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Controlled Release

CONTROLLED RELEASE

The frequency of dosing interval of any drug depends upon its t ½ or mean residence time (MRT) & its therapeutic index. But when the dosing interval is much shorter than t ½ of drug results in lamination:

1. Poor patient compliance
2. Peak valley plasma concentration –time profile makes attainment of steady state difficult.

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Unavoidable fluctuations in drug concentration leads to undermedication or overmedication.
Controlled drug delivery system: It is one which automatically delivers the drug at predetermined rate, locally or systemically for a specified time or they are concerned strickly with localization of drug or site specific/targeted.
Sustained release: Simply prolong the drug release and but not necessarily at predetermined rate.
So main objective of controlled drug delivery to reduce dosing frequency to an extent that once daily dose is sufficient for therapeutic management through a uniform plasma concentration at steady state.

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Disadvantages of controlled Release:

Decreased systemic availability in comparison to immediate release conventional dosage forms, this may leads to increased first pass metabolism, site-specific absorption, pH dependent solubility.

Possibility of dose dumping due to food.
Poor in vitro-in vivo correlation.

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Desired biopharmaceutic properties of drug used in controlled drug delivery system:
1. Molecular weight of the drug: Lower molecular weight, faster & complete absorption. Diffusivity is inversely related to size. The upper limit for passive diffusion is 600 daltons. Drugs with large molecular weight like peptides & proteins are poor candidates for oral controlled release system.
2. Aqueous solubility of drug: Good aqueous solubility mainly pH independent are good candidate for controlled release.
(a) For poorly soluble drugs the rate limiting step is dissolution which means controlled device does not control the absorption process.
(b) pH dependent aqueous solubility or drug with solubility in non-aqueous solvents like steroids are suitable to parenteral controlled release dosage form as drug precipitate at injection site and its released is slowed down.
(c) Partition coefficient of drug: Greater KD, Greater is rate & extent of absorption, mainly important parameter for determining the release rate of drug from lipophilic matrix/device.
A drug administered as controlled release, the desired rate limiting step is rate of drug release Kr.
Kr < < Ka (rate of absorption)

Drugs with t ½ is 2‐4 hrs is suitable for controlled release. For the drugs whose t ½ < 2 hrs a very large dose may be required to maintain the high release rate.
Drugs which undergoes rapid metabolism like propranolol is a good candidate for controlled rate.
Short Biological Half life = t ½ < 1 hr → Absorbed and excreted rapidly e.g. pencillins
Long biological half life = t ½ > 12 hr → e.g. Diazepam, Phenytoin
Large Dose requirement = > 1 g → e.g Sulphonamides
The above are characteristics for drug unsuitable for sustained release.

Oral Controlled Release System

(a) Continuous release: Release the drug to entire GIT length.
1). Dissolution controlled release system
2). Diffusion controlled released system
3). Dissolution + Diffusion release system
4). Ion-exchange resin – drug complex
5). Slow dissolving salts & complex
6). pH dependent formulations
7). Osmotic pressure controlled systems
8). Hydrodynamic pressure controlled system

Delayed Transits and Continuous release system

1). Altered Density systems
2). Mucoadhesive systems
3). Size based systems
Delayed release system: Design to release the drug at only specific site in GIT.
1). Intestinal release systems
2). Colonic release system

Dissolution controlled:

1). Either by incorporation of drug in slowly dissolving/erodible matrix/matrix devices.
2). Or by encapsulation with cellulose, PEG, Polymethacrylates etc. (also called as reservoir devices)/coating with slowly dissolving substance.

A. Matrix/Manolith system:
Used beewax, carnauba wax which control drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by decreasing the wettability/itself getting dissolved at slower rate.
Drug is embedded/dispersed the drug in molten wax.
B. Slow-dissolving salts :
Amine drug + Tannic acid (Tannate complex breakdown depend upon pH Gastric faster than intestinal fluid) → complex split in gastric acid and intestinal fluid
Penicillin G + N, N’ dibenzyl ethylene to give benzathine penicillin G.
C. pH – independent formulations:
Used buffering agents like salts of phosphoric citric or tartaric acid to eliminate the influence of changing GI pH on dissolution & absorption of drug.

Osmotic pressure controlled system/OROS
Osmotic substances like KCl or mannitol is formulated with active drug. This core is surrounded by SPM, coating of cellulose ester having an orifice 0.4 mm.

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GIT fluid water flows through SPM due to difference in osmotic pressure, which dissolves the drug that is released from orifice.

Hydrodynamic pressure controlled systems:

Hydrodynamic pressure is generated by swelling of gums like polyhydroxyalkyl methacrylate in presence of GIT fluids.

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Gum swell up in the presence of H2O generating hydrodynamic pressure which will squeeze the collapsible drug reservoir to release the medicament through delivery orifice at zero order kinetics.

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A. High Density pellets: The density of GIT fluids is around 1.4 g/cc so use of drug pellets above 1.6 g/cc results in prolonged residence time. To increase the density of drug pellets FeO, BaSO4, TiO2 are mostly used.
B. Low Density Pellets: Hydrodynamically balanced system: float on GI fluid & slowly release the drug. Generally, Hoprice or cellulose (HPMC) which form globular shells are mostly used for lower density system.
Floating tablets/buoyant tablets/capsules: are formulating by granulating a drug with 20-80% of hydrogel like HPMC, HPC, HEC. On contact with GIT fluids the tablets swells & form a diffusible gel
barrier that lowers the density of system to less than 1 allowing it float.

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Mucoadhesive systems: It uses bioadhesive polymer i.e. cross linked polyacrylic acid, acacia incorporated in a tablet, the allows it to adhere to gastric mucosa or epithelium, so such system
continuously releases a fraction of drug into the intestine over prolonged periods of time.
Size based systems: Gastric emptying is delayed if the dosage form 2.5 cm or larger.

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Peyer patches: in distal end of small intestine are mucosal lymphoid tissues that are known to absorb macromolecules like proteins/peptides and antigen by endocytosis. So selective release of such agent‟s to peyer‟s patch region prevents them for getting destroyed/digested by intestinal enzymes.
This site is utilized by oral delivery of insulin.
Lymphatic system on the other hand is known to absorb highly lipophlic agents directly to systemic circulation without first pass through liver.

Clonic release system:

For treatment of ularative colitis with mesalamine.
Systemic absorption of protein and peptide drugs like insulin. Therefore use of vinylbenzene cross-linked polymers that are cleaved only by azoreductase of clonic bacteria to release free drugs for local effect.
pH sensitive bioerodible polymers like polymethacrylates release the medicament only at alkaline pH of colon.
Phospholipids which are neutral charge at pH 7 → Phosphatidyl choline & phosphatidyl cholne
Phospholipids which are anionic at pH 7 → P Serine (-1), P. Inositol (-4)

In vitro Evaluation of SR Formulations:

In vitro evaluation of SR formulation are done for two purposes:
1. As a guide to formulation during development stage.
2. To ensure batch to batch uniformity.
In vitro evaluation for SR formulations are restricted to – Assay and Dissolution Studies

Assay: To ensure drug content, the SR formulations are assayed by colorimetric or spectrophotometric methods.

Dissolution: Dissolution testing for SR formulations are limited to USP dissolution testing methods, using either the rotating basket method (apparatus I) and the paddle type (apparatus 2).

Apparatus I: It is basically a closed compartment, beaker type of a cylindrical glass vessel with hemispherical bottom of 1 litre capacity partially immersed in water bath to maintain temperature at 370 C. A cylindrical basket made of mesh no. 22 to hold the dosage form is located centrally in the vessel at a distance of 2 cm from bottom and rotated by a variable speed motor through a shaft.

Apparatus II: The assembly is same as that of apparatus I except that the rotating basket is replaced with a paddle which act as stirrer.
The SR tablets are first kept in 0.1 N HCl for specific time (Stimulated gastric fluid) and followed by a media of pH 7.2 (Stimulated intestinal fluid) for specific time.
Beside the USP dissolution testing apparatus the rotating bottle, stationary basket and rotating filter, Sartorius absorption and solubility stimulator, the column type follow through apparatus are also used.

Rotating bottle: The rotating bottle apparatus consists of a rotating bottle of capacity 90 ml. 60 ml of stimulated fluid is kept at 370 C and rotates at a speed of 40 r.p.m. The tablet which has to be evaluated is introduced into the bottle and the samples are withdrawn at regular interval and is analysed.

Sartorius Device: The Sartorius device consists of an artificial lipid membrane which separates the dissolution chamber from a stimulated plasma compartment in which drug concentration are measured.

The time of testing may vary from 6-12 hours. Sink condition can be obtained by recirculating the media and thus cumulative release can be maintained. In certain case, the drug is exposed to media of pH 4-5, considering the transistion between gastric acid and intestinal pH.

Stability studies are completed since accelerated stability studies may induce changes in the system. For a sustained release product, the stability testing depends on the dosage form and its composition.

In vivo measurement of Drug availability: In vivo testing for drug is done in human beings or animal
models like dogs during the product development stage, animal models are preferred. In vivo drug availability of SR formulations are done either by periodic blood level determination or urinary excretion data.

In vivo measurements are done to find out release rate of drug and to notice the drug dumping. If drug level can not be measured in biological fluids, the pharmacological effect must be observed.

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