New Technologies in Topical Delivery Systems

November 10, 2005

Cosmetics can be administered through many pathways, but maintaining precise levels of actives remains problematic. Here are some ideas for effective delivery of cosmetic materials.

In recent years many new technologies have been developed to meet the personal care needs of the consumer. For example, due to the aging population in the U.S., demand for products containing anti-aging ingredients now outpaces de- mand for cosmetics that don't make anti-aging claims.

Some innovations meet all of the manufacturers' criteria; however, they often do not consider all the critical and fundamental needs of the customer. Many of the technologies have made rapid entry during the past decade into biology, material science and surface chemistry but applications in cosmetic often require simpler solutions.

Cosmetics can be administered through many routes by a variety of delivery systems. However, maintaining constant in-vivo concentrations for an extended period of time may be problematic. Peaks and troughs are often observed when the cosmetic actives are administered through the skin. Furthermore, high concentrations may cause irritation, whereas low active concentration may be sub-ameliorative. To alleviate this kind of problem, manufacturers have developed cosmetic patches, an idea that was adopted from the pharmaceutical industry.

In pharmaceutical practices, a number of other delivery systems such as oral controlled release dosage forms, transdermal and implantable delivery systems are available.

Unfortunately most of these are not feasible in the cosmetic industry. The good news is that there is an array of effective agents, including proteins, amino acids, peptides, vitamins and bioactives, for skin care applications.

Many of these are biologically active macromolecules and cannot be transferred to the sub-epidermal level. Most conventional methods release the active with no delivery or minute value. Therefore, there clearly exists a need for an effective system that delivers these bioactives at the site of action, while minimizing peak-trough fluctuations. Ideally such a system would eliminate undesirable side effects and reduce dosage and frequency of administration while improving visible effects.

A Host of Technologies
Many technologies are already in place, including multiple emulsions, microemulsions, microspheres, nano-spheres, microsponges, encapsulations, liposomes, cyclodextrins, skin patches and unit dosages. Among all these technologies, liposomes, microspheres and nanospheres are most suitable for transferring cosmetic actives into the sub-epidermal level. Another convenient delivery method is biodegradable polymeric matrices that deliver cosmetic macro or micro molecules onto or into the stratum corneum. Polymeric cosmetic conjugates can also be designed for specific target areas.

Effective delivery systems enable formulators to target specific skin maladies, such as dryness or oiliness. The linkage between the actives may be loose or stable depending on chemical bonding or loose affiliation such as surface adsorption or absorption on the polymer. A cosmetic active can be released onto the skin or within the stratum corneum by the cleavage of the cosmetic active and polymer chain link via hydrolysis or enzymatic degradation. This approach is especially suitable for delivering cosmetic actives such as vitamins, amino acids, peptides and lipids. Thanks to recent advancements in chemistry, the polymer cosmetic active can also be designed in such a way that only those enzymes present on the skin activate it.

Effective delivery systems can help reduce the appearance of wrinkles
Microspheres and nano particles are prepared by encapsulation techniques that allow liquid or solid substances to be encapsulated by polymers or waxy materials. A plethora of methods have been used to encapsulate cosmetic actives, including coacervation, phase separation, solvent-evaporation, spray-drying, spray-congealing, pan coating and fluid bed coating. Microspheres are available as a dry, free-flowing powder. These microspheres are suspended in a suitable aqueous or oily vehicle or embedded in solid makeup products. Skin care emulsions including liquid makeup and mascaras are the appropriate mediums for microspheres.

Glutaraldehyde cross-linked gelatin is the most appropriate material for preparing micospheres and as a result, gels that are loaded with cosmetic actives have become very popular. Several different types of gels have been investigated including gelatin, carrageenan, polysaccharides (galactomannin), silicone gels, waxes consisting of a gel matrix, acrylic acids or polyacrylates, aluminum monostearate and deodorant stearate soaps. The duration of effect can be designed based on the type of particle size (insoluble) or the selection of solvent in which the active has been dissolved. Solvents may be short-chain, long-chain or branch-chain emollient esters or polar or non-polar types.

Obviously the short- or branch-chains penetrate more quickly than long-chain polar compounds. Polyesters available from Inolex have the ability to concentrate select lipophilic or hydrophilic actives on or within the outermost layers of the stratum corneum and distribute other actives throughout the SC. Inolex has presented good data for these esters in evaluating lipophilic sunscreen actives and hydrophilic lactic acid (a-hydroxy acid) and dihydroxyacetone (the active ingredient used in sunless tanning preparations). Simi- larly, the viscosity plays a key role in the delivery of cosmetic active. Multiple emulsions, high viscosity emulsions or anhydrous products are designed for longer duration or sustained release effects.

Hydrophobic Gels
The same kind of hydrophobic gels have been prepared from blends of oils and fatty acids. An example includes vegetable oil and glyceryl palmitostearate. Other hydrophobic gels include: 12-hydroxy stearic acid, glyceryl behenate, N-acyl glutamic acid diamide and sucrose acetate isobutyrate. Sucrose acetate isobutyrate in particular, has been explored as controlled release drug delivery systems.

Hydrogels prepared with natural or synthetic biodegradable polymers have been extensively investigated for controlled release actives in cosmetics. Examples include keltrol, carrageen, acrylic acids, polyethylene glycol, gum Arabic, gelatin and celluloses. Bio-degradable hydrogels prepared with polyethylene glycol, acrylic acid and a-hydroxy acid have been investigated for controlled delivery of macromolecules. The release of macromolecules was controlled by the degradation of the three-dimensional network of the hydrogel.

Release can be controlled by several means, depending on the design of the delivery system and the way the molecule exists in the system. Other variables include the type of polymer used, polymer degradation and/or erosion. Polymer erosion or degradation plays a very important role in the release of actives from biodegradable delivery system. Polymer erosion mechanisms can be classified into the three basic types, based on the cleavage position of the polymer molecules.

Type I erosion refers to water-soluble polymers that have been insolubilized by covalent cross-links. Type II erosion refers to water-insoluble polymers that are solubilized by hydrolysis or ionization. Type III erosion refers to hydrophobic polymers that are converted to small water-soluble molecules by backbone cleavages.

The release of a cosmetic active from delivery systems prepared with a Type I biodegradable polymer is controlled by the biodegradation of the polymers. In this system, a three-dimensional network is formed by cross-linking the water-soluble polymer to entrap the active agents. Such a system may not be able to control the release of water- soluble, low molecular weight materials. However, these systems are especially suitable for water-soluble macromolecules. Even though the macromolecules are water-soluble, they cannot diffuse out from the system because of the network formed by polymer chain entanglement.

The preparation of these types of delivery systems can be achieved by the following procedure. Dissolve both the polymer and the macromolecule in an aqueous solution; add cross-linking agents or a polymerization or cross-linking to form a three-dimensional structure that constrains the macromolecules. With appropriate cosmetic active loading and cross-link density, no diffusional release of macromolecules will occur. Hence, the release of a macromolecule is only controlled by the degradation of the polymer network structure. This approach may have applications in protein, amino acid and peptide delivery. A similar approach has been tested to prepare albumin and gelatin microspheres.

Coupling hydrophobic agents with a water-soluble polymer makes the conjugate water-insoluble. Thus, active release from such a system is governed by Type II erosion mechanisms. Cosmetic actives are released to the surrounding medium by the hydrolysis or enzymatic degradation of the polymer-active conjugate. The release rate-limiting step is determined by the nature of the labile bond.

One such example of this mechanism is Bioetica's grafted Inulin Lifiderm, where lipophilic fatty chains (stearic and palmitic acids) have been grafted to hydrophilic macromolecules. Inulin is an oligopolymer with a single glucose molecule on the end. A typical inulin chain only has a dozen fructose units. Inulin is present in many plants and is a natural edible fiber. It is extracted from chicory.

The release mechanisms of cosmetic actives prepared with Type III erosion polymers can be classified into two fundamentally different approaches. One approach is a reservoir system where the release of a cosmetic active is controlled by diffusion. The other approach is a monolithic system where the release of the active is controlled by both diffusion and degradation. In the reservoir system, the active is surrounded by a rate-limiting biodegradable polymer membrane, which provides a constant release rate of the active. The membrane maintains its integrity until the entire active is released. Unlike the non-biodegradable delivery system, there is no need to remove the membrane after all the cosmetic active has been released from the system because it will completely degrade into non-useful products.

In a monolithic system, the cosmetic active is uniformly dispersed or dissolved in a polymer matrix. Active release from a biodegradable monolithic system is therefore predominantly controlled by diffusion or erosion of the polymer. Or the release may be controlled by diffusion and the Higuchi equation can be used to depict its release kinetics. When polymer erosion is faster than diffusion of the active, active release is controlled by polymer erosion. If the delivery system is prepared with a surface-erosion polymer, the release of the active can be controlled by varying active loading of the system and by varying the geometric dimension of the delivery system. But if the delivery system is prepared with a bulk-erosion polymer, the release of the active is unpredictable because of the changes occurring in the matrix during the process of matrix-erosion.

Another novel delivery system is the chemically conjugated Sepivital from Seppic. This phosphoric diester potassium salt of vitamin E and C is water-soluble. The antioxidant (in vitro) activity and anti-inflammatory (in-vivo) activity are very impressive.

The polymer, poly acrylo nitrile, is a relatively new controlled release system for the release of active ingredients for skin care products. This polymer consists of multi-block backbone and aminolysis derivatives on the side chains. The molecular weight of the polymer is several million Dalton, and its multi-block structure can be variable under different processing conditions. The polymer forms a clear gel when emulsified with water and its function as a release system is a result of its molecular structure. Each polymeric chain is composed of several sequences having a hydrophilic (soft blocks) pendant group and several unit sequences having a nitrile (hard block) pendant group. The relative length of each polymeric block and/or the chemical nature of the side group chains alters the overall properties of the polymer, such as the hydrophilicity or solubility. It imparts a continuous film on the skin that controls the release rate of actives, provides a good tactile skin feel and retains a substantial amount of active ingredients without irritation or inflammation. The polymeric film also allows selective permeability of molecules and functions as a rate-controlling element in the skin.

Advantages of Biodegradability
There are manifold advantages of a biodegradable delivery system:

. Maintenance of constant cosmetic active concentration for a desired time
  period at the target site, especially useful for providing moisturizers and
  other skin beneficial materials;
. Improved product stability;
. Reduced dosing time and an improved treatment effect;
. Elimination or reduction of side effects that also includes irritation and
. Precise local targeting to the site.

Thus the treatment agents that are suitable for biodegradable cosmetic delivery systems are generally those that: (a) need to be administered for long period of time, (b) are highly potent, (c) have a low dose (d) have a short biological active life and (e) have compliance issues.

The major advances in liposome technology in the past decade arise from the ability to produce well-defined liposomes composed of a variety of lipids with different physical and chemical properties. They have high cosmetic active loading capacities and a narrow size distribution (averaging less than 100nm in diameter). These physical and chemical properties significantly affect the stability and kinetic release of active from the liposome. Many procedures are involved to produce well-defined liposomes. These include extrusion, where the liposomes are filtered forcefully with well-defined pore sizes under moderate pressure, reversed-phase evaporation, sonication and detergent-based procedures.

The Advantages of Liposomes
Another significant advance has been the ability to hold more cosmetic active with high efficiencies while maintaining the integrity of the liposome structure. This cosmetic active loading can be achieved either passively (the active is encapsulated during liposome formation) or actively (after liposome formation). A hydrophobic cosmetic active can be directly incorporated into liposomes during vesicle formation, and the extent of uptake and retention is governed by active-lipid interactions. Trapping efficiencies of 100% are often achievable, but this is dependent on the solubility of the cosmetic active in the liposome membrane. Passive encapsulation of a water-soluble cosmetic active relies on the ability of liposomes to entrap an aqueous buffer containing a dissolved active during vesicle formation. Trapping efficiencies (generally less than 30%) are limited by the trapped volume contained in the liposomes and the solubility parameters of the cosmetic active.

Another approach is to impart an amphipathic nature to the cosmetic actives by conjugating or complexing with lipids. Alternatively, employing pH gradience can actively entrap water-soluble actives that have io nizable amine functions that can result in trapping efficiencies ap-proaching 100%.

Cyclodextrins are a class of non-reducing, cavity-containing, cyclic carbohydrates that form a specific type of complex known as a molecular inclusion complex. Cyclodextrins act as a host for entrapping other chemicals without the formation of covalent bonds. This polymer may be wholly or partially contained in the cavity. Cyclodextrins are enzymatically derived from starch hydrolysates. The enzyme, glucosyl transferase, creates cyclic structures by coupling glucose units into a truncated conical molecular structure with a hollow cavity of specific volume.

Cyclodextrins have six, seven or eight glucopyranose rings, known as alpha, beta and gamma cyclodextrins respectively. Chemical modifications can alter their physical properties, namely their solubility. Thus, hydroxylpropyl a-cyclodextrin exhibits a 10-fold higher solubility in water than b-cyclodextrin. There are many benefits to bring about improvements such as stabilization of light or oxygen-sensitive materials (including unsaturated or volatile essential oils), control of biologically active substances and modification of the chemical activity of guest molecules in the cyclodextrins.

Cyclodextrins are used in the cosmetic and personal care industry for:

. Stabilization;
. Odor control, especially in underarm products;
. Process improvement upon conversion of a liquid ingredient to a solid form;
. Flavor protection and flavor delivery in lipsticks;
. Water-solublity and
. Enhanced thermal stability especially to flavor and fragrance oils.

Hollow Sphere Technology
Sunspheres, a hollow sphere technology developed by ISP, optimizes the performance of organic and inorganic sunscreen actives. The spheres are made from styrene/acrylates copolymers. These water-filled spheres are incorporated into a base containing organic or inorganic sunscreens. When the finished product is applied to the skin, the internal water migrates irreversibly out of the shell to leave a voided sphere in the product film.

This voided sphere is critical to the performance of the product. Light passing through the voided sphere is refracted as a result of passing through media of several different refractive indices. The refractive index of a water-filled sphere is about 1.6, compared to an RI of 1.0 for an empty shell. The significant difference in refractive index between the polymeric sphere and the voided core causes the light to refract and exit the sphere at a different angle than it entered. When voided sphere polymers are present in the applied product film, ultraviolet energy that encounters a sphere is scattered. Scattering the energy increases the opportunity for it to encounter sunscreens in the film. It is noteworthy that the spheres do not act as sunscreen agents. They are merely the light scattering particles that optimize the effect of organic and inorganic sunscreens in a film by increasing the probability that ultraviolet photons will be absorbed or reflected by the actives.

Polypure (allyl methacrylate cross-polymer) is a polymeric material, which can entrap both hydrophilic and lipophilic cosmetic actives. It is available as powder with an average particle size from 5mm to 10mm. Special techniques are employed for entrapments. Once again, the primary mechanism for release is diffusion, however the release rate depends on many factors such as skin chemistry, temperature, solubility of ingredient, product formulation, and the method as well as entrapment chemistry system. Standard delivery systems are available from Amcol. Amcol can provide loaded polypore powders containing: Retinal 20%, Benzoyl peroxide 45%, Salicylic acid 50%, OMC 75%, Tocopherol 67%, Cyclomethicone 80%, water 75%. This technology has been successfully in place for quite sometime in lipstick, loose and pressed powders. Liquid makeups, sebum control and sunscreens.

The newest and most reliable delivery systems with a continuous release pattern of cosmetic actives are receiving great attention from cosmetic formulators who are interested in developing efficient cosmetic products, where conventional systems are not ideal. Today, novel technologies are available that provide rapid, slow, delayed and sustained release.

Formulators can provide a product for daytime or nighttime use. In fact, cosmetic manufacturers can even develop seasonal skin care products that deliver the correct amount of active in the spring, summer, winter or fall!

Although most systems perform quite well in vitro, their performance in vivo has yet to be improved. A major challenge to the industry is to obtain a better understanding of the influence of the biological environment on the release performance of various delivery systems. This may lead to the development of simple systems based on improved ingredients with a good in vitro-in vivo correlation.

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