The introduction of the 505(b)(2) application pathway by the USFDA has turned out to be a game-changer for pharma companies. Not only has it led to faster drug approvals compared to traditional pathways such as 505(b)(1) NDA applications, but it also has created an opportunity for the development of new, differentiated, and commercially viable products. Since this application allows the applicant to rely on safety and effectiveness data developed by other sponsors or data from the published literature and for which the applicant has no right of reference, it saves a tremendous amount of time and cost for the applicant. Plus, it also avoids the unnecessary duplication of research for an already approved drug. 

The 505(b)(2) application also provides a host of additional benefits to pharma companies.  

• It eliminates the need for most nonclinical studies and extensive safety and efficacy tests. 
• Since the application is for a previously approved drug, there is a low risk of rejection. 
• Drug development programs can be accelerated due to lower costs and fewer studies. 
• It has the potential of obtaining market exclusivity if your product qualifies as  

• A drug that required one or more clinical studies for approval, except BA/BE, and was conducted by the applicant (three years exclusivity) 
• orphan drug (seven years exclusivity) 
• NCE (five years exclusivity) 
• Pediatric drug (six months added to existing exclusivity) 

There are different types of applications that can be submitted under the 505(b)(2) category. Following are the few most common types. 

1. New chemical entity (NCE)/new molecular entity (NME) – For example, pro-drug or the active metabolite of an approved drug 
2. New active ingredient – Change in an active ingredient such as a different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of an active ingredient in a listed drug containing the same active moiety 
3. New dosage form – Change of dosage form 
4. Route of administration– Change in the route of administration 
5. New combination – A new combination product in which the active ingredients have been previously approved individually 
6. Substitution of an active ingredient in a combination product– Change in one of the active ingredients of an approved combination product for another active ingredient that has or has not been previously approved 
7. New formulation or other differences – A proposed drug product that contains a different quality or quantity of an excipient(s) than the listed drug where the studies required for approval are beyond those considered limited confirmatory studies appropriate to a 505(j) application (ANDA).  
8. Strength– Change to a lower or higher strength  
9. Dosing regimen– A new dosing regimen, such as a change from twice daily to once daily 
10. Rx to OTC – Change a prescription (Rx) indication to an over the counter (OTC) indication  

 Liquid-filled hard capsules – Ideal dosage form for 505(b)(2) applications 

Recently, there has been a renewed interest in using liquid-filled hard capsules by the pharma companies.  

Easy to develop and capable of providing faster testing of the in-house formulations at R&D- and large-scale, liquid-filled hard capsules accelerate the time to market profoundly. From the branding perspective, liquid-filled hard gelatin capsules offer a great opportunity to create distinct brand differentiation in the competitive pharma market. This novel dosage form can be utilised for reintroducing existing formulations in a new attractive format to revitalise the brand and extend its brand life. 

When it comes to capsule fills, liquid-filled hard capsules are quite versatile, covering a wide range including semisolid matrices, suspensions, pastes, semisolids, thixotropic gels, thermo-softened systems, and hot melts. Further, the capsule fill can be a combination of small capsules, tablets, caplets, or pellets in liquid.  

However, the biggest advantages of these capsules are their capability to formulate compounds with poor solubility and high potency. Also, liquid-filled hard capsules can solve several challenges associated with formulation development and drug delivery. 

• Improved bioavailability – A drug dissolved partially or fully or dispersed in a suitable liquid or semisolid matrix and filled in a capsule can dramatically increase the bioavailability of the product. One example of a marketed 505(b)(2) product is Absorica™(Sun Pharma), a hard gelatin capsule containing lipid formulation of isotretinoin. This product provides higher drug absorption in fasted state than the original Roccutane™/Accutane™ (Roche) softgel. Absorica contains excipients sorbitan monooleate, soybean oil, and stearoyl polyoxylglycerides as approved by US FDA in 2012.

• Self-emulsifying systems – These formulations can be prepared as liquid-filled hard capsules and are designed to self-emulsify in contact with aqueous media to form fine dispersions. This is another approach to improve drug delivery and bioavailability.  Biphenyl dimethyl dicarboxylate (BDD) is a poorly water-soluble drug used in the treatment of liver diseases. A liquid formulation containing BDD, dissolved in a concentrate mixture of Tween-80, Neobee M-5 and triacetin, filled into hard capsules was found to improve bioavailability significantly after oral administration.

• Sustained-release formulations – These are prepared using excipients that influence the hydrophilic-hydrophobic balance (HLB) of the semisolid matrix. An oily suspension of soyabean oil, glyceryl monostearate, and captopril in hard gelatin capsules was superior to standard captopril tablets (25 mg, Sankyo) in terms of the duration of the plasma concentration and AUC. A sustained release formulation of captopril is marketed in Japan as Captoril-R™ by Sankyo. In 1995, Bristol-Myers Squibb introduced a thixotropic, sustained release formulation of captopril as a liquid-filled two-piece hard capsule.

• Substitute for other dosage forms – Liquid-filled hard capsules are also being explored as an alternative to other dosage forms such as injections. Vancomycin hydrochloride had been previously available only as a lyophilised dry powder in sealed ampoules for reconstitution prior to administration. A formulation was prepared by thermo-softening technique with PEG 6000 that protected the drug from moisture uptake and produced a stable and effective preparation. The molten and flowable mixture was filled at 70°C as liquid in hard gelatin capsules. After cooling to ambient temperature, the matrix solidified and sealing of the capsules was not required. This capsule formulation produced fecal, plasma and urine levels of the antibiotic that were similar to those obtained with the solution.  It was initially marketed by Eli Lilly and later by Viro Pharma as Vancocin® HCL and as generic product by many other companies.

• Combinations – Liquid-filled hard capsules provide an excellent opportunity to fill pellets, small tablets, or other capsules along with a liquid. This allows combining two or more incompatible drugs in the same dosage form. Micro-FloraGuard® of BioCare, UK is capsule-in-capsule formulation with plant oil in outer capsule shell and probiotic bacteria with garlic in inner capsule, ingredients which normally would not be possible to take together. The design enhances product stability by protecting the inner probiotic capsule inside the HPMC capsule. This creates effective barrier to moisture which helps the probiotic remain inactive till consumed.Another example is Ibuprofen 200 mg, combined with pseudoephedrine HCl 30 mg and chlorpheniramine maleate 2 mg, in a hard capsule and marketed as Iburamin Cold™ by BERKO.

   

Conclusion  

90% of all prescriptions in the US are filled with generic drugs. They also represent 67% of prescription medicines dispensed in Europe. Competition in the pharma is fierce, and all eyes are on those who can differentiate their products. In the US, the 505(b)(2) pathway is becoming increasingly popular, and many generic firms are using it to increase profitability by diversifying into modified products. In effect, these generics firms will be competition-free for a longer period. Liquid-filled hard capsules provide a number of opportunities in innovations in dosage forms and have a great potential for 505(b)(2) applications. It would be interesting to see how pharma companies will use this opportunity for their brands in the long run.  

References: 

1. Guidance for Industry – Applications Covered by Section 505(b)(2) DRAFT GUIDANCE, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), October 1999. Available from: https://www.fda.gov/media/72419/download  
2. Milind K. Biyani, Selecting Excipients for Liquid-Filled Hard Capsules, Pharm.  Tech. Europe, S16-19, August 2018. 
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