The oral drug market continues to experience consistent growth. By the time the calendar flips to 2030, the market is predicted to be nearly $170 billion.1 Ease of administration, patient preference, and widespread use across various therapeutic areas are main reasons oral drugs have become a preferred dosage form, both in solid and liquid form.
Despite growing usage, oral drugs still present a series of challenges, from pre-formulation through commercialization. In this blog, we discuss different oral drug forms and associated challenges, as well as how Ascendia Pharmaceutical Solutions addresses them.
Solid oral dosage forms (SODFs) account for 80+% of marketed drugs that can be achieved by several methods. Wet granulation remains one method but it requires longer drying and processing times compared to dry granulation, roller compaction, and direct compression (DC). The latter options are preferred because of their smaller footprints and simplicity, yielding greater physico-chemical stability and manufacturing efficiency.
DC requires blending, mixing, and compression of the ingredients into tablets without going through wet granulation, as its associated with milling, drying, screening, and diluting with other ingredients before tableting (figure 1). DC of co-processed excipient mixtures is
Spray drying is a unique process for manufacturing composite particles of two or more ingredients with poorly soluble active pharmaceutical ingredients (APIs) dissolved in common organic and/or aqueous solvents. Spray drying excipients without a drug is also used to improve performance, as well as for enhancing tableting and the performance of solid oral dosages (SODs).
Ascendia Pharmaceutical Solutions Advantage: Our scientific team has expertise and access to cGMP manufacturing capabilities with ISO cleanrooms in our U.S.-based facility. It allows us to lead the way in expediting the formulation development of innovative molecules to the clinic faster. Our proprietary enabling technologies, AmorSol®, NanoSol®, EmulSol®, and LipidSol™, address the challenges of poorly soluble drugs in oral and parenteral formulations.
Low solubility, poor permeability, enzymatic degradation in the stomach and gastrointestinal (GI) tract, and the hepatic first-pass metabolism can lead to low bioavailability of oral drugs. The first-pass metabolism remains one critical impediment for enhancing drug absorption and bioavailability.
Lipid nanoparticles (LNPs) improve drug stability by encapsulating into interior aqueous and hydrophobic bilayers. Composed of a different class of lipids, short- and long-chain phospholipids, liposomes or different lipid assemblies protect drugs from harsh conditions in the GI tract and minimize the degradation by enzymes. So, drugs incorporated in lipids are stable and show higher concentrations in lymph and plasma, compared to a solution state. This indicates that lymphatic transport plays an important role in increasing the oral bioavailability of this drug.
Ascendia Pharmaceutical Solutions Advantage: LipidSol enables the encapsulation of LNPs by utilization of fatty acids and polar headgroup entities commercially available and listed in the FDA inactive ingredient database (FDA IID) or accessible to a novel lipid library. To better deliver the payload into the target cell, we source ionizable lipids from commercially available Generally Recognized As Safe (GRAS) material or from a proprietary lipid library for LNP formulations. Plus, we have state-of-the-art research, scale-up, and cGMP sterile manufacturing capabilities for LNPs that other CDMOs don’t.
Food-drug interaction plays an important role in determining drug efficacy and bioavailability. Most compounds prone to food effects belong to BCS class II and/or Class IV, especially the positive food effect. Only a few have shown the negative food effect.
Food intake can impact drug transport and may divert the transport via lymphatic or portal vein or could be preferential favoring one over other. There are no obvious reasons to believe which route will be preferred and the impact. There are pharmacokinetic models to evaluate the food effect on bioavailability of drugs. Lower absorption and bioavailability are markers for hepatic first metabolism.
Ascendia Pharmaceutical Solutions Advantage: LipidSol, EmulSol, NanoSol, and AmorSol offer formulation choices to design better oral liquid and solid dosages to mitigate the food effect and improve the oral bioavailability. Our team finds the appropriate class of lipids and surfactants, and oils to achieve the desired outcomes. This is essential and required for new chemical entities (NCEs) with solubility challenges and to improve bioavailability by directing them to lymphatic pathways.
Self-emulsifying/nanoemulsiying drug delivery systems (SEDDS/SNEDDS) have drawn attention lately because of their simplicity in scale up and manufacturing, cost effectiveness, and abilities to overcome the absorption via GI mucus barrier. This enabling technology represents an opportunity for treatment of life-threatening diseases because of lower cost, convenience, and wide acceptance.
SEDSS/SNEDDS are a homogenized pre-concentrate isotropic cocktail mixture composed of drug solubilized and encapsulated in oils, surfactants, and cosurfactant assemblies. They are alternatives to solid oral tablets for immediate release of drugs. Once dispersed in GI fluids, the preconcentrate simultaneously rapidly self-emulsified with aid of high concentration of solubilizers/surfactants to smaller particles or oil droplets ranging from 10-500 nm o/w emulsions, as shown in the figure below.
As more NCEs are discovered with fewer options to find the appropriate excipients and solubilizers for Class II and IV drugs, drug development teams are evaluating liquid SEDDS for expediting drugs to market. With the understanding of easier to scale up and manufacture than oral solid tablets and capsules, liquid capsules containing SEDDS have gained more traction for early development of NCEs. SEDDS is applicable to molecules across all modalities and therapeutic areas, especially those requiring stable formulations and targeted delivery.
SEDDS encapsulating peptides and proteins, and for biologics for unmet medical needs, can minimize enzymatic degradation and improve permeability across intestinal membrane. Supersaturable SEDDS (Su-SEDDS) are created by incorporating hydrophilic polymers/ solubilizers, such as poloxamers, may help precipitate drugs, allowing a drug to maintain its supersaturated state upon dilution in GI fluids. It is applicable to those drugs having a narrow therapeutic window.
Ascendia Pharmaceutical Solutions Advantage: Designed by selection of appropriate lipids, solubilizers, and surfactants, EmulSol-based solutions enhance solubility and bioavailability of molecules and biologics across all modalities. Our GMP manufacturing capabilities with state-of-the-art liquid capsule filling and banding equipment for formulation development and scale up offer choices to advance new therapy modalities from preclinical to the clinic studies quickly.
Faster absorption in the mucous civility makes orally dispersive tablets (ODTs) better for children, geriatric patients, and those who suffer from ailments like dysphagia. ODTs offer clinical safety advantages and improved efficacy for a broad range of therapeutic indications.
A typical ODT solid dosage form is aimed at improving the disintegrating and dissolution rate of a drug in a short time (30 seconds or less), leading to faster absorption and onset compared to conventional swallowed pills. ODT ingredients should meet certain criteria like hydrophilic in nature and quickly dissolves and possesses good mouthfeel and taste-masking effect.
ODT offers several advantages, including patient compliance, faster dissolution in saliva, rapid onset, greater stability, accurate dosing, easy manufacturing, small packaging size, and easy transportation.
Certain processing methods are used to prepare ODT dosages, including spray drying, extrusion, lyophilization, and molding. These technologies require expensive equipment compared to the standard direct compression manufacturing process, and often require special blister packaging to protect the drug from moisture to maintain the integrity of ODTs.
Ascendia Pharmaceutical Solutions Advantage: Our expertise in cGMP manufacturing helps clients developing ODTs. Our four enabling platform technologies can handle the challenging molecules across all modalities in oral tablets and liquids. Developing an ODT complements our expertise in SODFs.
As noted, solubility, permeability, and bioavailability create challenges when developing poorly soluble molecules for oral delivery, specifically large molecules like peptides and proteins. This is due, in part, to a lack of excipients and technologies to overcoming barriers stemming from appropriate stability and desired efficacy of drug molecules.
With few exceptions, many peptides and proteins are unstable in gastric and intestinal pH, and possess low permeability and absorption. Therefore, they are commonly administered parenterally. Due to their inherent limited permeability and solubility, the industry continues to evaluate innovative technologies as well as align with the desired pharmacological outcomes via oral delivery by modifying the structural changes. Permeation enhancers may play a crucial role to help facilitate the transport through gastric or intestinal epithelium membrane, leading to absorption via paracellular and/or transcellular routes.
Nanoparticles (NPs) comprised of surfactants, medium chain fatty acids and triglycerides, and bile salts can temporarily affect the membrane integrity through their lipophilicities, leading to increased permeability. Taken together, it is obvious that a drug’s permeability and absorption through nanoparticles composed of lipids and/or surfactants via epithelial membrane will help improve the oral bioavailability of peptide and protein drugs (PPDs).
Ascendia Pharmaceutical Solutions Advantage: Our enabling platform technologies are used for innovative large molecules in oral delivery of peptides and proteins. With its state-of-the-art cGMP manufacturing capabilities, we design and manufacture drugs for oral delivery of PPDs.
Contact our business development team today to discuss our how we can be your Partner of Choice for your drug development project across all modalities regardless of dosage form.