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Pediatric Antibiotic Innovations
The document discusses the development of a novel peanut butter-based formulation of amoxicillin, designed for children who struggle with traditional antibiotic forms. This formulation, known as Nutmox, is stable, does not require refrigeration, and is lightweight, making it suitable for use in low-resource settings. The project includes stability testing, pharmacokinetic studies, and a plan for regulatory approval to ensure effective deployment in communities with high rates of childhood pneumonia.
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Pediatric Antibiotic Innovations
- 1. Sangwei Lu, Ph.D. Schoolof Public Health University of California Berkeley, California U. S. A. Email: sangwei@berkeley.edu Phone: (510) 643-4986 Website: http://sph.berkeley.edu/sangwei-lu Novel, Peanut Butter – Based Formulation of Amoxicillin - Toward a child–friendly formulation of amoxicillin that is stable, ready to use and nutritious
- 2. The Need fora Child –Friendly Formulation of Amoxicillin • Young children cannot swallow pills. • Needs clean water to reconstitute • Needs refrigeration once reconstituted • Heavy to transport once reconstituted Peanut butter – based formulation of amoxicillin (NutMox) • Child-friendly and nutritious • Ready to use and light weight; no refrigeration necessary • Can be combined with RUTF therapy based on updated WHO guidelines of management of severe acute malnutrition in children Sangwei Lu, PhD, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
- 3. Design of PeanutButter–Based Formulation of Amoxicillin packaged and distributed as a single course of antibiotic treatment Advantages • Easy to handle • Easy to track • Helps ensure completion of full course of treatment and prevent emergence of drug resistance Sangwei Lu, PhD, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
- 4. Project Plan • Formulatea suitable peanut butter base for amoxicillin • Test the long term stability of amoxicillin in the peanut butter base under various storage temperatures • Determine the pharmacokinetics of NutMox in an animal model • Test the efficacy of NutMox in a mouse pneumonia model. Preliminary Results • Amoxicillin is very stable in peanut butter base with various ratios of peanut butter, sugar, vegetable oil and dry milk. • Peanut butter base does not prevent amoxicillin from being released into mouse bloodstream. Sangwei Lu, PhD, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
- 5. • Prepare invitro data for FDA Investigational New Drug (IND) filing. • Clinical trial – bioequivalence study • FDA New Drug Application (NDA) filing • Partner with pharmaceutical companies, NGOs and non-profit organizations. Future Directions - Path to Clinical Use Community Input • Requirements and feasibility of NutMox in the field • Regulatory requirements of the countries NutMox is most likely to be used • Route of distribution • Connection with clinicians and organizations Sangwei Lu, PhD, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
- 6. UCL SCHOOL OFPHARMACY BRUNSWICK SQUARE Child Friendly Formulations of Amoxicillin: RAMOX Dr Catherine Tuleu, Reader of Pharmaceutics Dr Sara Hanning, Research Associate UCL School of Pharmacy, London, UK
- 7. UCL SCHOOL OFPHARMACY BRUNSWICK SQUARE Paediatric Pharmacy R & D Manipulation & Compounding – Reformulation/repurposing of API for (ultra) rare diseases – Palliative care Excipients tolerability and safety – STEP Database (www.eupfi.org) Appropriateness of dosage forms (including acceptability) – RAMOX – Multiparticulates – Flexible solid oral dosage forms Palatability of formulations – In vivo (human panels)/in vitro (BATA model) tools – HME for TM of FDC TB drugs – Cocrystals for TM for neglected infectious diseases Drug delivery/administration devices – Nipple shield 7
- 8. UCL SCHOOL OFPHARMACY BRUNSWICK SQUARE Child-friendly formulations of amoxicillin: Exploring the rectal route Jannin V, Lemagnen G, Gueroult P, Larrouture D, Tuleu C (2014). Advanced Drug Delivery Reviews 73(0):34-49. 8
- 9. UCL SCHOOL OFPHARMACY BRUNSWICK SQUARE Advantages Low manufacture cost Ease of administration (no need for trained carers) Avoidance of taste/swallowability concerns Challenges Ability to withstand high- temperature environments Offer immediate and predictable drug release in vivo The rectal route
- 10. UCL SCHOOL OFPHARMACY BRUNSWICK SQUARE Screen potential excipients for irritability Development, optimisation and characterisation of formulations Physical and chemical data essential to ensure quality, stability and an immediate drug release profile PPI …to bring forward to Phase II Clinical efficacy Paediatric Investigation Plan (PIP)/Paediatric Use Marketing Authorisation (PUMA) Educational material to promote and support rectal administration Phase I: Pharmaceutical development 10 Phase II: Translation of research
- 11. The Challenge Beta-lactam bondsin amoxicillin are hydrolyzed (broken down) by water causing reconstituted amoxicillin the degenerate within 2 weeks and faster if no cold chain (refrigeration) is present. DOM (dissolved organic matter) also contribute to 48-74% of amoxicillin loss if reconstituted with natural waters. Direct sunlight further contributes to the photochemical degradation especially in the presence of DOM. Problems encountered in low resource settings No refrigeration “Dirty” water – leading to contamination of the reconstituted antibiotic – also contains DOM High temperatures in some parts of the developing world – Africa, South East Asia etc Hypothesis If water hydrolyzes the Beta-lactam bonds it is acceptable to say oil will not. An oil based suspension will lead to a suspension that will stay chemically stable with therapeutic efficacy intact for periods of up to 2 years, without cold chain and at very high temperatures as experienced in many parts of the world.
- 12. Water: is a polarmolecule with a dipole moment can act as an acid or a base (Bronsted Lowry) has strong hydrogen bonds Amoxicillin: is predominantly a polar molecule (polar dissolves in polar) Oil : is a non-polar molecule Other issues with water in LMICs: Water is mostly contaminated and contains dissolved organic matter DOMs accelerate hydrolysis PH also plays a role – should be between 3 and 6 (approximate) Temperature – in water should be at between 4 and 8 Celsius At temperatures above 37 Celsius – hydrolysis is accelerated Direct sunight – accelerates photolysis Benefits of an oil based suspension: • Such a suspension will not require refrigeration, • will eliminate contamination risks • stay stable at very high temperatures of 40 to 50 degrees Celsius. • Added benefit of using oil is that oil provides plus minus 9 calories per gram, giving more energy to the child to fight the infection. • Individualized dosing units clearly marked for populations of LMICs
- 13. • Mix amoxicillinwith various non-volatile oils and triglycerides. • Add silicon dioxide as adsorbent and anti-caking agent • Any flavoring and colorant can be added Testing conditions as per generic protocol (WHO) and USP • Long term testing conditions for South Africa (Zone II) = 25°C/60%RH • Long Term Testing conditions for Zone IVB countries (hot and very humid conditions) + intermediate conditions for Zone II = 30°C/75%RH • Accelerated stability testing conditions = 40°C/75%RH • *%RH = Relative Humidity .
- 14. Stability Testing PhaseI Method and Metrics Desired Outcome Physical analysis: Description and Appearance; odour, colour, palatability, uniformity, dissolution Original physical properties are retained Chemical analysis: Ph, density, viscosity Original chemical properties are retained Re-suspendability Suspendability is retained Uniformity of dosing units: weight variation Chemical integrity and labelled potency are retained Chemical assay: Assay Amox Suitability of method must be proven Sterility No contamination Microbiological: resistance to microbiological growth and no contamination Amoxicillin retains its antimicrobial effectiveness Photostability: direct sunlight Determine suitability of amber/clear ampoules
- 15. Research Phase II Methodand Metrics Desired Outcome Therapeutic efficacy Remains unchanged Bioavailability Remains within specified limits Safety Safety remains within current limits Toxicological No increase in adverse events and side effects Our product will be safe with no added allergens and we expect no increase in side effects and adverse events. Conclusion Amoxicillin is an existing API - all testing should remain within current limitations. However, if we could include a comparative study our data will be more unbiased and we will be able to accelerate phase I and II drastically – especially if we could test both child formulations 125mg/5ml and 250mg/5ml. THANK YOU
- 16. A Thixotropic Systemfor Oral Delivery of Amoxicillin in Treating Pneumonia in Children Chenjie Xu Assistant Professor School of Chemical and Biomedical Engineering Nanyang Technological University Singapore 16
- 17. Challenges of AmoxicillinDelivery to Children (0-5 yrs) at High Burden Countries http://www.envita.com/ Amoxicillin 17
- 18. Criteria of anIdeal Formulation 1. Taste-masked 2. Easy to swallow 3. No need of clean water 4. Improved shelf life without the need of refrigeration 5. Low cost http://gcgh.grandchallenges.org/Explorations/Topics/Pages/ChildhoodPneumoniaTreatment_Round14.aspx 18
- 19. Birth of Idea Imagesare adapted from Waker silicone electronic business. Co. Ltd 19
- 20. Components of aThixotropic System 1. A coating that blocks the unappealing taste and odor of Amoxicillin; 2. A water-containing matrix that disperses, stabilizes, and delivers the drug. 20
- 21. Spray-drying Synthesis ofAmoxicillin Micro/nano-particles • Poly(meth)acrylates polymer (trade name: EUDRAGIT® E) seals taste and masks odor. • Soluble in solution (pH <5.0) Amoxicillin • Poorly water-soluble (0.004g/ml) • Insoluble in organic solvents like chloroform. • Its sodium salt is soluble in water (0.05g/ml) An acidic solution of Amoxicillin sodium and Eugragit E Harsha S. Drug design, development and therapy 2013, 7, 1027 Khachane,P et al, Journal of biomedical nanotechnology 2001, 7, 590 21
- 22. Encapsulation of AmoxicillinParticles in Sodium Carboxymethyl Cellulose Hydrogel High and medium-viscosity types of sodium carboxymethyl cellulose (SCC) solution exhibit thixotropic behavior and acts like liquid under the pressure. http://www.dow.com/; Lee, C.H., Moturi, V. & Lee, Y. Journal of Controlled Release 2009, 136, 88 + SCCAmoxicillin Particles Mechanical Stirring 22
Editor's Notes
- #7 Intro – rectal amoxicillin Outline – background into research group, outline of our project, plan of attack
- #8 Former CPPR (center for paediatric pharmacy research since 2002) – long established relationship with ICH and GOSH Formulation but also research capacity on PK PD PG + drug use and safety Formulation team = 4 post doc 1RA 5 PhD 2 Msc 2 visiting students (undergrad Mpahrm research students) Formulations for developing countries
- #9 State aim: To address the paucity of age appropriate amoxicillin formulations by developing an innovative, child-friendly rectal dosage form of amoxicillin Pneumonia is the leading cause of mortality in children < 5 First-line treatment: amoxicillin 250mg Child-friendly dosage forms unavailable in many countries Manipulation of adult dosage forms Compromised efficacy, adherence, medicine stability
- #11 Phase 1 -Screen potential excipients for irritability using slug assay -Development, optimisation and characterisation of formulations -Generation of essential physical and chemical data to ensure quality, stability and an immediate drug release profile to bring forward to Phase II
- #18 Amoxicillin is an antibiotic useful for the treatment of a number of bacterial infections. it is better-absorbed, following oral administration, than other β-lactam antibiotics. Amoxicillin is one of the most common antibiotics prescribed for children.
- #23 Amoxicillin particles will be embedded in a gel-like sodium carboxymethyl cellulose solution to protect and stabilize the formulation for long-term storage. Challenges: Recommended child oral dosage of amoxicillin for pneumococcus is ~50 mg/kg every 12 hours. For a 10-20kg child, 0.5-1g amoxicillin is to be delivered. As a child can usually swallow <5 ml solution at a time, the concentration of amoxicillin in the hydrogel would be ideally above 0.1g/ml.