7A: Formulation Perspectives in Treatment of Infectious Diseases Flashcards
Impacts of formulation on antibiotics
Formulation science may help with the following goal(s) in treatment of ID:
- Improve physicochemical characteristics of antibiotics e.g, increase stability, solubility
- Improve patient compliance, e.g. sustained release (reducing dosing frequency), taste-masking etc
- Delivering antibiotics to the infected sites, e.g. overcoming physiological barriers (cellular membranes etc)
Results in increased efficacy & safety
Stability of some antibiotics:
Benzylpenicillin (Penicillin G):
- Gastric absorption of penicillin G is poor because it is rapidly hydrolysed in low pH
- Penicillin G is administered by injection - sterile, pyrogen-free powder to be reconstituted prior to injection
Gastric acid destroys erythromycin:
- In stomach 70-90% of dose can be destroyed in 15 minutes
- Can be overcome by using enteric coated delayed release tablets
Enteric coated tablets/pallets
Is designed to hold a tablet/pallet together in stomach & break down in the intestines
- Utilises polymer-based thin film coating on the surface of a solid dosage
- Polymers are insoluble in acidic environment, but soluble in the mildly acidic to neutral environment
3 reasons for enteric coating:
- To protect the drug from degradation in the stomach
- To protect the stomach from the drug (irritating)
- To release the drug in the intestines for local action
Procaine Penicillin G injectable suspension
A complex of procaine – local anaesthetic with Penicillin G
- Avoid pain on injection
- Provides prolonged drug release (IM injection)
- Improve chemical stability
How suspension improve drug stability?
- Drug in suspension (particles) is more chemically stable than a drug solution (less contact with water)
- More ‘taste masking’ than a drug solution (oral)/pain reduction (injection)
- Also, suspension is an option for patients who have difficulty swallowing tablets
Note: Some drug molecules are in solution (depending on stability)
Gentamicin injection
Aminoglycoside antibiotic injectable formulation
Sterile solution (pH 3-3.5) containing:
- Gentamycin (as sulphate salt) 40 mg/mL
- Disodium edetate (EDTA) – stabiliser by sequestering metal ions in a solution, thus preventing oxidation reactions
- Water for injection
Amoxicillin: Moxatag (extended release tablets)
Amoxicillin is time-dependent antibiotic – longer time over MIC is desirable however, its half-life is just 1 hour
MOXATAG is an extended-release tablet formulation consisting of 3 components:
- An immediate release granulation (Pulse 1)
- 2 delayed-release pellets (Pulse 2, Pulse 3)
+ Release drug in a different region of the intestines, from different film coating
Clinical benefits:
- Longer T>MIC than amoxicillin suspension = efficacy
- Once daily – higher patient compliance
Posaconazole injection (Noxafil)
Posaconazole has a poor aqueous solubility <1µg/mL
Injection formulation (300 mg/20 mL/vial) containing:
- Posaconazole 15 mg/mL
- Sulphobutylether-beta-cyclodextrin – solubilizer
- Disodium edetate (EDTA) – stabiliser
- HCl/NaOH – pH adjustment
Product is to be diluted in 0.9% saline or 5% dextrose solution prior to IV infusion
The use of beta-cyclodextrins is also found in other IV formulations, including itraconazole & voriconazole (both FDA-approved)
Amphotericin B - anti fungal antibiotic
- Its low solubility & permeability (BCS Class IV drug) has posed major hurdles for oral administration due to its low bioavailability (=poor absorption rate)
- Thus, it is administered by IV infusion – very slow IV injection)
- Its well known for its severe & potentially lethal side effects
- Only used to treat progressive & potentially life-threatening fungal infections
- Large molecular weight: 924
Amphotericin B - AmBisome
Liposome formation:
- 100 nm in diameter
- Liposome bilayer – hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol (DSPG) & cholesterol
- 50 mg Amphotericin B per vial (lyophilised)
Clinical benefits:
- High plasma concentration
- Slow renal clearance / long half-life
- Lower levels of side effects including IV infusion related adverse effects & nephrotoxicity
Liposomes
- Liposomes are spherical vesicles composed of phospholipid bilayer surrounding one or more aqueous cores
- Liposomes form when phospholipids are hydrated:
1. Forming laminar sheets with hydrophilic heads projected to aqueous environment (both sides) & lipophilic tails packed in the bilayer
2. Form a spherical structure (to keep energy low) – liposome - Can be a multilamellar or unilamellar liposomes
- Can be large of in nano-scale
Liposomes – a versatile drug carrier
Liposomes are attractive drug carriers because they are:
- Biodegradable, biocompatible & relatively nontoxic
- Able to incorporate a wide range of drugs
+ Lipophilic drugs in the lipid bilayers (=solubilisation)
+ Hydrophilic drugs in the aqueous cores
- Able to stabilise the encapsulated drug (in vitro & in vivo)
- Able to deliver drug into targeted cells (nanosized liposome via endocytosis)
Delivery drug to the infected site
Some areas can be difficult for drug to reach:
- Reduced efficacy
- Results in drug resistance
The site of infection can be anywhere in the body:
- E.g. skin, eye, respiratory, reproductive systems, CNS, urinary tract etc
- Sometime on surface & sometime inside cells
Locations of pathogens at cell level
Extracellular bacteria: e.g. V. cholera do not invade cells, & proliferate instead in the extracellular environment (V cholera can adhere to epithelial surfaces of the small intestine
- An infectious & often fatal bacterial disease with acute severe diarrhoea
Intracellular bacteria:
- Antibiotics need to enter the cells in order to exert their antimicrobial effect
Challenges to delivery drug to treat intracellular infections
Intracellular infections remain difficult to eradicate due to poor intracellular penetration of most of the commonly used antibiotics:
- Cell membranes are relatively impermeable to many antibiotics
- E.g. Gentamycin is a highly water-soluble drug & penetrates cells poorly – not effective for treating intracellular bacterial infections
- This problem may be solved by nanotechnology using ‘drug delivery systems’ (nano carriers)
- E.g. Nano-liposomes
