SBIR-STTR Award

Pediatric drug development presents many unique challenges in the effective treatment of diseases in children, from adequate dosing information and pediatric-specific testing to palatable flavor profiles and effective delivery formats. A novel technology that masks bitter drug flavors while providing flexibility in dose design and format would enable formulation of existing adult pharmaceutical products into medications specially designed for pediatric patients. Our proposed strategy uses Precision Particle Fabrication (PPF) to develop pediatric drug-loaded microparticles that mask bitter flavors and allow for flexible dosing and formats. The central advantage of PPF technology lies in its precise control of particle size, shape, material, and release rates. Our long-term goal is to adapt this flexible, user-friendly, inexpensive technology to create a platform for microencapsulating unpalatable pediatric active pharmaceutical ingredients (API's). We hypothesize that the uniform, precisely engineered microparticles produced by PPF will create effectively taste- masked formulations for pediatric drugs while also allowing for the swift and controlled release of the active agents under digestive conditions. We further hypothesize that this robust microparticle strategy will allow for accurate, flexible dosing and adaptation to multiple drug delivery formats. Our research team will develop and characterize model bitter API-containing microparticles with precisely controlled physicochemical features that are designed to meet palatability standards (Aim 1). We will then optimize the release characteristics and taste-masking performance of these model microparticles (Aim 2). The result will be model drug-loaded microparticles that meet palatability standards based on particle size, homogeneity, and drug surface concentration and that can be tailored for desired release profiles under digestive conditions. After establishing the feasibility of precisely engineering these microparticles, Phase II will focus on the clinical evaluation of organoleptic properties of taste and mouth feel as well as demonstration of dosing accuracy, titration, and format flexibility. This PPF-based encapsulation strategy addresses issues of palatability, dosage accuracy, and format flexibility in pediatric drugs, while improving upon existing encapsulation techniques that are costly and time-consuming and produce poorly controlled, heterogeneous batches of microparticles. In adition, this PF technology is highly adaptable to multiple drugs and matrix/coating materials as well as large-scale production. The result will be an inexpensive, highly flexible pediatric platform for creating palatable, age-appropriate, and accurate dosage forms, leading to safer pediatric formulations and improved patient compliance.

Public Health Relevance:
Inadequate pediatric pharmaceutical formulations impair effective treatment of diseases in children due to poor compliance, ad hoc formulations, and dangerous medication errors. At the foundation of the problem are palatability, accurate dosing, and age-appropriate dosage format challenges. Development of a user-friendly, inexpensive development platform for pediatric reformulation of existing adult drug products to administer taste-masked active pharmaceutical ingredients (APIs) with controlled release rates is needed. Using model bitter APIs, this project aims to test the feasibility of Precision Particle Fabricatio technology to produce palatable, age-appropriate, and accurate doses as a means to safer pediatric medications and better compliance.

Public Health Relevance Statement:
Inadequate pediatric pharmaceutical formulations impair effective treatment of diseases in children due to poor compliance, ad hoc formulations, and dangerous medication errors. At the foundation of the problem are palatability, accurate dosing, and age-appropriate dosage format challenges. Development of a user-friendly, inexpensive development platform for pediatric reformulation of existing adult drug products to administer taste-masked active pharmaceutical ingredients (APIs) with controlled release rates is needed. Using model bitter APIs, this project aims to test the feasibility of Precision Particle Fabricatio technology to produce palatable, age-appropriate, and accurate doses as a means to safer pediatric medications and better compliance.

NIH Spending Category:
Bioengineering; Dental/Oral and Craniofacial Disease; Neurosciences; Patient Safety; Pediatric

Project Terms:
Address; Adult; Age; base; Biocompatible Coated Materials; Biological Assay; Caliber; capsule (pharmacologic); Chairperson; Characteristics; Child; Childhood; Cities; Clinical; Compliance behavior; controlled release; design; Development; Disease; dosage; Dosage Forms; Dose; Drug Delivery Systems; drug development; Drug Formulations; Drug Industry; effective therapy; Encapsulated; Engineering; Ensure; Evaluation; experience; Feasibility Studies; Flavoring; flexibility; Foundations; Goals; Hospitals; improved; Incentives; Industry; Kansas; large scale production; Masks; Medical Research; Medication Errors; meetings; Missouri; Modeling; new technology; Oral cavity; particle; Particle Size; Patients; pediatric pharmacology; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physician Executives; Positioning Attribute; Principal Investigator; Production; Property; Proteins; Provider; Research; research clinical testing; segregation; Shapes; Solutions; success; Surface; Tablets; Taste Perception; Techniques; Technology; technology development; Testing; Thick; Time; Titrations; Universities; user-friendly; Work

New dosage forms are needed to address the shortcomings of current practice with regard to administration of medications to pediatric populations. Specifically, in the absence of pediatric-specific products - formulations that are both palatable (to ensure compliance) and titratable (to meet the weight/surface area- appropriate dosage) - providers either utilize adult-approved liquid formulations or manipulate available products to create extemporaneous formulations (e.g., by crushing a tablet). Liquid suspensions, while titratable and largely preferred by children over tablets and capsules, are often poorly palatable and thus suffer from poor compliance. Ad-hoc formulations can also alter the performance and risk the likelihood of under or over-dosing. Orbis Biosciences's has developed a free-flowing drug-loaded microcapsule-based powder that will taste-mask bitter pharmaceutical actives during ingestion and exhibit complete dosage form dissolution in the gastrointestinal tract. This microcapsule platform is made possible by utilizing Precision Particle Fabrication (PPF) to place a pH-responsive shell over a solid-dispersed core of poorly water-soluble drug in a water-free, single step process. The first product to use Orbis's microcapsule approach to taste masking will be ORB-101, a prednisone-loaded microcapsule formulation. Upon successful FDA approval, ORB-101 will compete with oral liquid formulations or prednisone and prednisolone, products that suffer from poor palatability. Under the Phase I SBIR work, Orbis successfully developed two formulations, ORB-101 and ORB-102, containing prednisone and ritonavir, respectively. The microcapsule powders were able to: (1) reduce the presence of prednisone and ritonavir in neutral dissolution medium at 2 minutes by 55 and 92% respectively, compared to the RLD syrups for these two drugs, and (2) still exhibit 100% dissolution by 30 minutes when placed in acidic medium. The objective of this Phase II proposal is to optimize the prednisone formulation (ORB-101) into a shelf-stable powder in vitro (Aim 1), verify it's superior palatability compared to the RLD in a human taste screening (Aim 2), and demonstrate its bioequivalence to the RLD in a human pharmacokinetic study (Aim 3). The completion of this Phase II SBIR program will facilitate the efficient and timely submission of an IND filing to the FDA (Phase III SBIR) and have an immediate and lasting impact on the best practices for treating prednisone-responsive pediatric disorders by: (1) establishing the improved palatability or ORB-101 in the first human trials while, (2) readying ORB-101 and the PPF platform on which it is based for a co- development agreement or venture capital funding.

Public Health Relevance Statement:


Public Health Relevance:
Inadequate pediatric pharmaceutical formulations impair effective treatment of diseases in children due to poor compliance, extemporaneous formulations, and dangerous medication errors. At the foundation of the problem are palatability, accurate dosing, and age-appropriate dosage format challenges. Development of a user-friendly, inexpensive development platform for pediatric reformulation of existing adult drug products to administer taste-masked active pharmaceutical ingredients (APIs) with controlled release rates is needed. Using prednisone as a model foul-tasting API, this project aims to develop pediatric-specific formulations using Precision Particle Fabrication technology that are palatable, age-appropriate, and allow for accurate dosing as a means to safer pediatric medications and better compliance.

Project Terms:
Acids; Address; Adolescent; Adult; Age; Agreement; Appearance; Architecture; Area; base; Biological Availability; Caliber; Capital Financing; capsule (pharmacologic); Child; Childhood; Compliance behavior; controlled release; cost effective; Crossover Design; design; Development; Disease; dosage; Dosage Forms; Dose; Drug Formulations; Drug Kinetics; effective therapy; Engineering; Ensure; Evaluation; Exhibits; Female; Flavoring; flexibility; Foundations; Gastrointestinal tract structure; Genetic Crossing Over; Goals; Health; hedonic; Hospitals; Human; improved; In Vitro; in vivo; Ingestion; innovation; liquid formulation; Liquid substance; male; Masks; Medication Errors; Medicine; meetings; Microcapsules drug delivery system; Modeling; neonate; Oral; Oral cavity; particle; Particle Size; Pediatric Hospitals; Performance; Pharmaceutical Preparations; Pharmacists; Pharmacologic Substance; Phase; Placebos; Population; Powder dose form; prednisolone; Prednisone; Process; programs; Property; Provider; Randomized; Relative (related person); Risk; Ritonavir; Sampling; screening; seal; Shapes; Simulate; Small Business Innovation Research Grant; Smell Perception; Solid; Solutions; Stomach; success; Surface; Suspension substance; Suspensions; Tablets; Taste Perception; Techniques; Technology; Therapeutic Equivalency; Time; user-friendly; Water; Weight; Work