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Q&A: Lipid-Based Formulation – The Impact on Biopharmaceutics and Patient Centricity

Dr. Yi-Ling Hsieh, AbbVie

Q: What is the evidence for inhibiting efflux?
A: There is quite a bit of literature on this. For example, Vit E TPGS has been studied for Pgp efflux inhibition (Collnot et al, Int J Phar 2006, https://doi.org/10.1016/j.jconrel.2005.11.005). I suggest further reading on the following publications if interested:
https://doi.org/10.1002/jps.20780
https://doi.org/10.1517/13543776.2011.561784

Q: Have ionic liquid fills progressed into the clinic? What are your thoughts on their potential?
A: Some clinical examples of ionic liquids can be found in the review by Williams et al. (https://doi.org/10.1016/j.addr.2019.05.008)

I think IL has significant potential. However, screening for IL should be performed in parallel with the conventional salt screening in the early development stage for it to progress further in the development process.

Q: Is there any in-vitro model to determine lymphatic availability
A: I suggest reading Dr. Natalie Trevaskis’ extensive publication on lymphatic delivery. For example, this publication shows the correlation between the drug’s affinity to lipoprotein vs. lymphatic delivery: https://doi.org/10.1007/s11095-010-0199-2

Q: Have LBF been applied in the CBD and Cannabis industries in regards to THC and can LBF help endocannabinods exp.. CB1 and CB2 receptors in Bioavilability?
A:
Marinol is a good example that has been approved for treating anorexia: (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/018651s029lbl.pdf).

Q: You mentioned the advantages of lipid formulations. What are some of the disadvantages of lipid formulations?
A:
Major disadvantages of LBF are mainly associated with developability, such as stability of API in the lipidic excipients, compatibility between capsule material and fill formulation, and soft gel capsule manufacturing capability. 

Q: According to your slides, the last commercial LBF was approved in 2012. What does that say about the applicability/appeal for these formulations?
A: The examples shown in the presentation are limited and not fully representative of the current landscape. The review by Savla et al in 2017 shows the last commercialized LBF being 2016 (https://doi.org/10.1080/03639045.2017.1342654). It is likely there are more soft gelatin capsules approved since then. It is also worthwhile to mention that many OTC products are soft gels (e.g. Advil, Dayquil/Nyquil and fish oil)

Q: Since this is a liquid formulation, how can we develop a discrimination dissolution method for evaluating different lipid excipients and developing IVIVC?
A: To develop a dissolution method that is discriminating and also predictive of in vivo performance, one may incorporate biorelevant media to mimic the physiological condition. However, IVIVC is highly API- and formulation-dependent so if there are underlying mechanisms that cannot be addressed by the dissolution behavior (i.e. permeability limited, active transport), it is likely very difficult to predict the in vivo performance using dissolution. If the formulation contains significant digestible excipients, I would also recommend evaluating the formulation with lipolysis study (lipid digestion). 

Q: It’s not always clear which LBF type is best for BA improvement for the API. What are the main things you look for to help determine which type might be best for an API?
When developing LBF, the first thing I would focus on is finding suitable excipients based on API solubility and stability. This could potentially limit the types of LBF that are developable for an API. One should also consider the physical chemical properties of the API; for example, if the API is very lipophilic (logP>5), it may have the potential for significant lymphatic delivery and the significant amount of lipid in the formulation (i.e. type 1 and 2) may aid this process by providing the source for lipoprotein. In vitro evaluation by looking at how the API precipitate out in the aqueous media after dispersing the prototype LBF is very helpful. Depending on the API, type 3 or type 4 LBF could be prone to drug crashing out during dispersion.

Additionally, think about why you want to develop LBF. Is it to improve BA? Reduce food effect? Pediatric formulation? These considerations could also help you narrow down the LBF type.

Q: What is recommendation about using long-chain vs medium chain lipids for formulation? Your examples of commercial products show that long-chain is used more. Do you try both for your formulation, or prefer one over other?
A: I would try both long-chain and medium chain fatty acid in the preliminary stage of excipient screening for an API.

Q: Can a polar solvent replace the co-solvents? The solubility and permeability properties of DMSO could it work to speed up formulation development?
A: In the early stage development, DMSO may be used for POC. However, for the clinical and the ultimate commercial dosage form, one need to consider the viability of incorporating DMSO in the formulation. Think about the target product profile and capsule compatibility.

Q: How do you choose a compound for LBF, is there any particular properties that hold it potential for LBF?
A: The developability of LBF for a compound depends on the physical chemical properties of the molecule, such as logP, solubility and stability in lipidic excipient. I would also consider designing formulation appropriate for the compound, think about the indication, the disease state, the patients, and the problems you would like to solve/improve. Take compound A for an example, the area of improvement is the positive food effect and after evaluating several formulation strategies, we find LBF to be the platform that is most likely to improve it. 

Q: What might be the main advantage that get while you choose LBF over ASD?
A: Both LBF and ASD have the potential of improving BA, which most of the time is the rationale of developing enabling formulation. LBF could be superior over ASD in certain aspects in terms of biopharmaceutics and patient centricity. For example, food effect is improved using LBF as demonstrated in the case study presented in the webinar. On the other hand, it has been shown that ASD may be superior regarding food effect for lopinavir/ritonavir (Klein et al, JAIDS, 2007). So, I recommend designing formulation based on the molecule, its physical chemical properties and the consideration over biopharmaceutics.

Q: What are the preferred lipid excipients for lipid solidification by spray drying?
A: Medium chain triglyceride (MCT) has been used in spray dried formulations. 

Q: What’s the mechanism by which a LBF suspension or LBF supersaturated forms improve bioavailability?
A: IVIVC (in vitro in vivo correlation) is to correlate in vitro results (i.e. dissolution, dispersion, lipolysis study…etc.) with in vivo data (animal or human). As shown in the slide deck, it is greatly dependent on the API and formulation.
As for the predictability of the animal model, it is of course always desirable to have a validated animal model. If not, dog seems to be the preferred model based on dietary consideration. However, we should keep in mind the difference between dog and human regarding GI physiology (i.e. dog stomach pH tends to be highly variable, and may have “leaky” guts” so permeability may be higher).

Q: Fine emulsion can be called nanoparticulate delivery system, it can behave like other nanoparticle based formulation behavior?
A: There are characterization techniques that can be used to differentiate different nano structures (i.e. emulsion, crystal, amorphous..etc.), including microscopy (i.e. TEM), thermal analysis (i.e. DSC), particle size and zeta potential. Regarding in vivo performance, it would likely depend on the extent and the kinetics of the drug released from the nanostructures and dissolved in the physiological environment, since the different nanostructures likely would have different drug release profiles.

Q: Is lipolysis study really important? If the formulations produce micro or nanoemulsions with very low globule size, shouldn’t the drug readily come out the formulation?
A: I would recommend performing lipolysis study if the excipients used in the formulation are highly digestible.

Q: Oil based fine emulsion can be injected intravenously?
A: Yes, there are commercially available lipid nanoemulsions administered via intravenous route (Intralipid and ClinOleic).

Q: How many products are on the market using LBF?
A: Please refer to this review article: https://doi.org/10.1080/03639045.2017.1342654

Q: The Softgel industry is over 87 years old since Robert Scherer invented rotary die encapsulation process, why this technology is not as popular in pharma industry as tablets?
A: It is likely due to multiple factors. One is the concern over stability, such as stability and capsule compatibility. The industry has extensive history and experience in making tablets and the equipment and training for the unit operations are more prevalent than softgel. There might also be consideration over COG.

Q: What’s the absolute oral bioavailability of compound A in the dog under fed condition as the optimized LBF? That will enable us to judge if there is further room for improvement.
A: Based on the dog PK data, we see about 50% absolute BA for compound A in LBF under both fed and fasted condition. This is a significant improvement over the tablet formulation, with about 8% and 24% aBA in fasted and fed state, respectively.

Q: What you consider to high marginal food effect?
A: I would say greater than 2 fold difference in fed over fasted state could be considered significant food effect.

Q: How you ensure the softgel shell formulation is compatible with the fill?
A: Conducting capsule compatibility with the fill is essential. Additionally, information on capsule compatibility is usually provided by excipient vendors so I would suggest reaching out to the manufacturer for more information.

Q: On slide 9 the last marketed LBF product was 2012 based on 2017 data. Have there been additional products marketed since then?
A: Yes, kindly refer to this review article: https://doi.org/10.1080/03639045.2017.1342654

Q: What are the highest allowable amount of surfactants such as labrasol, tween 80, cremophore, TPGS, and concerns around DDI
A: Sources such as Inactive Ingredient Database on FDA website can be very useful. Excipient vendors also can provide helpful information. For example, Gattefosse usually has tox and safety data on their products which can be very useful.

Q: How Soft gelatin process compares to liquid filled hard gelatin capsules?
A: Hard gelatin capsules are ready made capsules that can be purchased from vendors. Hard capsules have two components, the cap and the body. Unlike hard gelatin capsules, soft gelatin capsules are made by using rotary die process and flat ribbons prepared by casting gelatin formulation in cooling drums, thus it may require upfront investment in equipment and training if outsourcing is undesirable.

Q: Lipid based formulation are known for food induced higher bioavailability. Have you ever seen negative food effect with formulation based on lipidic excipients?
A: If negative FE is induced by lipidic excipients, it can be due to several factors, such as interaction with the drug, entrapment of the drug in the lipidic excipients, and inhibition of uptake by transporters. I would like to note that many BCS III compounds also exhibit negative food effect, such as fexofenadine.

Q: Are there any LBF filled hard gelatin capsule products on the market?
A: Yes there are a few LFHC on the market, i.e. Claravis (isotretinoin). More examples can be found here: https://tabletscapsules.com/wp-content/uploads/pdf/tc_20170901_0038.pdf

Q: What is mechanism of LBF helping PPI?
A: The PPI effect discussed in the webinar pertains to how the change in the stomach pH induced by PPI would reduce BA, mostly for basic drugs. If the drug molecule has high affinity to the lipidic excipients used in LBF, the drug is more likely to remain solubilized due to higher solubilization capacity created by the excipients and less likely to precipitate out in the higher pH environment induced by PPI.

Q: One of the concerns is the higher dose range limitation of LBF, any comment
A: This is definitely a concern if the dose is high. It is less desirable to have patients taking multiple capsules. I recommend looking for excipients that would give sufficient solubility in order to fit the dose into one capsule. Also, consider the BA enhancement by LBF that could possibly lower the dose.

Q: Many animal models (especially dogs) poorly tolerate lipid-based vehicles. How do you recommend overcoming this problem?
A: The tolerability can be dose dependent. I would recommend finding excipients that are more tolerable and also provide higher solubility for the drug of interest.

Q: How is the feasibility to deliver biologics orally using LBF?
A: Biologics may potentially benefit from this type of formulation due to the presence of permeability enhancing excipients (i.e. surfactants). With that being said, pre-formulation work must be thoroughly performed to find compatible excipients for the biologics.

Q: Which is better formulation approach Amorphous vs lipid formulation? How do we select the formulation approach?
A: Both ASD and LBF are potential formulation platforms for increasing solubility and potentially BA. Having said that, I recommend designing formulation based on the physical chemical properties of the API, the indication and the biopharmaceutics consideration. For example, the model compound in the presentation shows significant positive food effect and the dosing regimen requires patients to take the drug with food. However, the typical patient population for this indication tends to be overweight/obese and would likely be put on a diet by their physicians. Patient on diet may not get the optimal PK exposure as if they are taking the drug with a full meal. LBF is thus developed for the purpose of improving patient centricity.
I would say it’s all about the problems one is trying to solve. Additionally, other factors such as developability should be taken into consideration as well.

Q: How to differentiate the solid lipid nanoparticle (SLN) and LBF in the nanorange?
A: There are common techniques including evaluating zeta potential/polydispersibility and particle size distribution to characterize SLN and LBF. Differential scanning calorimetry and microscopic techniques such as TEM can also provide additional information.

Q: Is the in-vitro assessment method approved to corelate to bioavailability for lipid base dosage forms?
A: Examples provided in the presentation show that correlating in vitro assessment with in vivo data (i.e. BA) is highly API and formulation dependent. IVIVC should be demonstrated if the in vitro method is used for predictive purpose.

Q: LBF variants #3 and #4 showed higher bioavailability compared to the IR tablets both in the fasted and fed states. In your opinion, could the LBF be promoting lymphatic uptake of compound A hence increasing BA?
A: LBF has been shown to improve BA via lymphatic uptake. For the model compound shown in the presentation, it’s certainly possible due to this compound’s high lipophilicity and high solubility in lipids. However, further studies are needed to demonstrate lymphatic delivery of this molecule.

Q: Is also max dose as capsule possible a factor? How does it compare to other approaches such as amorphous formulation approach?
A: Dose is a part of developability assessment that needs to be taken into consideration when developing LBF in capsule. Sometimes solubility is too low to fit the dose into one capsule. If there is significant pill burden, LBF may not be the best formulation strategy. Think about: what are the reasons to make amorphous vs LBF? Is it for improving BA? Food effect? Manufacturability? Patient compliance? One should evaluate all these aspects holistically when designing formulation.

Q: What are the primary considerations that would drive a given API to be formulated with LBF vs. HME or spray-dried dispersion or other techniques, given the pros and cons of the various available formulation technologies?
A: I would say the decision should be driven by the API physicochemical properties, the indication and the patient population, the biopharmaceutics, and the developability of the formulation platform for the molecule of interest.

Q: Can you comment on the pk variability and food effect of amorphous solid dispersion approach vs lipid based formulation?
A: Both ASD and LBF have the potential to improve PK variability and food effect. I think it’s highly dependent on the molecule. LBF is shown to be effective at reducing food effect and potentially reducing PK variability for the model compound in the presentation. However, it is not the same for the lopinavir/ritonavir (Klein et al, JAIDS, 2007).

Q: Is LBF appropriate for just pre-formulation for animal tox?
A: It should be appropriate if the excipients are used under ADI.

Q: How much lipid induces a fed state? Recorded data suggests the number to be 7 grams. Is a unit dose enough to induce a fed state and thus lead to bile secretions?
A: There is evidence showing lower quantity of long chain fatty acid is capable of inducing fed state (Kossena et al, Pharm. Res., 2007). Furthermore, the reduction in FE by LBF is associated with multiple mechanisms in addition to inducing bile secretions, including improving the solubilization capacity and keeping the drug solubilized.

Q: Can you talk about some challenges on LBF product on stability (long term and short term)?
A: Same as any other formulation platform, long-term and short-term stability should be conducted for LBF. Since most drug is dissolved in LBF as liquid fill, chemical degradation of the API may occur in a greater extent than solid formulation (i.e. tablet). Oxidation is common in LBF so adding anti-oxidant can help. Physical stability could also be an issue for LBF, such as API precipitation/crystallization in the fill and capsule compatibility. These issues can be mitigated by making sure the API concentration is well below the solubility limit and conducting fill-capsule compatibility study early on in the development.

Q: What medium composition do you use to mimic gastric phase in-vitro?
A: The medium composition can be found in this article by Jennifer Dressman (https://doi.org/10.1007/s11095-008-9569-4)

Q: How can use that by bioinformatics?
A: Apologies. This is an area I am not familiar with.