Oral modified release formulations Flashcards
discuss the disadvantages of conventional formulations
1) If the drug has a short half-life, it has to be administered frequently, so there are chances of missing the dose.
2) concentration-time profile obtained is not steady.
The fluctuations of drug plasma level that occurs during conventional release may produce under medication or overmedication.
3) Poor patient compliance.
at steady state the average concentration of drug remains constant. what does the time to reach steady state depend on?
1) half time of the drug and is independent of the dose size and the dosing interval
is a once daily formulation the best?
1) Very little evidence that once a day dosing is best!
2) Unless there is a good reason otherwise probably safer to give a drug twice daily rather than od – no possibility of dose dumping
how are modified release formulations classified?
Categorized based on the release profile using plasma concentration plasma curve
describe the first-order kinetics model of drug release for conventional dosage forms.
In First-order model, drug release is dependent on the amount of drug available for release and therefore the rate of release declines exponentially with time.
describe the rate of drug release from Extended release dosage forms
1) Extended release dosage forms are governed by zero-order kinetics in which the rate of release is independent of amount of drug remaining in the dosage form.
2) Therefore a constant amount of drug will be released over time from extended release dosage forms
what are the advantages of modified release formulations?
1) Reduced dosing frequency
2) Dose reduction
3) Improved patient compliance
4) A constant level of drug concentration in blood plasma
5) Reduced toxicity due to overdose
6) Reduces the fluctuation of peak-value
7) night time dosing can be avoided
one advantage of modified release formulations is that the total amount of drug administered can be reduced. what are the benefits of this?
1) Maximizing availability with minimum dose
2) Minimize or eliminate local side effects
3) Minimize or eliminate systemic side effects
4) Minimize drug accumulation with repeated dosing.
outline the disadvantages of modified release formulations
1) Possibility of dose dumping
2) Reduced potential for dose adjustment
3) Cost of single unit higher than conventional dosage forms
4) Increased potential for first-pass metabolism
5) Decreased systemic availability in comparison to immediate release conventional dosage forms
6) Poor in vitro and in vivo correlations
discuss what information we need to know in order to select a drug for modified release?
requires knowledge on the absorption mechanism of the drug from the gastrointestinal (GI) tract, the general absorbability, the drug’s molecular weight, pKa, solubility at different pH, and apparent partition coefficient
outline the characteristic that makes a drug unsuitable for modified release formulation
1) Short elimination half-life, i.e t1/2 <2 hrs
2) Long elimination half-life, i.e t1/2 >8 hrs
3) Narrow therapeutic index
4) Large doses
5) poor absorption
6) Low or slow solubility
7) Extensive first-pass clearance
define sustained-release (SR)
These are drug delivery systems (DDS) that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single-dose of drug
what is meant by a Controlled-release dosage form?
planned, predictable, and slower-than-normal manner for a longer period of time
what is meant by Extended release?
especially selected to release the drug over longer periods, typical drugs short t1/2 such as Phyllocontin Continus
what is meant by Delayed release?
The drug is released at a specific site such as in the colon, PENTASA® (mesalamine)
what is a Repeat action DDS?
If granules are partly coated, some will dissolve in stomach (uncoated) and some in the intestine to achieve repeated or controlled release
explain what is meant by a Prolonged release system?
designed to release the drug slowly and to provide a continuous supply of drug over an extended period. They prevent very rapid absorption of the drug, which could result in extremely high peak plasma drug concentration
outline the physiochemical factors that affect the release rate of a drug
1) Aqueous solubility: low solubility→ drug loss
2) Partition coefficient: High Log P→ low permeability
3) Drug pKa and ionization at physiological pH→ ionization vs permeability
4) Drug stability→ hydrolysis, e.g. penicillin
5) Molecular weight and diffusivity: Large MW→ low permeability
discuss the desirable physicochemical parameters for drug selection
1) molecular weight: <1000 daltons
2) solubility: >0.1mg/ml
3) partition coefficient: high
4) absorption mechanism: diffusion
5) absorbability : from all GI segments
6) release: not influenced by enzymes or pH
discuss the biological factors that affect the release rate of a drug
1) It is essential that the rate of release is much slower than the rate of absorption.
2) Drugs with high apparent volume of distribution, which influence the rate of elimination of the drug are poor candidate for oral SR drug delivery system.
3) A drug which extensively metabolizes is not suitable for SR drug delivery system. A drug capable of inducing metabolism, inhibiting metabolism, metabolized at the site of absorption or first-pass effect is poor candidate for SR delivery, as it could be difficult to maintain constant blood level.
If we assume the transit time of dosage forms in the absorptive areas of GI tract is about 8-12 hours, what should the maximum half-life for absorption be?
the maximum half-life for absorption should be approximately 3-4 hours. Otherwise the dosage form will pass out of absorptive regions before drug release is complete.
summarise the USP requirements and FDA guidance for Drug release of modified-release dosage forms
1) The USP test for drug release for extended-release and delayed-release articles is based on drug dissolution from the dosage unit against elapsed test time
- 1.0(hr) - Amount dissolved between 15% and 40%
- 2.0- between 25% and 60%
- 4.0- between 35% and 75%
- 8.0- not less than 70%
summarise the USP requirements and FDA guidance for modified-release dosage forms with regards to Uniformity of dosage units
Uniformity of dosage units may be demonstrated by either of two methods, weight variation or content uniformity
In vitro/in vivo correlations (IVIVCs) are part of the requirements for USP and FDA guidance. why are IVIVCs important?
IVIVCs is critical to the development of oral extended-release products. Assessing IVIVCs is important throughout the periods of product development, clinical evaluation, submission of an application for FDA-approval for marketing, and during post approval for any formulation or manufacturing changes which are proposed.
IVIVC is categorized into level A, level B, level
C. define the 3 levels.
1) Level A: A predictive mathematical model for the relationship between the entire in vitro dissolution/release time course, e.g., the time course of plasma drug concentration or amount of drug absorbed.
2) Level B: A predictive mathematical model of the relationship between summary parameters that characterize the in vitro and in vivo, time courses.
3) Level C: A predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time (or T50%) and a summary parameter that characterizes the in vivo time course (e.g. Cmax or AUC).
what are the USP requirements and FDA guidance for the labelling of modified-release dosage forms?
The USP indicates labeling requirements for modified-release dosage form articles in addition to general labeling requirements.
what information should be given to patients regarding modified drug release products ?
1) dose and dosing frequency of modified drug release products and instructed to not use them interchangeably or concomitantly with immediate-release forms of the same drug.
2) Should not be crushed or chewed since such action would compromise their drug release features.
3) Modified-release tablets and capsules are packaged and stored in the same manner as conventional products.
Formulation methods used to manipulate drug release profiles are based mainly on two principles. what are these two principles?
1) physical (diffusion, erosion, and osmotic pump)
2) chemical principles (drug–polymer complex, drug–polymer conjugate, prodrug, and ion-exchange resin)
the matrix system is a diffusion controlled system. describe what a Diffusion matrix system is
1) The drug is embedded in a matrix of insoluble drug, when exposed to water, the drug will diffuse and rate of diffusion is controlled by the affinity of the drug towards the polymer
2) The matrix can be formed from hydrophobic polymeric, hydrophilic/gelling polymeric or fatty/wax based. Release kinetics can be predicted using Higuchi equation
discuss the advantages and disadvantages of a matrix system
1) Advantages: Easier to make, low cost, can be used to protect drug, can deliver high mol. wt compounds
2) disadvantages: zero order more difficult to achieve
the reservoir system is a diffusion controlled system. describe what a reservoir system is
1) Diffusion reservoir system: In this system, a water insoluble polymer is used to form a reservoir by which the drug diffusion and dissolution is controlled through permeation through the membrane.
(The drug is contained in a core, which is surrounded by a polymer membrane & release by diffusion through the rate limiting membrane.)
discuss the advantages and disadvantages of a diffusion reservoir system
1) Advantages: Zero order is possible, release rates can be modified with polymer type & concentration
2) disadvantages: high MW drug cannot be used, cost and safety concerns if dumping
- Rupture can result in dangerous dose dumping
1) what is the dissolution matrix reservoir?
2) state if it is better than the Diffusion matrix system?
1) Dissolution matrix reservoir: Commonly used approach (Enteric coating) where a matrix and a polymeric coat can be used to coat the drug.
- Example include eudragit polyerms (methacrylic acid derivitaves) and soluble cellulose based polymeric.
2) Possibility to control release but not as accurate as diffusion
what is the Dissolution matrix system/pulsed?
Same principle as the reservoir, but the drug is embedded in the matrix with the possibility to achieve pulsed release
what are the two classes of dissolution controlled release systems?
1) Matrix dissolution control
2) Encapsulation dissolution control
what is Matrix dissolution control?
The rate of penetration of dissolution fluid in to the matrix determines the drug dissolution and subsequent release.
summarise the preparation of dissolution based drug delivery systems
1) By Microencapsulation or by altering layers of drug with rate-controlling coats
2) Systems involve coating of individual particles of drug with a slow dissolving material & the coated particles can be compressed directly into tablets or placed in capsules.
3) dissolution rate of coat depends upon stability & thickness of coating. also masks colour, odour, taste ,minimising GI irritation.
describe the mechanism of drug release
1) Drug encased in a partially soluble membrane.
2) Pores are created due to dissolution of parts of membrane.
3) It permits entry of aqueous medium into core & drug dissolution.
4) Diffusion of dissolved drug out of system.
- Ex- Ethyl cellulose & PVP mixture dissolves in water & create pores of insoluble ethyl cellulose membrane.
what are Ion-exchange resins?
1) Ion-exchange can be defined as an electrostatic interaction of ions between ions in solution and ion-exchange resins without significant change in the structure and properties of the resins.
2) The ionic interactions are strongly dependent on the pH and the competing ions in the reaction medium.
what can happen to an ion-exchange resin if the medium has many ionic species, and how can we use this to our advantage?
1) If the medium has many ionic species, it may decrease the electrostatic interaction between the resin and the ionic drug due to shielding and competitive binding effect.
2) the interaction can be exploited in oral drug delivery since the resin can carry the drug and release it in the gastrointestinal (GI) tract due to the pH change or the presence of competing ions.
explain how a Osmotic drug delivery system is different from other technologies used in controlled-release formulations
1) The key distinguishing feature of osmotic drug delivery systems is that they release drug at a rate that is independent of the pH and hydrodynamics of the external dissolution medium
2) The result is a robust dosage form for which the in vivo rate of drug release is comparable to the in vitro rate, producing an excellent in vitro/in vivo correlation.
Semipermeable Membranes are common excipients used in controlled delivery formulations. State which formulations uses Semipermeable Membranes and give some examples.
Semipermeable Membrane in osmotic pump DDS
1) Since the membrane in osmotic systems is semipermeable in nature, any polymer that is permeable to water but impermeable to solute can be selected - Example: cellulose acetate, some other polymers such as agar acetate, and Eudragits can be used as semipermeable film-forming materials.
1) how do Floating drug delivery systems work?
2) give an example of a floating DDS drug
1) The density of gastric contents is about 1g/ml, it is possible to design a dosage form with lower density pellets able to float on the contents and take longer to dissolve
- Popcorn, poprice, and polystyrol have been exploited as drug carriers
2) Madopar® -is an example of a floating DDS
1) Osmogens are common excipients used in controlled delivery formulations. how do Osmogens work?
2) give examples of osmogens
1) Upon penetration of biological fluid into the osmotic pump through semipermeable membrane, osmogens are dissolved in the biological fluid, which creates osmotic pressure buildup inside the pump and pushes medicament outside the pump through delivery orifice. They include inorganic salts and carbohydrates.
2) Mostly, potassium chloride, sodium chloride, and mannitol used as osmogens.
