1.1 CONTROLLED DRUG DELIVERY SYSTEMS (CDDS)

Now a day’s on the development of Novel drug delivery systems (NDDS) marked consideration has been focused. The method of drug delivery to the site of action shows a significant effect on its efficacy. It leads to the development and evolution of novel drug delivery systems that enhanced performance of potential drug molecules. Novel drug delivery systems play a key role in pharmaceutical research and development. Since when compared new chemical moiety the developmental cost and time required for introducing NDDS is relatively low.

Oral route remains one of the most ‘natural’ routes of drug administration and has seen remarkable accomplishments in the last couple of decades towards optimization of oral delivery of drug molecules. Oral ingestion is one of the oldest and most extensively used routes of drug administration. They provide an effective method of obtaining systemic and local effects.

Drug delivery describes a process whereby a therapeutic agent is administered to the body in a controlled manner. The product’s commercial and clinical value, product differentiation can be improved by developed drug delivery technologies. These advanced technologies serve as an advanced resource to outreach the competition. By simplifying the administration and dosing regimen drug delivery technologies make medicine more acceptable and convenient to a patient.

Any drug molecule by using Novel drug delivery system (NDDS) can get a ‘new life,’ and thus improving the competitiveness, patent life and market value. Among different NDDS present in the market, the major share in the market is hold by the oral controlled release systems because of its greater benefits of patient compliance and ease of administration. The development of novel and highly versatile delivery systems and osmotic drug delivery systems are the major contribution in oral NDDS.

Basically, there are three novel modes of drug delivery, i.e.

1. Targeted delivery,
2. Modulated release and
3. Controlled release.

Targeted delivery refers to the administration of a drug carrier systemically in order to deliver drug to the specific type of cells, tissues or organs. Modulated release implies use of a drug delivery device that releases the drug under controlled environmental conditions, bio feedback, sensor input or an external control device at a variable rate. Controlled release refers to a specific device that delivers the drug at specific release profiles or at a predetermined rate into the patient body.

1.1 CONTROLLED DRUG DELIVERY SYSTEMS (CDDS)

The nature of the controlled release dosage form is such that the release is determined by the design of the system and the physiochemical properties of the drug and is independent of the external factors or the microenvironment in which the dosage form is placed. These products typically provide significant benefits over immediate-release conventional dosage formulations. Optimum therapy with repetitive administration of conventional dosage forms (e.g. injectables, liquids or tablets) can classically be pursued by dosage scheduling. The aim of this process is to maintain drug concentration in a therapeutic range, above the minimum effective concentration and below the toxic concentration.

Thus CDDS avoids the undesirable saw tooth characteristics of the plasma concentration vs time profiles of the conventional drug products.

A diagrammatic illustration of controlled versus conventional dosage delivery is shown in Figure-1.

Fig 1.1 Plasma & Time profile of controlled drug release and conventional release

The plasma concentration of the drug reaches a maximum (crest) with conventional dosage forms and then decrease (trough) at the point where repeated administrations becomes necessary to maintain the plasma drug concentration. Very often the initial concentration is above the therapeutically effective level that may increase the risk of side effects. Conventional dosage forms can thus result in a drug regimen in which the drug concentration oscillates between alternating periods of overdose and inefficiency.

The delivery of drug at controlled rate over an extended period of time is represented mathematically:

Rate in = Rate out = K_e x C_d x V_d

Where Cd is the desired drug level, Vd is the volume of distribution and K_e rate content for drug elimination from the body.

Added to this, the high cost of development of new, safe, specific and effective drug molecule is prohibitive and developing nations virtually cannot afford such integrated multi-group cost intensive drug development ventures. Therefore, many pharmaceutical industries and drug research institute oriented their efforts to develop pre-programmed unattended delivery of drug at a rate and for a period to meet and achieve the therapeutic need. These systems are coined as Controlled drug delivery systems

Table 1.1 Classification of oral controlled release systems depending on mechanism of

Release ³ (vyas etal,2002)

1.1.1. ADVANTAGES OF CONTROLLED RELEASE PRODUCTS ⁴

As controlled release dosage form are slightly expensive than conventional formulations, they cannot be justified unless they offer come clinical or practical advantages given below:

• Reduction in dosing frequency
• More uniform effect
• Reduced fluctuation in steady levels
• Increased safety margin of high potency drugs
• Improved patient convenience and compliance
• Reduced in total amount of dose administered
• Avoidance of night time dosing
• Reducing of GI irritation and other dose related side effects and
• Reduction in health care cost.

1.1.2.DISADVANTAGES OF CONTROLLED RELEASE PRODUCTS ⁴

However, controlled drug delivery systems also have some disadvantages. They include,

• High cost;
• Poor systemic availability;
• Unpredictable and often poor invitro-invivo correlation;
• Possibility of dose dumping;
• Dosage adjustments potential is reduced;
• First pass clearance potential is increased;
• In case of hypersensitivity reactions, toxicity or poisoning drug retrieval is difficult;
• Effect of oral dose depends on Mean Residence Time.

To control or change the drug release from a dosage form there will be a number of design options. Most of the per oral controlled release dosage forms comes under the category of osmotic, matrix or reservoir systems. The polymer matrix contains embedded drug in matrix systems in which the release occurs by partitioning of drug into the release medium and polymer matrix. In case of reservoir systems a rate controlling membrane is surrounded and coated around the drug core. But, drug release from conventional controlled systems i.e., reservoir and matrix systems is affected by various factors like presence of food, pH and different physiological factors. In case of osmotic systems the drug is delivered based on the principles of osmotic pressure. The drug release from this system doesn’t depend on the pH and various physiological parameters and thus by optimizing the drug and systems properties the release characteristics can be modulated.

1.2. OSMOTIC DRUG DELLIVERY SYSTEMS – A REVIEW

1.2.1. HISTORICAL BACKGROUND

In 1955 Rose and Nelson utilized the principles of osmotic pressure in drug delivery for the first time. They described two systems; one that delivered 0.02 ml/day for 100 days and another that delivered 0.5 ml/day for 4 days, both for use in Pharmacological research.

In the 1970s, Higuchi and Leeper proposed a series of variations of the Rose-Nelson pump⁵. Theeuwes further modified the Rose-Nelson pump and developed a system. Small osmotic pumps of these forms are sold under the trade name ALZET (Alza Corp., CA). The device has a volume of approximately 170µl, and the normal delivery rate is 1µl/hr.

A major milestone was achieved in 1974 with the description by Theeuwes and Alza’s co-workers of a tablet design composed of a compressed tablet-core surrounded by a semi permeable membrane with a single orifice, so-called Elementary osmotic pump (EOP). This design adaptation for human use was conveniently processable using standard tabletting and coating procedures and equipment. The first two products indomethacin, Osmosin⁶ and phenylpropanolamine, Acutrim TM⁶ were launched in the 1980s.

Oral osmotic drug delivery system (OODS) development continued with two new OODS designs, the controlled-porosity osmotic pumps (CPOP) and the push-pull osmotic pumps (PPOP). The first of these was the CPOP, which was designed to decrease the risk of extremely localized drug-induced irritation at the site close to the orifice.

In the 2000s, a new drug product based on OODS technology was formulated to deliver methylphenidate to children (above the age of 6 years) with attention-deficit hyperactivity disorder (ADHD). These delivery systems were based on a new design, the push-stick osmotic pumps (PSOP), which combined immediate and sustained drug release phases.

The drug release from this system doesn’t depend on the pH and various physiological parameters and thus by optimizing the drug and systems properties the release characteristics can be modulated. In the last few years more number of patents are granted on these oral omotic drug delivery systems. These systems has ability to improve therapeutic agents clinical profile and so they are becoming one of the most attractive technologies today.

Osmotically controlled oral drug delivery system for the controlled delivery of active agents follows osmotic pressure principle. For the controlled drug delivery osmotic devices are most assured strategy based systems. Among the controlled drug delivery systems these are most reliable systems. Osmotic systems could be used in the form of implantable devices or oral drug delivery systems. Osmotic pump tablet (OPT) generally consists of a core including the drug, an osmotic agent, other excipients and semi-permeable membrane coat.

1.2.2. THEORY

Osmosis can be defined as spontaneous movement of a solvent from a solution of lower solute concentration to a solution of higher solute concentration through an ideal semi permeable membrane, which is permeable only to the solvent and impermeable to solute. The pressure applied to the higher-concentration side to inhibit solvent flow is called osmotic pressure⁸.

Osmotic pressure is a colligative property, which depends on concentration of solute that contributes to osmotic pressure. Solutions of different concentrations having the same solute and solvent system exhibit an osmotic pressure proportional to their concentrations. Thus a constant osmotic pressure, and thereby a constant influx of water can be achieved by an osmotic delivery system that results in a constant zero order release rate of drug⁸.

PRINCIPLE OF OSMOSIS

An osmotic system releases a therapeutic agent at a predetermined, zero order delivery rate based on the principle of Osmosis, which is movement of a solvent from lower concentration of solute towards higher concentration of solute across a semi-permeable membrane.

When osmotic system is administered, from the one or more delivery ports the drug that contain suspension or solutions is pumped out of the core due to the hydrostatic pressure developed by the imbibition of water in to the core osmotically through the semi-permeable membrane. By the water influx through semi-permeable membrane the delivery of drug from this system can be controlled.

Osmotic pressure is directly proportional to temperature and concentration and the following equation describes the relation between them:

Π = ØcRT

where

OP = osmotic pressure,

Π = osmotic coefficient,

c = molar concentration,

R = gas constant,

T = Absolute temperature.

OSMOTIC PUMPS

Osmotic pump is a new delivery device, which delivers drugs or other active agents at a controlled rate by the principle of osmosis. Control resides in the water permeation properties of the formulations

Table: 1.2 Examples of some marketed band of Osmotic drug delivery system⁷

DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY, SVCPPAGE 1