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Combination Drugs: Adding Up the Opportunities
Combination products encompass a wide range of products, including drug–device combinations. By regulatory definition, a combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological
product; or a drug, device, and a biological product (1, 2). Under 21 CFR 3.2 (e), a combination product is defined to include:
Combination products also include oral fixed-dose combination drugs of two or more APIs in a single product form (i.e., tablet and capsule). According to 21 CFR 300.50, "two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug" (4).
Gilead Sciences received FDA approval for two oral fixed-dose antiviral combination products—Complera (emtricitabine, rilpivirine HCl, tenofovir disoproxil fumurate) in 2011 and Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumurate) in 2012—and received a new indication of treating HIV infection in 2010 with Truvada (emtricitabine and tenofovir disoproxil fumurate). Novartis developed two fixed-dose combination products using aliskiren hemifurmate, the API in its antihypertensive drug Tekturna. In 2010, Novartis received FDA approval for Amturnide (aliskiren hemifurmate, amlodipine besylate, and hydrochlorothiazide) and for Tekamlo (aliskiren hemifumarate and amlodipine besylate). Daiichi Sanyko also used amlodipine with one of its APIs (olmesartan) for the combination product, Tribenzor (olmesartan medoxil, amlodipine besylate, and hydrochlorothiazide), which FDA approved in 2010. Bayer gained approval for several oral contraceptive fixed-dose combinations (see Table II) .
Recently approved fixed-dose combination products use various strategies. Merck & Co.'s Janumet XR is an extended-release metformin core tablet coated with an immediate-release layer of sitagliptin. The sitagliptin layer is coated with a soluble polymeric film (7). Merck's Juvisync is a bilayer tablet containing sitagliptin phosphate and simvastatin (8). Vivus's Qsymia is a capsule consisting of immediate-release phentermine HCL and extended-release topiramate (9). GlaxoSmithKline's Jalyn consists of one dutasteride soft-gelatin capsule, dissolved in a mixture of butylated hydroxytoluene and mono-diglycerides of caprylic/capric acid, and pellets of tamsulosin HCl with excipients of methacrylic acid copolymer dispersion, microcrystalline cellulose, talc, and triethyl citrate, encapsulated in a hard-shell capsule (10). Reckitt's Suboxone is a sublingual film (11).
Tablets are the main product form for fixed-dose combinations, but other technologies can be used. For example, Procaps, which recently partnered with Patheon in softgel development and manufacturing services, offers its Unigel technology, which provides various forms for fixed-dose combinations, such as a softgel in a softgel, a tablet in a softgel, granules in a softgel, or any combination to address challenges of multiactive formulation (6). The Indian drug manufacturer Cipla is partnering with the Drugs for Neglected Diseases initiative (DNDi) to develop a four-in-one fixed-dose combination antiviral therapy using a "sprinkle" formulation of lopinavir and ritonavir, combined with one of two other antiviral APIs, abacavir/lamivudine or zidovudine/lamivudine. Cipla is developing a sachet product in which the four antiviral drugs will be in tastemasked and put in granular form for mixing into food or liquids with the aim of registering the drug by 2015, according to a July 20, 2012, DNDi press release.
1. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Chapter I, Part 3, Subchapter A, Sec. 3.2 (e).
2. FDA, FY 2011 Performance Report to Congress for the Office of Combination Products (Rockville, MD).
3. FDA, "Frequently Asked Questions About Combination Products" (Rockville, MD), www.fda.gov/CombinationProducts/AboutCombinationProducts/ucm101496.htm, accessed Sept. 15, 2012.
4. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC) Chapter 1, Part 300, Subpart B, Sec. 300.50.
5. FDA, FDA Approved Drugs, Drugs@FDA, accessed Sept. 15, 2012.
6. A. Kane, D. Monterroza, and C. Salazar, "Unlocking the Power of New Softgel Technology for Multiple Formulations" Webcast, Pharm. Technol., www.PharmTech.com/apiformulations, accessed Sept. 15, 2012.
7. FDA, Label for Janumet XR (Rockville, MD, 2012).
8. FDA, Label for Juvisync (Rockville, MD, 2011).
9. FDA, Label for Qsymia (Rockville, MD, 2012).
10. FDA, Label for Jalyn (Rockville, MD, 2010).
11. FDA,Label for Suboxone Sublingual Film (Rockville, MD, 2010).