The Search for Alternative Delivery Methods Continues

Biologics Feature: Part 2

While biologic drugs offer numerous advantages, the need to administer them parenterally is a significant limitation. Efforts continue to identify alternative formulation solutions for ease of use and effective delivery. 


The global market for biopharmaceuticals is expected to see a compound annual growth rate of 8.6% from $192 million in 2016 to $291 billion in 2021, according to Mordor Intelligence. Biopharmaceuticals represent approximately 20% of the entire pharmaceutical market revenue, and more than half of the current top 20 blockbuster drugs are biopharmaceuticals.1

Because of their physicochemical properties, most biopharmaceuticals are formulated for parenteral delivery. Unlike small molecule APIs, proteins, peptides, antibodies and other large biologics do not readily pass through biological membranes, such as the epithelial layer in the intestinal tract (for oral delivery) and nasal mucosa (for inhalation). 

In addition, biomolecules are less physically and chemically stable than most chemical APIs and cannot easily withstand, for instance, the harsh environment in the gut. Consequently, there have been ongoing efforts across the supply chain and in academia to develop delivery options for biologics that combine the high efficacy of parenteral administration with convenience and ease of use.

Oral Delivery

Oral administration is the preferred method of drug delivery for good reason. Patients find oral medications easier to take, which leads to greater adherence. Their production also tends to be less costly than other dosage forms. Injections can be painful and often require attendance at a hospital or doctor’s office. 

Even those biopharmaceuticals that can be self-administered using prefilled syringes, cartridges or pens pose challenges. Furthermore, most oral medications — unlike parenteral biologic products — do not require low-temperature storage, which reduces costs and facilitates their use in developing nations with limited cold chain capabilities.

The oral delivery of biologic APIs has been a tremendous goal of pharmaceutical drug delivery from the earliest days of the industry. However, there are two main issues to overcome. First, proteins and peptides undergo hydrolytic degradation in the acidic media of the gut and enzymatic degradation in the intestine. Second, high molecular weight biomolecules have polar surfaces and thus are hydrophilic, resulting in poor permeability across the epithelium in the stomach.

Only two oral peptide products have been approved by the FDA for systemic therapy: desmopressin and cyclosporine. The oral desmopressin product has a very low bioavailability of 0.08%-0.16%, whereas cyclosporine is formulated as a lipid-based self-microemulsifying system that displays uniform and relatively high bioavailability.2

In addition to forming lipid systems, the most common technologies for overcoming the oral bioavailability challenge posed by biologics include encapsulation in polymeric coatings and forming nanoparticles by three basic methods: formulation, drug molecule modification or biological system modification. Many companies combine these approaches, as all have their pros and cons.2

Most formulations include permeation enhancers, such as bile salts, fatty acids, surfactants, salicylates, chelators, chitosans and zonula occludens toxin, and often enzyme inhibitors, including sodium glycocholate, bacitracin and soybean trypsin inhibitor.3 Permeation enhancers increase the spaces between epithelial cells in the gastrointestinal (GI) tract lining, while enzyme inhibitors prevent degradation in the intestine. Chitosan and chitosan derivatives are often used to encapsulate biologics in nanoparticulate form to facilitate easier penetration.3 

Interesting technologies under development include ‘robotic’ pills from Rani Therapeutics. These consist of needles that deliver the biologic active through the intestinal wall. The needles are pushed into the intestinal wall by self-inflating balloons that only function in the intestine.

Applied Molecular Transport’s TRANS­INT platform, meanwhile, uses the non-toxic portion of the protein cholix toxin, a natural, active transporter of peptides and proteins across the GI tract. TRANSINT covalently binds the biologic API to the toxin and has technologies for delivery to both the GI tract and the liver. Another approach is to genetically engineer bacteria found in the intestine to produce desirable biologic APIs with attractive absorption profiles and deliver them to the intestinal wall.

Catalent has adopted a parallel screening approach, as no single technology is suitable for all APIs. The company recently launched OptiForm® Solution Suite Bio, which includes two screening technologies: OptiGel BioTM for duodenal delivery and Zydis Bio® for buccal absorption.

Also interesting is Capsugel’s new enTRinsicTM drug delivery technology, which incorporates an enteric polymer in the capsule shell. This overcomes the need to protect biologic APIs from the GI tract environment and can be used in conjunction with standard biologic APIs and pro-drugs for either systemic or local gut delivery.2 The company is also applying particle engineering based on new spray-drying technologies to achieve the thermal stabilization of peptides, proteins, vaccines and live cells.4

Significant progress has been made in the development of biologic drug formulations for nonparenteral delivery, but much remains to be achieved. 

Inhalation Delivery

Delivery of drugs to the lung is advantageous for several reasons. The lungs have a large surface area, combined with higher permeability through the thin alveolar layer, which also has numerous blood vessels for systemic delivery. Enzymatic degradation in the intestine and first-pass hepatic metabolism are avoided.3 To date, most inhaled therapies have been for local treatment of lung diseases, but there is growing interest in this route for a wider range of indications. 

The FDA has approved two biologic drugs designed for inhalation to date. Pulmozyme® by Genentech is administered using a nebulizer that generates an aerosol and is designed for local treatment of cystic fibrosis with no penetration in the deep lungs. Afrezza® by Mannkind is a dry powder formulation formulated to reach the deep lungs for the systemic treatment of diabetes. 

The key to success for inhaled drugs is particle and droplet engineering, including size, size distribution and other properties, such as hygroscopicity. Permeation enhancers such as surfactants, phospholipids and polymers are also often effective.3 

To this end, growth and innovation has been seen in spray drying development, which uses particle-engineering technology to gently process peptides and proteins into room temperature–stable formulations. These formulations can be inhaled using specially designed dry powder inhalation (DPI) capsules and readily available DPI devices, with over 90% of the particles generated in the appropriate size range.4 

Transdermal Delivery

Transdermal and ocular administration routes have also garnered attention. The former is attractive because it avoids both potential degradation in the GI tract and first-pass metabolism, which are issues with oral delivery. Moreover, it is attractive for the treatment of skin disorders where the sites of action are within the skin.3

To achieve transdermal delivery of biologics requires the use of chemical and physical penetration-enhancement techniques to disrupt the stratum corneum barrier or generate temporary pores in it. Chemical penetration enhancers alter the lipid structure of the stratum corneum. 

Encapsulation in polymeric or lipid carriers, most often liposomes, has also been used. Examples of penetration techniques include sonophoresis, laser ablation, microneedle technology and electrically assisted methods (e.g., iontophoresis, electroporation, radiofrequency ablation).3 

Much Work to Do

Significant progress has been made in the development of biologic drug formulations for nonparenteral delivery, but much remains to be achieved. The continued growth of the market and the high level of interest in this field will drive further development and innovation in non-invasive biologic drug treatments.2 

Indeed, work to date has focused on the reformulation of biologic drug substances initially engineered with parenteral administration in mind. Greater success might, therefore, be achieved if biologic APIs are initially designed for an alternative route of administration.2 Further advancement will also require extensive cooperation between experts in many different disciplines. 

Read Making Strides: Biologics Push Forward Part 3 – Biopharmaceutical Manufacturing Goes Mainstream



  1. Global Biopharmaceuticals Market Growth, Trends & Forecasts (2016 - 2021). Rep. Mordor Intelligence. Sep. 2016. Web.
  2. Challener, Cynthia A. “Oral Delivery of Biologic APIs: The Challenge Continues.” Pharmaceutical Technology. 1 Mar. 2017. Web.
  3. Non-Invasive Macromolecule Drug Delivery Guide. Rep. Catalent Applied Drug Delivery Institute. Web.
  4. Challener, Cynthia A. “New Drug-Delivery Methods: From Concept to Patient.” BioPharm International. 1 Oct. 2016. Web.


Cynthia A. Challener, Ph.D.

Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.