The increasing occurrence of highly potent or frequent-administration therapies in the drug development pipeline means that the low solubility of drugs is becoming a potential bottleneck for pharmaceutical formulators. This not only makes getting new medicines to market more time-consuming, but it also hampers the lives of patients in need. In this case study, Losan Pharma – a contract development and manufacturing organization (CDMO) focusing on improved active pharmaceutical ingredient (API) performance – and BENEO, a multifunctional excipient supplier, pool their collective resources. In doing so, they managed to develop a convenient-to-take once-a-day oral solid dosage form prototype of Dexa-methasone, an API that’s practically insoluble in water.
One of the most challenging issues to overcome in terms of getting a new chemical entity (NCE) to market, or reaching its full potential, is solubility. Approximately 60% of potential new products exhibit greater or lesser solubility problems, with some industry experts suggesting that the proportion of poorly soluble drugs in the current pipeline is as high as 90%.1,2 Not only do APIs with solubility issues require more complex preclinical studies and clinical trials, they also present formulators with considerable technical challenges.3 The search for appropriate technologies and formulation methods to enhance aqueous solubility, permeability and dissolution rate can be problematic; plus, poorly water-soluble drugs often need high doses to reach therapeutic plasma concentrations after oral administration.4 It perhaps comes as no surprise, therefore, that improving drug solubility and, consequently, bioavailability, remains crucial for the entire pharma sector.
Wanted: An Easy-to-use Glucocorticoid
The demand for pharmaceutical substances with improved properties continues to drive progress in the field of outsourced product development. Today, many pharma companies are turning to external specialists that offer formulation know-how, appropriate technologies and available capacity – key requirements to reduce both research and development (R&D) costs and time to market. To cite a recent example, two Europe-based experts in formulation development – Losan Pharma and BENEO – joined forces to design a novel administration format for the poorly soluble glucocorticoid medication: dexamethasone (with Dexamethason- ratiopharm® 4 mg as a reference listed drug). To reach this goal, Losan Pharma applied its long-term expertise in the development of nanoformulations with improved API performance. BENEO supplied the carrier, which needed to both convert the API suspension into a dry format and bring the chosen administration format to fruition; this was a convenient and easy-to-use stickpack containing biphasic release pellets (Figure 1).
From API to administration:
optimizing drug delivery Dexamethasone is a synthetic corticosteroid with anti-inflammatory and immunosuppressive properties. It is primarily used to treat various inflammatory and autoimmune conditions, such as allergies, asthma, rheumatoid arthritis and inflammatory bowel disease. 5 According to the National Cancer Institute (USA), dexamethasone is also approved in combination with other drugs to treat certain types of cancer, including leukemia, lymphoma and/or multiple myeloma.(6) In recent times, dexamethasone has gained attention for its potential to reduce mortality in hospitalized COVID-19 patients requiring
oxygen support or mechanical ventilation.7 “In this project, dexamethasone served as a model drug because it is practically insoluble in water,” said Oliver Luhn, Head of Pharmaceutical Technology at BENEO. Generally, the solubility of an API is a critical factor for drug formulators as, first and foremost, it determines the overall efficacy of the drug. If the API is only partly or not fully dissolved in the gastrointestinal fluids at the site of absorption, the drug can’t properly reach the systemic circulatory pathway and evoke the required pharmacological response.4
Oliver Luhn continues: “When administered in tablets, dexamethasone needs to be taken at a high frequency during the day for most indications. This means
that patients need to adhere to a special dosage regime, which can pose a considerable challenge to them. Thus, we were tasked by Losan Pharma to deliver a carrier system that facilitated the development of an alternative oral dosage form with increased API bioavailability and minimized the need for repeated administration throughout the day.”
The developers opted to use stick packs with dual-release pellets: the overall formulation contained both immediate-release (IR) and delayed-release (DR) pellets. Although the API released from the IR component reaches the bloodstream quickly after administration, the drug in the DR portion maintains the effective therapeutic dose for a prolonged period of time. This biphasic drug delivery system allows the frequency of dosing to be reduced and contributes to the long-term therapy of chronic disease conditions by maintaining the patient’s drug plasma concentration within its therapeutic range. (8) Matthias Rischer, Director of Drug Delivery & Innovation Projects at Losan Pharma, comments: “We see stickpack technology as a way to facilitate oral intake and increase both application convenience and patient compliance, especially for elderly people and for frequently dosed formulations. Last but not least, drugs in a stick pack provide an easy-to-use administration format as they can be swallowed without water.”
Fast-track Development of an API Nanoformulation
The drug formulation process centered on establishing a stable API nanosuspension. Pharmaceutical nanosuspensions are defined as submicron colloidal dispersions of nanosized drug particles stabilized by surfactants and polymers.9 Generally, creating nanosuspensions offers a way to enhance the solubility of “brick dust” APIs. Reducing the particle size to nanoscale significantly increases their surface area, which results in a much higher dissolution rate.3 This may subsequently contribute to improved bioavailability.
