The basic rationale of a sustained drug delivery system is to optimize the Biopharmaceutic, Pharmacokinetic and Pharmacodynamic properties of a drug in such a way that its utility is maximized through reduction in side effects and cure or control of condition in the shortest possible time by using smallest quantity of drug, administered by the most suitable route.
The novel system of drug delivery offer a means of improving the therapeutic effectiveness of incorporated drugs by providing sustained, controlled delivery and / or targeting the drug to desired site. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration.
There is a continuously growing interest in the pharmaceutical industry for sustained release oral drug delivery systems. There is also a high interest for design a dosage formulation that allows high drug loading, particularly for actives with high water solubility.
Oral route has been the most popular and successfully used for sustained delivery of drugs because of convenience and ease of administration, greater flexibility in dosage form design and ease of production and low cost of such a system. The sustained release systems for oral use are mostly solid and based on dissolution, diffusion or a combination of both mechanisms in the control of release of drugs.
In this type of dosage forms, a sufficient amount of drug is initially made available to the body to cause a desired pharmacological response. The remaining fraction is released periodically and is required to maintain the maximum initial pharmacological activity for some desirable period of time in excess of time expected from usual single dose.
MECHANISM OF DRUG RELEASE
On exposure to aqueous fluid, hydrophilic matrices take up water, and polymer starts hydrating to form a gel layer. Drug release is controlled by diffusions barriers / or by surface erosion. An initial burst of soluble drug may occur due to surface leaching when a matrix containing a swellable glassy polymer comes in contact with an aqueous medium, there is an abrupt change from a glassy to a rubbery state which is associated with swelling process with time, water infiltrator deep into the case increasing the thickness by the gel layer. Concomitantly the outer layer becomes fully hydrated and states dissolving or eroding. When water reaches the center of the system and the concentration of drug fells below the solubility value, the release rate of drug begins to reduce. At the same time, an increase in thickness of the barrier layer with time increases the diffusion path length, reducing the rate of drug release. Drug release kinetic associated with these gel – layer dynamic, range initially from Fickian to annomalous (Non – Fickian) and subsequently from quasi – Constant ( near Zero order ) to constant. In general, two major factors control the drug release from swelling controlled matrix system. They include
1. The rate of aqueous medium infiltration into the matrix, followed by a relaxation process (hydration, gelatin or swelling)
2. The rate of matrix erosion
FIGURE 1
As a result of these simultaneous processes, two front are evident, a swelling front, where the polymer get hydrated, and an eroding front. The distance between these two fronts are called diffusion layer thickness. Diffusion layer thickness depends on the selective rate at which the swelling and eroding fronts move in relation to each other. If the polymer gets slowly, solvent can penetrate deep into the glassy matrix the dissolving the drug; there for gel layer thickness and it stability are council in controlling drug release.
Swelling of HPMC matrix tablet was higher for higher a molecular weight. They attributed this to the large hydrodynamic volume occupied by higher molecular weight chain when hydrated. As the polymer chain becomes more hydrated and the gel becomes more dilute, the disentanglement concentration may be reached that is, the critical polymer concentration below which the polymer chain disentangle and detached from gelled matrix.
Potential advantages and disadvantages of sustained release dosage forms 3, 4
Advantages:
i] Patient Compliance:
Lack of compliance is generally observed with long term treatment of chronic disease, as success of drug therapy depends upon the ability of patient to comply with the regimen. Patient compliance is affected by a combination of several factors, like awareness of disease process, patient faith in therapy, his understanding of the need to adhere to a strict treatment schedule. Also the complexity of therapeutic regimens, the cost of therapy and magnitude of local and or systemic side effect of the dosage form. The problem of lack of patient compliance can be resolved to some extent by administering controlled release drug delivery system.
ii] Reduced 'see- saw' fluctuation:
Administration of a drug in a conventional dosage form [except via intravenous infusion at a constant rate] often results in 'see – saw' pattern of drug concentration in the systemic circulation and tissue compartments. The magnitudes of these fluctuations depend on drug kinetics such as the rate of absorption, distribution, elimination and dosing intervals. The 'see-saw' or 'peak and valley' pattern is more striking in case of drugs with biological half lives of less than four hours, since prescribed dosing intervals are rarely less than four hours. A well designed controlled release drug delivery system can significantly reduce the frequency of drug dosing and also maintain a more steady drug concentration in blood circulation and target tissue cells.
iii] Reduced total dose:
Controlled release drug delivery systems have repeatedly been shown to use less amount of total drug to treat a diseased condition. By reducing the total amount of drug, decrease in systemic or local side effects are observed. This would also lead to greater economy.
iv] Improved efficiency in treatment:
Optimal therapy of a disease requires an efficient delivery of active drugs to the tissues, organs that need treatment. Very often doses far in excess to those required in the cells have to be administered in order to achieve the necessary therapeutically effective concentration. This unfortunately may lead to undesirable, toxicological and immunological effects in non-target tissue. A controlled release dosage forms leads to better management of the acute or chronic disease condition.
v] Economy:
(a) In comparison with conventional dosage forms the average cost of treatment over an extended period may be less.
(b) Economy also may results from a decrease in nursing time and hospitalization. Also
1. Reduce blood level oscillation characteristic of multiple dosing of conventional dosage forms.
2.Reduce amount of drug administration
3.Maximizing availability with a minimum dose.
4.Control of drug absorption; high peak level peaks that may be observed after administration of high
availability drug can be reduced.
5.Safety margin of high potency drugs can be increased.
vi} Improved therapy:
a) Sustained blood level: The dosage form provides uniform drug availability / blood levels unlike peak
and valley pattern obtained by intermittent administration.
b) Attenuation of adverse effects: The incidence and intensity of undesirab effects caused by excessively high
peak drug concentration resulting from the administration of conventional dosage forms is reduced.
c) It is seldom that a dose is missed because of non-compliance by the patient.
Disadvantages:
i) Dose dumping: Dose dumping is a phenomenon where by relatively large quantities of drug in a controlled release formulation is rapidly released, introducing potential toxic quantities of the drug into the systemic circulation. Dose dumping can lead to fatalities in case of potent drug, which have a narrow therapeutic index e.g. Phenobarbital.
ii) Less flexibility in accurate dose adjustment: In conventional dosage forms, dose adjustments are much simpler e.g. tablet can be divided into two fractions. In case of controlled release dosage forms, this appears to be much more complicated. Controlled release property may get lost, if dosage form is fractured.
iii) Poor In Vitro – In Vivo correlation: In controlled release dosage form, the rate of drug release is deliberately reduced to achieve drug release possibly over a large region of gastrointestinal tract. Here the so called ‘Absorption window’ becomes important and may give rise to unsatisfactory drug absorption in vivo despite excellent in-vitro release characteristics.
iv) Patient variation: The time period required for absorption of drug released from the dosage form may vary among individuals. Co-administration of other drugs, presence or absence of food and residence time in gastrointestinal tract is different among patients. This also gives rise to variation in clinical response among the patient.
Factors of consideration in Design of sustained Release Dosage Forms: 5,6,3,7,4,8,9
The therapeutic efficacy of drug under clinical conditions is not simply a function of its intrinsic pharmacological activity but also depends upon the path of the drug molecule from the site of administration to the target site. Different conditions encountered by the drug molecule while traversing the path of distribution may alter either the effectiveness of the drug or affect the amount of the drug reaching the receptor site.
A] Pharmaceutics: This refers to the development/manufacturing of an efficient delivery system in which the drug has
maximum physiological stability and optimum bioavailability.
B] Biopharmaceutics/ pharmacokinetics: This involves the study of absorption, distribution, metabolism and excretion of
the drug, before and after reaching the target site and evaluation of the relationship between delivery
system and therapeutic response.
C] Pharmacodynamics/ Clinical Pharmacology: It is the study of the mechanism of action and clinical efficacy of a drug
administered in dosage form in terms of onset, intensity and duration of pharmacological activity.
Table.1 - Characteristics of Drugs Unsuitable for oral Sustained Release Forms
Characteristics Drugs
Not effectively absorbed in the lower intestine Riboflavin, Ferrous salts
Absorbed and excreted rapidly; short biologic half-lives (< 1hr) Penicillin G, furosemide
Long biologic half-lives (>12 hr) Diazepam, phenytoin
Large doses required (>1g) Sulfonamides
Cumulative action and undesirable side effects; drugs with low therapeutic indices. Phenobarbital, digitoxin
Precise dosage titrated to individual is required Anticoagulants, cardiac glycosides
No clear advantage for sustained release formulation Griseofulvin
BIOPHARMACEUTICAL FACTOR’S
Dissociation constant “Pka”: A drug to be absorbed it first must dissolve in the aqueous phase surrounding the site of administration and then partition in the absorbing membrane. Two of the most important Physicochemical properties of a drug that influence its absorptive behavior are its aqueous solubility and if it is a weak acid or base its Pka. These properties pay an influential role in the performance of controlled release systems.
Partition Coefficient: The partition coefficient is another important drug property, which influences the design of oral
controlled delivery by two ways; it is an important property that governs the permeation of drug
particles through biological membrane. The diffusion of drug molecules across rate controlling
membrane or through the matrix systems essentially relies on partition coefficient.
Drug stability: The stability of the drugs at the site of its release and exposure bio-milieu is one more drug property that
can influence the design of oral controlled drug delivery. Drugs that are unstable in gastric pH can be
developed as slow release dosage form and drug release can be delayed till the dosage form reaches the
intestine. Drugs that undergo gut-wall metabolism and show instability in small intestine are not suitable
for controlled drug delivery systems.
Absorption: The rate, extent and uniformity of absorption of a drug are important factors when considering it’s formulation
into a controlled – release system. Since the rate limiting step in drug delivery from a controlled – release
system is its release from a dosage form, rater than absorption, a rapid rate of absorption of drug relative to
its release is essential if the ‘system is to be successful.
Distribution: The distribution of a drug into vascular and extra vascular spaces in the body is an important factor in its
overall elimination kinetics. Two parameters that are used to describe the distribution characteristics of a
drug are its apparent volume of distribution and the ratio of drug concentration in the tissue to that in plasma
at the steady state called T/P ratio. The magnitude of the apparent volume of distribution can be used as a
guide for additional studies and as a predictor for a drug dosing regimen and hence the need to employ a
controlled – system.
Metabolism: Drugs that are significantly metabolized before absorption either in the lumen or tissue of the intestine can
show decreased bioavailability from slower – releasing dosage forms. Formulation of these enzymatically
susceptible compounds as Prodrug is another viable solution.
Side Effects and Safety considerations: The side effects of some drugs are mainly developed due to the fluctuation in the
plasma concentrations. The incidences of side effects can be minimized by controlling the concentration
within therapeutic range at any given time.
Disease State : Even, in some cases are considered before the designing of an oral controlled delivery. This can be
explained by the following classical examples. Aspirin is a drug of choice for rheumatic arthritis, and it is not
a suitable candidate for sustained release dosage form. Still an aspirin sustained release dosage from could
be advantageous to maintain therapeutic concentrations, particularly through out the night, thus alleviating
morning stiffness.
Criteria to be met by drug proposed to be formulated in sustained release dosage forms. 10,11,2,3,12
a)Desirable half-life:
The half life of a drug is an index of its residence time in the body. If the drug has a short half life (less than 2 hours), the dosage form may contain a prohibitively large quantity of the drug. On the other hand, drug with elimination half life of eight hours or more are sufficiently sustained in the body, when administered in conventional dosage from, and controlled release drug delivery system is generally not necessary in such cases. Ideally, the drug should have half-life of three to four hours.
b) High therapeutic index:
Drugs with low therapeutic index are unsuitable for incorporation in controlled release formulations. If the system fails in the body, dose dumping may occur, leading to fatalities eg. Digitoxin.
c) Small dose:
If the dose of a drug in the conventional dosage form is high, its suitability as a candidate for controlled release is seriously undetermined. This is chiefly because the size of a unit dose controlled release formulation would become too big, to administer without difficulty.
d) Desirable absorption and solubility characteristics:
Absorption of poorly water soluble drug is often dissolution rate limited. Incorporating such compounds into controlled release formulations is therefore unrealistic and may reduce overall absorption efficiency.
e) Desirable absorption window:
Certain drugs when administered orally are absorbed only from a specific part of gastrointestinal tract. This part is referred to as the ‘absorption window’. Drugs exhibiting an absorption window like fluorouracil, thiazide diuretics, if formulated as controlled release dosage form are unsuitable.
f) First pass clearance:
As discussed earlier in disadvantages of controlled delivery system, delivery of the drug to the body in desired concentrations is seriously hampered in case of drugs undergoing extensive hepatic first pass metabolism, when administered in controlled release forms.
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