In this article, we summarise data obtained from examining label declarations about excipients used in both ‘small molecules’ and biological/protein products approved by the FDA between 2007 to 2009 and 2017 to 2019. The aim is to identify any trends in the way excipients use has changed over this time period.
Dr. Enosh Mwesigwa | Pharmacentral.com Contributing Writer
Excipients play a key role in the drug product development process, facilitating the formulation of stable dosage forms while also aiding their administration. The criteria for selecting excipients, their concentration, grade, and functionality evolves along with developments in biopharmaceutical sciences, regulatory landscape as well as wider societal demands.
New drug approvals between 2007 – 2009, and 2017 – 2019
Table 1 lists the number of new drug application approvals segmented by molecule type. The data is publicly available on the FDA portal. Generic product approvals were excluded.
Table 1: New drug approvals by molecule type for the period between 2007 – 2009 and 2017 – 2019
*2019 data only up to June 2019
For the period between 2007 and 2009, the US FDA approved a total of 69 new drug applications. The majority of approvals were ‘small’ chemical entities (78.3%). Biologicals accounted for less than one fifth (i.e 17.4%). The rest of the approvals (such as contrast media agents and inorganic substances) accounted for 4.3%. Fast forward a decade on, the number of approvals is 75 but importantly, the contribution of different categories much different. Thus, while ‘small’ chemical entities still account for the bulk of approvals at 64.1%, the proportion of biologicals approved has doubled, accounting for 35% (roughly 1 in 3), pointing to the increasing importance of biotechnologically-derived medicines.
New drug approvals by dosage form
Table 2 is a breakdown of new drug application approvals by dosage form for the period between 2007 – 2009 and 2017 and 2019.
Table 2: New drug approvals by dosage form for the period between 2007 – 2009, and 2017 – 2019
|Other oral solutions, powders & liquids||1||1||0||2||2||0|
|IV, SC, IM Injections||6||17||8||18||23||6|
|Patches, Creams, Lotions, etc||1||2||1||0||0|
|MDIs, DPIs, Nebulisers||0||1||0||0||1||0|
Oral route still ahead, but only just
The oral route (tablets, capsules and other oral formats) accounts for just over a half of all approvals (54% during 2017 – 2019 vs 53.3% for 2007 – 2009). This is a remarkable drop from historical levels, where the oral route was the main route of drug administration, accounting for over 75% of all marketed products1. With the increasing contribution of biotechnology to new drug discovery, the vast majority of which are delivery parenterally, it is understandable why the proportion of new drugs delivered orally has decreased.
Table 3 Frequency of dosage forms manufactured in the UK (historical data)1
|Hard & Soft capsules
|Oral Solutions, Suspensions, etc||16.0|
|IV, SC & IM Injections||15.0|
|Topical (Patches, Creams, Lotions, etc)||3.0|
|MDIs, DPIs, Nebulisers||1.2|
|Suppositories, pessaries, etc||3.6|
And the rest?
The data shows the inhalation, ophthalmic and topical routes are as less used today as they were a decade ago, accounting for 6.5% during the 2007 – 2009 approvals versus 5.3% for 2017 – 2019 approvals. These formats have tended to be used for very specific therapeutic objectives, and new drugs developed this way are far in between.
Excipient distribution in new drug approvals
Table 4 ranks different excipients by order of appearance in manufacturer-declared labels for those products intended to be administered orally.
Table 4: Excipients in new drug approvals (between 2007-2009, and 2017 – 2019)
|2007 – 2009||2017 – 2019|
|Microcrystalline cellulose (all grades)||21||42|
|Functional & Aesthetic Coatings (Total)||18||29|
|PVA film coatings||6||15|
|Hypromellose film coatings||11||13|
|Methacrylic co-polymers (Enteric)||1||1|
|Other coatings systems||0||0|
|Colloidal Silicon dioxide||13||23|
|Lactose (all grades)||17||20|
|Povidone (all grades)||8||14|
|Hypromellose – for tablet cores||14||11|
|Sodium starch glycolate||6||9|
|Sodium stearyl fumarate||2||8|
|Native & modified corn starch||5||4|
|Carboxymethyl cellulose sodium||0||4|
|Flavours (all types)||1||4|
|Hypromellose acetate succinate||1||4|
|Sweeteners (Sucralose & Aspartame)||1||3|
|Calcium phosphate (all grades)||4||2|
|Hydroxypropylcellulose (all grades)||5||2|
|Xanthan gum, Carageenan and other gums||0||1|
|Methacrylic co-polymers (Matrix)||0||1|
|Polyethylene glycol (solid grades)||1||0|
Fillers and diluents
Diluents/fillers are included in solid dosage forms as a way to increase weight and improve content uniformity. Many materials have been used as diluents, including starches and its derivatives, lactose, sugar alcohols such as sorbitol, xylitol and mannitol, as well as several inorganic salts.
Data shows that a decade ago (i.e 2007-2009), microcrystalline cellulose was the most widely used filler/diluent, appearing in 51.2% of all oral products approved by the FDA. A decade on, it remains just as popular, appearing in a remarkable 68.8% of approvals. It’s multifunctional properties (filling, binding, lubricity, minimal bulk density and cost-effectiveness) put it in good stead among formulators and manufacturers, so it is no surprise how popular it is.
Lactose, which by virtue of its excellent compressibility, cost advantages and availability was one of the most commonly used filler/diluent a while back has, however, decreased in usage (from 41.5% usage to 32.8% over the period of study) while ‘newer’ materials such as mannitol are seeing a resurgence (from 24.4% to 32.8%). It is difficult to figure out the reasons for this decrease in usage but it could well be due to anxieties around lactose tolerance, perceived animal origin risks, etc.
Inorganic fillers, such as calcium hydrogen phosphate, offer different functionality to organic materials and have had their merits (density, flowability, compressibility, chemical stability, etc). Yet their usage consistently remains low among new approvals over the study period.
The data also shows that manufacturers have embraced tablet film coating technologies over the last 10 years. For example, between 2007 – 2009, 61.1% of all approved tablet were film coated tablets, which rose to 69.5% during the 2017-2019 period. A decade ago, only about 50% of new tablet approvals were film coated. Hypromellose-based coatings were the most widely used systems at 30.6% while polyvinyl alcohol-based systems accounted for only 16.7%. Today, the usage of tablet film coatings has grown to 63% as manufacturers increasingly appreciate the performance advantages of coating dosage forms. Interestingly, the popularity of polyvinyl alcohol-based systems has grown to 32.8% while that of hyromellose systems have dropped slightly to 27.9%.
Binders are some of the most essential ingredients in a formulation. Their purpose is to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. The data shows that povidone and copovidone are the most popular binders today, appearing in 30% of all solid dosage approvals. Usage of hypromellose has decreased over the years, dropping from 34% a decade ago to 18% today. Starch (both native and pregelatinised has also decreased from 12.2% to 6.6%. Further details are shown below:
Disintegratants and superdisintegrants
Disintegrants and superdisintegrants are used in oral solid dosage forms to cause a rapid break-up of solids as a first step to dissolution. Traditionally, the most commonly used agents included crospovidone, croscarmellose sodium, starch and sodium starch glycolate. The data shows that superdisintegrants are the most preferred materials, with croscarmellose sodium being the most popular disintegrant (appearing in just under 40% of the 2017-2019 approvals vs 31.7% during 2007-2009 approvals). The second most popular disintegrant is sodium starch glycolate (used in approx. 15% of approvals) while crospovidone is the third-most popular agent, representing 13% approvals (compared with 20% a decade earlier). Low subsitituted HPC and starch were the least used disintegrants.
Lubricants and glidants
Lubricants are materials added in small quantities to tablet and capsule formulations to improve to decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches & dies. Lubricants also prevent sticking to punch faces and in the case of capsules, sticking to machine dosators and tamping pins. Glidants, on the other hand, enhance flowability by reducing particle-particle interactions.
Of all the lubricants available for use, magnesium stearate is by far the most widely used lubricant, appearing in 74% of new approvals in 2017-2019 (versus 61.5% in 2007-2009). It is also often the cause of a number of problems experienced in solid oral dosage manufacturing, including slowing down dissolution. As a result, newer lubricants have been introduced, such as sodium stearyl fumarate. However, its usage remains low (at 14% in 2017-2019 approvals).
When it comes to glidants, colloidal silica is the most popular glidant, being present in between 33 and 40% approvals across the years of study. Other materials, such as talc and glyceryl monostearate did appear to have fallen out of favour and are apparently absent in the studied products.
Other dosage forms
Table 5 shows a list of excipients used in the rest of product formats, i.e parenteral, topical, inhalation and oral solutions.
Table 5: Excipients used in parenteral, topical, inhalation and oral solutions dosage forms
|2007 – 2009||2017 – 2019|
|Sodium phosphate (all grades)||6||8|
|Sodium lauryl sulphate||5||2|
|Polyethylene glycol 400||6||7|
|Lipid excipients (all)||1||7|
Parenteral products can be solutions, suspensions, emulsions for injection or infusion, powders for reconstitution before injection or infusion, and implants for placement into the body. When a solution is required, water for injection can be used and for less soluble actives, a co-solvent or surfactant can be utilised. In some instances, solubility enhancers such as cyclodextrins are used. A range of vegetable oils can also be used either as emulsions or to create non-aqueous solutions.
pH is one of the critical considerations when formulating parenteral products. Buffers are therefore routinely used to achieve a desired pH, which can be close to physiological pH where desired, or for the case of peptide and protein drugs, a pH that ensures stability. With the exception of Polysorbate 80, which we found routinely used in the vast majority of parenteral products (44.7% during 2017-2019 and 29.0% during 2007-2009), there was no consistency among other excipients. The buffers in use included sodium acetae – glacial acetic acid, sodium phosphate dibasic and sodium dihydrogen phosphate, tromethane, l-histidine, and glycine.
Finally, a key consideration for biological drugs, and protein molecules in particular, is the requirement for stabilization. A number of excipients are added, not only during manufacture, but also in the final formulation, to retard degradation or prevent aggregation. The six main types of materials used include buffers, salts, amino acids, polyols, disaccharides, surfactants, and antioxidants. Trehalose, sucrose and albumin were the only materials we found to be in use as stabilisers during the study period.
Inhalation, Ophthalmic and Topical Products
The final group of dosage forms to consider are inhalation (metered dose inhalers, dry powder inhalers or nebulisers), ophthalmic solutions and topical products. As the data above in table 5 shows, the number of approvals in this sub-category were comparatively few, and correspondingly, the number of excipients used.
Among the excipients of interest are preservatives – typically used in ophthalmic and topical products to limit the growth of bacteria. Within approvals, different products used different materials, including phenol, parabens, potassium sorbate, benzyl alcohol and benzalkonium chloride, with no single agent being a clear dominating material.
Excipient selection is guided by many factors, including limiting characteristics of the active ingredient, such as dose, stability, compactability, and solubility, and others such as functionality, supply availability, compatibility with the active ingredients, individual company policies as well as formulators’ familiarity with a given material.
In the 1980s and early 1990s, excipient functionality was a big deal- product developers selected excipients with quantifiable physicochemical properties. In the late 1990s and early 2000s, focus shifted to excipients that aided the optimization of API bioavailability. Later on, the rise in senior citizen population and the recognition of paediatric consumers brought to light the need for technologies that could aid ease of administration and or palatability. More recently, society’s quest for sustainability, health and wellbeing has had a noticeable uptick in the use of materials that draw upon these themes.
A period of twelve years is not long enough to allow us to draw concrete conclusions, and above all, from a limited data set that we’ve selected for analysis. Yet, there are some noteworthy changes, not least the increase in the number of biological drugs vis-à-vis ‘small’ molecules. It is not very long ago when oral dosage forms represented the bulk of approved drugs – sometimes as high as 80%. In the last decade, biotechnology has created entirely new classes of therapeutic molecules, including monoclonal antibodies, cancer vaccines, gene therapy, antisense strands, enzymes, and proteins, leading to a rapid increase in the number of parenteral drugs, which are now accounting for up to 50% of approved drugs. This will have important implications to the traditional excipient landscape, going forward.
- AULTON, M. E., & TAYLOR, K. (2018). Aulton’s pharmaceutics: the design and manufacture of medicines. Edinburgh, Churchill Livingstone/Elsevier.
- United States Food & Drug Administration. Inactive Ingredient Search for Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
- Hamman J, Steenekamp J. Excipients with specialized functions for effective drug delivery. Expert Opin Drug Deliv. 2012 Feb;9(2):219-30. doi: 10.1517/17425247.2012.647907. Epub 2011 Dec 23. PMID: 22196483.