Patient-Centric Optimal Dosage Forms

The increasing complexity of compounds in the discovery pipeline means that many small molecule drugs are facing the challenge of lower bioavailability. This may often be combined with other technical or clinical formulation challenges, such as complex release profiles, the desire to simplify complex regimens with combination drugs and customised dosage forms for specific patient populations and indications. Decisions taken during the drug substance and drug product design process can have a major impact on patient outcomes. These include improved adherence to the regimen, reduced side-effects and fewer instances of discontinuation of compliance.

Optimizing pharmaceutical formulations offers numerous benefits that help differentiate products by delivery route, dosage form, improvements in safety and efficacy, and most importantly, to meet patient needs. Thus the 'patient voice' becomes a value driver during the early-stages of formulation development rather than an after-thought in late-stage formulation development.

There are many factors and options to consider during early drug formulation and dosage form development. A scientifically based approach which focuses on the drug's ability to treat diseases through enhancements in bioavailability and to better address patient-specific needs such as ease of administration, food effects, and less frequent dosing, is the ultimate goal for a patient-centric approach to formulation development. Fortunately, there are many products, technologies, and insights available to make the drug development journey a more cost-effective and efficient process.

Even with the advanced technologies available today for drug development there are still challenges to be overcome. Drugs with poor solubility, or poor permeability, or both, leading to poor bioavailability can be developed into effective medicines for large and diverse populations, and enhance patient compliance. There are multiple formulation strategies employed during the drug development process based on the target product profi le (disease state, physiology, route of administration, etc.) and properties of the drug. Currently three of the most widely used strategies for improving dosage forms are particle size reduction, amorphous solid dispersion, and lipid based technologies.

Particle Size Reduction is a technology used for small molecule drugs in various types of dosage forms. It's beneficial in improving an API (active pharmaceutical ingredient) content uniformity for commercial tablet manufacturing, suspension stability and/or texture of oral, topical, or ocular formulations, and is still a conventional technology for enhancing the oral and pulmonary bioavailability of small molecules.

Hot Melt Extrusion (HME) is another technology that is proving to be very valuable to the pharmaceutical industry due to its ability to generate physically stable and processable solid dispersions of amorphous APIs. Relative to crystalline APIs, amorphous solid dispersions improve bioavailability in more than 80 percent of cases where it is employed. HME processing systems disperse APIs in the polymer matrix at the molecular level to form solid dispersions or solid solutions.

Lipid-based formulation technologies can be employed to solve complex formulation and development challenges, including improvement of solubility, permeability, or both to enhance bioavailability.

Each of these enabling technologies can be employed to improve the bioavailability of many poorly soluble drugs, and in the case of lipid-based formulations, poorly permeable drugs as well. Advancing these challenging drugs through development to the market is critical to provide options for patients with unmet medical needs to have their illnesses treated. The Drug Classification System (DCS) provides insight into appropriate early development technologies that may be employed to overcome PK (pharmacokinetic) issues in enhancing drug solubility, adsorption, and permeability in the gastrointestinal tract. For example, DCS I molecules are typically presented as conventional solid dosage forms. Molecules in categories DCS IIa may be formulated with micronized or nanosized active pharmaceutical ingredients (APIs). Molecules in the DCS IIb category require lipid-based formulations or amorphous solid dispersions as solubility -enhancing technologies, sometimes along with particle size reduction for those cases where the API is dispersed (or suspended) as solid particulates in a lipid-based suspension or solid dispersion HME, for effective formulation development of a poorly soluble drug.

Most APIs (70%) in current development fall into DCS quadrant II1, with poor solubility but acceptable permeability. Quadrant II may be further subdivided into categories for which molecules are either dissolution rate limited in the gastrointestinal tract (classification IA) or solubility -limited (IIB), as delineated by the Solubility-Limited Absorbable Dose Rule.

The DCS groups drugs in these categories:

Class I - high permeability, high solubility
These compounds are well absorbed and their absorption rate is usually higher than excretion.

Class II - high permeability, low solubility
The bioavailability of these products is limited by their solvation rate. A correlation between the in vivo bioavailability and the in vitro solvation can be found.

Class III - low permeability, high solubility
The absorption is limited by the permeation rate but the drug is solvated very quickly.

Class IV - low permeability, low solubility
Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.

Particle Size Reduction - A Straightforward Solution for Oral Bioavailability Enhancement
For molecules falling under the DCS IIA classification, the dose is expected to dissolve completely during the ~3 hour transit through the small intestine provided the drug particle size is less than the calculated target particle size based on the Drug Classification System.

Particle size reduction works by increasing the surface area of the drug that is exposed to fluids in the gastrointestinal tract, thereby increasing the dissolution rate of the drug. Drugs that dissolve rapidly are naturally more quickly absorbed. However particle size reduction does not affect a drug's intrinsic solubility. Numerous drugs' oral bioavailability have been improved by micronizing or wetmilling(nanosizing). These include DCS category IIa drugs (nitrendipine, carvedilol), and category IIb drugs that lay close to the Solubility-Limited Absorbable Dose Rule line.

In looking at the patient-centric approach to formulation development, the particle size of the drug is critical when understanding the effect of food consumption on bioavailability of the drug compound. Danocrine, which treats pelvic pain and infertility in women, shows a six-fold food effect (fed vs. fasting), which was eliminated by formulating the drug as a nanocrystalline suspension.1 Drugs in the DSC IIa classification, with poor solubility but adequate permeability, tend to have a higher AUC and Cmax when administered with food. The positive impact of nanoparticle formulations is believed to arise due to increased contact area between nanosized drug particles and biological membranes.2 By reducing food effects, nanosizing also enhances dose tolerance, compliance, safety and efficacy. 3

Tricor from Abbvie Inc. is an example of a drug for which particle size engineering provided differentiation and follow-on approvals. Tricor-1, a non -micronized product approved in 2001 for lowering triglycerides, had a substantial food effect.

This was followed by FDA approval in 2003 of Tricor-2, a micronized, lower -dose formulation also with a food effect, for the broader indication of lowering low-density lipoprotein. The third iteration of this drug, the nanomilled Tricor-3 approved in 2004, did not show a food effect.

Lipid-based Formulation Encapsulated in Soft Capsules - An Oral Delivery Option for Enhanced Bioavailability
Softgels are an ideal option to deliver lipid-based formulations developed for improving bioavailability and better patient compliance. Through the use of material sparing techniques, feasibility studies can be performed to develop prototype lipid fill formulations when API quantities are scarce. Laboratory-scale encapsulation of these fills provides small batches of soft capsules that can be used for in-vitro testing as well as in-vivo animal PK studies. Lipid-based formulations in soft capsules are readily scalable from laboratoryscale to pilot-scale to production-scale thereby allowing for reduction in overall product development cycle times.4 One of the fastest growing segments of the pharmaceutical industry is the development of highly potent drug products.5 Unlike tablets that involve powder generating production steps, lipid-based formulations which are liquid or semisolid in nature, followed by their encapsulation in soft capsules, do not present issues such as dust generation, and as a result the risks of employee exposure and product cross-contamination are minimized. Lipid formulations in soft capsules are often the delivery option of choice for highpotency APIs, not only for the safety and contamination concerns mentioned previously, but for also achieving excellent dose uniformity even for drugs dosed at microgram levels.

More recently it has been shown that lipidbased formulations and enteric coated soft capsules enable the oral delivery of peptides and proteins. By using lipidbased formulations, whose end products of digestion serve as permeation enhancers to open up tight junctions between cells, enteric coated soft capsules offer an excellent means of delivering these lipid formulations containing peptides and proteins to their site of absorption. Importantly, this technology protects the API from degradation while providing high local concentrations of intact API and permeation enhancer to maximize the potential for absorption Conventional soft capsules use gelatin as the film -forming polymer in the capsule shell, which can successfully be used for a wide range of API's and lipid-based formulations. However, there are instances, where a gelatin-based soft capsule cannot be used for some fill formulations due to resulting physical instability. Examples include fill formulations that have a melting point higher than gelatin, fills that are highly alkaline in nature, and fills containing certain surfactants or low to medium chain free fatty acids. The use of plantderived polysaccharides in place of gelatin allows the encapsulation of these types of challenging fill formulations. Hot filling of lipid-based formulations that are semisolid at room temperature and require heating to higher temperatures for flow into soft capsules during encapsulation have enabled the filling of semi-solid formulations for extended release of poorly soluble compounds thereby optimizing drug product pharmacokinetics and potentially reducing dosing frequency.

Hot Melt Extrusion: Enhancing Bioavailability to Create Stable and Versatile Dosage Forms
Hot melt extrusion (HME) technology is the process of formulating an API within a polymer by applying heat and shear stress utilizing a twin screw extruder to create an amorphous solid dispersion. It is a solventless continuous manufacturing technology that offers a lot of flexibility with the use of excipients and in-line process analytical tools to achieve the desired drug loading with good physical stability. Melt extrusion process technology may also allow for high drug loading which reduces pill burden and enhances patient compliance. The melt extruded solid dispersions provides increased bioavailability, product differentiation, and shortens time-to-market.

HME covers a wide variety of extrusion processing technologies such as melt extrusion, wet, dry and melt granulation. The extruded materials can be processed to generate final dosage forms such as tablets (Fixed-dose combinations, complex tablets, multi-layer), capsules (fixed-dose combinations, powder-filled, bead-filled) and stick packs.

Melt-extruded solid dispersions consists of several formulation components apart from API itself. It may include carrier polymer, plasticizer and solubilizer. The early phase preformulation assessment of API's molecular, chemical and physical properties will help in rapid prototyping of early formulations. These formulations can be then scaled-up to provide clinical supplies for phase I and beyond.

The twin screw extrusion technology enables the interplay of the product and process variables to develop formulations for mid and late stage clinical supplies. Understanding and measuring the impact of equipment & process variables such as extruder type, screw configuration, die design, screw speed, feed rate, barrel temperatures on the product quality attributes such as physical and chemical stability, dissolution at an early stage will lead to technically sound scale-up process required to support midand late stage clinical phase supplies.

Recently, there are many products that are being developed utilizing twin screw melt extrusion technology to offer the clinical advantage of bioavailability enhancement to the patients. There are few products on the market with twin screw melt extrusion that have used the enabling advantage of this technology. Merck's Noxafi l tablet and Abbvie's Kaletra tablet are excellent examples of utilizing melt extrusion technology for improving the therapeutic effi cacy of the product.

Noxafil Advantage
Merck reformulated the oral suspension of antifungal drug, posaconazole to develop melt-extruded amorphous solid dispersion tablet of Pocaconazole. The new tablet Noxafil with enhanced solubility and bioavailability also demonstrated consistent pharmacokinetics and several other advantages over the marketed oral suspension of Posaconazole. In addition, the bioavailability of posaconazole with the new melt-extruded tablet formulation did not appear to be significantly affected by food or the concomitant use of medications that raise gastric pH or speed gastric motility. Currently available as 100 mg tablets and approved for dosing as a 300 mg twice-daily on the first day and 300 mg once-daily dose thereafter, features the posaconazole API, mixed with the pH-sensitive polymer hypromellose acetate succinate (HPMCAS) via hotmelt extrusion technology. The melt extrusion process technology helped to maintain the amorphous state of the drug, preventing crystallization and improved the drug's solubility, thus improving the bioavailability of the drug.

Kaletra Advantage
Abbvie's Kaletra tablets for treatment of HIV(lopinavir and ritonavir) also use amorphous dispersion technology in order to achieve advantages in terms of dosing regimen and bioavailability enhancement. Abbvie used hot melt extrusion technology to reformulate the existing soft gelatin capsules, to improve pill burden, pharmacokinetic variability, and product stability.

Hot melt extrusion appears to have overcome the poor solubility and negligible oral bioavailability of previous experimental solid formulations of lopinavir/ritonavir. In addition, and more importantly, the reformulated tablets require fewer doses to be taken each day, do not require refrigeration, and do not need to be taken with food.

Incorporating the 'patient's voice' during drug development is a relatively new strategy. Factors contributing to patientcentric drug development include scientific expertise (e.g. greater understanding of PK/PD), pharmacogenomics, and the realization that few diseases are adequately addressed by a one-sizefits- all approach to dosing, dosage form, and formulation. Companies seeking development partners must keep in mind that without these three factors, tailoring new drugs in a patient-centric manner is a matter of hit or miss. Sponsors should also consider development timelines, the 'fourth dimension' of drug development.

Sponsors also need to ask these few questions to their development partners: Does the contract development company possess these capabilities during preclinical stages, in clinical phases 1 through 3, and through product commercialization? Can it apply lessons learned during one stage to subsequent development stages? These questions become critically important to the successful pursuit of patient-centric drug development for DCS category IIa and IIb compounds, and for more accessible category I and more challenging category IV molecules as well.

1. Merisko-Liversidge E et al; Nanosizing: A formulation approach for poorly -watersoluble compounds; Eur. J. Pharm. Sci.; 18 (2) (2003) 113–120.

2. Kakran M et al; Overcoming the challenge of poor drug solubility; Pharmaceutical Engineering; July/August 2012; vol. 32, no. 4.

3. Junghanns J et al; Nanocrystal technology, drug delivery, and clinical applications; Int’l J Nanomedicine; 2008; Vol. 3, no. 3; pp 295-309.

4. Fulper D; Softgels: Overcoming formulation challenges and winning customer acceptance; Tablets & Capsules; March 2016.

5. Siew A; Liquid encapsulation for HPAPIs; Pharmaceutical Technology; 40 (1 ); 2016.

6. Catalent Pharma Solutions; Technology profile: OptiGel Bio technology: Meeting formulation and delivery challenges for macromolecular drugs; (ebook ) From Molecule to Dose Form: Bioavailability Toolkit to Fast Track Development; Accessed at: