Pharmaceutical and nutritional companies today require a diverse range of technologies and dosage forms to develop customized solutions that improve delivery of their products to the body. New compounds in the pharmaceutical pipeline are increasingly complex and typically require enabling technologies to address challenges such as solubility, permeability, stability, metabolism, regional absorption, or food/pH sensitivity. Advancing these compounds also can require specialized processing techniques and often require high containment to handle an increasing number of highly potent applications.

Liquid fill hard capsules (LFHC) technology is one delivery method that is popular due to its simplicity in manufacturing design and technology transfer process, and its versatility in providing sophisticated solutions for a vast range of pharmaceutical formulation and delivery needs. LFHC technology is increasingly utilized to address key formulation challenges in advancing new chemical entities or improving existing products, including enhancing bioavailability, highly potent and low dose applications, combination products, intestinal targeting and colonic delivery. This is because the principle requirement for LFHC technology is that the formulation is liquid at the time of filling in the capsule. Applicable formulations can be liquid at ambient temperature, or liquid at an elevated temperature during filling, but solids or semi-solids at room temperature. With this flexibility, drug formulators can incorporate an array of well-established pharmaceutical excipients into an LFHC formulation to achieve pre-determined target product profiles.

Below are 12 reasons why drug formulators and manufacturers are more often turning to LFHC technology to bring new and improved products to market.

A simple manufacturing process
The LFHC technology process is relatively simple in concept: a typically non-aqueous liquid is filled into the body of the capsule using precision pumps that can deliver a fill weight of 100mg to 1.5 grams as required. The caps are then placed onto the bodies of the capsules. Either a seal or a band is then applied around the join. Sealing is typically applied via a fine spray of the sealing solution onto the join, which is drawn into the space between the body and the cap through capillary action, thereby sealing the capsules. Alternatively, a banding solution is applied through a rotating wheel that delivers the banding solution on to the join. The banding solution is typically prepared from gelatin or HPMC depending on the types of shell materials used.

Shortened development cycle through efficient technology transfer
The typical LFHC manufacturing process involves mix preparation (compounding), filling and banding (or sealing) and packing. These are well-defined unit operations. As such, a distinct advantage of the LFHC process is its scalability. With increased regulatory demand on process understanding, LFHC technology offers a potentially straightforward pathway for technology transfer and new product introduction.

The mixing operation is similar to all other pharmaceutical mixing processes with temperature, mixing speed in recirculation or homogenization mode often determined as the critical control parameters. The filling and banding processes are often synchronized to allow a continuous process. Though simplistic in concept, the challenge of the filling and banding is that this process often operates at a speed upward of 60,000-90,000 capsules/hour, or more than 1,000 capsules/minute. It is critical that the setup for both the filler and bander are optimal, which requires significant experience from skilled operators.

A distinct advantage of the banding process is that it is relatively “formulation independent” because the band does not come in contact with the fill formulations. As a result, despite the complexity during setup, the banding operation is often well controlled through the quality process such as an SOP. In terms of control strategy for filling and banding, product quality is assured by fill weight control, such as regular weight checks throughout the process, so long as the homogeneity of the bulk mix is assured. Finally, the banded capsules can be packed in either bottles or blisters using standard pharmaceutical packaging processes.

Throughout process development and technology transfer, the process quality risk assessment can focus on a few well defined process parameters that allow the determination of the criticality of these parameters with greater clarity, providing flexibility for scale up operations. For example, a lipid-based formulation that becomes a true solution when reaching a minimum temperature, and is stable below a maximum temperature. In this case, the temperature range becomes the critical process parameter, while the operating mechanism and mixing time/speed is not critical. Because it is a true solution within the defined temperature range, once fill weight is controlled, then uniformity of dose is assured. As such, the in-process fill weight control becomes one of the most important control strategies.

A safe manufacturing option for high potency drugs
More than 25% of pharmaceutical drugs today contain highly potent active pharmaceutical ingredients (HPAPIs).  Projections indicate that the global market for HPAPI drugs will grow by a compound annual growth rate of nearly 10% between 2012-2018, with the prevalence of oncology products in the pharmaceutical pipeline being a key driver. LFHC technology is ideal for high potency drug manufacture. Once the HPAPI is added to the mixer to form a liquid, its potential for airborne and accidental exposure is greatly reduced in contrast with other oral solid forms, which require much more stringent control, especially during the preparation of the final dosage forms directly from powders such as tableting and powder filling.

An effective approach for low dose formulations
Uniformity of dose poses the most significant challenge for the formulation of low dose products (5 mg or less) throughout development, validation and commercial manufacture. A benefit of LFHC technology is that once a liquid solution is prepared, dose uniformity is assured through excellent weight control attainable during filling (mostly <1% RSD). This provides a simple solution for assuring uniformity for low dose applications which, aligned with highly potent compounds, are increasingly prevalent in pharmaceutical development pipelines.

A key approach for enhancing drug solubility
Poor aqueous solubility represents a significant barrier to drug bioavailability and a dominant issue in drug pipelines. Estimates indicate that 40-90% of new compounds have low solubility and are classed as either BCS II or IV. LFHC technology using solvents or co-solvents is one approach to addressing low solubility. A number of non-aqueous excipients such as polyethylene glycol, tocopheral polyethlene glycol succinate have demonstrable solubility enhancement properties and are ideal for the LFHC process.

A solution for lipid-based formulations
Another approach to improving bioavailability involve self-emulsifying drug delivery systems (SEDDS) and self-micro emulsifying drug delivery systems (SMEDDS), which are formulations that form emulsions or micro emulsions upon contact with aqueous media. These formulations can be tailored to overcome poor solubility and poor permeability. Additionally, these formulations are generally well absorbed within the gastrointestinal tract and are useful when drug absorption is significantly affected by food effect. Typically, lipid-based formulations consist of oils, surfactants and cosolvents that are ideally suited for LFHC technology.

Though the manufacturing process is not demanding, formulation design and development for lipid-based formulation requires much iteration, often through trial and error and by the construction of a state diagram. This is simplified, however, through the use of a database-driven expert system that includes numerous phase diagrams experimentally generated through many years of research. These phase diagrams cover some of the most widely used commercially available excipients—ranging from oils to hydrophilic solvents—as well as surfactants with various hydrophilic/lipophilic balances and assorted chemical families.

The SEDDS and SMEDDS formulation approaches represent a major advancement in pharmaceutical formulation to address the issues of variability and bioavailability—and LFHC technology is an ideal vehicle for their delivery.

In-situ generated nano formulations for enhanced processing safety
Alongside many advances in absorption enhancement formulations, particle size reduction still remains one of the most trusted techniques. However, milling and micronization can be hazardous and require stringent environmental control to be safe and effective. A significant technical challenge is that the milled/micronised particles are prone to aggregation. An alternative approach is to carry out milling in the presence of a non-aqueous solvent, such as an oily medium that is naturally inhibitive of particle agglomeration. In this way, both the environment hazard and the technical demand are addressed through a single pot process. The milled suspension can be subsequently encapsulated in a hard capsule using LFHC technology (Patent US9241940).

An option for providing abuse deterrence
Pharmaceutical actives that impact the central nervous system with indications for pain, anxiety, depression and hyperactivity are often the targets of patient misuse and abuse, and are increasingly being regulated. Efforts to reformulate some opioids have been ongoing for more than two decades. Recently, the U.S. Food and Drug Administration issued a guidance document on the evaluation and labeling of abuse deterrent opioids in recognition of the problem of widespread opioid abuse.

One development approach is to focus on formulations that physically limit the ability of drugs to be mechanically or chemically modified for the purpose of injection, insufflation or rapid oral absorption. For example, this includes sustained pain relief formulations that can be extracted with alcohol or other solvents using common kitchen chemistry techniques in order to induce a high. This type of extractability can be substantially reduced with a high melting wax-based matrix formulation, which maintains the slow release characteristics, for example, 85% release over 24 hours. LFHC technology is a viable route for processing such a formulation, since mixing and filling can be completed at a temperature exceeding the melting point of the designated waxy component.

Since many abuse deterrent formulations are used in second- and third-generation generic products, the 505(j) is often the preferred regulatory pathway. As such, bioequivalence to the Reference Listed Products that in most cases, immediate release formulations will be required, for example, 85% release over 60 minutes. To achieve this, formulations incorporating a liquid carrier and hydrophilic polymers are designed to achieve a careful balance of high viscosity to reduce syringeability, for example, and sufficient mobility to allow high-speed filling in the LFHC technology process.

An effective option for targeted delivery to specific intestinal sites
Many drug products are liable to degradation when passing through the very hostile environment of the stomach. Therefore enteric protection is essential for the delivery of these products. Other products may have been determined to be optimally absorbed on a specific intestinal site in the duodenum, the jejunum or the ileum. In these cases, functional coatings that typically dissolve over a set pH range can be applied to the filled capsules to provide targeted release and to promote optimal absorption.

Improved approach for colon drug delivery
Since the 1990s, intense academic research and industrial development activities have been conducted to devise colon-targeted delivery systems. Though most commercialized colon-targeted drug products utilize a pH-sensitive polymer to coat a granule, a capsule or a tablet, this approach is often criticized because of the variability of the pH in the GI tract between individuals and within an individual that can also be influenced by their disease state and food intake. These challenges raise questions about whether targeted delivery can be reliably and consistently achieved.

One innovative approach that has reached Phase 3 clinical development is to incorporate a starch fraction: a resistant starch, in the coating composition. This starch is resistant to digestion in the upper gastrointestinal tract, but fermented by the large population of bacteria that reside in the colon (Phloral). Functional coating incorporating resistant starch can be applied to LFHC technology.
Combining a colon-specific coating system with LFHC technology is advantageous for drug absorption because the water content is low in the colon to facilitate drug dissolution. Therefore, a liquid fill formulation provides far greater mobility in the locality of colon.

Precise colon targeting using the resistant starch approach is particularly relevant in order to achieve systemic absorption and to prevent any premature release in the distal intestine. When persistent local action is required, however, the application of a simple pH coating system can be beneficial. This can be achieved through a matrix-based fill formulation that allows a gradual release of the therapeutic component. Essentially, as the coating formulation dissolves away around the ileocecal junction, the matrix formulation prevents the complete release of the active at this point. Rather, it ensures release throughout the passage from the distal intestine to the colon, maximizing the topical effect. 

An option for combination products
A capsule-in-capsule technology has been successfully commercialized. The technology allows the insertion of a pre-filled smaller capsule containing either a liquid or semi-liquid formulation into a larger LFHC. This allows for the delivery of a combination product that contains two actives that are otherwise incompatible in a single dosage form. Combination products are increasingly being formulated for therapeutic benefit, reduced dosing requirements, and as an increased barrier to replication by generic companies.

Achieving variable release profiles within a single dosage form
Given the increased recognition of the circadian and other rhythmic cycles in diseases such as psychiatric and somatic illness, it is desirable to schedule drug administration, taking into account the pharmacokinetics of the active to maximize effectiveness and to minimize side effects. One approach is to vary the release profiles of a single active to maximize pharmaceutical effects.

The above-mentioned capsule-in-capsule approach provides a simple solution to achieve the variable release profiles. Examples 1 and 2 use two actives to illustrate the concept more clearly. If a single active is used, then the release profile will be cumulative of the two. Other profiles can be designed to achieve the target product profiles.

In Example 1, the larger LFHC is released immediately, whereas the small inner capsule is released with a sustained release profile to maintain a desired therapeutic level. In Example 2, the larger LFHC is designed to release immediately, whereas the small inner capsule is delayed. The capsule-in-capsule approach incorporating LFHC technology is ideal to derive such release profiles.

Conclusions
LFHC technology is a relatively straightforward and can be utilized to meet a number of formulation and manufacturing challenges. At its core is the filling and banding operation, which is comparatively speaking “formulation-independent.” This offers tremendous advantages in process development and technology transfer, thereby accelerating the pharmaceutical development cycle.

LFHC technology provides versatile solutions to a number of significant challenges facing the pharmaceutical industry. This includes the large number of drug candidates that are poorly soluble, the suboptimal tailoring of drug release profiles to maximize efficacy and minimize side effects, the low dosage required of some medications, and the stringent manufacturing containment policies required for HPAPIs.

It is the combination of such simplicity and versatility that makes LFHC technology particularly relevant to modern product life cycle management, where there are increased regulatory demands on product and process understanding on the one hand, and ever aggressive generic competition on the other. 

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Stephen Brown is managing director, Encap Drug Delivery, a division of Capsugel Dosage Form Solutions. For the past nine years, Dr. Brown has led the expansion of Encap Drug Delivery from a regional CMO to a rapidly growing global business within Capsugel Dosage Form Solutions.

Wei Tian is director of formulation at Encap Drug Delivery, a division of Capsugel Dosage Form Solutions. Dr. Tian is responsible for advancing client projects from early formulation evaluation to late stage process scale up, as well as the development of novel platform formulation technologies.