Softgel
technologIeS
to DelIver
Poorly Soluble
MoleculeS
eserved
Advancing Softgel Technology
for Poorly Soluble or Highly
Potent APIs
By Cynthia A. Challener
Opportunities with Softgels
By Stephen Tindal
Bioavailability Enhancement
with Lipid-Based
Drug-Delivery Systems
By Adeline Siew, PhD
03
11
By Adeline Siew, PhD
Experts from Capsugel and Catalent discuss
the rationale of using lipid-based formulations
to improv the oral bioavailability of poorly
soluble drugs.
Poor solubility remains an ongoing challenge in formulation development. “the abundance of poorly soluble drugs is often attributed to the manner by which companies build large compound libraries (usually via combinatorial chemistry techniques) and/or the use of high-throughput screening assays to identify potential candidates,” explain eduardo Jule, PhD, senior manager, and hywel williams, PhD, senior scientist, both with capsugel’s Dosage form Solutions business unit. “In the latter, the identiication of potential hits will often be measured by how readily a particular compound binds to a receptor. because receptor binding will involve a level of hydrophobic interactions between the drug and receptor, these assays may, therefore, preferentially select those drugs that are intrinsically hydrophobic.”
Julien Meissonnier, vP, Science and
technology, catalent, notes that while poorly
ARTICLE
lIPID-BASeD DelIVeRY SYSTeMS Click to
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VIDEO
Softgel Technology to Deliver Poorly Soluble APIs Click
soluble drugs are here to stay, this issue is, however, not currently addressed appropriately due to the multiple existing and emerging technologies arising in the area, as well as the lack of clarity around the beneits and options that these technologies can provide to formulation scientists. “also, a large portion
of the current solubility-enhancing technologies bring incremental development complexity (such as increased incompatibilities, complex scale-up, and clinical acceptability) resulting in loss of time and additional risks,” says Meissonnier. “as a result, achieving a clear picture of the solubility-enhancement space has become
increasingly complex.”
there is a growing interest in lipid-based drug-delivery systems as a means to improve the bioavailability of poorly soluble drugs. Jule, williams, and Meissonnier discuss the advantages of this approach and the challenges in developing lipid-based formulations.
PharmTech:First of all, what is the rationale of using lipid-based drug-delivery systems?
Jule and Williams (Capsugel): lipid-based drug-delivery systems have the proven capacity to improve the oral bioavailability of a drug via several
mechanisms, with the unique potential to address both physicochemical and biological obstacles to systemic exposure. It is, therefore, appropriate to describe these mechanisms in relation to the fate of a lipid-based formulation in the gastrointestinal (gI) tract:
Stomach. lipid-based formulations
containing the drug, either dissolved or suspended, are typically administered via hard or soft capsules. following rupture and disintegration of the capsule shell in the stomach, the formulation mixes with gastric luid to an extent that is governed by formulation composition and stomach contents. In the fasted state (which is usually more challenging for poorly soluble drugs than fed-state conditions), those formulations containing a mixture of oil and surfactant(s) will self-emulsify before entering the small intestine--the primary site of drug absorption.
Small intestinal lumen. here, a high
administer the drug pre-dissolved in the formulation matrix is such that dissolution can be bypassed altogether, while the lipidic components of the formulation (dispersed and/or digested) mix with endogenous bile salts and phospholipids to form a range of colloidal species that increase drug solubility and present the drug in a well-dispersed and
readily absorbable form. Small colloidal species formed by lipidic excipients and endogenous solubilizers will also enhance drug transport through the unstirred water layer, which can be slow and potentially limiting to absorption when the drug is lipophilic.
enterocyte. lipid-based formulations
may also impact post-absorption events to improve bioavailability of drugs that are subject to:
■ intestinal eflux—fatty acids and
nonionic surfactants commonly used in lipid-based technologies have been shown to reversibly inhibit P-glycoprotein and breast cancer resistance protein (bcrP) eflux transporters or increase transcellular permeability.
■ high irst-pass metabolism—
surfactants have been shown to inhibit cytochrome P450 enzymes known to extensively metabolize
drugs in the intestinal wall, while lipidic excipients can, for highly lipophilic drugs, increase the fraction of absorbed drug that enters into the lymphatic system where hepatic metabolic pathways are avoided.
Meissonnier (Catalent): lipid-based formulations of poorly soluble drugs generally exist during development where drug substance solutions remain itn a solution form in the gI luids prior to facing the gI walls. this means the formulation must irst resist its dispersion in the gI luids by maintaining the
drug in solution. upon dispersion, the formulation could be present in different states, ranging from coarse emulsions to thermodynamically stable microemulsions, which present different features. after the lipid components of the formulation are subjected to the action of the lipase (pancreatic lipase being the primary contributor), which acts speciically at the oil/water interface, the lipids undergo de-esteriication into fatty acids and partial glycerides. again upon digestion, it is important to ensure that the poorly soluble drugs remains in solution form before facing the enterocytes.
formulation’ has come to mean one of a large group of formulations that share some common features. lipid systems may include triglycerides, mono- and diglycerides, lipophilic surfactants, hydrophilic surfactants and cosolvents--excipients with a wide variety of physicochemical properties.
In 2000, colin Pouton irst established an effective classiication system for lipid-based formulations, which was completed in 2006 (1). based upon their qualitative and quantitative composition, the lipid formulations might exhibit different behaviors upon dispersion and digestion. the classiication system consists of four broad categories (1) .
briely, type I formulations are oils that require digestion; type II formulations include water-insoluble self-emulsifying drug-delivery systems (SeDDS); type III systems include SeDDS or
self-microemulsifying drug-delivery systems (SMeDDS) that contain some water-soluble surfactants and/or cosolvents (type IIIa) or a greater proportion of water-soluble components (type IIIb); and type Iv formulations contain no oils and represent the most extremely hydrophilic formulations.
the advantage of moving from type I toward type Iv formulations is to enhance the solvent power of the formulation (hence, majority of high-dose anti-proteases have been formulated
as type Iv systems). Surfactants offer much greater food solvent capacity on dilution (as a micellar solution) than cosolvents. however, moving in this direction requires increased proportions of hydrophilic surfactants with Macrogol (polyethylene glycol) chains that cover the oil/water interface and provide steric hindrance to pancreatic lipase action, thus inhibiting formulation digestion.
the application of SMeDDS to oral cyclosporine has revolutionized organ transplantation therapies, which has consequently triggered a strong focus on SMeDDS development. while bringing more complexity, the development of microemulsion concentrates is
perfectly suited to enhancing exposure, while resolving variability issues and food effect for drugs with narrow therapeutic windows. Indeed, being thermodynamically stable by deinition, those systems are much less sensitive to change in physiological conditions such as food intake, bile salts, and ph. those requisites, however, do not apply to all target product proiles (tPP) where more simple, fast-to-develop lipid systems would apply.
match some more complex tPPs. the proper selection of lipid ingredients can inhibit eflux transporters, extensively affect presystemic metabolism and inluence the route of absorption, for example, by enhancing the lymphatic uptake of highly lipophilic actives.
PharmTech: What are the beneits of using lipid-based drug-delivery systems for solubility/bioavailability enhancement compared with other available methods?
Meissonnier (Catalent): lipid systems allow manufacturing operations to progress rapidly, and may accelerate access to early clinical phases and future scale-up steps. using a rational approach in preformulation operations with liquid systems not only enables accelerated predictability of drug/
ingredient interactions but also, with the use of in-vitro and in-silico development
tools, assists in tailoring the optimum lipid formulation system and increasing predictability of in-vivo performance.
working with liquid and semi-solid systems, catalent has developed a standard procedure, whereby low batch sizes (hundred grams of formulation) are produced under cgMP conditions using commercial encapsulation equipment, enabling quality-by-design integration from the irst preclinical batches through
to manufacture.
Jule and Williams (Capsugel): as mentioned previously, lipid-based technologies offer the possibility to address both physicochemical and biological barriers to bioavailability, which is particularly advantageous when events post-absorption are such that bioavailability remains low, in spite of increased solubility and dissolution rate. owing to fast capsule rupture and the absence of dissolution, lipid-based formulations also may be designed to provide fast rate of absorption, which is often desirable when a rapid onset of action is needed.
aside from performance advantages, lipid-based formulations offer a
straightforward way of formulating drugs that are low melting (i.e., < 100 °c)
route, particularly when working with homogenous solutions.
PharmTech: Can you describe a stepwise approach for formulation development of lipid-based drug-delivery systems?
Jule and Williams (Capsugel): once a lipid-based approach is determined to be the optimal technology for improving bioavailability, the irst step to the
development of a robust lipid-based formulation is to further qualify the drug candidate in terms of physicochemical and biopharmaceutical properties. this ensures that a range of lipidic excipients (oils, cosurfactants, surfactants, and cosolvents) is selected based on the drug characteristics. from here, solubility testing is performed to identify excipients toward which the compound exhibits a high afinity. Selected
excipients are then progressed into the formulation design phase; this stage of development can often be slow and rate-limiting given that a wide number of potential excipients and excipient combinations can be theoretically explored. to accelerate the formulation design process, capsugel uses a lipid expert system—an in-silico database
based on hundreds of phase diagrams coupled to a decision tree--to identify concept formulations based on drug
solubility in lipid excipients, target dose, and the dispersibility of several hundred different placebo formulations across a range of different dilutions.
concept formulations are then progressed into a performance testing program. here, formulations are
subjected to dispersion and simulated digestion tests to ascertain the likely fate of the incorporated drug as the lipid formulation is processed via the highly eficient lipid digestion and absorption pathway. the most robust formulations are those that solubilize high compound concentrations in both the dispersed and digested state (i.e., minimizing drug precipitation), with limited change in performance on changing certain experimental factors, such as bile salt concentration and extent of dilution. our experience tells us that such formulations are less likely to show variable and/or poor performance in-vivo.
Meissonnier (Catalent): the development of lipid systems
encompasses the standard steps found in pharmaceutical development. the state of excellence is reached through the internal development of formulation-speciic analytical techniques, enabling access to a more complete and accurate dataset earlier and faster to ensure proper risk mitigation earlier in the development cycle.
complementing further drug
characterization studies, preformulation studies are based upon the kinetic evaluation of drug solubility in various classes of ingredients, in parallel with chemical compatibility screens. these tests are enabled by speciic automated platforms and predictive tools.
when progressing to the
formulation development stage, to select a formulation that is resistant to precipitation under dispersion and digestion, catalent operates proprietary
in-vitro and in-silico models, including
a computerized database of digestion proiles, and also pseudo-ternary diagrams generated at its ive primary global development sites dedicated to lipid-based systems development. these systems improve the eficiency of formulation determination, as well as predictability to progress in further clinical studies. the excipient selectionprocess is also based upon careful selection of the ingredients in light of their global approvability and existing safety status. a wide majority of lipid ingredients are generally recognized as safe (graS) and several studies are under way on novel functional lipids to broaden their existing safety data.
Reference
The lipid-based method provides a tool for delivery of highly potent, poorly soluble, and unstable APIs. And new in-process capsule printing and shell technologies expand softgels’ applications further.
By Cynthia A. Challener
Softgel capsules are a drug-delivery form
that offers pharmaceutical manufacturers a
tool to overcome the growing formulating
challenges presented by poorly soluble drugs
and highly potent APIs. Advances in softgel
technology are making it possible to use this
drug-delivery approach for a wider selection of
APIs, including those that must be processed at
higher temperatures or wider pH ranges. New
printing methods also reduce process time
and make counterfeiting more difficult. Kevin
Li Product Marketing Manager, Rx Softgel
Technologies, spoke with Cynthia Challener,
editor of the Pharmaceutical Technology, about
these developments and future applications of
softgel technology.
Addressing bioavailability concerns
Pharmaceutical Technology:What are the key trends driving interest in softgel technology?
li (Catalent): bioavailability challenges associated with poorly soluble aPIs
(biopharmaceutics classiication System (bcS) class II and Iv) are driving a lot of interest in
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Technology- Innovations for Oral Macromolecule Delivery
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lipid-based drug-delivery systems that are ideal for softgel formulations. as drug-discovery teams travel deeper into libraries and derivatives, the resulting, more complex leading candidates are typically less soluble and/or permeable than previously developed drugs. It is estimated that as many as 70% of new chemical entities are either poorly soluble, poorly permeable, or both.
Softgel technology offers a drug-delivery solution with the formulation lexibility to overcome these challenges. for example, lipid-based formulations can be used to overcome issues created by aPIs that are practically insoluble in water and that spontaneously emulsify in gastric juices by keeping these aPIs in solution for absorption and preventing precipitation. the technology offers good in-vivo performance with fast
release of ill, has good development proiles, and is compatible with a wide range of excipients and formulations.
In addition, as clinical trials become more complicated and expensive, companies are increasingly looking for the optimal therapeutic proile; softgels can in many cases provide the fastest path and best chance for clinical success.
Expanded applications
Pharmaceutical Technology:When are softgels an appropriate delivery vehicle?
li (Catalent): Softgels are the ideal delivery vehicle for an increasing number of applications. we have demonstrated that our softgels are particularly suited for very low dose aPIs where content uniformity can be problematic (< 3 mg); potent compounds, hormones, and cytotoxic compounds where safe handling is required; poorly soluble or poorly permeable aPIs; oxygen-labile aPIs; aPIs that are unstable in light or liquids; and in abuse- deterrent applications. In addition, we have
developed a new technology that allows semisolid ills with a wider range of excipients, enhancers, and aPIs, thus enabling more drug candidates to beneit from the therapeutic advantages of
softgel technology.
New printing and ingredient
technologies
Pharmaceutical Technology:What are some recent advances in softgel capsule technology?
li (Catalent): the two technologies that I think are worth noting are inline printing and the use of new materials in the shell that impart added performance properties.
encapsulation. the advantages of labelling prior to encapsulation include product differentiation through branding, process-time reduction, and reduced risk for counterfeiting because the label is in the same location on each and every capsule. the process also ensures a higher level of quality; mislabelled products may be outside of speciication in some other way and can be quickly identiied.
Meanwhile, softgel capsules manufactured using our [catalent] new optiShell technology containing starch and carrageenan in the shell, makes it possible to use a wider range of excipients, which in turn, expands the range of ph values and processing temperatures (up to 70 °c) that can be tolerated. as previously mentioned, these softgels can also be illed with semisolids.
Technology assessment
Pharmaceutical Technology:What are the limitations of the technology?
li (Catalent): a key limitation that we ind is the perception that the softgel form is a “low” technology solution. although there are tremendous advantages to formulating as a softgel, including a faster formulation time,
improved stability, and a better therapeutic proile, the balance between the shell, excipients, and ill formulation is crucial for
the long-term success of therapies. we are working to overcome this challenge by developing in-depth expertise in softgel formulation. In addition, with our in-house component library, it is possible to rapidly develop an optimal formulation and provide a smoother and quicker path to commercialization.
another perceived limitation of the technology is that softgels are primarily an immediate-release technology. with recent advances in shell and ill formulations, such as shell technology with starch and carrageenan, it is now possible to provide a much wider range of therapeutic proiles, including extended-t and modiied-release.
Converting from intravenous
to oral dose
Pharmaceutical Technology:Where do you see softgel capsule technology going in the future?
li (Catalent): as the number of lead candidates that are dificult to formulate continues to grow and the costs of commercialization increase, softgel technology will continue to provide the industry with a faster, more effective path to market.
and bring their innovative products to market. one such example is the opportunity presented by the conversion of intravenous formulations to oral dose
SoftgelS
By Stephen Tindal
Softgel technologies offer an alternative
drug-delivery vehicle for lead candidates that are
difficult to formulate.
Softgels are gaining widespread acceptance as a drug-delivery system for pharmaceuticals, particularly for lead compounds that present solubility and permeability challenges during formulation development. with advances in softgel technologies ever since the invention of the manufacturing process by rP Scherer in the 1930s, it is now possible to create solid dosage forms from liquids, pastes and even powders that could not be developed into tablet forms, notes Stephen tindal, director, formulation and Site r&D lead at catalent Pharma Solutions.
“commonly used in medicines and food supplements alike, the softgel capsule has moved on from the simple gelatin shell, with new materials and modiied delivery proiles enabling improved drug-delivery forms to be created,” says tindal. he further explains that although gelatin is an ideal material for the shell of a softgel, it is not suitable for vegetarian diets. “Moreover, the appearance of bovine
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TECH NOTE
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spongiform encephalopathy (bSe) in the 1990s led to the avoidance of the commonly used bovine gelatin in favour of porcine material.”
according to tindal, vegetarian
alternatives have been developed in the past decade or so, solving all of these problems in an instant. “they typically combine a carrageenan with a corn or potato starch derivative, and shelf-lives of three years or more are possible with no loss of shell integrity.” the additional advantage is that ills can be carried out at higher temperatures for lipids that are semi-solid at room temperature, tindal points out.
enteric coatings can be applied to softgels to prevent the capsule from dissolving in the acid environment of the stomach so that drug release is delayed until it has moved further down the gastrointestinal tract. “this feature is important if the contents are acid sensitive, if they might cause damage to the stomach lining, or if absorption is actively required in the intestines,” explains tindal. “rapid intestinal
absorption can be achieved if the shell is designed to dissolve very quickly and permeation enhancers are added
to the contents, enabling high local concentrations to be achieved.”
“Softgels can even be made chewable, making them particularly suitable for paediatric formulations,” says tindal “this is achieved by combining the capsule contents with lavouring and taste-masking agents and making the shell out of a ribbon that is made weaker, perhaps by mixing the gelatin with a starch. Printed patterns can also be applied.”
according to tindal, researchers are currently developing new softgel formulations to deliver biological molecules, such as peptides, proteins and macromolecules. “lipid-based formulations that self-emulsify are able to enhance bioavailability, minimising absorption variability with negligible food effect, while lipid-based solution and suspension formulations can have a major impact on bioavailability, whether that is by enabling digestion in-vivo by lipolysis
or even modifying the absorption route to allow lymphatic transport.”
