Gransolve DMI Application Guide

Application Guide


Benzoyl Peroxide Formulations:

Dimethyl isosorbide (DMI) has demonstrated exceptional benefits in formulations containing benzoyl peroxide, that are used primarily in the treatment of acne vulgaris, cutaneous fungal infections and poison ivy.

  • DMI is an excellent solvent for benzoyl peroxide and is chemically stable to its oxidizing effects
  • DMI actually improves the stability of benzoyl peroxide in aqueous media [1,2]
  • DMI improves the performance of benzoyl peroxide in at least two ways:
    1. It prevents the crystallization of benzoyl peroxide during the evaporation of the formulation in the skin, thereby increasing the skin retention time and efficacy.
    2. It reduces the skin irritation effects of the benzoyl peroxide [3].
Most formulations using DMI with benzoyl peroxide also use additional solvents along with other formulation ingredients, the selection of which will depend on whether the formulation is a rinse-off product (e.g., cleanser), or a leave-on product (e.g., lotion, cream or gel). It has been found that certain other solvents can also improve the performance of benzoyl peroxide, and that mixed solvent systems are usually preferred. Solvents that have been used effectively in combination with DMI in benzoyl peroxide formulations include ethoxydiglycol (Transcutol™--Gattefosse), C12-15 alkyl benzoate, aryl benzoates, propylene glycol, ethyl alcohol and others [4, 5, 6]. The use levels for DMI vary greatly and depend on the specific formulation type, ranging in cleansers from 1% to10%, in creams and lotions from 5% to 40%, and in gels and ointments from 40% to 90%.

Active Delivery in Skin Care:

DMI has been shown to solubilize and enhance performance of many different topical skin actives besides benzoyl peroxide, including benzocaine [7], pyruvic acid [8], ferulic acid [9], methyl salicylate and salicylic acid [10], acetylsalicylic acid (aspirin) [11], nicardipine hydrochloride [12], 5-aminolevulinic acid [13], potassium nitrate (in combination with water for the desensitization of teeth) [14], hydrocortisone, dexamethasone and tretinoin (transretinoic acid) [15], dihydroxyacetone [16], metaxalone , methocarbamol and meprobamate [17], tetracyclines [18], cyclosporins [19], triamcinolone acetonide, halcinonide, progesterone, testololactone, econazole nitrate, miconazole and nystatin [20], erythromycin [21, 22], neomycin, indomethacin [23], ibuprofen, flurbiprofen and naproxen [24], dibenzylidene sorbitol [25], isosorbide mononitrate and dinitrate [26], diazepam [27], minoxidil, prednisone and estradiol [28], betamethasone [29], phenylephrine hydrochloride and tetrahydrozoline hydrochloride [30], betulinic acid [31] and many other active ingredients of limited water solubility such as vitamins A, D, and E, cholesterol.

In aqueous systems, the optimum solubilizing effect of DMI with most active ingredients has been found to be at a mole ratio of 1:2 (DMI:water) [32]. This is probably due to the fact that DMI has two hydrogen bonding sites, each of which is capable of complexing a molecule of water. On a weight basis this translates to approximately 5:1 (DMI:water). However, the optimum skin penetration of the active often occurs when the active is solubilized in a mixed solvent system and not at the maximum solubilization in the formulation. Actually, Wiechers et al. have shown that the active should be close to its solubility limit in the formulation to increase the thermodynamic activity of the active, thus setting up a driving force to move the active out of the formulation and into the skin [33].

In addition to its solubilizing benefits for a wide variety of actives, DMI has also been shown in a number of the cases listed above to reduce the skin irritation properties of the active in the formulation, and the efficacy of the active was also reported to be improved in some cases.

Deodorants and Antiperspirants:

DMI has been reported to be an effective coupling agent in deodorant gel sticks, and can be used in combination with volatile silicones (e.g., cyclopentasiloxane) and dibenzylidene sorbitol (gelling agent), as well as with antimicrobial agents such as triclosan [34]. In antiperspirants, it has been shown to be an effective replacement for volatile silicones in aluminum zirconium trichlorohydrex glycine-based sticks. In this application, it is claimed that DMI reduced the staining on fabric and improved the skin-feel [35].

Sunless Tanners:

DMI has been found to have several benefits for sunless tanning products. Most of these products are based on the cosmetic tanning agent, dihydroxyacetone (DHA). DHA is a water soluble, but highly crystalline material. DMI has been found to improve color development on the skin both in color intensity and uniformity [16]. This effect is most likely due to the improved spreading by DMI as well as through solubilization of DHA by DMI. Since DMI is relatively non-volatile and an excellent solvent for DHA, it prevents the crystallization of the DHA during evaporation on the skin, increasing the time for effective reaction of DHA with the skin and thereby increasing the development of color. DMI, along with ethoxydiglycol, has been shown to be especially effective in alcohol- and oil-free spray or mist self-tanners, allowing a deeper, more natural tan when compared to lotion or cream-based products [36]. In addition, DMI and ethoxydiglycol have also been shown to be effective in self-tanning formulations in which cyclodextrins have been used to encapsulate the DHA, and thereby reduce the lingering malodors often associated with the use of these products [37].

Permanent Waving and Hair Removal (Depilatories):

DMI has been shown to be an effective solvent for high pH, sulfur-based products such as permanent waves and depilatories. The actives in these products include ammonium thioglycollate, thiolactic acid, cysteine and cysteamine [38].

Anti-wrinkle and Anti-ageing Products:

DMI has been found to be an excellent solubilizer and excipient for anti-wrinkle products based on matrix metalloproteinase (MMP) inhibitors. MMP inhibitors are known to inhibit the degradation of proteins found in the skin including collagen, elastin and other basement membrane and extracellular matrix proteins [39]. In another example, Shah et al. have shown that DMI and ethoxydiglycol are excellent vehicles for an anti-wrinkle composition based on oligopeptides, fulvic acid and colloidal gold, a system designed to stimulate dermal fibroblasts and increase collagen production in the skin [40]. Additionally, DMI has been shown to be an excellent solvent or co-solvent for a variety of anti-ageing ingredients, including L-ascorbic acid when combined with N-methyl pyrrolidone [41].

Formulating with Dimethyl Isosorbide:

As can be seen from the examples cited above, a very wide variety of actives can be formulated using DMI, and a broad range of formulation types can be readily achieved, including spray mists, light emulsions or milks, solutions, ointments, pastes, solids, gels, lotions, creams, transdermal patches, aerosols, towelettes, and many others.

For most skin care applications, the recommended use level for dimethyl isosorbide ranges from 5% to 50% in aqueous systems (e.g., gels, lotions, creams, etc.). For non-aqueous systems (e.g., ointments, soft solids, etc.), the use level will depend upon the specific active being solubilized or dispersed, and in most cases will range from 40% to 90% of the formulation.

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Restrictions:

For skin care applications including rinse-off and leave-on uses, there are no known use level restrictions in the US or EU countries. To date, there has been no CIR report issued on dimethyl isosorbide. In addition, there have been no issued opinions or use level recommendations from the Scientific Committee on Consumer Products (SCCP) or COLIPA. For pharmaceutical applications, the only known use level guidance is that dimethyl isosorbide is listed for topical use in emulsions and creams as an inactive ingredient by the FDA with a maximum dose level of 15% (can be found at the website: www.accessdata.fda.gov/).

1. US Patent 4,923,900: Therapeutic compositions containing benzoyl peroxide. De Villez R L, 1990.
2. US Patent 5,086,075: Therapeutic compositions containing benzoyl peroxide. DeVillez R L, 1992.
3. Weinberg J M. The utility of benzoyl peroxide in hydrophase base (Brevoxyl) in the treatment of acne vulgaris. J. Drugs Dermatol. 5(4), 344-349 (2006).
4. Majekodunmi B D, Lau-Cam C A, Nash R A. Stability of benzoyl peroxide in aromatic ester-containing topical formulations. Pharm. Dev. Technol., 12(6), 609-620 (2007).
5. US Patent 7,445,729: Stable organic peroxide compositions. Faryniarz JR and Rami-rez JE-2008. US Patent 7,556,820: Stable organic peroxide compositions. Ramirez J E, Faryniarz J R, 2009.
6. US Patent 7,560,119: Stable organic peroxide compositions. Faryniarz J R, Ramirez J E, 2009.
7. Reed KW and Yalkowsky SH. J. Parenter. Sci. Technol. 39(2): 64-68 (1986).
8. Berardesca E, Camili N, Primavera G, Carrera M. Clinical and instrumental evaluation of skin improvement after treatment with a new 50% pyruvic acid peel. Dermatol Surg. 32(4): 526-531 (2006).
9. US Patent 5,824,326: Activity enhancement of ferulic acid with dimethyl isosorbide in cosmetic compositions. Crotty, BA, Znaiden AP, Johnson A, 1998.
10. Simonsen L, Petersen MB, Groth L. In vivo skin penetration of salicyclic compounds in hairless rats. Eur. J. Pharm. Sci. 17(1-2): 95-104 (2002).
11. US Patent 4,228,162: Dimethyl isosorbide in liquid formulation of aspirin. Luzzi LA and Ma JKH, 1980.
12. Aboofazeli R, Zia H, Needham TE. Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement. Drug Delivery 9(4): 239-247 (2002).
13. Gruning N, Muller-Goymann CC. Physicochemical characterization of a novel thermogelling formulation for percutaneous penetration of 5-aminolevulinic acid. J. Pharm Sci. 97(6): 2311-2323 (2008).
14. Hodosh M. Potentiating potassium nitrate's desensitization with dimethy isosorbide. General Dentistry 49(5): 531-536 (2001).
15. US Patent 6,028,105: Topical drug delivery composition and method. Nigra TP, 2000.
16. Rossi P, Wiechers JW, Kelly C. Improved delivery and efficacy with dimethyl isosorbide. Cosmetics & Toiletries 120(3): 107-111 (2005).
17. US Patent 3,699,230: Dimethylisosorbide solvent for muscle relaxant drugs. Beauchamp Jr. RO, Ward JW, Franko BV, 1972.
18. US Patent 3,219,529: Stable tetracycline solutions. Nash RA, Haeger, BE, 1965.
19. US Patent 5,670,478: Pharmaceutical containing N-methylated cyclic undecapeptides (cyclosporine) with dimethylisosorbide. Stuchlik M and Pavelek LM, 1997.
20. US Patent 4,082,881: Topical and other type pharmaceutical formulations containing isosorbide carrier. Chen JL and Battaglia JM, 1978.
21. US Patent 6,723,755-Method of treating rosacea. Chomczynski P, 2004.
22. Brisaert M, Heylen M, Plaizier-Vercammen J. Investigation on the chemical stability of erythromycin in solutions using an optimization system. Pharmacy World and Science 18(5): 182-186 (1996).
23. US Patent 5,036,100-Pharmaceutical method and preparation containing indomethacin. Deboeck AM, Baudier PR, Fossion JJ, Maes PJ, 1991.
24. EP0215423-Transdermally resorbable aqueous compositions of arylpropionic acid derivatives and process for their preparation-Lohner M and Wagener H-1991.
25. US Patent 4,816,261-Deodorant gel stick-Luebbe JP, Tanner PR, Melanson, Jr. JD-1989.
26. US Patent 5,837,289-Transdermal delivery of medications using a combination of penetration enhancers. Grasela JC, Grasela JE, Jubenville RM, McCloskey JJ-1998.
27. US Patent 4,859,709-Pharmaceutical composition-Rawlins DA-1989.
28. US Patent 6,101,716-Pharmaceutical composition for transdermal administration. Saunal H and Illel, B-2000.
29. US Patent Application 2008/0102039-Betamethasone spray. Tickle S-2008.
30. US Patent 7,288,263-Compositions and methods for treatment of skin discoloration. Boxrud C-2007.
31. US Patent 6,451,777-Method for regulating hair growth. Bradbury BJ, Soper SJ, Kaczvinsky, Jr. R, Bailey DL, Gale CD-2002.
32. Zia H, Ma JKH, O'Donnell JP, Luzzi LA. Cosolvency of dimethyl isosorbide for ster-oid solubility. Pharm. Res. 8(4): 502-504 (1991).
33. Wiechers, J. W., Kelly C. I., Blease T. G., and Dederen J. C. Formulating for efficacy. International Journal of Cosmetic Science 26: 173-182 (2004).
34. US Patent 4,816,261-Deodorant gel stick-Juebbe JP, Tanner PR, Melanson, Jr. JD-1989.
35. UK Patent Application GB2139496-Antiperspirant stick with low staining potential. Geria, N-1984.
36. US Patent 5,662,890-Self-tanning cosmetic compositions and methods of using the same. Punto LL, Zecchino JR, Lentini PJ-1997.
37. US Patent 5,514,367-Skin tanning compositions and methods for their preparation and use. Lentini PJ and Zecchino JR-1996.
38. EP 0302265A1-Depilatory and permanent wave compositions-Greich, Y, Hartmann P, Kohler J-Wella Aktiengesellschaft-1988.
39. US Patent Application 20090068255-Use of matrix metalloproteinase inhibitors in skin care. Yu B, Hashat A, Anderson DG, Puerta DT, Adams B, Clark S, Kim Y, Spengler EG, McLaughlin RP, Bedford SE, Li Z-2009.
40. US Patent Application 20090136595-Anti-wrinkle cosmetic composition. Shah AR, Gormley JR, Majewski GP-2009.
41. US Patent 6,645,508-Stable L-ascorbic acid composition. Chen JR, 2003.