What if it was much easier to distribute, store and give antibiotics to sick children? In low resource settings where pediatric formulations of antibiotics are rare, this could mean the difference between life and death? Learn more about four promising innovations including: peanut-butter infused amoxicillin that is easy to swallow, tastes good and also treats malnutrition (from Sangwei Lu at U Cal Berkeley); an amoxicillin suppository (from Catherine Tuleu and Sara Hanning at UC London); oil-based amoxicillin (from Connie Louw at Gateway Health Institute); and amoxicillin that you squeeze out of a tube like toothpaste (from Chenjie Xu at Nanyang Technical University). Who said there was no innovation in antibiotics?
1. Sangwei Lu, Ph.D.
School of 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 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, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
3. 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, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
4. 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, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
5. • 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, sangwei@berkeley.edu Novel, Peanut Butter – Based Formulation of Amoxicillin
6. 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
7. 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
8. 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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9. 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
10. 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
11. The Challenge
Beta-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 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 polar molecule 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 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
.
14. Stability Testing Phase I
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
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.
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 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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17. Challenges of Amoxicillin Delivery to Children
(0-5 yrs) at High Burden Countries
http://www.envita.com/
Amoxicillin
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18. 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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19. Birth of Idea
Images are adapted from Waker silicone electronic business. Co. Ltd
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20. 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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21. 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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22. 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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Editor's Notes
Intro – rectal amoxicillin
Outline – background into research group, outline of our project, plan of attack
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
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
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
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.
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.