OR WAIT null SECS
Robert Strub is director of business development at Gaylord Chemical Company LLC.
The authors review the regulatory changes associated with the use of dimethyl sulfoxide in finished pharmaceutical dosage forms.
Dimethyl sulfoxide (DMSO) has long been appreciated as a versatile reaction solvent for the production of active pharmaceutical ingredients. It is also established as an important material in medicinal chemistry and as a compound storage medium. The most significant use trend for DMSO in the past 10 years has, however, been its increased adoption in finished pharmaceutical dosage forms and medical devices.
In these applications, DMSO is directly administered to humans and animals as a component of regulated pharmaceutical formulations.
This article updates an earlier review (1) on this subject to include developments from the years 2007-2014, in particular, new drug formulation approvals and changes in the regulatory affairs associated with the use of Dimethyl Sulfoxide USP, Ph.Eur.
Topicals. The November 2009 launch of Pennsaid (diclofenac sodium topical 1.5%) was notable in that it was the first DMSO-containing topical formulation to obtain FDA marketing approval. The product is manufactured in Canada by its originator company, Nuvo Research (formerly Dimethaid Research). The US approval followed earlier approvals in other parts of the world.
Penn said is a nonsteroidal anti-inflammatory formulation indicated for treatment of osteoarthritis of the knee. The active ingredient in Pennsaid is diclofenac sodium; Dimethyl Sulfoxide USP, Ph.Eur. is included as an excipient in the formulation at the significant concentration of 45.5% w/v.
The formulation includes other inactive ingredients (alcohol, propylene glycol, type H hydroxypropyl cellulose, and water). Pennsaid is packaged as a dropping dispenser with patient instructions to apply 40 drops by hand or directly to the knee, four times per day.
In 2011, the original intellectual property protection surrounding the Penn said formulation expired. Generic competition to produce bioequivalent products immediately emerged. Nuvo initiated litigation against the generic entrants based on a newly issued patent (US 8,217,078) (2). This patent discloses safe and effective methods to use the Pennsaid formulation and is among related patents listed in FDA’s list of Approved Drug Products with Therapeutic Equivalence Evaluations (The Orange Book) (3). A settlement agreement reached in January 2013 allowedApotex to launch its generic version of the Pennsaid product in May of 2014, after Nuvo’s commercial delivery of its next generation Pennsaid product. Verresfield (UK) Ltd. also sells a dichlofenac sodium 1.5% w/w formulation that contains DMSO; apparently this product (Inflaforte) is only marketed in Greece.
Nuvo received FDA approval for its Pennsaid 2% (diclofenac sodium topical solution) 2% w/v in 2014. Advantages for this product relative to the original include a metered dose pump bottle, simplified dosing regimen (two versus four applications per day) and increased viscosity. Pennsaid 2% is also composed of 45.5% w/v Dimethyl Sulfoxide USP. The company continues to innovate beyond its original DMSO-based platform. Nuvo has developed a novel DMSO foam product (Ibufoam) designed for the topical application of ibuprofen. At the time of writing, the Ibufoam product is in preclinical trials (4).
Topical 5% idoxuridine in DMSO for the treatment of Herpes Zoster has been marketed in the United Kingdom (Herpid, Astellas Pharma) and elsewhere (5). An ophthalmic idoxuridine product (Antizona) was sold by Sanofi-Aventis.
There are other topicals, which include DMSO as an excipient, that have been approved outside of the US. In eastern Europe and Russia, there is a healthy market for DMSO-based over-the-counter (OTC) topical “sports medicine” products, containing popular pain-relief ingredients (i.e., capsicum, heparin, menthol, and methyl salicylate) (5). These products include Espol (Nitzpharm), Chondroxide (Nitzpharm), Assan Rem (Permamed), Onychofissan (GlaxoSmithKline), Roll-Bene (Mepha), Venugel (Permamed, Lubapharm), and Neo-Liniment (Neomed). These products have been marketed in Europe and the former Central and Eastern European (CEE) and the Commonwealth of Independent States (CIS) countries for many years.
The Pharmacircle database (6) discloses the use of DMSO in Actikerall and Verrucare, for the treatment of actinic keratosis (grade I/II) in adult patients. These products are fluorouracil/salicyclic acid formulations and are marketed by Almirall Hermal GmbH and Laboratório Medinfar, respectively. Dendracin Neurodendracin (Physicians Science & Nature Inc.) is a DMSO-containing OTC “sports medicine” formulation sold in the US. It lists capsaicin, methyl salicylate, and menthol USP as active ingredients. Related products have been marketed in Europe and the former CEE countries for many years.
Parenterals. The adoption of DMSO as an ingredient in injectable drugs and medical devices is maturing. Some roles for DMSO in injectable products include as a vehicle for the delivery of medical polymers--viz. poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA)--and as a preservation media in stem-cell therapeutics. Prochymal (Osiris Therapeutics, Inc.) is a stem-cell suspension for IV infusion that contains 10% DMSO; the product was approved in Canada and New Zealand in 2012 (7).
Oral dosage forms. DMSO has not been formulated into approved oral delivery systems to this point. DMSO may participate as a component of an active drug substance, either as ligand in a metal complex or as a solvate molecule. There is recent evidence that the use of DMSO as a laboratory solvent for platin chemotherapy drugs is problematic, due to ligand displacement by DMSO (8). In 2013, GlaxoSmithKline received approval to market Mekinist (trametanib dimethyl sulfoxide) as a melanoma treatment. Mekinist is administered once daily and delivers 2 mg equivalent basis of the (non-solvated) active substance trametanib. As such, the concentration of DMSO in the dose is quite low. Table I summarizes the pharmaceutical formulations that incorporate DMSO as an active ingredient or as an excipient (9).
The Pharmacircle database shows that there have been a total of seven US drug master files (DMF) for DMSO dating back to 1964. Only one of these is still active: a type II DMF originally submitted in 1997. This DMF is maintained by Gaylord Chemical Company, which manufactures the product in compliance with International Council for Harmonization (ICH) Q7 Good Manufacturing Practices (GMPs). The company uses dedicated manufacturing equipment to produce Procipient (Dimethyl Sulfoxide USP, Ph.Eur.) in its production facility located in Tuscaloosa, Alabama, USA. The Tuscaloosa facility went into service in late 2010 and has been inspected by FDA. No form 483s have been issued.
In March of 2014, a certificate of suitability to the European Pharmacopeia Monographs (CEP) was granted for DMSO by the European Directorate for the Quality of Medicines and Healthcare (EDQM). A CEP certificate serves several purposes. It provides a mechanism to certify the suitability of a substance’s European Pharmacopoeia (Ph. Eur.) monograph to control its chemical and microbiological quality. It also certifies GMP compliance at relevant manufacturing and distribution facilities. A CEP monograph plays many of the same roles of the US DMF for countries of the European Union. It facilitates a relationship between regulatory authorities and industry by assessing the chemistry, manufacturing, and controls (CMC) associated with the production of an active substance or excipient. The drug application process is simplified as the CEP for an ingredient may be used in the quality section of a drug’s marketing authorization application. The CEP monograph number for DMSO is 00763; Gaylord Chemical Company is the holder of the CEP certificate.
As DMSO has found use in generic-drug products and has applications as an API, it is subject to the Generic Drug User Fees Amendments of 2012 (GDUFA) in the US. GDUFA requires API (DMF Type II holders) and finished dosage form manufacturers to “self-identify” and pay an annual fee. These funds are intended to address the rising cost of generic-drug applications and reduce the backlog of applications under review. FDA publishes a complete list of GDUFA paid facilities (10).
Since the initial version of this review was published in 2008, a significant regulatory framework has been implemented in the EU: The Registration, Evaluation, Authorization, and Restriction of Chemicals legislation known commonly as REACH. As a requirement to market chemical substances in the EU, a manufacturer must assess and control risks to human health and environmental quality. Compliance with REACH is most often associated with the trade of commodity chemicals; the fee structure and regulatory requirements are tiered based on sales volume. DMSO was successfully registered under REACH by a consortium of producers (registration number 01-2119431362-50-0001). The regulated pharmaceutical DMSO product, Procipient, is not controlled under REACH.
The history of abuse of DMSO in the hands of the public during the 1960s and 1970s is well documented elsewhere (11). In recent years, however, DMSO has matured as a useful and recognized excipient in regulated and some lightly controlled pharmaceutical applications. In 2011, Health Canada added DMSO to its Natural Health Products Ingredient Database (NHPID). NHPID-listed materials can be freely used in natural health products without a prescription. These are products “used in traditional medicine and in Western natural health product formulations to maintain and improve health” (12). There has been notable movement against purveyors of unregulated DMSO-based therapies by FDA in recent years; one envisions that this enforcement activity will continue. A modern review of all manner of DMSO therapies was published in 2015, coauthored by the late Dr. Stanley Jacob (13). The passing of Dr. Jacob--perhaps the earliest and most devoted champion of the pharmaceutical development of DMSO--in 2015 was a noteworthy event in the history of this unusual substance. Table II summarizes the various regulatory filings associated with DMSO.
Odor. Historically, DMSO products have suffered from malodor and color problems. Interestingly, DMSO is essentially odorless in a highly purified state. Odor and color problems are largely attributable to trace levels of thiochemical impurities, which can include dimethyl sulfide, dimethyl disulfide, and bis-(methylthio)methane. The human nose is extremely sensitive to these substances, which have odor thresholds in the single-digit, part per billion range (14).
A patented process used to manufacture Dimethyl Sulfoxide USP, Ph.Eur. produces a liquid that is odorless and water-white. These attributes are desirable features for topical dosage forms. Although odor is a subjective measure and the perception of odor varies between individuals, modern organoleptic analytical methods demonstrate clear differences between the odor profile of non-GMP produced DMSO products and a product suitable for use in finished dosage forms. Figure 1 provides principal component analysis data generated by Alpha M.O.S. using their α-Fox “e-nose” instrument. Compared were a Procipient (DMSO USP Ph.Eur.) sample--labeled ‘USP grade’--and a series of technical grade DMSO products that had been purged for various times to remove traces of odorous impurities. The method was capable of measuring odor quality differences between the Procipient sample and the technical DMSO samples, as shown by the areas and location of the sample data on the principal components analysis (PCA) representation map. The data further support the idea that volatile, low molecular weight impurities are the principle source of malodor associated with inferior DMSO products: purge treatment caused the odor profile of the technical grade DMSO product to approach that of the Procipient sample. It is worthwhile to note that these odor differences are apparent despite the fact that the nominal purity of the technical grade DMSO samples was quite high--approximately 99.98 % by gas chromatography-flame ionization detector (GC-FID).
Figure 1: Odor profile comparison: industrial-grade dimethyl sulfoxide (DMSO) product samples to Dimethyl Sulfoxide USP, Ph.Eur. sample (manufactured by Gaylord Chemical Company) (15).
Sterility. As growth in injectable and other parenteral dosages develops, appropriate sterilization methods for DMSO are needed. The manufacturer of Procipient (Dimethyl Sulfoxide USP, Ph.Eur.) makes no claims regarding product sterility but does support the product with representative biological endotoxin testing (BET) and bioburden assay data as a courtesy. DMSO is not amenable to heat sterilization as some product decomposition occurs. Chemical sterilization using ethylene oxide (EO) and other oxidizing agents is also not practical as DMSO itself is susceptible to oxidation. Radiation sterilization methods (X-ray, E-beam, γ-ray) are not well developed for DMSO and apparently also lead to decomposition.
The preferred sterilization for DMSO method has become sterile filtration using 0.22 μ filters and, importantly, in DMSO compatible housings. A difficulty arises during the sterilization of viscous DMSO formulations, such as devices based on solutions of medical polymers. This issue may require the manufacturer to compound separately sterilized components (i.e., DMSO and polymer powder), which are aseptically filled into a sterile container. Vendors who provide filtration media that they recommend for use with DMSO include EMD Millipore and Pall. The use of DMSO as a cryoprotectant for cells and living tissue has grown steadily over time. Supplies of Dimethyl Sulfoxide USP, Ph.Eur. have been sterilized and repackaged into smaller volumes. Smaller packages better suit the needs of cord blood banks and researchers; such products are available from cell media companies.
A literature search for the period from 2007 to January 2014 produced many hundreds of relevant papers. A few highlights from this search, categorized by dosage form type, are discussed in the following.
Topical products. It has been long recognized that DMSO is amenable to gel preparation using established thickening excipients, such as carbomer or methylcellulose. An exciting topical drug-delivery system capable of producing DMSO-based pharmaceutical foam formulations has been developed by Foamix Pharmaceuticals (Rehovat, Israel). Foam-based delivery systems offer advantages over semi-solids (ointments, gels, and creams), including a more appealing residual feel after product use (16).
Parenterals. Stable DMSO formulations have been developed for the parenteral injection of peptide drugs (17). Options for nonaqueous storage and delivery of hydrolytically sensitive active ingredients are a valuable aspect of such inventions.
Medical devices. Patented uses for DMSO as a safe vehicle for medical polymers have proliferated. Polymers such as ethylene-vinyl alcohol (EVOH) copolymer or PLGA form in-situ implant devices, which can provide structural benefits. BIOS2 Medical reported an EVOH composition that cures when applied to bone, thereby improving load-bearing capacity (18).
A polymer-drug mixture so implanted may also be designed to deliver an active ingredient in a controlled manner. A sustained-release implant that releases a breast cancer drug has been invented. The innovators describe the use of DMSO to deliver the polymer/drug formulation into the body (19).
Use as a processing aid. DMSO has been reported as a processing solvent for polymer/drug compositions applied to implantable medical devices. A recent example discloses its use as a purifying agent to remove impurities from EVOH copolymer. This purification step is intended to produce polymer suitable for use in drug-eluting stents (20).
Since the last published review on this subject, significant new registrations have occurred for DMSO-based pharmaceutical products. The use of DMSO as an excipient is diversifying to include examples in both topical and parenteral products. Regulatory acceptance of DMSO products manufactured under GMPs has broadened to the EU, with the establishment of a CEP in 2014. These advances, in combination with a growing appreciation of the performance properties of DMSO, suggest that interest in this substance persists.
The authors would like to gratefully acknowledge the special contribution of Thomas C. DePaul (Pharmacircle). Analysis from the Pharmacircle drug delivery database was useful in the development of this review paper.
1. A.S. McKim and R.T. Strub, Pharm. Tech. 32 (5) 74-85 (2008).
2. Mallinckrodt et al. v. Apotex Inc. et al., Delaware case number 1:12-cv-01087 RGA (2012).
3. United States Food and Drug Administration (2016) Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, accessed July 20, 2016.
4. Nuvo Research website, www.nuvoresearch.com/products/pipeline/, accessed Jan. 21, 2016.
5. Drugs-about.com website, entry “dimethyl sulfoxide,” referenced Feb. 5, 2016.
6. A database product of Pharmacircle (www.pharmacircle.com)--Search results are from January 2015.
7. A. Pollack “A Stem Cell Based Drug Gets Approval in Canada” The New York Times, May 17, 2012.
8. M. Hall et al., Cancer Res. 74 (14) 3913-3922 (2014).
9. Approval year and DMSO dose content collected from product package inserts. For a review of the withdrawn Tegress product, see R. Dmochowski Rev. Urol. 7 (1) S22-S26 (2005).
10. FDA website, accessed Jan. 5, 2016.
11. P.W. Davis, Social Problems 32 (32) 197-212 (1984).
12. Health Canada Natural Health Products Ingredient Database, accessed July 8, 2016.
13. S. Jacob and J. De La Torre, Dimethyl Sulfoxide (DMSO) in Trauma and Disease, CRC Press; Boca Raton, FL. (2015).
14. S. Schiffman, J. L. Bennett, and J. H. Raymer, Agricultural and Forest Meteorology, 108, 213-240 (2001).
15. J.C. Mifsud, unpublished data courtesy of Alpha MOS Corporation (20 avenue Didier Daurat, 31400 Toulouse,France)
16. D. Tamarkin Formulating Topical Applications--A Practical Guide, N. Dayan Ed., Carol Stream, IL p. 233-260 (2013).
17. S. Prestrelski and J. Kinzell, “Stable formulations for parenteral injection of peptide drugs,” WO2012122535, Nov. 2012.
18. J. D’Agostino et al., “Implantable polymer for bone and vascular lesions,” US20120263797, Oct. 2012.
19. R. Franco and A. Gutierro, “Injectable compositions comprising letrozole or anastrozole,” WO2014019972A1, Feb. 2014.
20. J. Pathak and F. Tang, “Method and system of purifying
polymers for use with implantable medical devices,” US 7645474 B1, Jan. 2010.
APIs, Excipients, and Manufacturing Supplement
When referring to this article, please cite it as A. McKim and R. Strub, "Advances in the Regulated Pharmaceutical Use of Dimethyl Sulfoxide USP, Ph.Eur.," APIs, Excipients, and Manufacturing 2016 Supplement to Pharmaceutical Technology 40 (9) 2016.