Adeline Siew is editor for Pharmaceutical Technology Europe. She is also science editor for Pharmaceutical Technology.

Adeline Siew, PhD

	Smart Skin Technologies has developed a drone-based online pressure monitoring system to measure forces influencing container integrity during the filling process. Online measurements help identify weak points in the filling line. The information can then be used to optimize the process. 

	The motivation for in-line force analysis was mainly driven by the need to reduce losses in parenteral production. Pharmaceutical manufacturers want to avoid glass defects and interruptions of filling lines but realized that there was insufficient understanding of the problem affecting the production process. 

	“In-line analysis is all about understanding where on the manufacturing line forces occur that create damage to the product,” says Joe Norris, head of New Product Development at Smart Skin Technologies. “With the help of data, critical areas and opportunities for optimization can be identified. Following the analysis, lines can be modified to reduce the force applied to the vials, syringes, or cartridges to reduce the damage events. Oftentimes, small adjustments such as lowering the edge of a wedge or optimizing the synchronization between moving parts of the line can significantly reduce breakage.”

	Smart Skin’s drone system is a vial clone with sensitive surface material. “Up to 192 force sensors in the surface of the vial-like drone measure force, and other electronics measure how it spins and tilts as it moves through the production line, and where it is subjected to shock,” explains Norris. “The data are transferred to a Microsoft Surface tablet by Bluetooth and with our Quantifeel software, which prepares easily understandable reports. With help of the data, the software can also calculate where scuffing occurs.” 

	“One drone moves though a certain section of the line at a time,” he says. “After six to 10 rounds, the customers can already identify certain patterns. These patterns can be displayed in heat maps, and additional video material can be used to identify sections where action is needed. Later on, the drones can help to validate whether the corrective measure brought about the desired effect.”

	Norris highlights that the system works with vials, syringes, and cartridges. “Each customer receives a customized set of drones from us, depending on the type and size of the packaging that is filled or produced on the respective line. The customer also receives the software along with training, and we help them interpret the data in the beginning. After that, they use the system independently-for example, for quality assurance, after
	maintenance shut-downs (to ensure a correct restart of the line), for breakage investigations, or line commissioning audits,” he says. 

	According to Norris, the roots of Smart Skin Technologies lie in the food and beverage industry. The impetus to apply the technology also in the pharmaceutical industry came from Roche in Switzerland in 2015. “The challenge was to ‘shrink’ the drone, which originally had the size of a drinking bottle, to the size of a pharmaceutical vial. This is exactly the reason why this technology, which easily helps to reduce breakage and increase cosmetic quality, is still new for the pharmaceutical industry,” explains Norris. 

	“During the project, a drone system for parenteral vial filling, inspection, and packaging lines was developed. The system helped Roche to define relevant limits for glass damage,” says Norris. “Roche can really be seen as a pioneer in this field, and other leading pharma companies have followed.”


	Vol. 30, No. 1
	January 2018
	Pages: 15


	When referring to this article, please cite it as A Siew, “In-Line Force Analysis During Vial Filling,” 

Articles

Measurements by a drone-based online pressure monitoring system help identify weak points in the filling line, enabling the process to be optimized. 

In-Line Force Analysis During Vial Filling

	Packaging plays an important role in preserving the stability and quality of pharmaceutical products so that they are safe and effective when patients use them. Selecting the right type of packaging material to use is, therefore, crucial, especially if it is in direct contact with the product. The packaging must not have an adverse effect on the product, but it is also equally important to ensure that the product does not change the properties of the packaging and affect its protective function. Glass and plastic are well established primary packaging materials for the pharmaceutical industry but they both have their advantages and disadvantages. 

	Many medicines do well when packaged in both glass and plastic, observes Jens Heymann, senior vice-president, Europe & Asia Tubular Glass, Gerresheimer. “How well glass or plastic tolerates an active ingredient depends on its composition. Drugs must be carefully examined at an early stage, ideally when clinical tests with the primary packaging begin. The pharmacist must ensure that all possible interactions between the contents and the packaging are recorded and assessed for risk,” he explains. 

	“Depending on the field of application, the pharmaceutical company may decide to use type I, type II, or type III glass, based on the hydrolytic resistance required,” says Heymann, highlighting that Gerresheimer’s range extends from cough syrup bottles made from amber glass to sterile ready-to-fill (RTF) vials made from tubular glass designed for special injectables. “We constantly adapt our production processes to meet increasingly stringent market requirements,” he adds. Gerresheimer’s Gx Elite Vials, for example, are produced using a conversion process that has been optimized to design out the risk of flaws during production (1). Heymann explains that all glass-to-glass or glass-to-metal contact is removed, beginning from tubular glass right through to the final packaging. The Gx Elite Vials have better quality as a result. The highly shatter-resistant vials are durable and free of cosmetic defects. They have a robust structure and their resistance to delamination protects the drug inside (1).

	Gerresheimer also has expertise in making glass syringes. In January 2017, Gerresheimer announced the introduction of a new metal-free technology for residue-free cone shaping (2). “The technology allows the syringe’s cone hole to be shaped using ceramic materials instead of metal or a tungsten pin, which leaves behind traces of tungsten that can lead to unwanted reactions with the active ingredient, particularly for biologics,” Heymann says. 

	In contrast to glass, plastic is shatterproof and lightweight and can be made flexible, soft, or hard depending on the requirements-a versatility that glass cannot offer, notes Jens Friis, vice-president, Europe & Latin America Plastic Packaging, Gerresheimer. “When choosing the appropriate plastic container, it is important to consider whether the drug is solid or liquid and how it is dispensed, taken, or administered,” he says. “Our Duma tablet container, for example, is for solid active ingredients taken orally. This container has already been around for 50 years in a broad and varied range, featuring tamper- and child-proof closures, integrated desiccant, and much more.” 

	Friis highlights that Gerresheimer recently introduced alternative packaging solutions made from highly transparent cyclo-olefin-polymer (COP) plastic for new alkaline parenteral formulations and toxic drugs. “COP combines many of the properties of glass with the shatter-resistance of plastic,” he points out. “The COP contact surface also improves the stability of highly sensitive medicines, such as the new generation of biopharmaceutical active ingredients, and minimizes the interaction between the drug and the packaging.” 

	“For specific requirements, Gerresheimer has developed the multi-layer Gx MultiShell Vial made from COP and a polyamide barrier layer,” says Friis. “This combination makes it possible to enhance the vial’s oxygen-resistant properties many times over that of traditional COP monolayer vials.” According to him, Gerresheimer produces plastic syringes in Germany for the ClearJect brand, which also uses COP. “Prefillable plastic syringes do not contain any tungsten left over from the production process and are made without any needle adhesive. They are also shatter-proof and customizable,” he explains. “They are similar to glass syringes in terms of their functional properties such as break loose and gliding forces. The highly transparent material makes ideal primary packaging for sensitive medicines for use in oncology, ophthalmology, or other fields of application.”

	Heymann points out that for most, deciding between glass and plastic depends on the following questions: How and where will the medicine be used? How will it be dispensed? Who is it for and how will it be administered or taken? “And then, there is still the question of how the medicine is to be bottled,” he adds. “For example, we have agreed with our competitor Nuova Ompi that we will use the same secondary packaging in the form of nests, trays, and tubs to package our Gx RTF vials-which is the well-known Ompi EZ-Fill packaging format. This way the customer can receive identically packaged sterile injection vials from two different manufacturers, which enables them to start filling the vials straight away without the need for any intermediate process steps.”

	Glass and plastic complement each other with their specific properties and benefits, notes Friis. “Although the active ingredient is the top priority, many other factors influence the choice of primary packaging,” he says. “One of our key objectives is to increase the efficiency of drugs by ensuring that they are delivered in the most targeted and complete way possible. User-friendliness and safety in application play an important role in everyday use.”

	1. Gerresheimer, “Perfect Gx Elite Vials Presented by Gerresheimer at CPhI Worldwide,” Press Release, 25 Sept. 2017.
	2. Gerresheimer, “Gerresheimer Introduces Metal-Free Syringe,” Press Release, 12 Jan. 2017.


	Vol. 30, No. 1
	January 2018
	Pages: 16

	When referring to this article, please cite it as A Siew, “Glass or Plastic-A Question of Use,” 

Glass and plastic are well established primary packaging materials for the pharmaceutical industry but they both have their advantages and disadvantages. 

Glass or Plastic—A Question of Use

	Cambrex was awarded the 2017 CPhI Pharma Award for Excellence in Pharma: API Development for developing a novel method to synthesize ospemifene more efficiently. According to Jonathan Knight, vice-president, New Product Development, Cambrex, the major challenges with the original published route were mainly associated with the number of chemical steps, which typically involved seven to eight steps. “This obviously has an effect on the amount of production equipment used, as well as the overall solvent requirements,” Knight said. He added that another important consequence of a multi-step synthesis was the formation of unwanted impurities at each intermediate stage, which increased the need for in-process analysis and often resulted in extensive purification, which had ramifications in the overall waste and environmental impact. “The original route was not ‘atom efficient’ in design, meaning that it lost molecular weight at the end of the synthesis, and that has a direct effect on yield and processing time, which can dramatically impact the cost of goods,” he explained. Knight spoke to 

 about the approach taken by Cambrex in this API development project. 

	How did Cambrex go about developing a more efficient process?

	Cambrex’s approach was always to develop an ‘atom efficient’ process. What we mean by this is to try to make the synthesis not only as short as possible but also to avoid protection–deprotection steps, and build the molecular weight during the synthesis. We also look at ‘process efficiency,’ which includes minimizing the number of chemical steps, and in particular, the isolated steps, while keeping the concentration as high as possible.

	The goals that we set from the start were to develop a process that is robust, with a short route of synthesis and good capacity utilization. We wanted to start from commercially available raw materials and develop a process that is sustainable from an environmental standpoint. All these goals were achieved; many actually exceeded our expectations, and the result was to reduce a seven-step synthesis to a two-step synthesis.

	Can you tell us about the new method developed by Cambrex and what competitive edge it brings to the table?

	Cambrex actually developed three novel routes to the target API, each building upon the previous one. The third route, and the one for which we won the prize, is a two-step synthesis, in which both steps are coupling steps (increasing the molecular weight), starting from cheap and commercially available raw materials. The first step is run neat (i.e., no added solvents), which gives a high capacity of more than 400 g/L, as well as a 95% yield and 99.7% purity without the need for crystallization. The total processing time, including workup, is less than 24 hours. The second step is a McMurry Coupling, which was more challenging than the first step to develop due to the amount of potential impurities that could be formed. Following an extensive critical parameter study and formal design-of-experiment (DOE) study, the second step was successfully developed.  This step results in a robust, high-yielding process meeting the tight specification after only one recrystallization.

	Based upon the publically available information of the original route, the novel Cambrex route has shown clear advantages that have resulted in a strong improvement in the process and a dramatic reduction in the synthesis costs. These improvements include the overall reduction of the number of chemical steps from seven to two (resulting in a significant increase in yield and plant efficiency); the demonstration of a robust, reproducible process that only requires one crystallization to achieve an overall purity of 99.9%; and a significant (>75%) reduction in waste.

The method developed by Cambrex uses standard plant equipment and requires only two synthetic steps and one recrystallization, minimizing waste and use of solvents.

A New Efficient Synthesis of Ospemifene

	Orbis Biosciences’ Optimµm Platform, an encapsulation technology developed for oral drug products, won the 2017 CPhI Pharma Award for Excellence in Pharma: Formulation. In an interview with 

, Nathan H. Dormer, vice-president of Research & Development, Orbis Biosciences, shares insights on the challenges in manufacturing controlled-release drug-delivery systems, the limitations of traditional methods used to coat microparticles, and the innovation behind Orbis’ Optimµm Platform.

What are the challenges in manufacturing controlled-release microparticle drug delivery systems? 

Micro- and nanoparticulate powders are manufactured with a myriad of processes, but the primary motivation is integration of controlled-release mechanisms to govern particle disintegration and API dissolution. The requirement of achieving controlled release universally relies on physical sequestration of the API via one or more physicochemical mechanisms, which typically requires multiple steps. A powder form, however, can present unique challenges to achieving controlled-release coatings due to the high surface area of the particles, the irregular sizes of particles within the powder, and the number of process steps required to ensure predictable performance and reasonable quality of the final product. Nonetheless, taste-masking can still be achieved with powders when a coating or other chemical modification is applied.

 What are the different steps involved in coating microparticles?

The most straightforward method for achieving taste-masking and controlled release with coated powders involves a two-step process in which a precursor particle is manufactured by various means, then coated with one or more layers containing controlled-release materials. Precursor particles can either be finely-milled API crystals, crystalline or amorphous API co-mixed with inert bases or controlled-release materials, or an entirely inert core without API. These three types of precursors can be manufactured by one or more means, which include traditional vibratory methods, congealing/spinning disk atomization, prilling, hot-melt extrusion (HME) and spheronization, aqueous dispersion, blending/bulking, electrohydrodynamic spraying (EHDS), spray drying, or ion exchange resins. Material selection for the precursor particle relies on process capabilities, the desired end-product controlled-release properties, API thermal and oxidative stability, and the desired physical properties (such as surface features, density, friability, and hardness, among others). Once the precursor microparticulate is manufactured, the product is then sieved to remove out-of-specification particles and coated for taste-masking, delayed-release, or stability-enabling properties. The precursor particle advances to subsequent traditional coating steps using fluidized beds, Würster coaters, dry polymer coating, spray coating, pan coating, or coacervation. The materials of choice for the secondary coating steps are selected for reasons commensurate with the precursor particles (i.e., material compatibility, controlled-release behavior, and stability). The final dosage form can then be bottled for resuspension at time of use, packaged in sachets or sprinkle capsules, placed in dissolving tongue strips, co-lyophilized with other materials for orally-disintegrating tablets (ODTs), or reconstituted in syrup if liquid stability is not an issue. 

 What are the limitations of traditional technologies? 

The approach of manufacturing controlled-release powders by adding multiple coating steps to API-rich precursor particles is an accepted method for powder dosage forms. These techniques are, however, divergent from state-of-the art approaches that focus on chemical modification or comlexation of the API and/or substrate using ion-exchange resins. The main advantages that ion exchange resins can yield are liquid stability and deterring abuse of scheduled APIs, such as opiates and amphetamines. Although it is innovative, drug complexation involves a number of manufacturing steps and quality control aspects that far surpass that of simple bead layering, and it still usually includes a final coating step. The major criticisms of all traditional methods, however, focus on the sheer number of process steps to achieve particle size distributions that contain a considerable amount of fine and large out-of-specification particle sizes.   

Can you tell us more about Orbis’ Optimµm Platform? What challenges does it solve and what makes the technology unique?

Orbis’ Optimµm Platform leverages its Precision Particle Fabrication technology to deliver oral pharmaceutical products that have both controlled release and taste-masked attributes. Orbis’ controlled-release capabilities are unique in that they are achieved in a single manufacturing step and do not require additional coating steps to achieve taste-masking, extended release, or modified release. Optimµm technology incorporates vibration with a scalable nozzle approach to create both microspheres and microcapsules in a single manufacturing step. The Optimµm technology produces uniform microspheres or microcapsules exhibiting a narrow size distribution, offering precise control over particle morphology (e.g., porosity, coating thickness, etc.) and therefore precise control over the release kinetics. These release kinetics can include extended or modified release options. The flexibility of Optimµm technology allows for production of a wide range of particle materials, sizes, and desired characteristics in a single-step process that scales linearly by simply adding additional nozzle heads. Scale-up has been successfully validated with the commissioning of Orbis’ cGMP compliant manufacturing system, which has a minimum of 60 times more throughput than a laboratory-scale unit.

Can you provide some examples of how the Optimµm Platform was used to address key formulation or manufacturing challenges?

In one example, Orbis used its novel core-shell technology to enable modified-release options such as enteric or reverse-enteric delivery in a format-flexible powder. Specifically, Orbis created an enteric-coated bead with a pure ibuprofen core.

dissolution shows that API release is limited to less than 10% for two hours in gastric conditions with immediate release when exposed to neutral pH similar to the small intestine. This modified-release approach is accomplished by fabricating a microcapsule with an engineered shell of uniform thickness designed for targeted release specifications. Efficiencies are gained using the Orbis process by eliminating the secondary coating step for applying the enteric coating.

	In another example, Orbis used its Optimµm technology to create an immediate-release, taste-masked, microcapsule-based powder, which contained the very bitter drug, prednisone. The prednisone powder was found preferable over the traditional pill in taste testing, and had similar taste to a placebo microsphere powder with no encapsulated drug. Additionally, the powder provided equivalent total body exposure of prednisone and active metabolite, prednisolone, in a randomized, open-label, two-product, two-period, crossover study in a fasted state comparing 10-mg prednisone taste-masked microspheres to a 10-mg prednisone tablet.

Orbis Biosciences’ Optimµm Platform delivers microparticulate dosage forms with controlled-release and taste-masked properties in a single manufacturing step. 

Manufacturing Microparticles in a Single Step

The pharmaceutical industry is mainly dominated by tablet formulations, but softgels are gaining widespread acceptance as a preferred dosage form. “Softgel capsules are a popular dosage form in the consumer healthcare market because of their unique benefits, such as ease of swallowing and quicker onset of action in relation to tablet formulations,” says Kaspar van den Dries, senior director of formulation sciences, solid dosage forms, and softgels at Patheon, part of Thermo Fisher. “These are important considerations for patients when they are choosing treatment of pain or allergies.” He also notes that a softgel formulation can be used for lifecycle management approaches to prescription, generic, and over-the-counter (OTC) drugs, for cases in which softgel technologies can be used to generate improved versions of existing drugs.

	“In the consumer healthcare market, there are plenty of examples of softgel success stories. Compounds such as ibuprofen, naproxen, and diclofenac, when formulated into softgels, have improved performance, which is an important consideration for the patients,” van den Dries highlights. “Another example is chewable ibuprofen, a softgel formulation specifically designed for patients having difficulty swallowing. This product was launched through a lifecycle management approach to existing children’s suspension products and has been well-received in the European market.” 

	According to van den Dries, it is increasingly difficult and complex to develop new compounds, especially with the majority of lead compounds in the drug development pipeline presenting with solubility and bioavailability challenges. “In this case, a lipid-based formulation in a softgel capsule can provide significant advances by improving the bioavailability of these compounds and increasing the chance to obtain proof of concept for these molecules,” he explains. 

	“Softgel is still the most popular enabling formulation for bioavailability enhancement, compared to other solubilization approaches such as spray drying, hot melt extrusion, or particle size reduction,” van den Dries says, highlighting that most products being approved to date are lipid-based formulations. “Softgels based on lipid formulations make use of the body’s digestive pathways. This approach is, therefore, a well-established route for improving bioavailability, but it is sometimes overlooked or considered as a key risk in development, mainly because of time and cost pressures in early development, as companies don’t want to overspend in early development, when the probability of success is still low. The experienced formulators and senior management responsible for these compounds are aware of these risks and options to reduce them. However, because not all companies have the internal experience or know-how on softgel technologies, you still see programmes with suboptimal formulations, which could have been mitigated by considering softgel formulations early in development.” 

	There are also other areas where softgel formulations are being considered, observes van den Dries. “For example, softgels can provide reduced exposure for highly potent compounds (because no powders are involved in the manufacturing process) and improved uniformity for low-dose APIs compared to tablets,” he says. 

	Softgel versus liquid-filled hardgel capsules 

	In terms of the manufacturing process, softgels provide a number of benefits over liquid-filled hardgel capsules. “Liquid-filled hardgel capsules are produced through a two-step process. The first step is to fill a two-piece hardgel cap with liquid, and the second step is the subsequent banding of these capsules. Small-scale batches are produced using a different type of equipment from that used to make commercial-scale batches,” explains van den Dries. “In contrast, the production of softgel capsules, for both large- and small-scale batches, can be done on the same equipment without the necessity of banding. This flexibility provides significant cost advantages, both on unit price and total development costs. In addition, a softgel formulation is more versatile. By changing the composition of the fill or the gel material, you can obtain a chewable, gummy formulation that makes the medication easy to ingest for children, or people who have difficulty swallowing (e.g., elderly). With softgels, there are also opportunities to create an enteric-release formulation, or even a controlled-release, abuse-deterrent formulation. All of these formulations can be produced on the same equipment. Globally, there is more capacity available in softgel manufacturing than there is available for liquid-filled hardgel capsules, hence, providing more flexibility in the supply chain of products.

	Softgels are dynamic systems where the fill and shell compositions, fill–shell interaction, and process parameters can have a substantial influence on the softgel integrity, highlights Melanie Bayarri, formulation development scientist at Patheon, part of Thermo Fisher Scientific. She observes that with increasing quality requirements, there is a need for pharmaceutical manufacturers to focus on making smart choices early in the development programme. “The burst strength test is an important technique to support formulation and process choices made throughout softgel product development. It is an established method to assess softgels shell robustness,” she says.

	“It is performed with a Dr. Schleuniger Pharmatron 400 N model 6D(SG) softgel tester. The apparatus is similar to a tablet tester and compliant with the specifications as laid down in the 

-Chapter <1217> (2). It is easy to operate,” Bayarri explains. “A softgel sample is placed individually between two jaws that compresses it at a fixed rate of 2.5 mm/second until the sample bursts or until the maximum force of 400 N. The force (N) required to burst the sample is recorded and in case the softgel does not burst, the result is noted as > 400N,” she says. 

	“The evaluation of softgels shell robustness is not only based on the number of bursts and the withstood force before burst, but also on the relative shell flexibility as the apparatus records as well the diameter (mm) of the softgels before compression and at maximum compression,” Bayarri highlights. “Using this test, we can evaluate the influence of critical parameters on the softgels shell robustness related to the formulation design (e.g., fill formulation, gel formulation, fill-gel interaction), process design (e.g., die design, ribbon thickness, hardness, and drying time), and storage temperature.”

	“During product development, we assess softgel shell robustness using the burst strength test, and we have been able to establish a good correlation between the burst strength test results and product performance,” Bayarri says. According to her, the generated data are used to support the selection of:

		Adequate shell formulation for a particular product

		The most suitable process parameters, such as the die design, for a specific fill and shell combination

		The optimal target hardness range per product, balancing water activity (related to microbial safety) with hardness and drying time impacting shell robustness.

	“The burst strength test is useful to establish formulation and process parameters that not only ensure optimum product performance through shelf life but also guarantee that the product will withstand physical stresses that can occur during packaging and transport activities,” Bayarri sums up.

 Chapter 2.9.8 “Resistance to Crushing of Tablets” (EDQM, Strasbourg, France, 2016) p. 313.
	2. USP, 

 General Chapter <1217>, “Tablet Breaking Force,” 

 (US Pharmacopeial Convention, Rockville, MD, 2007), p. 726.


	Vol. 41, No. 12
	December 2017
	Page: 24–27

	When referring to this article, please cite it as A. Siew, “Opportunities with Softgels,” 

Softgel capsules are a popular dosage form among patients but they also provide a number of manufacturing benefits over liquid-filled hardgel capsules.

Opportunities with Softgels

	Lipid-based systems with modified-release profiles present exciting opportunities for drug developers. “On the one hand, lipid-based formulations provide benefits such as solubility and permeability enhancement, modulation of transporter, elimination of food effects, reduction of inter-patient and intra-patient variability, greater API loading, and the avoidance of dose dumping,” observes Julien Meissonnier, vice-president of Science & Technology at Catalent. “On the other, with extended or sustained drug release, dosing frequency can be reduced; peaks and troughs of drug levels in the blood are dampened, which consequently optimizes therapeutic effectiveness while minimizing concentration-dependent adverse effects.”  

	Meissonnier explains that in some cases, conventional approaches for modified-release drug delivery may prove difficult because of physicochemical and pharmacokinetic challenges posed by the drug compounds. “For example, most APIs in today’s development pipeline are poorly soluble or poorly permeable, and some have low melting points. When these physico-chemical challenges are not addressed properly by the formulation technology, it often results in extensive positive food effects, which when combined with a narrow therapeutic window, can trigger a potential risk to the patient, with the potential risk of dose dumping,” he says. “Modified-release lipid-based formulations in softgel capsules can address these challenges. For poorly soluble compounds, lipid-based formulations promote solubilization along the gastrointestinal tract; whereas for poorly permeable compounds, lipid-based systems facilitate transcellular or paracellular transport by exploiting the lipid assimilation pathway as well as potential uptake through the lymphatic pathways. Lipid excipients can be used to modulate transporter and pre-systemic metabolism. All these mechanisms result in increased drug exposure, reduction of inter-patient and intra-patient variability, and elimination of food effects,” he explains. “In addition, dose dumping can be eliminated with lipid-based matrix systems.”

	The dosage form of choice for a modified-release lipid-based formulation is a soft capsule. “Soft capsules are the proven dosage form for lipid-based formulations,” says Meissonnier. “They have good developability and manufacturability. They are compatible with the wider range of lipid liquid and semi-solid excipients and formulations. Moreover, soft capsules do not compromise the performance of the lipid-based fill.”

	According to Meissonnier, there are various ways of modifying the release of actives through the lipid-based fill or the soft capsule shell. “Whereas monolithic softgels can be designed, the preference would be to leverage multi-particulate soft-gelatin capsules to further reduce variability. These softgels can be designed to have a solid lipid matrix core that will extend release rate through an erosion diffusion process. The other option is a film-coated soft-gelatin capsule with a liquid fill where the drug release profile is facilitated using coated beadlets, and controlled by the nature of the coating polymer.”

	Meissonnier cites a case study where an extended-release lipid-based formulation was developed using Catalent’s OptiShell soft capsule technology. The formulation was approved by the United States Food and Drug Administration in 2016. 

	“This is the first FDA-approved treatment using OptiShell soft capsule technology to deliver an extended-release semisolid formulation in a softgel format,” says Meissonnier. “The active ingredients are used to increase vitamin D levels, but peak concentrations or ‘surges’ in 25-hydroxyvitamin D3 levels induce the expression of the metabolizing enzyme Cytochrome P450 subfamily 24, resulting in lesser activity attenuating the inhibition of parathyroid hormone,” he explains. “Controlling the drug release maintains 25-hydroxyvitamin D3 levels in the blood above the 30 ng/mL concentration, avoiding peaks that result in lesser activity. In addition, gradual repletion of 25-hydroxyvitamin D3 could provide more predictable maintenance of serum levels below the poorly defined safe upper limit of approximately 100 ng/mL, allowing for more consistent dosage.”

	The product’s controlled-release system is a semisolid lipid-based matrix and, according to Meissonnier, “lipid-based matrices, in which the drug is homogeneously dispersed/dissolved, are the system of choice for low-dose potent compounds. Catalent’s OptiShell soft capsule technology uses a precisely controlled hot-filling process for encapsulation of the lipid-based matrix, providing content uniformity performance above standard oral solid forms.” He adds that the patented shell composition can handle encapsulation of high-temperature fill formulations for semisolid and highly viscous fill formulations. It can also handle higher pH fill formulations.


	Vol. 41, No. 12
	December 2017
	Page: 26

	When referring to this article, please cite it as A. Siew, “Bringing Together the Benefits of Lipid-Based Formulations and Modified-Release Drug Delivery,” 

Modified-release lipid-based formulations in softgel capsules can address physiochemical and pharmacokinetic challenges posed by drug compounds. 