Question: Describe the differences between top-down and bottom-up approaches in liposome production, including an example of each approach.
10 Oct 2022,2:06 AM
Tablets are often coated using a film coating process. Discuss the reasons why film coatings may be applied to tablets.
The thermoresponsive polymer poly(N-Isopropylacrylamide) (PNIPAAm) has properties that make it useful for drug delivery.
(a) Fully explain how the thermoresponsive properties of this polymer enable in-situ implant formation.
[75%]
(b) List FIVE factors that can alter its lower critical solution temperature (LCST).
[25%]
Describe the differences between top-down and bottom-up approaches in liposome production, including an example of each approach.
Discuss the advantages non-viral vectors have over viral vectors for nucleic acid delivery.
Discuss the composition, structure, and nucleic acid release mechanism of the Pfizer BioNTech vaccine for COVID 19 that have led to the positive immune response in humans.
A research and development department in a large multinational biopharmaceutical company is looking to develop an oral anti-cancer medicine. The initial hit compound has shown over 90% protein binding efficiency, high membrane permeability but very low solubility (BCS II compound). To enhance the bioavailability of the compound, the company has decided to utilise an amorphous solid dispersion formulation strategy.
(i) What are amorphous and amorphous solid dispersions?
[20%]
(ii) What are the advantages of this amorphous solid dispersion strategy?
[30%]
Immunogenicity is a significant problem within protein therapeutics. Discuss thoroughly why such immunogenic reactions occur.
Naproxen is a popular nonsteroidal anti-inflammatory drug (NSAID) that is a widely used oral dosage form for mild-to-moderate pain. The chemical structure of naproxen is shown in Figure 1 (pKa = 4.15).
Figure 1 Chemical structure of naproxen.
- What is the % ionisation of naproxen at pH=5?
[20%]
- According to the Merck Index, naproxen has a solubility of 0.0159 mg/mL in water and good membrane permeability. The maximum dose of naproxen for adult patients is 500mg (tablet) twice per day. Based on the given information, which BCS class is naproxen? Clearly explain your reasoning.
[20%]
- Naproxen sodium is a modification of naproxen with greater water solubility at 250 gram/L. Please explain the reason behind the increase in water solubility for naproxen sodium. Also explain how the increased solubility of naproxen sodium would affect the bioavailability of the drug.
[20%]
- Company A is trying to produce a generic product for naproxen sodium using a wet granulation process. Please explain the potential process-induced phase transformations that can occur and the methods used to characterise them.
- In 1975, Chien et al. published a research article entitled 'Controlled Drug Release from Polymeric Delivery Devices III: In Vitro-In Vivo Correlation for Intravaginal Release of Ethynodiol Diacetate from Silicone Devices in Rabbits'. In that study, female rabbits (n=40) were implanted with silicone vaginal rings containing ethynodiol diacetate for up to 8 weeks. In an effort to establish an in vitro-in vivo correlation, Chien and his co-authors produced the following graph, showing the correlation between the plasma concentration (CB) of norethindrone (the major metabolite of ethynodiol diacetate) and the in vitro release rate (Q/t; referred to as 'flux' in the figure caption) at various time points.
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- What level of in vitro-in vivo correlation (IVIVC) do the data in the figure represent? Give a reason for your answer.
[10%]
- Across how many time points were the in vivo and in vitro data collected?
[10%]
The article also includes the following graph, showing in vitro cumulative drug release (Q) versus the square root of time for a silicone elastomer ring device initially containing 30 mg ethynodiol diacetate.
- Based on the data presented in this in vitro release graph, comment on the type (i.e., the design) of the vaginal ring that was tested.
[20%]
- How might you change the formulation to increase the rate of release of ethynodiol diacetate?
[10%]
- With reference to a specific example you have studied, outline the experimental techniques that can be used to investigate microbial penetration across microneedle-punctured skin.
[50%]
Expert answer
There are two ways to make liposomes: the top-down way and the bottom-up way. In the top-down way, you start with a large container and then cut it into smaller pieces. The smaller pieces are then used to make liposomes. In the bottom-up way, you start with very small pieces of material and then build them up into larger pieces that become liposomes. An example of the top-down approach is when you make a cake: you start with a large pan and then cut it into smaller pieces. An example of the bottom-up approach is when you grow a plant from a seed: you start with very small seeds and then build them up into larger plants.
Liposomes are made from lipids, which are molecules that have a hydrophilic (water-loving) head and a hydrophobic (fat-loving) tail. The hydrophilic head is attracted to water, and the hydrophobic tail is repelled by water. When you put lipids in water, they spontaneously form into spheres with the hydrophilic heads on the outside and the hydrophobic tails on the inside. These spheres are called liposomes.
The size of a liposome can range from about 5 nanometers to about 200 nanometers. A nanometer is one billionth of a meter. To give you an idea of how small this is, a human hair is about 80,000 nanometers wide.
Liposomes are made from a variety of different materials, but the most common type is made from phospholipids. Phospholipids are lipids that contain phosphate groups. The two most common types of phospholipids are lecithin and cephalin.
The most common way to make liposomes is to use a phospholipid that is naturally liquid at body temperature, such as lecithin. The lecithin is dissolved in water, and the desired molecule is added to the solution. This solution is then passed through a filter that has pores that are small enough to allow the liposomes, but not the water, to pass through.
