Pediatric Antibiotic Innovations

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

mailto:[email protected]

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


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.


• 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


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


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


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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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


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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Birth of Idea

Images are adapted from Waker silicone electronic business. Co. Ltd19

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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http://www.dow.com/

Health & Medicine

Pediatric Antibiotic Innovations