Combination Drugs: Adding Up the Opportunities

As pharmaceutical companies face shortfalls in R&D productivity and increased generic-drug incursion, product lifecycle management becomes increasingly important. Combination therapies provide an opportunity for innovator drug companies to extend the lifecycle of a given API by developing a fixed-dose combination product that may offer improved and synergistic efficacy, improved dosing regimes, and greater patient compliance. Combination drugs also allow specialty pharmaceutical companies to use specialized drug-delivery and formulation strategies for product differentiation. Challenges, however, exist in developing fixed-dose combination products compared with single API products, such as maintaining the physical and chemical stability of the APIs and modulating drug release.

(ILLUSTRATION BY DAN WARD)

Regulatory framework

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:

• "A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity" (e.g., a monoclonal antibody combined with a therapeutic drug, a device coated or impregnated with a drug or biologic, prefilled syringes, insulin injector pens, metered dose inhalers, and transdermal patches).

• "Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products" (e.g., drug or biological product packaged with a delivery device).

• A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and…the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose)."

• "Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect" (e.g., photosensitizing drugs and activating laser/light sources and iontophoretic drug delivery patches and controllers) (1–3).

In fiscal year 2011, FDA received 288 original applications classified into nine categories of combination products (see Table I). These applications included 26 new drug applications and 134 new investigational new drug applications, of which the majority were drug–device combinations (see Table I) (2).

Table I: Number and type of combination drug products for original applications for new drug applications (NDAs), biologics license applications (BLAs), premarket approval applications (PMAs), premarket notifications (510(k)s, investigational new drugs (INDs), investigational device exemptions (IDEs), and humanitarian-use exemptions (HDEs) received in fiscal year 2011 by FDA.

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).

Market positions

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).

Table II: Examples of FDA approvals of solid-dosage combination drugs, 2010–2012 (Ref. 5) (Contin. on page 47).

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

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).

Nano-syringes for delivering combination-drug therapies

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.

References

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).