Oleogels for drug delivery

March 2019

• Oleogels are versatile alternatives to widely studied systems like hydrogels and organogels for applications requiring an injectable drug depot that slowly releases a pharmaceutical to a treatment site.
• In vivo studies indicate that oleogels are capable of acting as a drug delivery depot that administers treatment over a couple of weeks, but more research is needed.
• Bigels, the newest type of gelation system for drug delivery, capitalize on the advantages of both hydrogels and oleogels allowing a researcher to tune its properties to best suit a given pharmaceutical treatment.

As consumers began avoiding saturated fats and governments started banning trans fats, food ingredient formulators sought a healthy alternative that offered similar stabilizing and binding properties without compromising texture and rheology (https://doi.org/10.1016/B978-0-08-100596-5.21662-4). They discovered that they could retain these traits and provide structure by trapping a liquid oil in a lattice of non-fat material. At the same time, researchers acknowledged that the gelation of liquid oils, known as oleogels, had the potential to act as a drug delivery mechanism for hydrophobic active pharmaceutical ingredients (APIs). Researchers are now studying these new materials in hopes that oleogels are the key to providing targeted, long-term drug delivery for a variety of complex pharmaceutical treatments.

The soft, psuedoplastic make-up of oleogels means they can be left under the skin or in a muscle as a drug depot for an extended period without the patient discomfort experienced with rigid implants. In addition, an oleogel encapsulated drug can be injected with a needle instead of by a surgical procedure as required for stiff devices.

From hydrogels to oleogels

For more than two decades, scientists have studied a drug delivery system known as hydrogels (https://doi.org/10.1016/j.polymer.2008.01.027). Hydrogels are three-dimensional, cross-linked networks of water-soluble polymers whose biocompatibility and highly porous structure make them a good candidate for releasing drugs into the body.

Though biomedical engineers have studied hydrogels extensively, they have been unable to resolve several limitations. Since hydrogels are water-filled with large pores, APIs can spill into the body within hours, contrary to their intended function as a slow-release mechanism. Hydrogels tend to be too rigid to inject through a needle and may require surgical implantation. Even then, hydrogels can float away from a treatment site. Most importantly, hydrogels are not robust enough to protect the proteins and peptides that make up the latest medicines, and they cannot house hydrophobic APIs.

Some scientists have proposed a hydrophobic, organic alternative to address hydrogels’ limitations. Organogels form a drug depot in situ when a mixture of polymer, API, and organic solvent is injected into the body. Gelation occurs as the organic solvent leaches from the implant. Though a slow diffusion of drug is more effective with organogels, the obvious downside is that organic solvents are released into the blood stream as well.

Oleogels could provide the ideal drug delivery matrix. Much of the research on oleogels to date has been conducted with the intention of understanding their use in food applications. This is an advantage for drug delivery researchers, since a wealth of research exists on how to adjust a gel’s mechanical properties for a given application.

Chun Wang, associate professor of biomedical engineering at the University of Minnesota, Minneapolis, USA, says that as non-covalent, self-assembled systems oleogels exhibit a flexibility and reversibility that are ideal for a treatment requiring long-term delivery. “You can take the drug and mix it with the oleogels very easily. It can be adapted to release all sorts of drugs,” says Wang. He points out a secondary advantage to using oleogels for drug delivery. “A lot of these oleogels are made of molecules that are biocompatible like fatty acids and lipids. As a result, they have very good safety records in humans.”

In a recent review article, Wang describes some of the materials and processes food researchers have used to optimize oleogels and how they may be applied for drug delivery. These biocompatible materials are composed of small, amphiphilic molecules that trap liquid oil as they self-assemble through non-covalent interactions. In addition, they exhibit desirable properties for slow-release drugs, like cancer or mental health treatments. Under mechanical force, oleogels become less viscous, but then recover when the force is removed. This property allows oleogels to provide protection for delicate protein or peptide treatments within a drug delivery device that is flexible enough to be injected through a needle.

Researchers have determined several gelation techniques for the formation of oleogels (Fig. 1). Examples typically involve supramolecular networks of protein or polysaccharide from gelatin or xanthan gum that encapsulate mineral, safflower, or sunflower oil. Gelation in these cases is most often induced by a solvent exchange. One unique gelation method involves an oleogel composed of an insect-derived polymer resin that crystalizes to entrap a rapeseed oil.

FIG. 1. An example of oleogel formation from an emulsified liquid oil that has been dried and sheared. Microstructure drawings depict emulsion droplets (yellow) with an adsorbed layer of gelatin (red) and sheets of xanthan gum (green). When water (blue) is removed with drying, the oil droplets pack tightly. The oleogel forms after shearing the dried oil, resulting in islands of packed droplets. This figure has been republished from [Patel, A.R., Langmuir 31: 2065–73, 2015] with permission under an ACS AuthorChoice License.

Though few in vivo studies have been performed, a research group at the University of Montreal in Montreal, Canada, conducted a thorough study of an oleogel for the delivery of Alzheimer’s disease medication. The drug rivastigmine is a cholinesterase inhibitor that helps delay the onset of Alzheimer’s by facilitating neurotransmission. However, patients with dementia are required to take the medication twice a day by mouth to slow their disease. Jean-Christophe Leroux and his team developed an oleogel by first dissolving rivastigmine in safflower oil and then adding N-stearoyl L-alanine methyl ester as a gelator. They injected the drug delivery system under the skin of rats to study how it performed. They demonstrated the feasibility of oleogel system with the successful delivery of therapeutic levels of rivastigmine for up to 11 days. A disadvantage of their gelator is that it incorporates an organic solvent that initiates gel formation as it evaporates into the body.

Bigels

A group of researchers at National Institute of Technology, in Rourkela, India, have developed a different strategy for slowly dispensing drugs. They have created a mixed matrix they call a bigel by blending a hydrogel and an oleogel. Like the researcher at the University of Montreal, this team has validated the feasibility of slow-release though not in vivo.

“Bigels are a new type of gel system which are bi-physical systems just like emulsions, but both the internal structure and the external structure are gel,” says Kunal Pal, assistant professor of biotechology who participated in the study. Pal says the team had been working on emulsion gels, a similar bi-physical system, with a liquid internal phase. “When we were working with these emulgels in the lab, we observed that the inner phase leached out when kept for a long duration,” he says.

By making the inner structure a gel, the researchers were able to prevent leaching. The team prepared the bigels by mixing an oleogel, made of rice bran oil in a stearic acid matrix, with a hydrogel made from tamarind gum surrounding a hydroethanolic solution. Immobilizing both phases prevents leaching or coagulation of the dispersed inner phase over time.

Pal says bigels have all the advantages of emulsion systems, but with the added stability of the inner phase. When the API is dissolved in a gel and dispersed through another gel it becomes a tunable time-release system. Drugs have to pass through two network structures, each with their own degree of attraction to the molecule. “The partition coefficient of the drug within the oleogel and then within the hydrogel plays an important role in the diffusion process,” says Pal. He adds that the diffusion through both networks determines when the drug is released, and changing the characteristics of either gel can regulate that rate (Table. 1).

Table 1. Composition of the formulations (Paul, S.R., et al, 2019)
Weight (g)
Formulations	Oleogel	Hydrogel	Moxifloxacin HCI
S1	30.00	0.00	—
S2	24.00	6.00	—
S3	12.00	18.00	—
S4	0.00	30.00	—
S1D	29.85	0.00	0.15
S2D	24.00	5.85	0.15
S3D	12.00	17.85	0.15
S4D	0.00	29.85	0.15

In addition, there is versatility in whether the system is primarily hydrophobic or primarily hydrophilic, so bigels can be used for a wide variety of drugs. Pal says they can disperse an oleogel in a hydrogel and dissolve hydrophobic drugs into the dispersed space. He says they have also done the opposite and made a reservoir for a hydrophilic molecule by dispersing a hydrogel into an oleogel (Fig. 2). “For example, if you have a hydrophilic drug you can put it into the aqueous phase and dump it into the oleogel and inject it into the body,” he says. “You can use this for vaccines because it will release the bioactive agents very slowly.”

FIG. 2 Bright-field micrographs of the formulations: (a) S1, (b) S2, (c) S3, and (d) S4; and confocal micrographs of the formulations: (e) S1, (f) S2 (inset: contrast- and brightness-enhanced section showing the dispersion of the aggregates), (g) S3, and (h) S4

Combination drugs

Perhaps the biggest opportunity for oleogels to improve drug delivery is their use with combination drugs that have multiple APIs, each requiring precise release rates. Wang has studied silica nanoparticle-infused polymers for this purpose. These colloidal systems are composed of porous nanoparticles loaded with small molecules or proteins within a supramolecular network containing other drugs. The physical dynamics of this system can provide the controlled release of each treatment within a drug cocktail. Wang says that to optimize nanoparticle systems there needs to be research efforts directed at developing materials from these gels that are biocompatible and biodegradable. He also recommends research focused on whether nanocarriers can be incorporated into polymers with bottle brush geometries for better tuning of drug release kinetics for combination drugs.

In general, Wang sees a lot of promise in the application of oleogels for drug delivery, but he says that not many people in the biomedical and drug delivery community are focusing their research on these materials. For oleogels to have any hope of being applied in the pharmaceutical industry, they have to be evaluated for safety, biocompatibility, and efficacy in cells and in animal models.

“One caveat here is that a lot of the GRAS [Generally Recognized as Safe] materials, like small molecule oils, are safe for oral consumption,” says Wang. “If we use them for drug delivery in other contexts, for example, as an injection into the muscle or into the skin, then the difference in the relative delivery has to be taken into account.”

Little is understood about how the API will interact with oleogel materials. And there have not been studies on the stability and retention of activity for protein drugs in a nonaqueous system. But the potential to address the challenges in the solubility of small molecule drugs and combination therapies make oleogels worth further exploration.

Rebecca Guenard is the associate editor of Inform at AOCS. She can be contacted at rebecca.guenard@aocs.org.

References

• Advances in edible oleogel technologies—A decade in review, Singh, A., et al., Food Res. Int. 97: 307–317, July 2017.
• “Oleogels in food,” Mttice, K.D. and A.G. Marangoni, Encyclopedia of Food Chemistry, Pages 255–260, 2019, Elsevier.
• Recent developments in protein and peptide parenteral delivery approaches, Patel, A., K. Cholkar, and A.K. Mitra, Ther. Deliv. 5: 337–365, 2014.
• “Oil structuring: concepts, overview and future perspectives,” Patel, A.R., Food Chemistry, Function and Analysis No. 3, Edible Oil Structuring: Concepts, Methods and Applications, The Royal Society of Chemistry, 2018.
• Biopolymer-based structuring of liquid oil into soft solids and oleogels using water-continuous emulsions as templates, Patel, A.R., Langmuir 31: 2065–73, 2015.
• Development of bigels based on stearic acid–rice bran oil oleogels and tamarind gum hydrogels for controlled delivery applications, Paul, S.R., et al., J. Surfact. Deterg. 21: 17–29, 2018.
• In situ-forming oleogel implant for rivastigmine delivery, Vintiloiu, R., Pharm. Res. 25, No. 4, April 2008.
• Gels without vapor pressure: soft, nonaqueous, and solvent-free supramolecular biomaterials for prospective parenteral drug delivery applications, Tabet, A. and C. Wang, Adv. Healthcare Mater., November 2018.