Question: Discuss the challenges associated with ocular drug delivery via different routes of administration.

10 Oct 2022,9:22 PM

 

Q1. During the manufacturing of a tablet formulation, you notice that the water-solubility drops below specifications for a batch that was left in the open air for a couple of hours. Initial analysis shows that the drug compound is intact, and you suspect that a change in crystal form of the active pharmaceutical ingredient has taken place.

 

• Discuss the different crystal forms the active pharmaceutical ingredient can exist in and which form is most likely the cause for the lower solubility. Fully explain your reasoning. [50%]

 

• Identify three different ways to avoid the phase transition you have identified as most likely in part (a). Fully explain your reasoning. [50%]

 

Indicative answer:

(a) The API can exist in anhydrous polymorphs (5%), hydrate incorporating water (5%), solvate incorporating organic solvent (5%), co-crystal as multi-component crystal without charge transfer (5%) or salt as multi-component crystal with charge transfer (5%).

In this particular case, the crystal forms present can be an anhydrous polymorph forming (5%), hydrate formation due to uptake of environmental water (i.e. humidity) (5%) or co-crystal/salt forming between the API and an excipient in the tablet (5%). In this case, hydrate formation is the most likely due to the reduced water solubility and the ubiquitous presence of water in the atmosphere (10% for a good reason). Alternatively, a co-crystal or salt could for, most likely in the presence of water but their connection to water-solubility is not given (10% for a good reason).

 

(b) Avoiding hydrate formation: store in a dry environment, e.g. through packaging (20%), coating of the tablet formulation to protect tablet from water exposure (20%), formulation of the hydrate in the first place and adaptation of the dose (20%). Give a proportion for good logical reasoning up to a maximum of 50%.

Avoiding co-crystal/salt formation: exchange excipient (20%), granulate API and excipient separately (20%), avoid exposure to water as this seems to be needed for the transformation (20%). Give a proportion of the marks for good logical reasoning up to a maximum of 50%.

 

 

Q2.  Process-induced phase transformations of active pharmaceutical ingredients (APIs) are an important consideration in the pharmaceutical industry. Various types of phase transformation are often observed that can alter an APIs chemical, physical, and mechanical properties and hence impact the quality and performance of a pharmaceutical product.

 

With the aid of diagrams, provide a short description of process-induced transformations that may occur during solid form processing and the impact this may have upon the quality of solid oral dosage forms (tablets). 100 marks]

 

Indicative answer:

A student should understand that understanding solid phase transitions of drugs is of fundamental importance when manufacturing a drug product.  Unplanned process-induced transformations can lead to potential loss of revenue, increased patient risk and reputational damage for a pharmaceutical company. It is common practice during research and development to isolate and characterise all potential solid phases. Process induced  transformations can potentially lead to undesirable product performance and can be avoided with comprehensive characterisation of drug solid phases, and the associated interconversion. This is reasonably easy to do at high drug loading but to understand transformations when drug loading is low is especially challenging.

 

Some relevant examples should be provided and discussed

• Loss of a hydrate upon heating including DSC, TGA and PXRD data
• Amorphisation upon milling (DSC, TGA and PXRD)
• Anhydrate to hydrate during wet granulation
• Polymorphic transformations during storage (DSC) 

 

 

Q3. Answer all parts

 

• 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%]

 

• Misoprostol is commonly administered intravaginally as an immediate-release tablet for cervical ripening and induction of labour. A new misoprostol vaginal insert, comprising misoprostol in a controlled-release hydrogel polymer, is being developed to address certain drawbacks with current formulations.

 

The chemical structure of misoprostol is presented in Figure 1. A graph showing the pharmacokinetics in women following administration of three different vaginal inserts (containing 100, 200 or 400 micrograms misoprostol) and a 200-microgram oral misoprostol tablet is presented in Figure 2. [50%]

 

• (i) With reference to the chemical structure of misoprostol (Figure 1) and the normal pH of the human vagina, explain why misoprostol acid, rather than misoprostol itself, is the measured in the blood plasma (Figure 2). [20%]

 

• (ii) Explain which pharmacokinetic profile belongs to the oral tablet formulation. [10%]

 

• (iii) From Figure 2, estimate the C_max and T_max values for each of the four pharmacokinetic profiles presented. You must construct a table for presentation of the values. [20%]

Indicative answer:

(a) Students were provided with the following paper as additional reading:

Donnelly, R.F., Thakur, R.R.S., Tunney, M.M., Morrow, D.I.J., McCarron, P.A., O’Mahony, C., Woolfson, A.D. (2009). Movement of microorganisms through microneedle-induced holes is possible, but initiation of infection is unlikely. Pharmaceutical Research. 26, 2513-2522.

Students’ answer should include a detailed discussion of the following:

 

In order to study microbial penetration, form a microbial coating on excised skin, puncture with microneedles and sample from a receiver compartment below the skin. Microbial content is the assayed using the Miles and Misra technique or, more reliably, liquid scintillation spectroscopy using previously radiolabelled microorganisms

 

(b)

3. Misoprostol contains a methyl ester functional group [4 marks] that is susceptible to enzymatic or hydrolytic cleavage in aqueous environments [4 marks]. Under normal vaginal pH conditions (pH 3.8–4.5) [4 marks], misoprostol will undergo enzymatic or hydrolytic cleavage in vaginal fluid to form misoprostol acid [4 marks]. The relatively stable misoprostol acid is readily absorbed and detected in the systemic compartment. [4 marks]
4. The pharmacokinetic profile represented by the unfilled triangles in the graph, showing peak plasma levels within 30 min of administration followed by steadily declining plasma levels, is due to the misoprostol oral tablet formulation. [5 marks] Oral administration of immediate-release formulations typically show rapid onset of action and rapid decline of blood levels. The other pharmacokinetic profiles in the graph are indicative of sustained release products. [5 marks]

• 3 marks for each Cmax and Tmax value, with correct units and assigned to the correct formulation. 6 marks for table format and labelling.

1.  

Graphical plot symbol	Drug formulation	Cmax (pg/mL)	Tmax
Triangle	200 mcg oral tablet	~600	10–30 min
Star	400 mcg vaginal insert	~300	4 or 6 hr
Circle	200 mcg vaginal insert	~60	6 hr
Square	100 mcg vaginal insert	~40	4, 6 or 8 hr

 

Q4. Discuss the challenges associated with ocular drug delivery via different routes of administration. [100%]

Indicative answer:

There are several possible routes of drug delivery into the ocular tissues. The selection of the route of administration depends primarily on the target tissue.

 

Topical administration (Solutions, suspension, ointments, Gels)

• Mostly eye drops to treat anterior segment diseases
• Limited uptake, tear dilution, short-acting, poor availability

 

Systemic (parenteral) administration

• Blood-aqueous barrier & blood-retinal barrier are major barriers for anterior & posterior segment of ocular drug delivery

 

Oral administration

• is a noninvasive & patient friendly route to treat chronic retinal diseases as compared to injectable route.
• limited accessibility to many of the targeted ocular tissues limits the utility of oral administration which necessitates high dosage to observe significant therapeutic efficacy - systemic side effects.

Periocular & intravitreal administration

• in intravitreal the molecules are directly injected into the vitreous
• Although not patient complaint, these routes are employed partly to overcome topical/systemic dosing
• Periocular - subconjuctiva, subtenon, retrobulbar, & peribulbar administration
• The periocular route has been shown to allow permeation of a large range of molecules, including corticosteroids, antisense oligonucleotides, immunoglobulins and DNA to the PS of the eye.
• However, this method has shown low intraocular bioavailability due to a delay in diffusion through the sclera, systemic clearance and loss of drug before reaching the target tissues (e.g. retina).
• Drug diffusion across the scleral membrane is dependent upon drug’s solubility, molecular weight/molecular radius, charge and polarity

 

 SECTION B (50%)

 

ANSWER ALL QUESTIONS

 

Q1. Biological products are used for a wide range of diseases and conditions, including severe and life-threatening conditions.

 

• How could drug delivery systems overcome protein and peptide delivery challenges? [20%]

 

• A patient has been prescribed a recombinant protein to manage his psoriasis (a skin disease). The patient was instructed by his consultant to initially take the medication for four months by weekly subcutaneous injection. After the eighth dose, the patient started to show some allergic reactions to the prescribed medication? Discuss all the changes that could have happened to the formulation to cause such a side effect. [25%]

 

• As a Formulation Scientist, you are requested to suggest a sustained-release injectable formulation for the biologic above to reduce administration frequency from once a week to once a month? Discuss your choice, including the mechanism of drug release. [35%]

 

 

• Discuss the analyses required for biosimilar manufacturing? [20%]

 

Indicative answer:

(a)

Main barriers for PPs delivery

1.Enzymatic :Breaks down peptides and proteins.

2. Physicochemical

-Peptides and proteins are primarily hydrophilic

-Will not partition well into the cell membrane (lipophilic).

-Different mucosae have varying limitations for the absorption of a peptide or protein drug

-Transportation of drugs across the cell membrane is also affected by:

- Permeability of the epithelium

Nasal - thinnest mucosae and least electrical resistance.

Buccal – thickest mucosae and has the highest resistance

 

Drug delivery system advantages in protein delivery

1. protect proteins from acid or enzymatic degradation upon loading into delivery systems (increased stability)

 

2. particle properties (size, surface properties) enhance protein delivery across different barriers by reducing water's hydrophilicity and facilitating nanoparticle permeation or endocytosis.

 

(b)

Structural alterations due to production method:-

• Aggregation (particles and polymers can stimulate B-cells directly)
• Conformational changes due to poor post-translational modifications (i.e. protein modifications such as glycosilation, phosphorylation not achieved properly during expression)
• Degradation
• Oxidation
• The new products appear as new antigens to the immune system.

 

(c)

- The student could suggest hydrogels or polymeric nanoparticles to release the protein.

- The answer should emphasis on the suitability of the procedure to maintain the functionality of the protein (no harsh conditions to be applied to the formulation)

- The student is expected to discuss how the protein will be loaded into the formulation and its release mechanism

 

(d)

A Biosimilar is a biologic medical product highly similar to another already approved biological medicine (the 'reference medicine').

 

*Additional analysis required for biosimilar

1. Structural Analysis-

Primary structure (i.e., sequence of the amino acids)

Post translational modifications

Mass spectrometry; protein crystallisation studies; edman degradation sequencing, DNA sequencing

2. Functional Assays

Binding assays – on and off rates for an antibody (Surface Plasmon Resonance); radioimmunoassay competition assays

Key is that kinetic information is prepared and that these are done with alongside original drug under the same conditions for fair comparison

3. Animal data

Could include efficacy, but normally it will be more to do with its bioavailability

PK/PD studies

Immunogenicity studies

Toxicology studies

4. Human clinical studies

Must demonstrate that the new product has neither decreased or increased activity in comparison to reference product

PK/PD

Immunogenicity

Safety and efficacy data*

*at FDA discretion

 

Q2. Ritonavir (RTV), sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). The maximum dose of Ritonavir is 100 mg. The solubility of Ritonavir is less than 0.4 μg/mL, the permeability of Ritonavir is considered as poor.

 

• Identify the BCS class for Ritonavir and explain why?
• Please make one example of how to improve the solubility of Ritonavir from the changes of solid forms and explain the reason.
• Formulation scientist has employed amorphous solid dispersion approach to improving the solubility of Ritonavir. (1) please give the definition and characteristics of amorphous solids. (2) Please describe the characteristics of drug release profiles for crystalline, amorphous, and amorphous solid dispersions forms of Ritonavir. (3) Please describe the potential drug-plasma concentration of Ritonavir when amorphous solid dispersion is employed.

 

Indicative answers:

• Student should be able to identify the BCS class to be IV based on given information, i.e. 100 mg of ritonavir would require ~250 litres of water to be fully dissolve.
• Student can make examples such as polymorphic form changes, cocrystal formation, amorphous form conversion, reduces the lattice energy, hence increase the solubility in water.
• The topic is about amorphous form and amorphous solid dispersion. (1) Amorphous is opposite to crystalline solid form, where a lack of long-ranged order in the molecular arrangement is commonly observed. The student can explain this by saying the disappearance of melting event in thermogram with the appearance of a glass transition. (2) the key words such as spring, parachute should be included. The increases on the solubility and the area under the curve for amorphous solid dispersion are the main advantages of this solids. (3) An increases on the solubility/area under the curve would normally provide an increased drug absorption in the drug-plasma concentration. However, a first-order elimination tail must be correctly described. Lecture_2, page 13 -17.