One obstacle drug developers face is ensuring the bioavailability of the active ingredients in the treatments they create. Many active pharmaceutical ingredients (APIs) don’t readily dissolve in water, which decreases their potency; increasing the concentration of the drug increases the cost and could negatively impact everything from the cost of the drugs to the incidence of side effects, and taste of the pills.
Outsourcing-Pharma spoke with Ameya Deshpande, formulation scientist at Avomeen, about how hot-melt extrusion could help reduce some of the challenges associated with drug formulation, improving bioavailability, and clearing other hurdles.
OSP: Could you please share the ‘elevator presentation’ description of Avomeen—who you are, what you do, key capabilities, and what sets you apart from the competition?
AD: Avomeen is an accredited, independent contract research organization (CRO) and contract development and manufacturing organization (CDMO), bringing chemists and scientists together to tackle scientific product-development challenges in the biopharmaceutical industry and across other industries and applications. The company’s unique approach is singularly focused on applying its expertise and working closely with clients to help transform their biggest goals into real solutions.
Throughout each step of product development, Avomeen’s scientists and experts work within a rigorous quality system to ensure products comply with regulatory requirements and consumer expectations. Avomeen’s facility is FDA-registered and DEA-Licensed (schedules 1-5), and its laboratories are also GLP/GMP-compliant, ISO 17025 accredited, and QP authorized for clinical trial material in the EU. Avomeen offers complete, comprehensive scientific solutions that support the entire product development lifecycle, with a focus on growing strategic partnerships.
OSP: You point out many APIs in drugs don’t readily dissolve in water. Could you please share with us the various challenges this poses to pharma developers and drug companies, and how companies typically try and overcome these challenges?
AD: Active pharmaceutical ingredients (APIs) in solid oral dosage forms such as tablets are only as potent as they are soluble in aqueous solutions since solubility directly impacts the bioavailability of the API. About 80% of all pharmaceutical products show low solubility in water, which reduces their absorption in the body and poses a significant challenge to pharmaceutical developers looking to produce safe and effective drugs.
Pharmaceutical developers often compensate for the low solubility of APIs by increasing the API concentration in their batches; however, this practice poses health risks to both production personnel and patients. For example, if the drug is highly potent, it can produce toxic effects in line workers. It can also increase the cost of medication, expose patients to additional risks of adverse effects, and make oral medications taste unpleasant, which can reduce adherence.
OSP: Please tell us about hot-melt extrusion, how it can improve dissolution, and how HME solves a lot of these challenges.
AD: HME is a common technique used for transforming poorly soluble crystalline APIs into amorphous, soluble forms to make them more bioavailable. Through HME, pharmaceutical developers pump the API and excipients, such as a binder and polymers, through a heated barrel at a controlled temperature, where these components get embedded in a carrier formulation that melts.
This process converts the mixture into a homogenous, amorphous molecular dispersion. HME increases the dissolvability, and therefore the bioavailability, of the API, as well as prevents recrystallization to increase the stability of the formulation.
This technique enables manufacturers to maximize efficacy and offer sustained, modified, time-controlled, and targeted drug delivery. Also, the polymers embedded in the formulation, especially if they bind strongly to the APIs, mask their unpleasant taste.
The consistent and accurate low-dose products it creates are safer and more reliable, reducing the risk of dosing errors and adverse effects, and, combined with their better taste, ultimately increase patient compliance and improve the overall efficacy of the drug.
HME also protects production personnel. Since the workflow is contained and controlled, line workers are not exposed to the API or the drug formulation.
OSP: Can you share with us an example of how the use of HME helped a particular drug overcome problems in design/delivery?
AD: Avomeen employed the use of HME in the development of a sustained-release drug-eluting implant for Drug Delivery Company (Salisbury, Maryland). The implant consists of a proprietary bioabsorbable matrix that has been optimized for sustained release of naltrexone over the course of many months. It is thought that the sustained release of this drug will provide a better treatment option for combating opioid use disorder.
By using HME, critical process parameters can be fine-tuned in a precise and consistent way. By implementing HME early in the formulation and process-development work (pre-clinical stage), there can be more confidence that the manufacturing process will be robust and scalable through clinical trial phases and eventually to commercial production.
OSP: Could you please share more information about thin film’s use in drug design/manufacturing—how does the use of this delivery method improve bioavailability, taste, and other problems?
AD: Oral thin films (OTFs) are polymeric films that deliver therapeutics into the mouth for absorption in the oral cavity and along the gastrointestinal tract. A large proportion of the API directly enters the circulatory system and acts quickly.
The primary advantage of OTFs is in the delivery method: patients don’t need to chew or swallow the drug or eat food or drink water with it. The films can be flavored and artificially colored to increase compliance among children. OTFs also offer more precise dosing and flexibility than standard dosage forms; they can be sized to deliver highly precise doses, which is ideal for low-dose prescriptions, such as for children or adults taking partial doses.
Recent research has shown that OTFs can be used to administer Biopharmaceutical Classification System (BCS) Class II/IV drugs (drugs that have low solubility in water). Manufacturing OTFs is easier, too; the manufacturing process only involves two steps. It can be done with powderless and aqueous-based processes and without solvents, allowing for continuous processing.
Finally, OTFs offer pharmaceutical companies more opportunities for profit. By reformulating an existing drug as an OTF, a pharmaceutical company can receive FDA approval for a novel oral film application, which entitles that company to three more years of market exclusivity.
OSP: Do you have anything to add?
AD: Knowledgeable formulation scientists who are working with thermally stable formulations will benefit from HME’s efficient and reliable production of solid molecular dispersions. The technique enables pharmaceutical developers to offer sustained and targeted drug delivery with increased stability and bioavailability. This technique will not only reduce costs for manufacturers by reducing the amount of API they need to incorporate into each dose, but it will also protect their workers and provide patients with equally effective, yet more palatable and cheaper drugs.
