Drug Delivery Systems Flashcards
Controlled Release Drug Delivery Systems (CRDDS)
- Maintain constant/desired level of drug in blood and tissue for extended period of time
- Predictable and reproducible drug release kinetics
- Rate and duration are designed to achieve a desired concentration
Disadvantages of Novel Drug Delivery Systems
- Possible toxicity or nonbiocompatibility of the employed polymeric carriers
- Unpredicted and poor correlation between in vitro release and in vivo release
- Undesired degradation products
- Difficulty in dosage adjustment
- Reduced potential for accurate dose adjustment
- Dose dumping
- Potential surgery for implantation and/or removal of the release system, patients’ displeasure
Modified release dosage forms
Dosage forms whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic, or conveniences objectives not offered by conventional dosage forms
Extended release dosage forms
The drug releases slowly so that the plasma concentration is maintained at therapeutic level for a prolonged period of time usually between 8 to 12 hours
Sustained release dosage forms
An initial release of drugs sufficient to provide a therapeutic dose soon after administration and then gradual release over an extended period of time
Advantages of Novel Drug Delivery Systems
- Improved patient compliance due to less frequent drug administration
- Reduced fluctuation in steady-state drug levels
- Increased safety margin of potent drug, and reduced drug accumulation
- Minimal side effects e.g. reduced GIT irritation
- Reduced healthcare costs through improved therapy
- Shorter treatment period
- Less frequency of dosing
- Maximum utilisation of the drug
- Improved bioavailability of some drugs
- Reduction in total drug usage when compared with conventional therapy
Repeat action dosage forms
Individual dose is released fairly soon after administration and subsequent doses are needed to release the drug at intermittent intervals
Controlled release dosage forms
Release drug at a constant rate and provide plasma concentration that remain invariant with time
Controlled vs Sustained release
- Sustained release is a slow release of medication over a period of time, whereas controlled release releases medication over time in correlation with concentration
- Sustained release medication is offered solely by way of oral dosage, while controlled release can be via oral, transdermal administration, or other means
- Sustained release technology is first-order kinetic and controlled release technology is zero-order kinetic
Conventional release systems
- Once administered they rapidly release pharmaceutical drugs in the body
- Abrupt increase in drug concentration in the bloodstream and quick reduction within a short period of time
- Repeated dosing may be required to maintain the drug concentration in the effective range
- Fluctuation of plasma drug level may be toxic and/or result in poor drug effectiveness
- Frequent administration of conventional dosing may cause displeasure to patients
Sustained Release Drug Delivery Systems (SRDDS)
- Achieve slow release of drug over an extended period of time after administration of single dose
- Drug released at predetermined rate
- Major goal is to modify and improve the drug performance
- Increasing the duration of drug action
- Used for drugs that are metabolised too quickly or eliminated from the body shortly after administration
Protein binding
- Distribution of drug into extra space is governed by dissociation of drug from protein
- Drug-protein complex acts as reservoir in the vascular space for sustained drug release to extra vascular tissue for drug exhibiting high degree protein binding.
The less protein bound a drug is, the more efficiently it can pass between fluid compartments
Aqueous Solubility
- Absorption process influences dissolution rate and concentration in solution
- Effect on the ability to penetrate tissues
- Drug molecules with very low aqueous solubility often have lower bioavailability (low dissolution)
Absorption
- Rate, extent and uniformity of absorption- all important factors when considering sustained release
- Release from dosage form is the rate limiting step in sustained release, therefore rather than absorption, rapid release is essential for a successful system
Challenges of drug delivery systems
- Unpredicted and poor correlation between in vitro release and in vivo release
- Undesired degradation products
- Difficulty in dosage adjustment- Reduced potential for accurate dose adjustment
- Dose dumping
- Potential surgery for implantation and/or removal of the release system, patients’ displeasure with an implanted device
- Cost of the formulation is high
Diffusivity
Defined as the ability of a drug to diffuse through the membrane
How are molecular size and difusitivity related?
They are Inversely related
What factors influence diffusitivity?
- size and shape of the cavities of the membrane
Applications of Novel Drug Delivery Systems
- Oral controlled delivery systems
- Transdermal
- Ocular
- Intestinal
- Colonic
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Partition coefficient
Reflects the permeability of the drug through the biological membrane and/or the polymer membrane
Ability of drug to cross lipid membranes is based of?
- is its apparent oil-water partition co-efficeint,
- defined as- K=Co/Cw
- high partition coefficient can easily penetrate biological membranes, as they are made of lipid bilayers, but are unable to proceed further because of a higher affinity to the membrane than the aqueous surroundings.
- Drugs with a low partition coefficient can easily move around the aqueous areas of the body, but will not cross the biological membranes easily.
Dose size
- For orally administered systems, there is an upper limit to the bulk size of the dose to be administered. In general, a single dose of 0.5-1.0 gm is considered maximal for a conventional dosage form.
- This also holds for sustained-release dosage forms.
- If an oral product has a dose size greater that 500mg it is a poor candidate for sustained release system
Drug stability
Once the drug is administered, biological fluids that are in direct contact with a drug molecule may influence the stability of the drug.
Drugs may be susceptible to both chemical and enzymatic degradation, which results in a loss of activity of the drug.
Drugs with poor acidic stability, when coated with enteric coating materials, will bypass the acidic stomach and release the drug at a lower portion of the GIT
Physiochemical properties of sustained release formulations
- Aqueous solubility
- Partition coefficient
- Drug stability
- Protein binding
- Molecular size and diffusitivity
- Dose size
Biological properties of sustained release formulations
- Absorption
- Distribution
- Metabolism
- Elimination and half-life
- Side effects
Elimination and biological half-life
- The goal of sustained-release products is to maintain therapeutic blood levels over an extended period
- The drug must enter the circulation at approximately the same rate at which it is eliminated, quantitatively described by the half-life (t1/2)
How does half life affect sustained release preparations?
- Therapeutic compounds with short half-lives are excellent candidates for sustained release preparations to reduce dosing frequency
- Drugs with half-lives shorter than 2 hours are poor for sustained release formulations, as are those with half-lives more than 8 hours since their effect is already sustained
Diffusion controlled release systems
- Drugs are trapped in and released via diffusion through inert water-insoluble polymeric membranes (reservoir systems) or polymeric matrices (monolithic systems)
- The water-insoluble polymeric material surrounds the drug reservoir
Approaches to design CRDDS
- Physicochemical approaches
* Diffusion controlled release system
* Dissolution
* Ion exchange principles - Biological approaches
* Biopolymers
* Pulse based
* Gastro retention based
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Distribution
- Distribution of the drug into vascular and extravascular spaces in the body affects its overall elimination kinetics
- The distribution of drugs into tissue can be an important factor in the overall drug elimination kinetics since it not only lowers the concentration of circulating drug but can also be rate-limiting in its equilibration with blood and extracellular fluid
Volume of distribution obeys only one compartment model where
v = dose/Co
- apparent volume of distribution relates the drug concentration in blood or plasma to the total amount of drug in the body
For two-compartment models volume of distribution is
Vss = (1 + k12/k21)/V1 where
* V1 is the volume of the central compartment
* K12 is the rate constant for distribution of drug from the central to peripheral compartment
* k21 is for peripheral to central
- Vss is the drug concentration in blood or plasma at steady state to the total amount of drug, estimating the extent of distribution in the body
The amount of drug in the body can be calculated by T/P ratio as?
T/P = K12 (K21-β) where
* β is the slow deposition constant,
* T is the amount of drug in the peripheral
Metabolism
- Conversion of the drug to other chemicals/metabolites
- Drugs significantly metabolized before absorption can show decreased bioavailability from slower-releasing dosage forms
- Most intestinal wall enzyme systems are saturable, so as the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specific period, allowing more complete conversion of the drug to its metabolites
- Formulation of enzymatically susceptible compounds as prodrugs is another viable solution
Disadvantages of Diffusion controlled release systems
- Not completely safe because of dose dumping from accidentally damaged systems, which may be toxic
- In some cases, a surgical procedure may be necessary to remove the device
- Obtaining perfect zero-order release kinetics and releasing high-molecular-weight drugs can also be challenging
Ion-Exchange Controlled Release Systems
- Generally uses resins composed of water-insoluble polymers cross-linked with abundant ionizable functional groups in the polymer backbone
Types of ion-exchange controlled release systems
There are two types:
1. cationic resin for release of anionic drugs
2. anionic resin for release of cationic drugs
Factors that control release rate in ion-exchange controlled release systems
Release rate can be controlled by several factors including pH and ionic strength of the release environment, molecular weight and charge density of both resin and drugs
Importance of ion exchange
Ion-exchange systems are useful for controlled release of ionic drugs due to their high loading capacity on the resin surface
Approaches to decrease rate of dissolution of drugs for sustained release preparations
preparing appropriate salts or derivatives, coating the drug with a slowly dissolving material, or incorporating it into a tablet with a slowly dissolving carrier
Release of drug from Resevoir follows which law?
- follows Fick’s first law of diffusion. J = - D dc/dx Where,
J = flux, amount/area-time
D = diffusion coefficient of drug in the polymer, area/time
dc/dx = change in conc. with respect to polymer distance
Types of diffusion controlled systems
- Resevoir
- Matrix
Reservoir
- The drug core is encased by a water-insoluble polymeric materials
- The mesh (i.e., the space between macromolecular chains) of these polymers, through which drug penetrates or diffuses after partitioning is of molecular level.
- The rate of drug release is dependent on the rate of drug diffusion but not on the rate of dissolution
Types of resevoirs based on Methods of Preparation :
- Coated Beads/Pellets
* Coating of drug solution onto preformed cores.
* Covering of core by an insoluble (but permeable coat).
* Pan Coating or air-suspension technique is generally used for coating.
* Pore forming additives may be added to the coating solution. - Microencapsulation
* This technique used to encapsulate small particles of drug, solution of drug in a coat (usually a polymer coat).
* Generally, any method that can induce a polymer barrier to deposit on the surface of a liquid droplet or a solid surface can be used to form microcapsules.
Techniques:
- Coacervation (Polymers: gelatin, acacia etc.)
- Interfacial polymerization (Polymers: polyurethanes, polyamides, polysulfonamides, polyphtalamides, etc.)
- Solvent evaporation
- Others (hot melt, spray-drying etc.)
Matrix
- A matrix or monolithic device consists of an inert polymeric matrix in which a drug is uniformly distributed.
- Drugs can be dissolved in the matrix or the drugs can be present as a dispersion.
**NOTE: **Matrix may be HOMOGENEOUS or POROUS with water filled pores.
State of presentation of this form affects the various release patterns:
- Dissolved drug
- Dispersed drug
- Porous matrix
- Hydrophilic matrix (gelation & diffusion)
Rate controlling step for matrix
- Diffusion of dissolved matrix
Types of matrix based on Methods of Preparation
- Rigid Matrix Diffusion Materials used are insoluble plastics such as PVP & fatty acids.
- Swellable Matrix Diffusion Also called as Glassy hydrogels (Popular for sustaining the release of highly water soluble drugs)
- Materials used are hydrophilic gums. Examples : Natural- Guar gum, Tragacanth. Semisynthetic -HPMC, CMC, Xanthan gum
Explain what occurs in Non-constant resevoir/monolithic solution systems
- In non-constant source reservoir or monolithic solution systems, the loaded drugs dissolve in aqueous solution below their saturated concentrations (time = 0). When released, drug concentration in the reservoirs/matrices reduces over time, resulting in a decrease in the amount released at time = t1 and t2.
Explain what occurs in Constant resevoir/monolithic dispersion systems
- In the constant source reservoir or monolithic dispersion systems, an oversaturated concentration of a mixture of saturated solution and undissolved crystal/amorphous drug aggregates is formulated (time = 0)
- When release of dissolved drug lowers its concentration within the system below its saturated concentration, drug aggregates dissolve to replace the released drug. As a result, the concentration of drugs within the system remains constant at time = t1 and t = t2
Differences between resevoir systems and monolithic systems
- In reservoir systems, drugs are protected inside polymeric membranes with low solubility. Drug release occurs upon dissolution of the polymeric membranes
- In monolithic systems, drug aggregates are distributed throughout the polymeric matrices, dissolution of the drug aggregates and release of the dissolved drug result when the matrices dissolve
Advantages of Dissolution controlled release systems
- have the potential to release high-molecular-weight drugs
- do not need to be surgically removed.
Disadvantages of Dissolution controlled release systems
- potential toxicity resulting from dose dumping and/or dissolved polymeric materials
- difficulty in obtaining perfect zero-order release profiles
Factors associated with metabolism
include
* the ability of the drug to induce or inhibit enzyme synthesis
* fluctuating drug blood levels and first-pass metabolism
