Rational for Controlled Drug Delivery

Just as cars are useless without roads, drugs are useless without an effective delivery system. The active ingredient in a medicine is only part of the arsenal against disease. The drug must somehow get to the right place at the right time. That's where drug delivery comes in.

 Drug delivery companies work to devise new dosage forms for medications. Historically, this has meant product life-cycle management, a process in which a pharmaceutical company looks for ways to set apart a product reaching the end of its patent lifetime from the inevitable generic competition. For example, a company might tinker with a drug that patients must take multiple times a day and reduce that to a single dose.

Nowadays, the competition is so intense in the pharmaceutical marketplace that companies look to drug delivery as a way to gain a competitive advantage. The value that drug delivery adds can be improved safety, efficacy, convenience, safety, efficacy, convenience, and patient compliance. compliance.

 As a result of biotechnology development, many people believe that proteins are going to comprise an increasing proportion of the new-drug newmarket. market. Many existing peptide and protein drugs are coming off patent, fueling the interest in developing new dosage forms. forms.

 There is the equivalent of a generic industry that will likely be developed for peptides and proteins, analogous to [what evolved with] small molecules. molecules. The race is on to develop alternatives to injection for macromolecules. The main macromolecules. methods being explored are pulmonary (inhalation) and oral formulations. In formulations. addition, transdermal and extended-release extendedinjectable formulations are being targeted. targeted.

THIS IS ACHIEVED BY
Better control of plasma drug levels and less frequent dosing. For Linear one compartment PK drugs: Dose interval ( ) < t1/2 (Ln TI)/Ln 2 TI is therapeutic index = Cmax/Cmin or LD50/ED50 For non-linear multi-compartment PK drugs: t1/2 is replaced by 0.693*MRT

The dosing interval may be increased by :

Modifying the drug molecule to decrease the rate of elimination. elimination. OR Modifying the release rate of a dosage form to decrease the rate of absorption. absorption.

1.

2. 3. 4. 5.

Factors influencing the design and performance of a controlled release systems Drug properties: physico-chemical (stability- solubility- partition coefficient.). Route of administration Target sites Acute or chronic therapy The pateint

Advantages of Controlled drug delivery systems

1. achieve more effective therapies while eliminating the potential for both underand overdosing. 2. the maintenance of drug levels within a desired range. 3. the need for fewer administrations, optimal use of the drug in question, and increased patient compliance.

Disadvantages of controlled drug delivery

1. the possible toxicity or nonbiocompatibility of the materials used. 2. undesirable by-products of degradation. 3. the chance of patient discomfort from the delivery device for instance if any surgery required to implant or remove the system. 4. the higher cost of controlled-release systems compared with traditional pharmaceutical formulations.

Oral Controlled Release Drug Delivery

Major challenges to an oral controlled release medication Unpredectable gastric emptying time. High variations in Gastric emptying due to factors such as age, race, sex, and disease states. Limited contact time at the site of absorption.

Oral Platform Drug Delivery Technology Matrix based on hydrophillic polymers. Diffusion-controlling Diffusionmembranes. Osmotic pumps. Diffussion controlled vesicle (DCV) (DCV)

Matrix based on hydrophillic polymers.

Drug and excipients are mixed with polymers such as Hydroxypropyl methylcellulose (HPMC) and Hydroxypropyl cellulose (HPC). (HPC). Tableted by conventional compression. compression. Release from the tablet takes place by combination of : - water diffuses into the tablet, swells the polymer and dissolves the drug. drug. - drug may diffuse out to be absorbed

Critical factors in Matrix based tablets

The rate of drug out-diffusion should be outslower than the rate of polymer swelling. swelling. Tablet porosity penetration. penetration. affects the water

Food may alter the rate of drug diffusion as a result of increased mechanical stress

Diffusion-controlling membranes.
In this type of drug delivery, a core of pure drug is coated with a permeable polymeric membrane.

Very rapid gelling and nearly complete hydration of OCAS delivery system in the upper GI tract ensures drug release throughout the entire GI tract, including the colon where water is poorly available. Reprinted from European Urology Supplements, 4(2), Michel MC, Korstanje C, KrauwinkelW, Kuipers M, The pharmacokinetic profile of tamsulosin oral controlled absorption system (OCAS1), pp 1524, 2005, with permission from European Association of

Osmotic pump
Is considered a special type of the previous type in which the semipermeable membrane : - allow the water to diffuse in. - prevent the drug to diffuse out. Drilling a hole in the outer membrane that allows the passage only of the dissolved drug.

Diffussion controlled vesicle (DCV) (DCV)

The principal of this system is : - The drug core is coated with a suspension of a water soluble pore former in a solution of impenetratable waterwater-insoluble polymer. polymer. - This process creates a macroporous membrane that controls the diffusion of drugs

Bioavailability of Deltiazem DCV Drug delivery compared with oral solution

Potential drug candidates for gastrogastroretentive drug delivery systems:

a. Weakly basic drugs that are poorly soluble in intestinal pHs and have better dissolution in the acidic medium of stomach. b. Drugs that have absorption windows in the upper part of the small intestine. They will gradually empty in solution form to the site of absorption. c. All drugs that are intended for local action on the gastro-duodenal wall e.g. therapeutic agents of ulcerous diseases.

Drugs that are unsuitable for gastro-retentive gastrodrug delivery system:

a. Enteric coated systems. b. Drugs intended for selective release in the colon e.g. 5aminosalicylic acid and corticosteroids. c. Drugs that have very limited acid solubility e.g. phenytoin. d. Drugs that suffer instability in the gastric environment e.g. erythromycin

Approaches for prolonging the gastric residence time:

HighHigh-density systems. Floating systems. Swelling and expanding systems. The use of passage delaying excipients. Superporous hydrogels. Mucoadhesive & Bioadhesive systems. Magnetic systems

High-density systems
Gastric contents have a density close to water ( 1.004 g cm 3). When the patient is upright small high-density pellets sink to the bottom of the highstomach where they become entrapped in the folds of the antrum and withstand the peristaltic waves of the stomach wall. wall. A density close to 2.5 g cm3 seems necessary for significant prolongation of gastric residence time. time. Barium sulphate, zinc oxide, iron powder,and titanium dioxide are examples for excipients used. used.

Floating systems
These have a bulk density lower than the gastric content. They remain buoyant in the stomach for a prolonged period of time, with the potential for continuous release of drug. They Include: Hydrodynamically balanced systems HBS Gas-generating systems Raft-forming systems Low-density systems

Schematic localization of an intragastric floating system and a high-density system in the stomach.

Hydrodynamically balanced systems: HBS

Schematic diagram shows the mode of action for HBSTM (Bogentoft, 1982).

GasGas-generating systems

Floating

(continued)

RaftRaft-forming systems

Schematic illustration of the barrier formed by a raftraftforming system.

Expandable systems

Different geometric forms of unfoldable systems proposed by Caldwell et al. From Caldwell et al. (1988).

Superporous hydrogels

On the left, superporous hydrogel in its dry (a) and water-swollen (b) state. On the right, schematic illustration of the transit of superporous hydrogel. From Gutierrez-Rocca, (2003).

Mucoadhesive or bioadhesive systems

The basis of mucoadhesion is that a dosage form can stick to the mucosal surface by different mechanisms. Examples for Materials commonly used for bioadhesion are poly(acrylic acid) (Carbopol, polycarbophil), chitosan, Gantrez (Polymethyl vinyl ether/maleic anhydride copolymers), cholestyramine, tragacanth, sodium alginate. the rapid turnover of mucus in the gastrointestinal tract is the main problem