Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals

Hao, Jing; Rodríguez-Monguió, Rosa; Seoane‐Vazquez, Enrique

doi:10.1371/journal.pone.0140708

Cited by 30 publications

(28 citation statements)

References 21 publications

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“…The ever-increasing role FDC products play in healthcare is evident from the increasing numbers available on the market. FDC approvals by the Food and Drug Administration (FDA) in the United States increased from 12 in the 1980s to 59 in the 2000s (Hao et al, 2015). The World Health Organisation (WHO) has also increased the number of FDC products on their essential medication list, with 32 FDCs on the March 2017 (World Health Organization, 2017) published list, which is nearly double the number of FDC products that were on the list in 2002.…”

Section: Introductionmentioning

confidence: 99%

A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products

Kelleher

Gilvary

Madi

et al. 2018

International Journal of Pharmaceutics

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The purpose of this work was to investigate the application of different advanced continuous processing techniques (hot melt extrusion and spray drying) to the production of fixed-dose combination (FDC) monolithic systems comprising of hydrochlorothiazide and ramipril for the treatment of hypertension. Identical FDC formulations were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Drug dissolution rates were investigated using a Wood's apparatus, while physical stability was assessed on storage under controlled temperature and humidity conditions. Interestingly both drugs were transformed into their amorphous forms when spray dried, however, hydrochlorothiazide was determined, by PXRD, to be partially crystalline when hot melt extruded with either polymer carrier (Kollidon® VA 64 or Soluplus®). Hot melt extrusion was found to result in significant degradation of ramipril, however, this could be mitigated by the inclusion of the plasticizer, polyethylene glycol 3350, in the formulation and appropriate adjustment of processing temperature. The results of intrinsic dissolution rate studies showed that hot-melt extruded samples were found to release both drugs faster than identical formulations produced via spray drying. However, the differences were attributable to the surface roughness of the compressed discs in the Wood's apparatus, rather than solid state differences between samples. After a 60-day stability study spray dried samples exhibited a greater physical stability than the equivalent hot melt extruded samples.

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Section: Introductionmentioning

confidence: 99%

A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products

Kelleher

Gilvary

Madi

et al. 2018

International Journal of Pharmaceutics

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“…The number of combination drugs approved by the US Food and Drug Administration that contain drugs already on the market has been increasing steadily from an average of 1.2 approvals of such drugs per year in the 1980s to 2.5 per year in the 1990s, 5.9 per year in the 2000s, and 7 per year from 2010 through 2012. 31 Nuedexta was the only combination drug studied with an active ingredient constituent (quinidine) not available in a dose that was similar or identical to the dose used in the combination product. Approved for the treatment of pseudobulbar affect based on studies of patients with amyotrophic lateral sclerosis or multiple sclerosis, this drug is often prescribed to treat agitation among patients with dementia for which its benefit-risk relationship is controversial.…”

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confidence: 99%

Medicare Spending on Brand-name Combination Medications vs Their Generic Constituents

Sacks

Lee

Kesselheim

et al. 2018

JAMA

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IMPORTANCE Brand-name combination drugs can be more expensive than the sum of their components, especially when the constituent products are available as generic medications. The potential savings that could be achieved using generic components is not known.OBJECTIVE To estimate the additional cost to Medicare of prescribing brand-name combination medications instead of generic constituents. DESIGN, SETTING, AND PARTICIPANTSRetrospective analysis for 2011 through 2016 using the Medicare data set of Part D beneficiaries prescribed any of the 1500 medications that accounted for the highest total spending in 2015. Brand-name combination drugs that had identical or therapeutically equivalent generic constituents were included.EXPOSURES Brand-name, oral combination medications with constituents available either as generic drugs or therapeutically equivalent generic substitutes. MAIN OUTCOMES AND MEASURESThe estimated difference between the amount spent by Medicare on brand-name combination drugs and the estimated amount that would have been spent on substitutable generic components.RESULTS Among the 1500 medications evaluated, 29 brand-name combination medications were separated into 3 mutually exclusive categories: constituents available as generic medications at identical doses (n = 20), generic constituents at different doses (n = 3), and therapeutically equivalent generic substitutes (n = 6). For the constituents available as generic medications at identical doses category, total spending by Medicare in 2016 on the brand-name combination products was $303 million and the estimated spending for the generic constituents would have been $68 million, which is an estimated difference of $235 million. For the generic constituents at different doses category, total spending by Medicare in 2016 on the brand-name combination products was $232 million and the estimated spending for the generic constituents would have been $13 million, which is an estimated difference of $219 million. For the therapeutically equivalent generic substitutes category, total spending by Medicare in 2016 on the brand-name combination products was $491 million and the estimated spending for the generic constituents would have been $20 million, which is an estimated difference of $471 million. In 2016, the estimated spending for the generic constituents for these 29 drugs would have been $925 million less than the estimated spending for the brand-name combinations. For the 10 most costly combination products available during the entire study period, the listed Medicare spending could have been an estimated $2.7 billion lower between 2011 and 2016 if the generic constituents had been prescribed. CONCLUSIONS AND RELEVANCEIn 2016, the difference between the amount that the Medicare drug benefit program reported spending on brand-name combination medications and the estimated spending for generic constituents for the same number of doses was $925 million. Promoting generic substitution and therapeutic interchange through prescriber education and more ...

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“…1 and 2 represent not barriers, but opportunities, because the patent holder’s monopoly brings with it a company that already has solved the technical and regulatory issues of their patented drug, and likely has the wherewithal and business interest to drive forward a new FDC including that drug. Indeed, evidence shows that companies become most receptive to develop new co-formulations as primary patents come close to expiring, so as to extend (or “evergreen”) market exclusivity [ 39 ]. See Table 2 for the age original patents on the active ingredients of the 48 drugs’ in descending order according to the Merck index [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Could patents interfere with the development of a cardiovascular polypill?

et al. 2016

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BackgroundThe Wellcome Trust, the World Health Organization, and cardiologists have advocated for the idea of a “polypill” containing multiple cardiovascular drugs to be co-formulated into a single pill for over a decade. Some cardiologists have asserted that the drugs commonly considered for inclusion into such a polypill are older and therefore free of patent protection. We tested this assertion. This project was requested by the World Heart Federation (WHF).Methods, data and materialsTwo cardiologists from the WHF provided a list of 48 cardiovascular drugs for evaluation. We designated the United States and Canada as the base jurisdictions for this patent study. We linked patent data from these countries’ national medicine patent registers to patent information in over 96 other countries using Derwent and INPADOC via Thomson Innovation. We expanded our study beyond the aforementioned data linkage through a systematic search of the World Intellectual Property Organization’s PatentScope, which was based primarily upon the drugs’ active ingredient names.ResultsIn the United States and Canada, eight of the drugs were only available in the patent-protected, brand name formulation in one or both countries. Another 21 drugs had relevant patents, but generic equivalents were nevertheless available. Only 19 drugs (40 %) appeared entirely post-patent. Broadening the co-formulation searches globally, the overwhelming majority of drugs (40/48) were mentioned in patent applications for cardiovascular drug combinations.ConclusionThe assertion that most of these cardiovascular drugs are post-patent is accurate, but only in the sense that many of the original patents on these active ingredients have expired and that generic alternatives are usually available. The landscape of patents covering novel (co-) formulations is far more complex, however. Most research and development for cardiovascular combination medicines are likely to be undertaken by companies whose original patents on the active ingredient will soon expire or have recently expired. Cardiologists looking to accelerate polypill development may consider approaching such companies to partner.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0997-3) contains supplementary material, which is available to authorized users.

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Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals

Cited by 30 publications

References 21 publications

A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products

A comparative study between hot-melt extrusion and spray-drying for the manufacture of anti-hypertension compatible monolithic fixed-dose combination products

Medicare Spending on Brand-name Combination Medications vs Their Generic Constituents

Could patents interfere with the development of a cardiovascular polypill?

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