`
`Diethylene glycol monoethyl ether: an emerging solvent in topical
`dermatology products
`
`David W Osborne, PhD
`
`TOLMAR Inc., Fort Collins, CO, USA
`
`Summary
`
`Background The solvent diethylene glycol monoethyl ether (DEGEE) is currently used in
`over 500 cosmetic products and has enabled the formulation of a topical 5% dapsone
`gel for the treatment of acne. It is anticipated that this common cosmetic ingredient will
`be a component in numerous future prescription topical products approved for the US
`market. Dermatologists are already treating patients that apply products containing
`5–40% of this solvent multiple times each day.
`Aims To provide dermatologists a review of this solvent’s safety and tolerance in addi-
`tion to describing how it interacts with the stratum corneum, sebum, and resident
`microflora.
`Methods To critically review technical and patent literature that provides insight into
`this novel solvent.
`Results Diethylene glycol monoethyl ether when used in a 99.9+% pure pharmaceutical
`grade is safe and well tolerated. Up to half of the applied solvent crosses the skin’s barrier
`and becomes systemic. For certain drug actives, this solvent provides for an intracu-
`taneous depot. This solvent has not demonstrated any inherent antimicrobial properties
`but was found to be mildly inhibitory toward Propionibacterium acnes.
`Conclusions This safe, well-tolerated solvent is already used in many cosmetics and will
`become an ingredient in an increasing number of prescription products. Its ability to
`modify the skin delivery of actives it is formulated with (or formulation components that
`are applied just shortly before or after) make it important for dermatologists to have an
`understanding of this emerging solvent.
`
`Keywords: acne, barrier function, topical administration, drug delivery formulation
`
`Introduction
`
`Diethylene glycol monoethyl ether (DEGEE) is a liquid
`with a long history of use in cosmetic and over-the-
`counter topically applied products. DEGEE is the official
`United State Pharmacopeia name for this solvent,
`although cosmetic products list this ingredient on their
`
`Correspondence: D W Osborne, PhD, Vice President, Product Development,
`TOLMAR Inc., 701 Centre Avenue, Fort Collins, CO 80526, USA. E-mail:
`dosborne@tolmar.com
`
`Accepted for publication September 1, 2011
`
`labels as ethoxydiglycol in accordance with the Inter-
`national Nomenclature of Cosmetic Ingredients (INCI)
`Dictionary. Both official names refer to the pharmaceu-
`tical ⁄ cosmetic solvent having the trade name TRAN-
`SCUTOL. The first FDA-approved prescription drug
`product to contain DEGEE was 5% dapsone topical gel.
`Other prescription topical products that contain DEGEE
`either have been approved or are currently under
`development. It is anticipated that this excipient will be
`a component of a significant number of dermatology
`products approved in coming years. It is the goal of this
`review to: (i) summarize the established safety and
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`tolerance data for DEGEE; (ii) introduce dermatologists to
`the properties of this solvent that makes it a preferred
`choice for dermatology products; and (iii) review what is
`known about how DEGEE interacts with the stratum
`corneum, sebum, and resident microflora.
`
`Chemistry, nomenclature, and purity
`
`With the molecular formula of CH3CH2OCH2CH2OCH2-
`CH2OH and a molar mass of 134.17, DEGEE is a solvent
`with many commercial applications that only relatively
`recently include use in topical products. The IUPAC
`name is 2-(2-ethoxyethoxy) ethanol [CAS Number 111-
`90-0] and has been used as an industrial solvent for
`many years under the trade names Carbitol, Dioxitol,
`Poly-solve DE, and Dowanal DE. DEGEE is compatible
`with alcohol, propylene glycol, and oleic acid, but is not
`mutually soluble with vegetable oils or mineral oil
`according to the TRANSCUTOL Technical Bruochure.1
`Atenolol, griseofulvin, clebopride, dexamethasone, and
`ivermectin are pharmaceutical actives listed as being
`successfully formulated using TRANSCUTOL.1 It
`is
`important to note that the industrial grades of this
`solvent are contaminated with relatively high levels of
`ethylene glycol and diethylene glycol. Toxicology studies
`completed on DEGEE prior to the 1990s used material
`that was at best 98% pure, with many of the observed
`adverse effects being attributed to the toxicity of the
`ethylene glycol impurity. USP-NF grades of DEGEE for
`use in pharmaceutical products contain not more than
`50 lg ⁄ g 2-methoxyethanol, not more than 160 lg ⁄ g
`2-ethoxyethanol, not more than 620 lg ⁄ g ethylene
`glycol, and not more than 150 lg ⁄ g diethylene glycol.2
`To put these numbers in perspective 500 lg ⁄ g is the
`same as 500 ppm or 0.05 weight percent. Thus,
`pharmaceutical DEGEE has >99.9% purity. The primary
`supplier in the US for pharmaceutical grade DEGEE is
`Gattefosse using the trade name TRANSCUTOL-P.
`
`Use of DEGEE in topically applied products
`
`Diethylene glycol monoethyl ether is commonly used as
`a solvent
`for topical products, with pharmaceutical
`formulators taking advantage of its ability to modify skin
`penetration and the cosmetic industry using it to alter
`product rub-in and feel. The Environmental Working
`Group’s ‘‘Skin Deep’’ cosmetic safety database (cosmet-
`icsdatabase.com)
`listed 509 products
`that contain
`DEGEE when accessed during the summer 2011.3
`DEGEE has been a favorite excipient for formulators of
`sunless tanning products because it spreads easily
`without streaking. These products often contain high
`
`DEGEE: an emerging solvent • D W Osborne
`
`concentrations of DEGEE (20–40%) and can be applied
`frequently to large skin surface areas. DEGEE is also
`contained in a wide range of hair coloring products that
`are rinse-off applications. Although some of
`these
`products are known to be irritating, DEGEE itself is not
`considered the source of irritation. However, DEGEE by
`virtue of its solvent properties may promote the delivery
`of other excipients that are contained in the product that
`are irritating to the skin.
`The Scientific Committee on Consumer Products
`(SCCP)
`issued an opinion on DEGEE in December
`2006.4 This opinion provides an excellent toxicological
`evaluation summary of DEGEE. Animal testing shows
`that DEGEE produces little repro- or hematotoxicity. Two
`negative in vivo mutagenicity studies and the structure
`of the substance caused the SCCP to not expect that
`DEGEE will have relevant mutagenic potential. A series
`of Gatteffosse reports cited in the SCCP review indicate
`that: (i) neat DEGEE dosed at 0.020 mL per about
`50 mm2 of human volunteer skin (occluded for 48 h)
`was well tolerated (n = 10); and (ii) use of Marzulli and
`Maibach’s method with 24 adult volunteers concluded
`that no pathological irritation or sensitization reaction
`significant to a cutaneous intolerance was noted.
`Although an adequate carcinogenicity study has not
`been published, a 40% DEGEE in water solution was
`orally administered to female rats for 92 weeks and male
`rats for 100 weeks as one of the control arms for the
`development of 5% dapsone topical gel.5 DEGEE used at
`this concentration was found to not be carcinogenic.
`The 5% dapsone topical gel vehicle, which contained
`25% DEGEE, was used as a control in a hairless mouse
`photocarcinogenicity study.6 In this 52-week study,
`male and female albino hairless Crl:SKH1-hrBR mice
`were dosed topically with product or vehicle and then
`given a cumulative UV dose of 600 Robertson–Berger
`units (RBU) per week. A total of 400 RBU approximate
`one minimum erythema dose in previously untanned
`human skin. In this study, the 5% dapsone topical gel
`vehicle containing 25% DEGEE demonstrated tumor
`growth essentially identical to untreated control animals
`when both groups received 600 RBU ⁄ week. As all
`animals in this carcinogenicity model develop tumors
`from the UV exposure, the study showed that DEGEE
`does not cause an increase in the number of tumors, nor
`does it cause the tumors to develop sooner. The 5%
`dapsone topical gel vehicle also contains water, <1%
`carbopol 980 gelling agent, and 0.2% methyl paraben
`that is pH adjusted with NaOH.
`The Scientific Committee on Consumer Products
`issued opinion on DEGEE4 provided a detailed synopsis
`of three well-conducted in vitro studies on percutaneous
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`Dapsone has negligible water solubility and is generally
`poorly soluble in the oils and solvents that are estab-
`lished inactive ingredients in FDA-approved topical
`products. Dapsone does have reasonable alcohol and
`glycol solubility, but the addition of even small amounts
`of water results in the rapid and dramatic precipitation
`of the dissolved dapsone. Building upon recent formu-
`lation success,9 the solubility of dapsone was tested in
`DEGEE and found to be remarkably high. More impor-
`tantly, blends of water and DEGEE produced a solubility
`profile (Fig. 1) that could be exploited for the treatment
`of acne when formulating an active having both
`antimicrobial and anti-inflammatory properties.
`The formulation strategy for how DEGEE might be an
`advantage in a formulation for the topical treatment of
`acne is described in US patents 5,863,56010 and
`6,060,085,11 Ideally, a topical antimicrobial would be
`primarily delivered into the pilosebaceous unit, with
`only minimal active crossing of the skin barrier. Intact
`stratum corneum lines the upper third of the piloseba-
`ceous unit, and it is into this upper third of the hair
`follicle that the sebaceous duct secretes sebum. Thus, a
`need exists for an acne treatment
`that maximizes
`antimicrobial drug levels in the upper third of the
`pilosebaceous unit. Additionally, when an anti-inflam-
`matory agent is used to treat acne, it is important to
`increase the level of drug that will cross the intact
`stratum corneum lining the upper third of the piloseba-
`ceous unit. By definition, inflammation is the response of
`the viable epidermis to irritants and sensitizers. To
`reduce the amount of inflammation, the active pharma-
`ceutical must penetrate past the stratum corneum and
`
`10%
`20%
`30%
`% Diethylene Glycol Monoethyl Ether in Water (wt/wt)
`
`40%
`
`6%
`
`5%
`
`4%
`
`3%
`
`2%
`
`1%
`
`% Dissolved Dapsone (wt/wt)
`
`0%
`
`0%
`
`Figure 1 Dapsone solubility as a function of increasing percentage
`of diethylene glycol monoethyl ether (DEGEE) blended with water.
`
`DEGEE: an emerging solvent • D W Osborne
`
`DEGEE absorption through excised human skin. Carbon-
`14 radiolabeled DEGEE was formulated at 5% and 10%
`DEGEE concentrations in a shampoo formulation, at
`15% DEGEE in a hydro-alcoholic gel formulation, and at
`2%, 5%, and 10% DEGEE in a Oil-in-Water (O ⁄ W)
`emulsion formulation. The shampoo formulation was
`applied to the skin for 30 min and then ‘‘rinsed-off’’.
`Twenty-four hours after initial application 21.6% of the
`applied dose had been absorbed (epidermis + dermis
`+ receptor fluid) for the 5% DEGEE shampoo compared
`with 17.5% of the applied dose for the 10% DEGEE
`shampoo. The hydro-alcoholic gel was studied with and
`without occlusion. In two studies without occlusion
`51.0% and 44.9% of the applied dose of DEGEE was
`absorbed, but only about 50% of the radioactivity was
`recovered. This was attributed to evaporation of radio-
`labeled DEGEE. When the hydroalcoholic gel was applied
`under occlusion, average recovery was 92% with 51.5%
`of the applied dose of DEGEE being absorbed. For the
`O ⁄ W emulsion, the studies completed without occlusion
`had about 50% total radioactivity recovery compared
`with about 90% recovery for the occluded samples. For
`the 2% emulsion, the percent of applied dose absorbed
`was 43.2% and 45.6% for the two experiments nonoc-
`cluded and 55.9% for the occluded study. For the 5%
`emulsion, results were 56.1% and 44.4% nonoccluded
`and 63.8% occluded compared with the 10% emulsion
`having percent of applied dose absorbed values of 50.4%
`and 51.6% nonoccluded and 56.4% occluded. As seen, a
`significant amount of the DEGEE applied to the skin
`becomes systemic. Fortunately, DEGEE’s low systemic
`toxicity results in a margin of safety (MOS) score of 102
`as calculated by the SCCP, where the MOS is the no-
`observed-adverse-effect level (NOAEL) divided by the
`systemic exposure dose (SED) following topical applica-
`tion. This MOS score means that dosing of the 2% DEGEE
`emulsified formulation will result in blood levels about
`100 times lower than the blood level at which DEGEE
`first causes observable adverse effects. Although hair
`dyes and sunscreens may have MOS scores above 500,7
`the primary requirement for drugs is that the MOS be
`above one.8
`
`Advantages of DEGEE as a solvent: the
`dapsone example
`
`Although DEGEE was used in cosmetic and hair care
`products for a number of years, the first use of this
`solvent in a pharmaceutical product was 5% dapsone
`topical gel. A quick review of the history of 5% topical
`dapsone development demonstrates the advantages of
`DEGEE as a solvent for topical dermatological products.
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`inflammatory events.
`interfere with the cascade of
`Ideally, delivery of an anti-inflammatory for acne
`requires that steady-state levels be sustained. By adjust-
`ing the ratio of dissolved dapsone to particulate dapsone,
`the amount of active crossing the epithelium (dissolved
`dapsone)
`to treat
`inflammation was optimized with
`regard to the amount of active agent targeted to remain
`within the follicle (particulate dapsone) to reduce the
`levels of Propionibacterium acnes. Although rigorous
`scientific proof of this optimization was not available in
`the mid-1990s, it is now well established that particles
`>10 nm in diameter will accumulate in the hair follicle
`openings, especially after rub-in.12
`Thus, the use of a novel excipient, DEGEE, allowed
`optimization of
`the ratio of dissolved to particulate
`dapsone by carefully selecting the ratio of DEGEE and
`water. For the 5% dapsone gel, approximately one-third
`of the dapsone is dissolved and two-thirds of the dapsone
`is suspended as uniformly dispersed drug particulates.
`Despite a relatively high amount of dispersed dapsone,
`the product does not feel gritty during rub-in. This is
`partly because of the dapsone crystalline particulates
`inherently forming flat plates that tend to break apart
`during the shear of rubbing-in the product. The particle
`size is controlled and monitored throughout the shelf-life
`of the product. In addition, a third factor was found to
`significantly impact the feel of the product. Water is
`more volatile than DEGEE; thus, as the 5% dapsone
`topical gel
`is being applied, evaporation of water
`effectively increases
`the ratio of DEGEE to water.
`Increased DEGEE improves the solubility of dapsone,
`further reducing particle size as the product is being
`rubbed-in. Having the better solvent being less volatile
`avoids having the drug active precipitate on the surface
`of the skin, even at a 5% level of drug loading. For this
`reason, properly formulated aqueous DEGEE gels will not
`leave a visible drug residue on patients.
`
`DEGEE as a skin penetration modifier
`
`Many studies evaluating DEGEE as a skin penetration
`modifier have shown that DEGEE enhances a permeant’s
`solubility in the skin without significantly influencing
`the diffusivity of the permeant in the skin, that is,
`stratum corneum.13–16 For the permeants dexametha-
`sone and hydrocortisone, the presence of DEGEE resulted
`in enhanced skin retention although the permeability
`and therefore the systemic uptake were significantly
`decreased.17 This effect has been called the intracuta-
`neous depot and can be conceptualized as DEGEE
`increasing the reservoir capacity of the stratum corne-
`um. Thus, although DEGEE is a skin penetration
`
`DEGEE: an emerging solvent • D W Osborne
`
`modifier, it is not accurate to describe DEGEE as a skin
`penetration enhancer. Solvents such as ethanol and
`propylene glycol are penetration enhancers18 that when
`used at sufficient concentrations increase the penetra-
`tion of dissolved drugs. Although enhancement ranges
`from minimal to dramatic, use of these solvents univer-
`sally enhances skin penetration. In contrast, DEGEE may
`increase penetration or it may significantly decrease
`systemic uptake of a dissolved drug. When formulating
`with DEGEE, it is difficult to predict how this solvent will
`modify skin penetration of drugs contained in the
`formulation.
`A review of the literature on the effect of DEGEE on
`skin permeation19,20 provides a number of
`in-vitro
`studies using excised animal skins and infinite dose
`applications (>5–8 lL ⁄ cm2 of skin surface area) show-
`ing that DEGEE increases the amount of permeant that
`crosses the skin. These penetration enhancement factors
`often do not translate into meaningful
`increases in
`delivery when the product progresses into the clinic. In
`vitro infinite dose animal skin studies tend to bias high
`the enhancement factors for any solvent that can extract
`the lipids from the stratum corneum. As excess product
`resides for hours on the skin surface, skin lipids
`are extracted and the barrier properties of the skin
`are reduced by a mechanism that cannot occur when
`a clinically relevant dose of product is rubbed into the
`skin.
`
`Does DEGEE have activity in the treatment of
`acne?
`
`When the topical dapsone clinical trial results were first
`published,21 the 40–42% reduction for inflammatory
`lesions for the vehicle seemed high, especially when
`compared to adapalene 0.1% cream in which one of the
`pivotal clinical trials reported only a 6% reduction in
`inflammatory lesions for the vehicle control group (17%
`reduction in inflammatory lesions
`for
`the active
`group).22 The vehicle for topical dapsone is <1%
`carbomer, water, 25% DEGEE, and a standard amount
`of methyl paraben. Carbomer gels containing methyl
`paraben have been used for over 40 years in pharma-
`ceutical and OTC products without any mention of
`activity in the treatment of acne. If the dapsone vehicle
`has activity in acne, it is likely that this activity will be
`linked to the 25% DEGEE in the formulation. To
`determine whether DEGEE has activity in acne,
`it is
`necessary to first compare the topical dapsone vehicle
`effect with other recently approved acne products. Is a
`40–42% reduction in inflammatory lesions for a topical
`vehicle unexpectedly high? Next, data on the microbial
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`properties of DEGEE will be summarized, and finally the
`unique interaction between DEGEE and skin lipids will be
`discussed.
`Does
`the ACZONE vehicle have activity in the
`treatment of acne? Based on package insert information
`for four recently approved acne products,23–26 each of
`these product vehicles had percent reduction in inflam-
`matory lesions at 40% or higher. The vehicle effect seen
`for ACZONE is not sufficiently different from other topical
`acne product vehicles to conclude that the ACZONE
`vehicle has activity in the treatment of acne.
`Does DEGEE have antimicrobial activity against
`P. acnes and therefore have activity in the treatment of
`acne? Some of the solvents used to dissolve pharmaceu-
`tical actives have well-established antimicrobial activity,
`and formulators use this information to develop self-
`preserving products or products that have minimum
`levels of a single preservative. Most notable is benzoyl
`alcohol, which has been used as an inactive ingredient
`at concentrations as high as 50% in an FDA-approved
`topical gel.27 Benzyl alcohol levels of 1–3% are adequate
`to fully preserve a topical product. Likewise, propylene
`glycol when used at concentrations around 20% is fully
`effective as a preservative for molds and yeast. When
`DEGEE was first selected as the solvent system for a
`topical dapsone gel, the potential preservative properties
`were thoroughly evaluated using the USP preservative
`efficacy test28 in which gram-positive, gram-negative,
`molds, and yeasts are inoculated into the product to
`assure that bacterial colony-forming units are quickly
`reduced, while molds and yeasts are not allowed to
`propagate. DEGEE repeatedly showed inertness with
`regard to microbial growth. DEGEE did not provide any
`bacterialcidal, bacterialstatic, or microbial
`inhibition
`with regard to the USP test organisms. Likewise, using
`a time-kill assay against P. acnes, a 10% aqueous
`solution of DEGEE showed only a slight inhibitory effect
`at 48 and 72 h.29 In summary, in-vitro microbiology
`testing does not indicate that DEGEE has significant
`antimicrobial activity.
`Does the unique interaction between DEGEE and skin
`lipids lead to activity in the treatment of acne? Exper-
`imentally, this question is very difficult to answer. As
`described in the skin penetration modifier section afore-
`mentioned, DEGEE blends very well with lipids of the
`skin. Although the epidermal lipids filling the intercel-
`lular spaces of the stratum corneum are different from
`lipids of sebaceous origin;30 from a penetration and
`blending with DEGEE perspective, skin surface lipids and
`epidermal
`lipids will both be very compatible with
`DEGEE. This ability of DEGEE to partition into and blend
`with skin lipids to change the physical properties of the
`
`lipids could impact the formation of acne lesions. DEGEE
`may fluidize the lipids and thus retard the formation of
`microcomedones. If DEGEE keeps the lipids from ‘‘gluing
`together’’
`the desquamated keratinocytes,
`then the
`number of plugged follicles and subsequently the num-
`ber of
`inflammatory lesions would be reduced. This
`would explain how a solvent known to partition into
`skin lipids could have activity in the treatment of acne.
`Although this mechanistic description is in agreement
`with the physical chemical properties of DEGEE, it is only
`speculation at this point.
`
`Conclusion
`
`Diethylene glycol monoethyl ether is a safe and well-
`tolerated solvent that has been an ingredient in cosmetic
`products for many years and in the last 5 years has
`become an FDA-approved inactive ingredient in prescrip-
`tion topical dermatology products. This molecule tends to
`penetrate the skin well with up to half of the applied
`concentration becoming systemic after topical applica-
`tion. The ability of DEGEE to dissolve active pharmaceu-
`tical ingredients not soluble in propylene glycol or alcohol
`make it a highly useful pharmaceutical excipient. DEGEE
`does not appear to possess significant antimicrobial
`properties, but may blend with skin lipids in a way that
`reduces microcomedone formation. Dermatologists will
`find that in the near future, this solvent will be a key
`component to many of the cosmetic and prescription
`products that their patients use on a daily basis.
`
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`DEGEE: an emerging solvent • D W Osborne
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