecting nasal drug absorption?

A
  • pH and osmolarity
  • Mucosal irritancy
  • Viscosity
  • Excipients
  • Dosage form
  • Drug distribution
  • Physical form of formulation
  • Drug conc, dose and volume of administration
  • Area of exposure
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13
Q

What are the four main types of nasal formulations?

A

Drops, aqueous sprays, pressurized sprays, dry powder systems

> liquid: aqueous-based in general

> powder: >10 um particle size

> nasal drops and metered dose sprays: instill within or sprayed into nasal cavity

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14
Q

What are examples of nasal formulations used in local treatment and what is it used for?

A
  • congestion (e.g. xylometazoline)
  • allergic rhinitis (e.g. budesonide)
  • cleansing (e.g. normal saline)
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15
Q

What are examples of nasal formulations used in rapid systemic delivery and what is it used for?

A
  • migraine (sumatriptan)
  • analgesia (fentanyl)
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16
Q

What are examples of nasal formulations used in nasal peptide delivery and what is it used for?

A
  • Calcitonin (Miacalcin®, Fortical®)
  • desmopressin (Desmospray®)
  • buserelin (Suprecur®)
  • nafarelin (Synarel®)
  • oxytocin (Syntocinon®)
17
Q

Rapid mucociliary clearance leads to short residence time and poor bioavailability. How to improve this?

A

Mucoadhesion and penetration enhancement strategies

18
Q

What are some nasal formulation considerations for liquid formulations (solutions and suspensions)?

A
  • Control pH of formulation (e.g. sodium citrate)
  • Tonicity (e.g. sodium chloride, glucose)
  • Choice of vehicle/co-solvents (e.g. propylene glycol)
  • Addition of viscosity-modifying agents (e.g. methylcellulose)
  • Preservatives (e.g. benzalkonium chloride)
  • Antioxidants (e.g. butylated hydroxytoluene)
19
Q

What are some nasal formulation considerations for powder-based formulations (solutions and suspensions)?

A

Particle size distribution, density, shape and flow will influence emission from device and particle deposition in nasal cavity

20
Q

What are examples and possible actions of the following absorption ehancers;

A) Fatty acids

B) Surfactants

C) Bile salts

D) Cyclodextrins and derivatives

E) Enzyme inhibors

F) Bioadhesive materials

A

A)

  • Dideconoylphosphatidylcholine, lysophosphatidylcholine
  • Membrane disruption

B)

  • Sodium lauryl sulphate, saponin, polyoxyethylene-9-lauryl ether
  • Membrane disruption

C)

  • Bile salts Sodium deoxycholate, sodium glycocholate, sodium taurodihydrofusidate
  • Open tight junctions, enzyme inhibition, mucolytic activity

D)

  • α-, β-, γ-cyclodextrin DMβ-, HPβ-cyclodextrin
  • Open tight junctions, membrane disruption

E)

  • Bestatin, amastatia
  • Enzyme inhibition

F)

  • Carbopol, starch microspheres, chitosan
  • Reduce nasal clearance, open tight junctions
21
Q

Short residence times can addressed by the application of in situ gelling systems, when the sol, the liquid form, is transformed into a gel by some physiological stimulus, upon instillation in the nasal cavity, allowing a prolonged residence time. What are the following gelation triggers for the following polymers;

A) Pecitin

B) Carbopol

C) Gellan gym

D) Chitosan

E) Poloxamer

F) Ethylhydroxyethylcellulose

A

A)

  • High methoxylation: pH activated in the presence of sugar
  • Low methoxylation: ion activated

B)

  • pH activated (but also temperature at low shear rate)

C)

  • Thermally dependant ion activated

D)

  • Thermally triggered in the presence of glycerophosphate

E)

  • Thermally triggered

F)

  • Thermally triggered
22
Q

What type of delivery system can be delivered nasally to circumvent the blood-brain-barrier (nose to brain delivery)?

A

Nanocarrier delivery systems (e.g. solid-lipid or polymeric nanoparticles, nanoemulsions, liposomes)

23
Q

What are three proposed pathways across the olfactory epithelium for nose-to-brain delivery?

A
  1. a transcellular pathway (receptor-mediated endocytosis, fluid phase endocytosis, or passive diffusion (unlikely for peptides)
  2. a paracellular pathway through tight junctions
  3. the olfactory nerve pathway (endocytotic or pinocytotic mechanisms) – via intracellular axonal transport to the olfactory bulb
24
Q

For vaccine delivery (nasal route);

A What can microfold cells (m cells) do?

B) What do nasal associated lymphoid tissue (NALT) generate?

C) What vaccines are avaliable?

A

A)

  • Microfold cells (M cells) can transcytose particulate matter across nasal epithelium to lymphoid follicles for uptake, processing and initiation of immune responses

B)

  • generates both cellular and humoral immune responses against pathogens

C)

  • Fluenz Tetra (AstraZeneca) is a live attenuated influenza vaccine available as a nasal spray suspension, (24 mths to 18 yrs), as divided dose in both nostrils
  • FluMist Quadrivalent (2-49 yrs)
  • GelVac™ dry powder formulation with GelSite® – Aloe vera derived polysaccharide polymer with mucoadhesive properties: in situ gelation increases residence time

Biopharmaceutical Technology (16 decks)

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