Factors in the Design of Controlled-Release Drug Delivery Systems

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Chapter: Biopharmaceutics and Pharmacokinetics : Controlled Release Medication

A. Biopharmaceutic Characteristics of a Drug in the Design of CRDDS B. Pharmacokinetic Characteristics of a Drug in the Design of CRDDS C. Pharmacodynamic Characteristics of a Drug in the Design of CRDDS


The basic rationale of a controlled release drug delivery system is to optimise 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.


A. Biopharmaceutic Characteristics of a Drug in the Design of CRDDS

The performance of a drug presented as a controlled-release system depends upon its:

1. Release from the formulation.

2. Movement within the body during its passage to the site of action.

The former depends upon the fabrication of the formulation and the physicochemical properties of the drug while the latter element is dependent upon pharmacokinetics of drug. In comparison to conventional dosage form where the rate-limiting step in drug availability is usually absorption through the biomembrane, the rate-determining step in the availability of a drug from controlled delivery system is the rate of release of drug from the dosage form which is much smaller than the intrinsic absorption rate for the drug (Fig. 14.2).

Fig. 14.2 Scheme representing the rate-limiting step in the design of controlled-release drug delivery system

The type of delivery system and the route of administration of the drug presented in controlled-release dosage form depend upon the physicochemical properties of the drug and its biopharmaceutic characteristics. The desired biopharmaceutic properties of a drug to be used in a controlled-release drug delivery system are discussed below.

1. Molecular Weight of the Drug: Lower the molecular weight, faster and more complete the absorption. For drugs absorbed by pore transport mechanism, the molecular size threshold is 150 Daltons for spherical compounds and 400 Daltons for linear compounds. However, more than 95% of drugs are absorbed by passive diffusion. Diffusivity, defined as the ability of a drug to diffuse through the membranes, is inversely related to molecular size. The upper limit of drug molecular size for passive diffusion is 600 Daltons. Drugs with large molecular size are poor candidates for oral controlled-release systems e.g. peptides and proteins.

2. Aqueous Solubility of the Drug: A drug with good aqueous solubility, especially if pH-independent, serves as a good candidate for controlled-release dosage forms e.g. pentoxifylline. The lower limit of solubility of a drug to be formulated as CRDDS is 0.1mg/ml. Drugs with pH-dependent aqueous solubility e.g. phenytoin, or drugs with solubility in non-aqueous solvents e.g. steroids, are suitable for parenteral (e.g. i.m depots) controlled-release dosage forms; the drug precipitates at the injection site and thus, its release is slowed down due to change in pH or contact with aqueous body fluids. Solubility of drug can limit the choice of mechanism to be employed in CRDDS, for example, diffusional systems are not suitable for poorly soluble drugs. Absorption of poorly soluble drugs is dissolution rate-limited which means that the controlled-release device does not control the absorption process; hence, they are poor candidates for such systems.

3. Apparent Partition Coefficient/Lipophilicity of the Drug: Greater the apparent partition coefficient of a drug, greater its lipophilicity and thus, greater is its rate and extent of absorption. Such drugs have increased tendency to cross even the more selective barriers like BBB. The apparent volume of distribution of such drugs also increases due to increased partitioning into the fatty tissues and since the blood flow rate to such tissues is always lower than that to an aqueous tissue like liver, they may exhibit characteristics of models having two or more compartments. The parameter is also important in determining the release rate of a drug from lipophilic matrix or device.

4. Drug pKa and Ionisation at Physiological pH: The pKa range for acidic drugs whose ionisation is pH-sensitive is 3.0 to 7.5 and that for basic drugs is 7.0 to 11.0. For optimum passive absorption, the drugs should be non-ionised at that site at least to an extent 0.1 to 5%. Drugs existing largely in ionised forms are poor candidates for controlled delivery e.g. hexamethonium.

5. Drug Permeability: The three major drug characteristics that determine the permeability of drugs for passive transport across intestinal epithelium are –

·            Lipophilicity, expressed as log P.

·            Polarity of drug which is measured by the number of H-bond acceptors and number of H-bond donors on the drug molecule.

·            Molecular size.

The influence of each of these properties has been discussed above.

6. Drug Stability: Drugs unstable in GI environment cannot be administered as oral controlled-release formulation because of bioavailability problems e.g. nitroglycerine. A different route of administration should then be selected such as the transdermal route. Drugs unstable in gastric pH, e.g. propantheline can be designed for sustained delivery in intestine with limited or no delivery in stomach. On the other hand, a drug unstable in intestine, e.g. probanthine, can be formulated as gastroretentive dosage form.

7. Mechanism and Site of Absorption: Drugs absorbed by carrier-mediated transport processes and those absorbed through a window are poor candidates for controlled-release systems e.g. several B vitamins.

8. Biopharmaceutic Aspects of Route of Administration: Oral and parenteral (i.m.) routes are the most popular followed by transdermal application. Routes of minor importance in controlled drug delivery are buccal/sublingual, rectal, nasal, ocular, pulmonary, vaginal and intrauterinal. The features desirable for a drug to be given by a particular route are discussed below.

(a) Oral Route: For a drug to be successful as oral controlled-release formulation, it must get absorbed through the entire length of GIT. Since the main limitation of this route is the transit time (a mean of 14 hours), the duration of action can be extended for 12 to 24 hours. The route is suitable for drugs given in dose as high as 1000 mg. A drug, whose absorption is pH-dependent, destabilized by GI fluids/enzymes, undergoes extensive presystemic metabolism (e.g. nitroglycerine), influenced by gut motility, has an absorption window and/or absorbed actively (e.g. riboflavin), is a poor candidate for oral controlled-release formulations.

(b) Intramuscular/Subcutaneous Routes: These routes are suitable when the duration of action is to be prolonged from 24 hours to 12 months. Only a small amount of drug, about 2 ml or 2 grams, can be administered by these routes. Factors important in drug release by such routes are solubility of drug in the surrounding tissues, molecular weight, partition coefficient and pKa of the drug and contact surface between the drug and the surrounding tissues.

(c) Transdermal Route: Low dose drugs like nitroglycerine can be administered by this route. The route is best suited for drugs showing extensive first-pass metabolism upon oral administration. Important factors to be considered for percutaneous drug absorption are partition coefficient of drug, contact area, skin condition, skin permeability of drug, skin perfusion rate, etc.

In short, the main determinants in deciding a route for administration of a controlled-release system are physicochemical properties of the drug, dose size, absorption efficiency and desired duration of action.


B. Pharmacokinetic Characteristics of a Drug in the Design of CRDDS

A detailed knowledge of the ADME characteristics of a drug is essential in the design of a controlled-release product. An optimum range of a given pharmacokinetic parameter of a drug is necessary beyond which controlled delivery is difficult or impossible.

1. Absorption Rate: For a drug to be administered as controlled-release formulation, its absorption must be efficient since the desired rate-limiting step is rate of drug release Kr i.e. Kr << Ka. A drug with slow absorption is a poor candidate for such dosage forms since continuous release will result in a pool of unabsorbed drug e.g. iron. Aqueous soluble but poorly absorbed potent drugs like decamethonium are also unsuitable candidates since a slight variation in the absorption may precipitate potential toxicity.

2. Elimination Half-Life: An ideal CRDDS is the one from which rate of drug of absorption (for extended period of time) is equal to the rate of elimination. Smaller the t½, larger the amount of drug to be incorporated in the controlled-release dosage form. For drugs with t½ less than 2 hours, a very large dose may be required to maintain the high release rate. Drugs with half-life in the range 2 to 4 hours make good candidates for such a system e.g. propranolol. Drugs with long half-life need not be presented in such a formulation e.g. amlodipine. For some drugs e.g. MAO inhibitors, the duration of action is longer than that predicted by their half-lives. A candidate drug must have t½ that can be correlated with its pharmacological response. In terms of MRT, a drug administered as controlled-release dosage form should have MRT significantly longer than that from conventional dosage forms.

3. Rate of Metabolism: A drug which is extensively metabolized is suitable for controlled-release system as long as the rate of metabolism is not too rapid. The extent of metabolism should be identical and predictable when the drug is administered by different routes. A drug capable of inducing or inhibiting metabolism is a poor candidate for such a product since steady-state blood levels would be difficult to maintain.

4. Dosage Form Index (DI): It is defined as the ratio of Css,max to Css,min. Since the goal of controlled-release formulation is to improve therapy by reducing the dosage form index while maintaining the plasma drug levels within the therapeutic window, ideally its value should be as close to one as possible.


C. Pharmacodynamic Characteristics of a Drug in the Design of CRDDS

1. Drug Dose: In general, dose strength of 1.0 g is considered maximum for a CRDDS.

2. Therapeutic Range: A candidate drug for controlled-release drug delivery system should have a therapeutic range wide enough such that variations in the release rate do not result in a concentration beyond this level.

3. Therapeutic Index (TI): The release rate of a drug with narrow therapeutic index should be such that the plasma concentration attained is within the therapeutically safe and effective range. This is necessary because such drugs have toxic concentration nearer to their therapeutic range. Precise control of release rate of a potent drug with narrow margin of safety is difficult. A drug with short half-life and narrow therapeutic index should be administered more frequently than twice a day. One must also consider the activity of drug metabolites since controlled delivery system controls only the release of parent drug but not its metabolism.

4. Plasma Concentration-Response (PK/PD) Relationship: Drugs such as reserpine whose pharmacological activity is independent of its concentration are poor candidates for controlled-release systems.

A summary of desired biopharmaceutic, pharmacokinetic and pharmacodynamic properties of a drug is given in table 14.1.

TABLE 14.1.

Factors in the Design of CRDDS

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