“The biggest impediment in addressing bioavailability issues likely lies with a lack of deep familiarity with enabling technologies,” says Dr. Masumi Dave, Application Laboratory Manager, Pharmaceutical Division, Gattefossé USA. “Im­proving drug bioavailability begins with a thorough evaluation of the API’s physical and chemical properties in relation to solubilization in the dose, but more importantly its dissolution in vivo at the site of absorption.”

These technologies, such as nanoparticles, cocrystals, computer-aided prodrug design, and electrospinning, repre­sent innovations aimed at enhancing the solubility of a candidate molecule, particularly in the gastrointestinal tract. “Technologies such as electrospinning, deep eutectic solvents, and ionic liquids are upcoming formulation approaches to enhance drug solubility, and as the science matures, and the relative strengths and weaknesses are better understood, we expect to see further application of these innovative ap­proaches,” says Nathan Bennette, Di­rector, Scientific Advisory, Catalent. “They have shown to be successful for some compounds, and have a place alongside other bioavailability en­hancement technologies, where each strategy has its benefits and corre­sponding liabilities. For them to be successful and widely adopted how­ever, they will also have to provide a compelling benefit compared with other well-understood, and commer­cially precedented technologies, such as amorphous solid dispersions and lipid-based formulations.”

In fact, according to Dr. Jessica Mueller-Albers, Strategic Marketing Director Oral Drug Delivery Solutions, Evonik Health Care, extreme com­pounds require either significant amounts of stabilizers to maintain the amorphous state or they are not amenable to common manufacturing technologies with reasonable cost of goods due to their low solubility in or­ganic solvents. These include amor­phous solid dispersions using polymethacrylate, cellulose, or povi­done-based polymeric carriers, she says. In addition, thermostability of new molecular entities becomes an issue as most new molecules have melting points well above 400°F. Alter­native production methods for amor­phous solid dispersions can address these issues.

In this annual Drug Development & Delivery report, interviewees de­scribe how they are using technologies such as lipid nanoparticles to achieve a high drug loading, combining anti-solvent continuous crystallization with micro-mixing technology to control crystallization and reduce crystal size, and robotic capsules to improve bioavailability in the range of 47% to 78%.

Ascendia Pharmaceuticals, Inc.: A Tailored Approach to Nanotechnologies

It is very challenging to improve solubility and bioavailability of a BCS II or IV API with a high melting point and a low solubility in a broad range of solvents. A high melting point makes it unfeasible to use hot melt ex­trusion to prepare amorphous solid dispersion, whereas low solvent solu­bility makes it challenging to spray dry or solubilize the compound in carriers. In some cases, these types of com­pounds can be nanosized by nanomilling, micro-fluidization or for­mulated into nano-emulsion or nanoparticles with an aid of a cocktail solubilizer combinations.

“Nanosuspension prepared by a top-down process such as nanomilling or high-pressure homogenization, amorphous nanoparticles by a bot­tom-up process or a combination of bottom-up and top-down process, and lipid nanoparticles utilizing lipid carrier, have been routinely used in Ascendia’s labs, attaining good results in achieving formulation with high drug loading and good bioavailabil­ity,” says Jim Huang, PhD, Founder and CEO of Ascendia Pharmaceuti­cals, Inc. “A tailored approach based on compound properties will always increase the chance of success using available nanotechnologies.”

For example, a BCS II compound (a high melting point and poor solu­bility in a range of solvents) was pre­sented to Ascendia with a request to formulate and manufacture cGMP CTM for a Phase I study in a six-month window. Dr. Huang explains that Ascendia was able to formulate the compound with lipid nanoparticle technology for an oral route of admin­istration, utilizing a combination of lipid and solubilizer to achieve a syn­ergetic effect in solubilizing the com­pound. On the other hand, for an IV dosage form, by leveraging Ascen­dia’s in-house capability in aseptic nano-milling and microfluidization technologies, a sterile nanosuspension formulation was developed to achieve a high drug loading that enabled tox­icology and Phase I dose range stud­ies.

Catalent: The Root Cause of Bioavailability

Solubility-limited absorption remains a key challenge in terms of bioavailability for a large number of compounds looking to progress from the discovery phase towards the clinic. Increasingly, these molecules also exhibit high melting points and poor organic solubility, making these so-called “brick dust” compounds extremely difficult to process using conventional solubility-enhancing methods such as hot melt extrusion (HME) or spray drying. Alternative solubility-enhancing technologies, alongside innovations in the HME and spray drying processes, may be required to enable the development of such challenging solubility-limited compounds.

“Additionally, we are seeing a significant increase in the number of compounds that are beyond Lipinski’s rule of five (bRo5) where bioavailability is limited by permeability through the intestinal epithelium,” says Nathan Bennette, Director, Scientific Advisory, Catalent. There are presently very few options for formulating and delivering permeation-limited molecules, and the success of programs for drugs with these properties will depend upon the development of new tools and approaches for enabling their bioavailability.”

To successfully address a bioavailability issue, it is critical to first understand the pharmacokinetics of a molecule and evaluate whether bioavailability is limited by poor absorption, a physiological process (e.g., efflux or metabolism), or a combination of the two. If poor absorption is the root cause, it is important to distinguish between an inadequate dissolution rate, low aqueous solubility, and poor permeability, and each of these physiological and physicochemical conditions will require a different formulation approach. For example, where metabolism is the key issue, it is sometimes possible to design formulations that target pre-gastric absorption or enhance lymphatic absorption, both of which bypass first-pass metabolism by the liver. Particle size reduction and amorphous dispersions are well-precedented strategies for addressing slow dissolution or poor aqueous solubility, respectively.

“Early application of physiologically- based pharmacokinetic modeling can provide significant insight and guidance, so that formulation strategies can be focused on developing solutions to the actual challenges of bioavailability enhancement,” says Mr. Bennette.

CycloLab Ltd.: Electrospun Nanofiber Form vs. Lyopholized Remdesivir

Remdesivir, a monophosphorami­date prodrug, was discovered and de­veloped by Gilead Sciences, Inc. It has been introduced as a promising new antiviral agent for the therapy against SARS-CoV-2 in the form of an intra­venous product marketed under tradename Veklury®. Due to the poor aqueous solubility of remdesivir (0.028 mg/mL at room temperature), a need arose for solubility enhance­ment. CycloLab performed research to explore possibilities for electrostatic fiber drawing.

Dr. István Puskás, principal scien­tist with CycloLab, explains that this was attempted by employing different solubilizer excipients, such as surfac­tants, polymers, co-solvents and sulfobutylether-beta-cyclodextrin (SBECD). Twenty percent (w/w) aque­ous solutions of Tween-80 provided 3.9 mg/mL dissolved remdesivir, PEG-400, dissolved 3.3 mg/mL, while SBECD at this concentration resulted in 8.5 mg/mL dissolved remdesivir.

The application of surfactants and polymers – despite their solubility-en­hancing effect – was found inade­quate for solubilizing enough active ingredient for a preferred formulation; the only satisfactory solubility en­hancement was achieved by using SBECD. Currently, 13 FDA-approved injectable products are on the market that contain SBECD-solubilizing excip­ient and numerous clinical candidates are under development. Isolation of solid drug/SBECD complexes from common solution might be performed by various solvent removal techniques.To compare the performance of solid complexes prepared by two methods suitable for manufacturing injectable products, two types of formulations with identical composition were pre­pared and investigated by lyophiliza­tion and electrospinning, respectively. Common aqueous solutions of remdesivir and SBECD were prepared and filtered at room temperature. The resulting clear filtrates were processed by lyophilization and electrospinning into solid binary formulations. This study aimed at the comparison of wettability and dissolution properties of freeze-dried and electrospun nanofiber formulations of SBECD-en­abled remdesivir compared to a mere physical mixture of the constituent powders (non-complexed form).

The CycloLab image demon­strates the differences of wettability, dissolution rate, and water solubility of the physical mixture of remdesivir and SBECD compared with those of the two complex formulations (lyophilized and electrospun samples). Dr. Puskás says the physical mixture did not dis­solve completely, the partial dissolu­tion of the composite powder could be attributed to the hydrophilic SBECD matrix. After 10 minutes measured from the addition of water (WFI), the lyophilized sample spontaneously dis­solved. Full dissolution of the electro­spun nanofibers was observed notably faster. The dissolution was completed in 5 minutes after contact with the dis­solution medium. Significant differ­ences were found in wettability and dissolution rates of formulations with identical average composition, indi­cating that solid-phase engineering and complexation with SBECD do matter.

“In conclusion, reconstitution and dissolution properties of an electro­spun nanofiber form of remdesivir were found to outdo those of the lyophilized formulation having identi­cal composition,” he says. “These su­perior wetting and dissolution properties of electrospun nanofiber offer the possibility to develop non-invasive, quickly absorbable dosage forms of a drug. Further studies are in progress to prove the feasibility of electrospun nanofiber made from SBECD-enabled remdesivir as a non-invasive therapeutic option.”

Enteris BioPharma: A Game Changer Transforms Treatments

With an increased number of “be­yond rule of 5” (bRo5) compounds in clinical trials and some recent drug approvals by FDA in the oncology space, there is heightened interest among pharmaceutical companies to pursue drug development of these compounds. bRo5 compounds, such as peptides, peptidomimetics, and a growing number of intermediate-sized molecules, are traditionally consid­ered undruggable for oral delivery due to low aqueous solubility, or poor permeability, and other challenges. The use of an external enabling tech­nology for oral delivery of these com­pounds combined with a scalable manufacturing process can present a win-win situation for drug makers and patients by reducing time to drug launch, speeding up market entry, and improving patient compliance.

While most enabling technologies can improve solubility, the ability to develop oral tablet formulations that address both the permeation and sol­ubility challenges represents a game changer for drug makers to enhance multiple drug products and transform entire treatment paradigms. Enteris’ ProPerma® and Peptelligence® plat­forms tackles both issues of solubiliza­tion and permeation using solubilizing agents that are also permeation enhancers,explains Dr. Rajiv Khosla, CEO of Enteris BioPharma. The Pro- Perma approach utilizes an enteric coating surrounding a tablet core con­taining the API, along with the en­hancing excipients. By delivering the formulation directly to the highly ab­sorptive area of the small intestine, such permeation enhancers enable the transport across the epithelium via diffusion through the tight junctions, or by the transcellular route, crossing the cell membrane. The technology em­ploys granulated citric acid, which acts as a permeation enhancer that makes the tight junctions more porous and removes diffusion barriers. It also pro­tonates basic drugs, adding positive charge, which increases water solubil­ity. In addition, the formulation con­tains a surfactant, suitable for tablet manufacturing, to further increase sol­ubility and permeation.

“The Enteris platform improves oral bioavailability through a combi­nation of the pH-lowering and solubilizing effects of the formulation in a highly-scalable solid oral dosage form, without making modifications to the API,” he says.

The process for testing oral feasi­bility using the Enteris platform in­volves a transparent review of the physicochemical properties of the partner’s API to determine fit and compatibility with the technology, using a developability assessment. Given an appropriate fit and align­ment with the partner’s goals, Enteris will then provide a plan to develop customized formulations containing enterically-coated tablet prototypes with the API to demonstrate proof-of-concept of oral bioavailability enhancement in nonclinical pharmaco­kinetic studies and ultimately human clinical trials.

As an example, Enteris recently worked with a partner to improve the bioavailability of a bRo5 compound with poor solubility and permeability. This compound had a molecular weight greater than 600 Da, with mul­tiple H-bond acceptors, poor solubility at neutral pH, and poor permeation. Enteris’ proprietary oral solid dose for­mulation technology improved bioavailability of the API, showing pharmacokinetics similar to a lipid-based formulation but with the con­venience of a solid oral dosage form.“Enteris’ technology provides a unique approach to addressing both solubility and permeation in a tablet formulation,” says Dr. Khosla.

Evonik Health Care: Optimized Compound Outcomes

Over the past few years, Dr. Jes­sica Mueller-Albers, Strategic Market­ing Director Oral Drug Delivery Solutions, Evonik Health Care, has observed that one of the most com­mon customer challenges is creating a development strategy for preclinical toxicology and first-in-human studies for poorly soluble drugs. “Small mol­ecules are continuing to become more complex so that more sophisticated formulation strategies are required,” she says. “Usually, the major chal­lenges, however, revolve around lim­ited budget and limited amounts of API. At the same time, the number of accelerated approvals from the FDA with Fast Track and Breakthrough des­ignations on low solubility compounds is increasing. This is especially true for oncology programs that show prom­ising early-stage results and may have reduced clinical study requirements.”

Miniaturized screening tools have been developed to support the design of the best formulation. But it is not only the formulation that has a strong influence on the pharmacokinetic pro­file and later performance of the drug product, she notes. The choice of the process technology is also key and can change during the development program when transitioning from early to later stages. Therefore, a seamless transition from drug discov­ery to preclinical toxicology to clinics and commercial manufacturing is still a hurdle for many programs. “All for­mulation and process development activities must have a strong sense of scalability early on to ensure this seamless transition and realize right-first-time formulation,” she says.

Pharmaceutical companies are looking for partnerships during the early phase of development to gain access to the newest and most inno­vative solutions and technologies. These are not limited to solubility-in­creasing solutions, but also focus on optimized targeting and delivery out­comes for the compound. One exam­ple of these new technologies is EUDRATEC® Fasteric, a bilayer formu­lation technology for enteric protection followed by rapid release in the prox­imal region of the small intestine, the duodenum. Several drugs require the release in the duodenum to avoid ex­posure to P-glycoprotein transporter, which increases towards the distal re­gion of the intestine. EUDRATEC Fas­teric can rapidly release 90% of the drug within 30 minutes of arrival at a specific, pre-defined pH level between 3.0 and 5.5 to precisely match the re­lease profile requirements of APIs, which have a narrow absorption win­dow. The formulation technology is suitable for use with a range of oral dosage forms, including multiparticu­lates, tablets, and capsules.

Gattefossé USA: Lipid-Based Excipients in Your Toolbox

Every formulation technology has its unique set of advantages and shortcomings. Salt formation or pro­drug design approaches, for example, necessitate medicinal chemists to go back to the drawing board, starting anew. Nanoparticles offer some inter­esting advantages that may address some but not all the challenges pre­sented by any given API. Solid disper­sions have their own limitations in terms of drug stabilization and devel­opment time. Most importantly many of these techniques are appropriate for late-stage formulation optimiza­tion and are inadequate for early pre­clinical handling of the API.

“However, lipid-based formulation technologies, notably SEDDS/ SMEDDS for oral delivery or mi­croemulsions for dermal/transdermal delivery, can be used as early as pre­clinical phases and carried throughout the development process,” says Dr. Masumi Dave, Application Laboratory Manager, Pharmaceutical Division, Gattefossé USA. “The lipid approach can help solubilization, dissolution in vivo, and improve absorption, notably by mitigation of the food effect. Our extensive work confirms that lipid-based excipients should be in the for­mulation toolbox to be considered from early- to late-stage formulation with no hiccups in the process.”

For a customer project, Gattefossé worked on a BCS Class II API that was initially developed as an injectable formulation. However, due to compli­cations involving sterilization of the API, the customer wanted to target an oral solid dosage form. After solubility screening studies, Gelucire® 48/16, Labrasol® ALF, and Transcutol® HP were selected given their ability to sol­ubilize the active at desired dosage levels, explains Dr. Dave. Gelucire 48/16 and Labrasol ALF are polyoxyl­glycerides with a high hydrophilic lipophilic balance (HLB) value and are widely used as solubilizers and bioavailability enhancers. Transcutol HP is the highest purity grade of dieth­ylene glycol monoethyl ether used as a solubilizer and topical permeation enhancer.

The performance of the formula­tion was assessed by checking its dis­persibility in aqueous media and its ability to maintain the API in solubi­lized form in vitro lipolysis testing. “This test is a great predictive tool to aid in screening formulations to be se­lected for clinical study,” she explains. “The formulation(s) with the ability to maintain the active in solubilized form throughout the test is selected for fur­ther evaluation in animal models. In the end, we were able to recommend formulations to the customer that should be selected for evaluation in animal models.”

Lubrizol Life Science Health: Polymers for IP-Protection & Lifecycle Management

While there are excipients and techniques available to address bioavailability and solubility, they often have low efficiency and lead to com­plex manufacturing processes or un­desired side effects for patients, says Robert W. Lee, PhD, President of the CDMO Division of Lubrizol Life Sci­ence (LLS) Health. Additionally, a lack of patented excipient options makes it difficult to formulate viable 505(b)(2) products.

“IP-protected polymers and tech­nologies not only solve difficult techni­cal challenges, but they also incentivize companies to pursue re-formulation of existing APIs and bring new/improved options to patients,” he says. “There are many polymer chemistries being explored for solubil­ity enhancement, but only a limited number have advanced beyond lab-scale into GMP manufacturing. To be a truly viable commercial option, ex­cipients require investment in process scale-up as well as regulatory and quality oversight.”

LLS Health’s oral-grade Apinovex™ and injectable-grade Apisolex™ poly­mers were designed to overcome poor solubility using simple, scalable man­ufacturing techniques. Apinovex and Apisolex are excipient-grade polymers that offer IP-protection and lifecycle management for BCS Class II and IV APIs. Apinovex polymers are GMP-val­idated, high molecular weight poly­acrylic acid excipients designed to provide both processing and formula­tion benefits for spray-dried amor­phous solid dispersions (ASDs).  Apinovex polymers enable formula­tors to achieve stable, high drug load­ing (up to 80%), and up to 10 times improvement in drug release for crys­talline APIs. “With Apinovex, formula­tors can develop efficient, IP-protected oral solid dosage forms for a range of poorly soluble APIs,” says Dr. Lee.

The Apisolex polymer is an in­jectable-grade poly(amino acid)- based co-polymer that has been shown to increase the solubility of hy­drophobic APIs by up to 50,000 times where other commonly-use excipients fail, he says. “Robustly patented, safe, efficient, and scalable, Apisolex for­mulations can achieve drug loading up to 40%, dramatically increase the achievable concentration of API in water, and reconstitute in saline in less than 30 seconds.”

In addition to these polymers, LLS Health routinely uses a variety of nan­otechnology-based drug delivery tech­nologies, including polymeric nanoparticles, solid lipid nanoparti­cles, nanoemulsions, and nanopartic­ulate suspensions (i.e., nanocrystals). “We frequently evaluate nanocrystals produced using a high energy media milling process (i.e., nanomilling) for water-insoluble APIs,” explains Dr. Lee. “We believe that Lubrizol does more nanomilling than most other CDMOs and since most of our pro­grams are intended for parenteral ad­ministration, we would consider this to be a trend and a go-to technology for sterile products.”

When it comes to sterile products, most nanocrystal formulations are not amenable to terminal sterilization, so LLS Health offers aseptic nanomilling to its clients. Using its proprietary Ster­iMill™ Technology, Lubrizol can scale aseptic nanosuspensions up to and in­cluding commercial batches.

“Nanomilling is a scalable, proven technology and we can achieve concentrations up to 50% API,” Dr. Lee says. “This leads to a more efficient process requiring fewer unit operations to produce the final drug product. Nanomilling ultimately facilitates scale up and eventual com­mercialization for our clients.”

Micropore Technologies Inc.: Controlled Crystallization

One way to improve solubility is through the control of the crystalliza­tion process of APIs. During a recrys­tallization process, control over the size, size distribution, morphology, and crystallinity of the crystals can be difficult. API crystallization is directed by supersaturation and can result in size growth as the driving force, result­ing in the formation of larger crystals. The rate of crystallization throughout the entire system can also be uneven and uncontrolled. This leads to a wide distribution of crystals of various sizes and morphologies. Crystallization also favors the formation of API crys­tals that are in a more structurally or­dered crystalline state. Ordered crystalline API crystals (unlike amor­phous particles) tend to have poor sol­ubility, which can also lead to poor bioavailability during medical use.

Micropore has combined reverse anti-solvent continuous crystallization with its micro-mixing technology, giv­ing a highly (or exquisitely) controlled crystallization process and environ­ment. “Through understanding the solubility of an API, we have found its controlled introduction to an anti-sol­vent can dictate the size, size distribu­tion of the crystals, their morphology, and, critically for bioavailability, we could dial in the degree of crys­tallinity,” says Dr. Matthew Bennett, Crystallization Scientist, Micropore Technologies Inc. “We have worked with drugs of low solubility and bioavailability and have succeeded in obtaining small particle sizes in amor­phous states. This breakthrough work will result in increased API solubility and bioavailability.”

One leading biopharmaceutical company approached Micropore for methods that reduced the size of crys­tals for one of its major APIs. Dr. Ben­nett explains that initial work involved replicating the company’s crystalliza­tion methods using Micropore’s ad­vanced crossflow (AXF) technology. Further worked involved changing the overall formulation while also carrying out the crystallization through AXF technology. The results showed the crystal’s average size was reduced from 240μm to that of almost a tenth of the size at 26μm along with a smaller size distribution.

Quotient Sciences: Integrated Development Strategies Overcome Solubility Challenges

There is no one-size-fits-all solu­tion for improving bioavailability and solubility, and what is correct for one molecule could be over-engineering, or worse, limiting the potential of an­other drug. It is therefore crucial for development teams to understand the drivers of a given molecule’s solubility and its permeability properties to se­lect the correct technologies for as­sessment, and then back up that selection with data. “One of the biggest challenges we see is the expectation of an in vitro/in vivo cor­relation in developing these technolo­gies, which is not realized when clinical data is obtained,” says John McDermott, Executive Drug Develop­ment Consultant, Quotient Sciences. “Having access to human data to as­sess formulation technologies for poorly soluble drugs is therefore cru­cial in guiding formulation selection and optimization.”

Quotient has had the opportunity to work on several programs that have assessed the clinical performance of some of these novel and emerging technologies to enhance drug bioavailability. “We have seen some great successes for some drugs, and we have also had experiences where performance observed in preclinical and in vitro studies have not translated into humans,” he says.

Quotient Sciences delivers fully in­tegrated programs incorporating for­mulation development with clinical manufacturing, regulatory support, and clinical testing. This platform, termed Translational Pharmaceutics™, can be applied to accelerate the pro­gression of prototype formulations to clinical assessment and onward, to ef­ficiently and accurately assess candi­date formulations, and to improve the likelihood of clinical and commercial success, explains Mr. McDermott.

In one recent case study, a cus­tomer with a BCS II molecule had completed its first-in-human study, which demonstrated inadequate ex­posure and a significant food effect. These issues were stalling the project from advancing into proof-of-concept patient studies. To respond to this, the client needed to rapidly evaluate sol­ubility enhancement technologies and demonstrate its utility to enable effi­cacy assessments in order to proceed to the next project milestone.

In this program, Quotient Sci­ences developed three different solu­bility-enhancing formulations: a micronized form of API; a self-emulsi­fied lipid delivery system; and a spray-dried dispersion. A Translational Pharmaceutics study was performed to achieve a quick proof-of-concept as­sessment, removing the need to con­duct larger scale, cost-prohibitive process development and lengthy sta­bility programs for multiple technolo­gies. The human pharmacokinetic (PK) study used a 5 period cross-over de­sign in 16 healthy volunteers with the micronized formulation delivering the best outcome.

“By applying our Translational Pharmaceutics approach, the overall timeline – from initiating formulation lab work to having clinical PK data to select the optimal formulation – was just six months,” says Mr. McDermott. “While it’s exciting to be involved at the forefront of research in drug deliv­ery technologies, it’s important to re­main focused on the patient – and the best model for assessing humans is a human.”

Pii: Creating Amorphous Material for Improved Bioavailability

The majority of new APIs are still poorly soluble in aqueous media and fall either under the BCS Class II or IV category. A drug molecule needs to be in a solution state to get across the in­testinal membrane at enough concen­tration and rate to elicit the desired pharmacological effect. Hence, solu­bilization and permeability are pre­requisites for good bioavailability. For a very poorly soluble drug with a lim­ited option of formation of salts, co-crystals or prodrug, finding GRAS solvent/excipient combination that can solubilize the drug at sufficient con­centration and prevent precipitation in the G.I. tract is a major hurdle to im­proving bioavailability, says Sundeep Sethia, PhD, Senior Director, Pharma­ceutical R&D at Pharmaceutics Inter­national, Inc. (Pii).

Dr. Sethia describes how Pii helped improve bioavailability of a poorly soluble drug, in combination with solubilizer/excipients. This drug showed an incomplete and very slow release profile. The product needed to be developed as a tablet dosage form. As a result, the combination of drug and excipients were dissolved in a solvent and spray dried to provide amorphous material. Soluble drug material was hygroscopic and static with poor flow. The material was roller compacted with a binder and glidant to achieve compacted material milled to get acceptable flow properties. The milled material was then final blended with lubricant and compressed in the tablet dosage form. Precaution was taken to ensure humidity controls dur­ing processing, and desiccants were used for storage of finished product. “The amorphous API in the tablets showed faster and complete release that yielded desired PK profile and much improved bioavailability com­pared to the micronized API tablets,” said Dr. Sethia.

Rani Therapeutics: Robotic Capsules Enhance Injectables Bioavailability

The vast majority of biologic drugs have to be delivered through an injection or infusion. The main imped­iment to oral delivery of biologics has been the catabolic nature of enzymes in the gut, which are extremely effi­cient at digesting biological matter and absorbing it as nutrients. Biolog­ics are also much larger in size and weight than small-molecule drugs, making permeation across the gut ep­ithelium a challenge. Thus, when taken orally, most biologics have ex­tremely poor absorption and low bioavailability.

Many attempts have been made to deliver biologics orally, most of which have taken a chemistry-based approach involving permeation en­hancers, protease inhibitors, or en­teric-coated capsules, explains Talat Imran, CEO of Rani Therapeutics. These mechanisms are used to encap­sulate or shield biologic drugs from the digestive action of gut enzymes and increase systemic uptake. How­ever, even the successful attempts have shown bioavailability no greater than ~1%, he says. Robotic pills are another approach, which may com­bine several features for targeted de­livery to the gut.

One example of a robotic pill having a successful outcome is in the case of octreotide, a synthetic hor­mone for the symptomatic treatment of acromegaly and carcinoid syn­drome. Acromegaly in particular im­pacts 25,000 patients in the US each year, who require ongoing treatment for chronic symptoms. However, cur­rent treatment using octreotide in­volves painful subcutaneous injections administered three to four times daily or an extended-release formulation via painful, deep intramuscular injec­tions every four weeks, and as many as 13% of patients cannot adhere to long-term therapy.

The majority of previous attempts to develop oral versions of biologics like octreotide were chemistry-based, and the best attempts have resulted in low bioavailability of certain peptides up to 1%. “Instead, we developed a robotic pill to deliver octreotide directly to the jejunum,” says Mr. Imran. The capsule has a protective enteric coat­ing designed to withstand stomach acid and only dissolve in the small in­testine. Once dissolved, intestinal flu­ids activate a self-inflating balloon, which deploys a microneedle contain­ing octreotide to deliver the biologic into the highly vascularized wall of the small intestine, where it easily enters the bloodstream. “Bioavailability for our robotic capsule has been in the range of 47% to 78%.”

In a Phase I clinical trial of 62 healthy patients, bioavailability of oc­treotide delivered by oral robotic capsule was 65% relative to the IV group, confirmed in one or more hourly blood samples.

Seqens: A Toolbox of Strategies

Fine-tuning the molecular design of APIs is required to enhance binding selectivity for a biological target. It is now common to observe new drugs weighting more than 800 Da, with multiple stereocenters. Among other consequences, the drug solubility or permeability is often reduced, result­ing in absorption issues, first pass me­tabolism, and elimination by the kidneys.

“Within the BCS classification, more than two-thirds of APIs present a bioavailability challenge –10% to 20% of them being classified as Class IV – suffering from both low solubility and permeability,” says Frédéric Schab, PhD, Drug Delivery Solutions Managing Director, Seqens. “Several strategies can be deployed to improve bioavailability, leveraging a wide range of scientific competencies.”

Reducing the particle size of APIs is one method to increase the surface area and improve the dissolution ki­netics. Physical post-treatments, like milling or micronization, are com­monly used tools, but more advanced technologies, such as cryomilling and nanomilling are deployed to treat more reluctant APIs, he says. One way to monitor the particle size is to control the granulometry during the crystal formation step. For instance, continu­ous crystallization (through plug flow tubular systems or continuous stirred-tank reactors) requires high process engineering know-how and can help to reach fine and tight particle size dis­tribution, avoiding an extra production step.

A second approach consists of altering the API’s solid state form to improve the physico-chemical proper­ties. “Pharmaceutical crystal engineer­ing, with high-class analytical and screening tools, allows us to investi­gate alternative salt forms with various counter-ions, perform polymorph screening (metastable form, hydrates), or develop co-crystals to enhance the absorption performances,” explains Dr. Schab.

A third strategy consists of formu­lating drug with carefully selected ex­cipients, such as polymers and lipids. These ingredients offer a level of cus­tomization potential, and open up enormous application potential, not limited to improving solubility. “Lipids recently marked a milestone in the medical field,” he says. “Due to their high biocompatibility and low im­munogenicity, lipids are the most commonly used non-viral vectors for nu­cleic acid delivery required for gene therapy and DNA/mRNA vaccines.”

Bioresorbable polymers, such as PLA/PLGA or polycaprolactone, are used in controlled-release drug for­mulations for their ability to protect APIs from degradation, reduce the number of intakes, and liberate the drug over a long period of time. Other hydrosoluble polymers (polyethyl­eneglycol, polyethyleneimine, polyox­azoline, copolymers) are widely studied to encapsulate APIs or design API-polymer conjugate prodrugs.

“Remarkably, hybrid polymers and lipids excipients also constitute major research tracks for the develop­ment of new improved delivery sys­tems,” says Dr. Schab.

Serán BioScience, LLC: Turning Technologies into Dosage Forms

Advances in human biology con­tinues to identify novel druggable tar­gets. These new targets create fundamental challenges for medicinal chemists. Many of these targets re­quire novel drug properties, such as hydrophobicity in order to achieve suf­ficient binding efficiency and to avoid off-target interactions. Many of these new molecules are insoluble in water and have limited permeability in the small intestine. These new molecules can therefore exhibit very low bioavailability in both preclinical species and humans. This is a daunt­ing problem to overcome for drug de­velopment.

New technologies enable suffi­cient bioavailability of these com­pounds; many of these technologies have been demonstrated at commer­cial scale. Examples include spray dried dispersions, nanomilling, and melt extrusion. Other approaches, such as salt forms and co-crystals are also applicable in many cases. With appropriate know-how and expertise, these technologies can be developed into various dosage forms, such as suspensions, capsules, and tablets.

Serán BioScience, LLC is a sci­ence-based CDMO that specializes in a variety of drug delivery and formu­lation approaches suited to optimizing bioavailability. Serán’s approach be­gins with a comprehensive review of the molecular properties of the drug and the client’s development goals to identify the preferred technical and development approach that can dra­matically reduce time to the clinic and launch. Often, the development path begins with preclinical studies that re­quire very high drug exposure (often 10-100 times greater than desired clinical exposure), explains Dan Smithey, PhD, CEO, Serán BioScience, LLC. This is a common challenge that requires engineered formulations to achieve consistent results in dose-es­calation and toxicology studies. These formulations (suspensions) ideally consist of particles specifically engi­neered for these studies. Amorphous particles in suspension can provide ex­posure at high doses, but stabilizing these suspensions is critical to main­taining exposure. “Serán has unique approaches that enable stable sus­pensions of amorphous particles,” he says.

Serán has developed a multitude of spray dryers that are capable of manufacturing formulations that en­hance bioavailability across a wide range of scales, from 100mg to 100kg. “All of our spray dryers have the ability to produce engineered par­ticles using virtually any type of nozzle system, including pressure nozzles, 2-fluid nozzles, and ultra-sonic nozzles,” says Dr. Smithey. “This capability pro­vides ultimate flexibility in formulation design to optimize exposure and downstream processability.”

In addition to particle engineer­ing, the development of a solid dosage form is key to successfully im­proving bioavailability. Due to the unique nature of engineered particles that are developed to enable bioavail­able formulations, solid dosage forms also need to be engineered to ensure the physical properties, performance, and stability of these particles is ac­ceptable. Typically, dry granulation using roller compaction is required to achieve acceptable dissolution. Gran­ulations can then be used to produce a final dosage form, such as a capsule or a tablet. Dr. Smithey says: “Serán’s approach to development of solid dosage forms enables the manufac­ture of clinical trial materials at virtu­ally any scale, from first-in-human clinical studies through commercial manufacturing.”