Market positions
Table II: Examples of FDA approvals of solid-dosage combination drugs, 2010–2012 (Ref. 5) (Contin. on page 47).
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Several high-profile solid-dosage fixed-combination therapies recently entered the US market (see
Table II
) with several large pharmaceutical companies either partnering on or singularly launching combination drugs (5). Earlier
in 2012, Boehringer Ingelheim and Eli Lilly received FDA approved for Jentadueto (linagliptin and metformin hydrochloride
[HCl]) for treating Type II diabetes. In January 2011, Boehringer Ingelheim and Eli Lilly formed a strategic alliance in diabetes,
and Boehringer Ingelheim partnered with the CDMO Patheon, in a three-year deal announced in October 2011, for developing fixed-dose
combination drugs to treat Type II diabetes. As part of their diabetes alliance, AstraZeneca and Bristol-Myers Squibb developed
Kombiglyze XR (saxagliptin HCl and metformin HCl), which was approved in 2010. In August 2012, the companies expanded their
alliance following Bristol-Myers Squibb's acquisition of Amylin Pharmaceuticals. Merck & Co. received approval earlier this
year for Janumet XR, an extended-release formulation of its fixed-dose combination of sitagliptin phosphate and metformin
HCl (see
Table II
).
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)
.
Formulation strategies
Nano-syringes for delivering combination-drug therapies
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Fixed-dose combination therapies are a challenge. The presence of an additional API or APIs adds complexity to the formulation
in maintaining the physical and chemical stability of the APIs, mitigating interactions (i.e., API–API, API–excipient, excipient–excipient),
reconciling incompatible pharmacokinetics, and addressing differing drug-release rates and targets in drug delivery. Some
ways to address these problems in solid-dosage fixed dose combinations include monolayer tablets, bilayer tablets, trilayer
tablets, inlay tables, and pellets or granules in capsules (6).
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.
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