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Renin Angiotensin Mechanism.

Controlled Drug Delivery System: Physicochemical and biological properties of drugs relevant to controlled release formulations.

 

Introduction:

  • Controlled drug delivery is one which delivers the drug at a predetermined rate, locally or systemically, for a specified period of time.

  • The rationale of controlled release dosage form can be summarized as below:

    • To provide a location-specific action within the GIT.

    • To avoid an undesirable local action within the GIT.

    • To provide a programmed drug delivery pattern.

    • To increase the rate and extent of absorption/bioavailability.

    • To extend the duration of action of the drug.

Factor Influencing the Design and Performance of Controlled Drug Delivery System:

  1. Biopharmaceutical characteristics of the drug:

    1. The molecular weight of the drug

    2. The aqueous solubility of the drug

    3. Apparent partition coefficient

    4. Drug pKa and ionization physiological pH

    5. Drug stability

    6. Mechanism and site of absorption

    7. Route of administration.

  2. Pharmacokinetic characteristics of the drug:

    1. Absorption rate

    2. Elimination half-life

    3. Rate of metabolism

    4. Absolute bioavailability

    5. Total clearance (CL)

    6. Apparent volume of distribution (VD)

    7. Therapeutic concentration (Css)

  3. Pharmacodynamic characteristic of the drug:

    1. Therapeutic index

1.1 The molecular weight of the drug:

  • Small molecules may pass through pores of a membrane by convective transport. 

  • This applies to both, the drug release from the dosage form and the transport across a biological membrane. 

  • For biologic membranes the limit may be a molecular weight of 150 and 400 respectively for spherical molecules and chain-like compounds respectively.

1.2 Solubility:

  • For all mechanisms of absorption the drug must be present at the site of absorption in the form of solution. 

  • During the Preformulation study it is necessary to determine the solubility of the drug at various pH values.

  • If the solubility is less than 0.1 μg/ml (in acidic medium) one may expect reduced bioavailability. 

  • It seems that drugs are well absorbed by passive diffusion from the small intestine upon oralApparent partition coefficient (APC) administration if at least 0.1 to 1% is non ionized form.

1.3 Apparent partition coefficient (APC):

  • Drugs being absorbed by passive diffusion must have a certain minimal APC. 

  • The higher the APC in an n-octanol/buffer system the higher is the flux across a membrane for many drugs. 

  • The APC should be determined for the entire pH range in the GI tract. 

  • The APC must also be applied for partition of the drug between CRDDS and the biological fluid.

1.4 General absorption mechanism:

  • For a drug to be a variable candidate for per oral CRDDS, its absorption mechanism must be by diffusion throughout the entire GI tract. 

  • The term diffusion here refers to the dual pathway of absorption either by partitioning into the lipid membrane (across the cells) or by passing through water filled channels (between the cells). 

  • It is also important that absorption occurs from all segments of the GI tract which may depend on the drug’s pKa, the pH in the segment, binding of drug to mucus, blood flow rate, etc. 

  • In any case, the drug release from the CRDDS should not be influenced by pH changes within the GI tract, by enzymes present in the lumen, peristalsis, etc.

  • The one compartment open model is quite suitable to design CRDDS for most drugs.

2.1 Absorption Rate:

  • In order to ensure that the release process is the rate controlling step, the intrinsic absorption rate constant should be higher than the desired release rate constant of the drug from the dosage form.

2.2 Elimination half-life:

  • Drugs having a t ½ of 8 hours are ideally suited for CRDDS.

  •  If the t ½ is less than 1 hour the dose size required for a 12 hour or 24 hour duration dosage form may be too large. 

  • If the t ½ is very long there is usually no need for a CRDDS.

2.3 Rate of metabolism:

  • The rate of metabolism directly affects the t ½ of the drug.

  • There are two areas of concern related to metabolism that significantly restrict CRDDS product design. 

  • First, if a drug upon chronic administration is capable of either inducing or inhibiting enzyme synthesis, it will be a poor candidate for a S/R/C.R product because of the difficulty of maintaining uniform blood levels of a drug.

  • Second, if there is a variable blood level of a drug  through either intestinal (or tissue) metabolism or through first pass effect.

2.4 Absolute Bioavailability:

  • The absolute bioavailability is the percentage of drug taken up into systemic circulation upon extravascular administration. 

  • For drugs to be suitable for CRDDS this value should be close to 100%.

2.5 Total clearance (CL):

  • CL is a measure of the volume of distribution cleared of drugs per unit of time. 

  • It is the key parameter in estimating the required dose rate for CRDDS, and predicting the steady state concentration.

2.6 Apparent volume of distribution (VD):

  • The Volume of distribution (VD), also known as the apparent volume of distribution, is used to quantify the distribution of a drug between plasma and the rest of the body after oral or parenteral dosing.

  • It is defined as the volume in which the amount of drug would be uniformly distributed to produce the observed blood concentration.

  • The apparent volume of distribution is a proportionality constant relating the plasma concentration to the total amount of drug in the body.

2.7 Therapeutic concentration (Css):

  • The therapeutic concentrations are the desired or target steady state peak concentrations (Css max), the desired or target steady state minimum concentrations (Css min), and the mean steady state concentration (Css avg). 

  • The difference between Css max and Css min is the fluctuation.

  • The smaller the desired fluctuation the greater must be the precision of the dosage form performance.

  • The lower Css, the smaller Vz, the longer t ½, the higher F and The less amount of drug is

  • required to be incorporated into a CRDDS.

3.1 Therapeutic index:

  • It is most widely used to measure the margin of safety of a drug.

  • TI = TD 50 /ED50

  • The longer the value of TI, the safer the drug. 

  • Drugs with very small value of Therapeutic index are poor candidates for formulation into CRDDS products.

  • A drug is considered to be safe if its T.I value is greater than 10.

Commonly Asked Questions.

  1. Define Controlled Drug Delivery System. Discuss different factors influencing the design and performance of controlled drug delivery system.
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