Principles of depot injections Flashcards
Advantages of long acting injections (7)
- Predictable drug-release profile during a defined period of time following each injection
- Better patient compliance
- Ease of application
- Improving systemic availability by avoidance of first-pass metabolism
- Reduced dosing frequency
- Decreasing incidence of side effects
- Cost reduction of medical care
Two types of routes for long acting injections
Subcutaneous (SC) and Intramuscular (IM)
Subcutaneous injections
Greater surface area for target Injection sites, use of shorter needles, ease of self-administration, less discomfort, better safety profile
– primary route for delivery of protein-based drugs
– the volume of SC injection are usually limited to no more than 1-2 mL
Intramuscular injections
Greater injection volume (2-5 mL) in the large skeletal muscles (these muscles are less richly supplied with sensory nerves)
3 types of long acting injections
Oil based solutions (Control the release of active drug for weeks)
Drug suspensions (weeks)
Polymer-based
Polymer-based acting time
Particulate: microsphere (months)
In situ-based gelling systems (months)
What may long acting injectables used for?
Steroid esters (contraception’s and hormone replacement therapy). antipsychotics
Formulations considerations for long acting injections (3)
drug solubility in oil vehicles
drug partitioning between oil and aqueous interface
vehicle viscosity `
What oil is usually used for long-acting injections?
Vegetable oils
Why are vegetable oils usually used in long-acting injections?
Contains various triglycerides in different proportion, which influences vehicle density and viscosity.
What in vegetable oil, cause a risk of oxidation?
They contain triglycerides, which contain fatty acids
Castor oil had high content of fatty acids with hydroxyl group (due to ricinolein acid)
Alternative oil used for long-acting injections
Synthetic fatty acid esters such as isopropyl myristate and ethyl oleate as alternative vehicles
What other biocompatible cosolvents may be used in formulations? (3)
aliphatic alcohols
benzyl benzoate
ethyl acetate
What is the partition coefficient (P) of a drug substance?
Ratio of drug activities (at equilibrium) in two immiscible solvents comprising the portioning system.
How to enhance drug affinity for the oil phase
Need to manipulate partition coefficients by transiently masking the drug in the form of a lipophilic prodrug.
How does a prodrug work (haloperidol e.g.)?
- Long lipophilic carbon chain attached to drug via an ester bond.
- The caron chain will be in oily phase
- The other part will be in aqueous phase
- Hydrolysis of the ester bond will release the drug in active form.
What is the rate-limiting step of drug absorption in drug suspension?
The dissolution of drug particles in the formulation or in tissue fluid surrounding the drug formulation.
What type of formulation can be used to control dissolution rate of drug particles, to prolong the absorption?
- Poorly water-soluble salt formulations
- Larger particle sizes
What does Polysorbate 8ti do in olanzapine pamoate
Non-ionic surfactant
Improves the dispersion of the formulation by a repulsive effect
What does hydrochloric acid and sodium hydroxide do in olanzapine pamoate
Allows for pH adjustment
What are Polymer-based systems used for?
For macromolecules (proteins and peptides)
Advantages of polymer-based systems?
- In-vitro and in vivo stabilization of macromolecules
- Extension of biological half-life
- Improvement of systemic availability
Types of polymer-based systems
Microspheres
In situ-forming gels
How are microspheres formed?
Polymer dissolved in solvent and gradually remove solvent. This will then form structure called microspheres. Drugs may also be adsorbed onto microsphere after.
What type of polymer needs to be used for microspheres?
Biodegradable
What controlled rate of drug release from microspheres?
Diffusion through polymer matrix, polymer degradation, polymer properties
Polymer properties that play a critical role in drug release
– Composition of copolymer ratios
– Hydrophilicity/hydrophobicity
– Molecular mass
– Glass transition temperature
How could increased hydrophobicity affect drug release?
Higher hydrophobicity can keep drug for longer time.
Release process of microspheres
From the surface
Through pores
Diffusion through intact polymer barrier
Diffusion through a water-swollen barrier
Polymer erosion
Bulk degradation
What does changing the ratio of the lactic acid and glycolic acid do?
It changes the release rate.
4 drug release mechanisms (microspheres)
A)Diffusion though water filled pores
B)Diffusion through the polymer
C)Osmotic pumping
D)Erosion
A)Diffusion though water filled pores
Microsphere gets hydrated and water channels formed. The drug molecules well and diffuse out.
B)Diffusion through the polymer
Not many pores so diffusion through polymer matrix and into aqueous phase
C)Osmotic pumping
Hydrated more, so cracks from in the polymer causing partial degradation allowing drug to be released.
D)Erosion
Usually at the end of the microsphere life span (e.g. happing after osmotic pumping)
What does a high Lactic acid and low glycolic acid ratio do?
Slower release rate (reduced hydrolysis)
What does do 50:50 ratio of lactic acid:glycolic acid do?
Faster release rate (increased hydrolysis)
Ratio of lactic acid:glycolic acid in order or release rate
Fast: 50:50 (40 days)
65:35 (80 days)
75:25 (100 days)
Slow 85:15 (120 days +)
What are in situ-forming gels?
Made of biodegradable products, which can be injected via a syringe into the body, and once injected, congeal to form a solid implant (e.g., Eligard: leuprolide, GnRH for prostate cancer)
In situ-forming gels mechanism
- Drug-polymer solution injected in suitable solvent system
- Solvent diffuse out – water insoluble polymer solidify and entrap the drug
- Drug slowly released from the biodegradable depot
Types of in situ-forming gels
Thermoplastic pastes
In situ cross-linked polymer systems
In situ polymer precipitation
Thermally-induced gelling systems
Thermoplastic pastes
Form a semisolid upon cooling to body temperature after injection
In situ cross-linked polymer systems
Ionic interactions between small cations and polymer anions
In situ polymer precipitation
Polymer precipitation from solution
Thermally-induced gelling systems
Liquid at low temp, gel at body temp
