Specialized Technologies for Optimal Ingredient Delivery

Skin is the body’s largest organ and a highly impermeable barrier system designed to protect the interior. Through its three layers— epidermis, dermis and subcutaneous tissue—the skin helps maintain the body temperature, evaluates sensory data and plays an active role in the immune system.

A number of biologically active macro-molecules may help support the health of the skin; compounds such as proteins, amino acids, peptides and vitamins have been shown to benefit collagen and elastin when taken internally. However, there is greater interest in delivering these compounds directly to the site of action, primarily to the dermal tissues. Researchers are hopeful that special delivery technologies could reduce dosages, eliminate certain side effects and provide more immediate impact.

Controlled release technologies have been used for years in a number of fields, including pharmaceuticals and agriculture. The Controlled Release Society noted the use of such technologies may have several objectives, including: “to prolong the duration of action of an active agent, to minimize adverse reactions, or to maximize efficacy. The objective may be achieved by control of diffusion, reaction rates or other physicochemical parameters through the use of rate-controlling materials, manipulation of the appropriate biological barriers, targeting, or manipulation of the fate of the agent once beyond these barriers.”

In the cosmeceutical field, formulators are making inroads with efficacious delivery of novel compounds. “The term controlled delivery refers to an active ingredient that has been combined with a delivery system (microcapsules, emulsions, liposomal) in such a way that allows the active ingredient to be released in a specific manner and place,” said Brittney Kennard, R&D chemist, Lipo Chemicals. “The delivery can be designed so that the active ingredient is released by a variety of mechanisms. The active ingredient can be released by physically rupturing the polymer wall, applying an emulsion or by solubility gradient.”

Dr. Fred Zulli, business unit manager, Mibelle Biochemistry, added: “Controlled delivery can mean time-released delivery of active molecules to the skin due to a specific retardation delivery system, and also controlled delivery of active molecules to deeper skin sites with a vector system.” There are a number of technologies already being used within the cosmeceutical space, ranging from microemulsions and liposomes to microencapsulations and nanospheres.

MICRO MANAGEMENT

Microencapsulation is a technology with a long history in the pharmaceutical, nutraceutical and food science fields. During the process of microencapsulation, small particles of bioactive substances are enveloped with a protective barrier coating; the interior is the core or fill, while the surrounding wall is sometimes called a shell, coating or membrane. This technology allows a compound to be encapsulated in a sphere that can be as small as 15 microns, approximately half the thickness of a human hair. The microspheres or microcapsules can then be suspended in an oil- or water-based matrix for delivery in a finished product.

Using this technology to create active microspheres offers several benefits to formulators. “By using microencapsulation, the active compound can be protected from its surrounding environment until it is ready to be deposited onto the skin,” Kennard said. This is particularly important for volatile actives or those that oxidize easily, which can otherwise adversely impact product shelf life. In addition, she added, microencapsulation can allow formulators to combine otherwise incompatible components in a product without risking undesirable interactions.

Microcapsules can be used in various emulsions to offer targeted release upon application. Tagra, for example, developed a proprietary delivery system for “controlled immediate release” (CIR) for color pigments and active ingredients like vitamins and botanical extracts. The actives are released immediately upon application, which Paula Keusch, vice president of marketing and sales, Tagra, called targeted release, which prevents degradation of the encapsulated active. “Tagra’s encapsulated actives can help the formulator to overcome problems of cross-reactivity, solubility, oxidation and other stability issues,” she said.

There are a number of actives that can be included in a microcapsule, whether vitamins, extracts or optical brighteners. However, there are challenges in using microcapsules, Kennard said, adding: “The formulator must ensure an even dispersion of the microcapsules throughout the formulation. They must also develop a matrix suspension to ensure the encapsulates remain uniformly distributed in the formulation. Temperature, pH and salt gradients must also be considered when using encapsulates.”

In addition, lipophilic and hydrophilic actives may need different delivery technologies, a situation Kemira Specialties addressed with its KemSpheres and Stableact systems. According to Elzbieta Kasprzyk, manager of laboratory services, KemSpheres form an occlusive film on the skin’s surface, contributing to an increase in skin hydration and mobility of lipid layers. “This allows for lateral diffusion of lipophilic actives into the epidermis,” she said, likening the mechanism of delivery to that of a patch. The Stableact technology dissolves hydrophilic actives in a polyol phase, which is then incorporated into oil-in-water emulsion, forming a multiple phase system.

LIPID LOVERS

Another option for controlled delivery is to encapsulate an active within a lipid layer, protecting the active during transport and dissolving upon arrival. Liposomes are perhaps the best known compound in this area, although nanosomes are the up-and-coming technology. Liposomes encapsulate an active, often aqueous solution, within a hydrophobic membrane. That lipid layer can interact with the cell membrane to help deliver the active contents. Nanosomes operate similarly, but inherent in the definition is a size characteristic; nanometer-sized vesicles of phosopholipid bilayers can encapsulate hydrophilic actives such as proteins or nucleic acids.

There are differences in formulation of these compounds. “Liposomes can encapsulate water-soluble actives in the core of the vesicle or alcohol soluble actives in the bilayer,” Zulli explained. “And nanoemulsion droplets can encapsulate oil-soluble actives at high concentrations.” Mibelle uses a vector system based on phospholipids and high pressure homogenization to produce liposomes or nanoemulsion droplets with very low particle sizes and negative ionic charge. The company is also using a new double nanoemulsion technology to formulate previously incompatible ingredients such as tocopherol and coenzyme Q10 (CoQ10) into the same nanoemulsion preparation.

Particle size is a key consideration when formulating with liposomes. Zulli said, “the droplets are small enough to penetrate as vesicle into the stratum corneum; there, these particles release since there is not enough free water present to stabilize the vesicles, and the released encapsulated molecules can then further penetrate into the skin by diffusion.” There are some concerns with liposomal phospholipids. Oxidation and hydrolysis can adversely affect the formulation, resulting in leakage of the internal contents and resultant instability. This can be a particular concern in delivery of proteins, peptides and enzymes. New developments are being reported that may marry micro-encapsulation and liposomal technology to develop a product with phospholipids and polymers that could be stored as powders.

Another new technology breakthrough involves the use of oilbodies, storehouses within seeds for emollient oils, antioxidants and moisture barriers. SemBioSys’s Botaneco division is using a patented process, DermaSphere, to isolate the oil-bodies from the seeds without using traditional crushing methods; the process involves no chemicals to capture the liposomes, thereby creating a natural, exceptionally mild material that serves as an emollient, emulsifier and moisturizer in formulation. This oil-in-water emulsion naturally delivers moisturizing oils, emulsifying proteins and phospholipids. Botaneco officially released a branded line of oilbody-based ingredients, Hydresia™, in late 2007. The company is working with potential marketing partners to encourage the use of Hydresia as a base emulsion.

UPCOMING OPTIONS

There are several other technologies available. Croda, for example, developed the Arlasolve system to help dissolve difficult actives, as well as higher quantities of active ingredients compared to commonly-used polar vehicles. “Arlasolve DMI increases the polarity of the stratum corneum without disrupting it, allowing for better delivery of polar actives into the upper layers of the skin,” said Mark Chandler, technical manager, skin care, Croda Inc.

Ray A. Matulka, Ph.D., senior toxicologist, Burdock Group, also mentioned the use of molecular carriers. “This method is a controlled delivery system where one substance binds the active ingredient to a substrate, changing the degradation properties, allowing the active substance delivery time to a surface where it’s released under appropriate conditions,” he said. “In addition, systems based on polymer and surfactant chemistry can effectively transport and release active molecules at desired rates.”

Ben Blinder, vice president, TRI-K Industries, concluded: “There are many and varied approaches to the concept of ‘controlled delivery’, all with specific and exciting benefits to the consumer. New developments will center around the expansion of the types of actives that can be delivered, and optimization of the types of formulations to which these technologies can be applied.”