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Sangwei Lu, Ph.D.School of Public HealthUniversity of CaliforniaBerkeley, CaliforniaU. S. A. Email: [email protected]: (510) 643-4986Website: 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
The Need for a 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, [email protected] Novel, Peanut Butter – Based Formulation of Amoxicillin
Design of Peanut Butter–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, [email protected] Novel, Peanut Butter – Based Formulation of Amoxicillin
Project Plan• Formulate a 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, [email protected] Novel, Peanut Butter – Based Formulation of Amoxicillin
• Prepare in vitro 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, [email protected] Novel, Peanut Butter – Based Formulation of Amoxicillin
UCL SCHOOL OF PHARMACY
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
UCL SCHOOL OF PHARMACY
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
UCL SCHOOL OF PHARMACY
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.
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UCL SCHOOL OF PHARMACY
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
UCL SCHOOL OF PHARMACY
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
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Phase II: Translation of research
The ChallengeBeta-lactam bonds in 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 settingsNo 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
HypothesisIf 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.
Water:is a polar molecule with a dipole momentcan 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 matterDOMs accelerate hydrolysisPH also plays a role – should be between 3 and 6 (approximate)Temperature – in water should be at between 4 and 8 CelsiusAt temperatures above 37 Celsius – hydrolysis is acceleratedDirect 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
• Mix amoxicillin with 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
.
Stability Testing Phase IMethod 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
Research Phase II
Method and 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.
ConclusionAmoxicillin 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
A Thixotropic System for Oral Delivery of Amoxicillin in Treating
Pneumonia in Children Chenjie Xu
Assistant Professor
School of Chemical and Biomedical Engineering
Nanyang Technological University
Singapore
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Challenges of Amoxicillin Delivery to Children (0-5 yrs) at High Burden Countries
http://www.envita.com/
Amoxicillin
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Criteria of an Ideal 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
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Components of a Thixotropic 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.
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Spray-drying Synthesis of Amoxicillin 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
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Encapsulation of Amoxicillin Particles 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
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