Over past 30 year as the expanse and complication involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug delivery systems. There are several reasons for the attractiveness of these dosage forms.
The goal of many of the original controlled-release systems was to achieve a delivery profile that would yield a high blood level of the drug over a long period of time. With traditional tablets or injections, the drug level in the blood follows, in which the level rises after each administration of the drug and then decreases until the next administration. The key point with traditional drug administration is that the blood level of the agent should remain between a maximum value, which may represent a toxic level, and a minimum value, below which the drug is no longer effective. In controlled drug delivery systems designed for long-term administration, the drug level in the blood, remains constant, between the desired maximum and minimum, for an extended period of time.
Caparison b/w Various Drug Delivery System
Potential Advantages of Controlled Drug Release System
Increase patient compliance
- Less frequent administration.
- Less invasive
Employ less total drug
- Minimize local and systemic side effects
- Decrease potentiating of drug activity with chronic use
- Decrease drug accumulation with chronic use
Improves efficiency in treatment
1. Cure or control conditions more promptly.
2. Improve control by reduction in fluctuation
3. Improve bioavailability of some of the drugs.
Many times economical
- Considering cost of drug, hospitalization and lab tests for side effects, etc.
Disadvantages of Controlled Dosage Forms
- They are costly.
- Unpredictable and often poor in-vitro in-vivo correlations, dose dumping, reduced potential for dosage adjustment and increased potential first pass clearance.
- Poor systemic availability in general.
- Effective drug release period is influenced and limited by GI residence time.
Factors affecting Controlled Release Dosage Forms
Physicochemical properties of drug
If an oral product has a dose size greater that 0.5gm it is a poor candidate for sustained release system, Since addition of sustaining dose and possibly the sustaining mechanism will, in most cases generates a substantial volume product that unacceptably large.
Aqueous Solubility :
Most of drugs are weak acids or bases, since the unchanged form of a drug preferentially permeates across lipid membranes drugs aqueous solubility will generally be decreased by conversion to an unchanged form for drugs with low water solubility will be difficult to incorporate into sustained release mechanism. The lower limit on solubility for such product has been reported 0.1mg/ml. drugs with great water solubility are equally difficult to incorporate in to sustained release system. pH dependent solubility, particularly in the physiological pH range, would be another problem because of the variation in pH throughout the GI tract and hence variation in dissolution rate
Partition Coefficient :
Partition coefficient is generally defined as the fraction of drug in an oil phase to that of an adjacent aqueous phase. Accordingly compounds with relatively high partition coefficient are predominantly lipid soluble and consequently have very low aqueous solubility. Compounds with very low partition coefficients will have difficulty in penetrating membranes resulting poor bioavailability.
Typical relationship between drug activity and partition Coefficient K, generally known as Hansh Correlation.
It is the relationship between Pka of compound and absorptive environment. Presenting drug in an unchanged form is adventitious for drug permeation but solubility decrease as the drug is in unchanged form
Drug Stability :
Orally administered drugs can be subject to both acid base hydrolysis and enzymatic degradation. Degradation will proceed at the reduced rate for drugs in the solid state, for drugs that are unstable in stomach, systems that prolong delivery ever the entire course of transit in GI tract are beneficial. Compounds that are unstable in the small intestine may demonstrate decreased bioavailability when administered form a sustaining dosage from. This is because more drug is delivered in small intestine and hence subject to degradation
Molecular size and diffusivity :
The ability of drug to diffuse through membranes its so called diffusivity & diffusion coefficient is function of molecular size (or molecular weight).
Generally, values of diffusion coefficient for intermediate molecular weight drugs, through flexible polymer range from 10-8 to 10-9 cm2 / sec. with values on the order of 10-8 being most common for drugs with molecular weight greater than 500, the diffusion coefficient in many polymers frequently are so small that they are difficult to quantify i.e. less than 16-12 cm2/sec. Thus high molecular weight drugs and / or polymeric drugs should be expected to display very slow release kinetics in sustained release device using diffusion through polymer membrane.
Biological Half Life:
The usual goal of an oral sustained release product is to maintain therapeutic blood levels over an extended period. To action this, drug must enter in the circulation of approximately the same rate of which it is eliminated. The elimination rate is quantitatively described by half-life (t1/2). Therapeutic compounds with short half lives are excellent candidates for sustained release preparations. Since this can reduce dosing frequency. In general drugs with half-lives shorter than 3hrs are poor candidates of sustained release dosage forms of dose size will increase as well as compounds with long half lives, more than 8 hrs are also not used in sustained release forms because their effect is already sustained.
The rate, extent and uniformity of absorption of a drug are important factors when considered its formulation into a sustained release system. As the rate limiting step in drug delivery from a sustained-release system is its release from a dosage form, rather than absorption. Rapid rate of absorption of drug, relative to its release is essential if the system is to be successful.It we assume that transit time of drug must in the absorptive areas of the GI tract is about 8-12 hrs. The maximum half life for absorption should be approximately 3-4 hrs. Otherwise device will pass out of potential absorption regions before drug release is complete.
The distribution of drugs into tissues can be important factor in the overall drug elimination kinetics. Since it not only lowers the concentration of circulating drug but it also can be rate limiting in its equilibrium with blood and extra vascular tissue, consequently apparent volume of distribution assumes different values depending on time course of drug disposition. For design of sustained/ controlled release products, one must have information of disposition of drug.
Drugs that are significantly metabolized before absorption, either in lumen or the tissue of the intestine, can show decreased bioavailability from slower-releasing dosage forms. Most intestinal wall enzymes systems are saturable. As drug is released at a slower rate to these regions less total drug is presented to the enzymatic. Process device a specific period, allowing more complete conversion of the drug to its metabolite.
Mechanism of Drug Release:-
There are three primary mechanisms by which active agents can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale—as through pores in the polymer matrix—or on a molecular level, by passing between polymer chains. Examples of diffusion-release systems are shown in Figures 1 and 2.
In Figure 1, a polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release.
Figure 1. Drug delivery from a typical matrix drug delivery system.
For the reservoir systems shown in Figures 2a and 2b, the drug delivery rate can remain fairly constant. In this design, a reservoir—whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix—is surrounded by a film or membrane of a rate-controlling material. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a nonchanging thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system. The system shown in Figure 2a is representative of an implantable or oral reservoir delivery system, whereas the system shown in Figure 2b illustrates a transdermal drug delivery system, in which only one side of the device will actually be delivering the drug.
Figure 2. Drug delivery from typical reservoir devices: (a) implantable or oral systems, and (b) transdermal systems.
Once the active agent has been released into the external environment, one might assume that any structural control over drug delivery has been relinquished.For the diffusion-controlled systems described thus far, the drug delivery device is fundamentally stable in the biological environment and does not change its size either through swelling or degradation. In these systems, the combinations of polymer matrices and bioactive agents chosen must allow for the drug to diffuse through the pores or macromolecular structure of the polymer upon introduction of the delivery system into the biological environment.
Routes of Delivery Systems
- Buccal drug delivery system
- Oral controlled drug delivery system
- Parental controlled release systems
- Infusion devices
- Transdermal drug delivery system
- Ophthalmic drug delivery system
- Intravaginal and intrauterine drug delivery system.