Development of more “User-Friendly” dosage form ultimately increases dosing convenience for the patient. Living organisms require different amounts of drug at predictably different times within the circadian cycle which will maximize therapeutic and minimize undesired drug effects. Concept of chronopharmaceutics wherein, research is devoted to the design and evaluation of drug delivery systems that release a therapeutic agent at a rhythm that ideally matches the biological requirement of a given disease therapy. Diseases where a constant drug levels are not preferred, but needs a pulse of therapeutic concentration in a periodic manner and diseases with established oscillatory rhythm in their pathogenesis includes asthma, arthritis, duodenal ulcer, cancer, cardiovascular diseases (example hypertension and acute myocardial infarction), hypercholesterolemia, and ulcer acts as a push for the development of “Pulsatile Drug Delivery Systems “. In these systems, there is rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off release period. Various techniques are available for the pulsatile delivery like pH dependent systems, time dependent systems, micro-flora activated systems, etc. which can be designed as per the physiology of disease and properties of the drug molecule. Pulsatile drug delivery system is time and site specific drug delivery system, thus providing special and temporal delivery and increasing patient compliance. Pulsatile drug delivery system is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after predetermined off-release periods i.e. lag time. Advantages of the pulsatile drug delivery system are reduced dose frequency; reduce side effects, drug targetting to specefic site like colon, protection of mucosa from irritating drug and many more. Now in market varies technologies of pulsatile drug delivery system like OROS, CODAS and etc. are launched by some pharmacuetical companies.
A Review on Latest Advancement in Patented Controlled / Sustained Release Drug Delivery System
For many disease states the ideal dosage regimen is that by which an acceptable therapeutic concentration of drug at the site (s) of action is attainted immediately and is then maintained constant for the desired duration of the treatment.1 Over the past 30 years as the expense and complication involved in marketing new drug entities have increased, with concomitant recognition of the therapeutic advantage of modified release per oral dosage forms, greater attention has been focused on development of sustained, controlled release and delayed release system.
There are several reasons for the attractiveness of this dosage form. It is generally recognized that for many disease states, a substantial number of therapeuticatty effective compounds already exist. The effectiveness of these drugs however is often limited by side effects or the necessity to administer the compound in a clinical setting.
The goal in designing delayed release sustained or controlled delivery system is to
- Reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required, or providing uniform drug delivery.
- It would be a single dose for the duration of treatment whether it is for days or weeks, as with infection, or for the life time of the patient, as in hypertension or diabetes.
- It should deliver the active entity directly to the site of action, minimizing or eliminating side effects.
- This may necessitate delivery to specific receptors or to localization to cells or to specific areas of the body.2
- The safety margin of high potency drug can be increase and the incidence of both local and systemic adverse side effects can be reduced in sensitive patient.3
Benefits of modified drug delivery system 4
ØDecreased in dosing frequency
ØReduced peak to trough ratio of drug in systemic circulation.
ØReduced rate of rise of drug concentration in blood.
ØSustained & Consistent blood level with in the therapeutic window.
ØCustomized delivery profiles
ØReduced side effects
ØImproved patient compliance
Modified release drug products have been successfully marketed for many years. These products include dosage forms for oral & transdermal administration, as well as injectable & implantable system. Some marketed modified release product are given below
Example of marketed modified release product 4
Cata Press TTS
Ortho - Mcneil
Trans Dermal Patch
Trans Dermal Patch
Trans Dermal Patch
Trans Dermal Patch
Angenia / Hypertension
Ovearian cancer and Kaposi’s sarcoma
Advance prostate cancer
There are also some patented technologies of modified release drug delivery system
3.Elan drug technology
4.Microchip technology for delivery of insulin
5.OROS Push pull technology
6.L – Oros technology
7.En Sotrol technology
8. DUROS Technology
Port technology 5
Port stands for programmable oral release technologies that use a unique coated in capsulated system with opportunity to provide multiple program release of drug. Port technologies offer significant flexibility in obtaining unique and desirable release profile to maximize pharmacological and therapeutic effect. There are mainly two dosage forms for port technology.
Tablet dosage form description
The dosage form consist form of polymer core matrix coated with the semi permeable, rate-controlling polymer. Poorly soluble drugs can coated with port properties solubilization agent to insure uniform control release from the dosage from
Fig.1 Drug release mechanism from the PORT tablet
Capsule dosage form description
The dosage from consist of a hard gelatin capsule coated with the semi permeable, rate controlling polymer. Inside coated capsule is the osmotic energy source, which normally contains the therapeutic agents to be delivers. The capsule is sealed with the water in soluble lipid separators plug and immediate release dosage can be edit above the plug the to complete the dosing option
Fig.2 Drug release mechanism from the PORT capsule
Example of port technologies:-
- Delayed release pseudoephedrine
- Multiple program release of phenylpropanolamine
Flamel micropump technology 6
Flamel micro pumps technologies a controlled release system which permits delayed and extended delivery, of small molecule drugs. T is suitable in particularly narrow window of absorption from the upper part of the small intestine.
Flamel micro pump technology consists of a multiple per capsule or tablet containing micro particles per capsule or tablet. The 200-500 mm diameter size microform in the stomach and pass into the small intestine, where each micro particle, operation delivery system release the drug by osmotic pump at a adjustable rate (micro pump 1st or delayed for micro pump 2nd) and over and extended period of transit of time.
Current Flamel products
Fig.3 Flamel micropump technology
The design of micro pump micro particle allows extended transit time enough plasma mean resident time extended up to 24hours, which is spatially suited drug known to be absorbed only in small intestine the micro particle design can be adopted to be each drug specifically modifying the coating thickness and composition include the expedients (encapsulation) reduce toxicity and or reduces C max or peak drug concentration in the plasma (an improve patients regimen)
- Permit the extended delivery of drugs with a narrow window of absorption.
- Allow the controlled release of poorly soluble and as well as highly soluble drug
- Applicable to low dosage (4mg) and high dosage (100mg)
- Easy to swallow (due to the micro particle size)
- Test masking
- Good tolerability
- Avoid dosage dumping
- Reduce intra and inter variability
- Allows combination of different drugs who’s release can be controlled separate
- Easy to scale up to industrial high volume production
- Cost effective process
- Strong interactual properties position (over 40 patients)
Elan drug delivery technology 7
Elan offers more than 30 years experience in product development, optimization and manufacture and has engaged in successful coloration with more than 30 of the world’s leading pharmaceutical companies.
ELAN is focus on providing superior technologies platforms that can offer innovative high value, quality technologies to address the drug delivery challenges of the pharmaceutical industry.
ELAN delivers extecive scientific expenditure to help save difficult drug delivery and life cycle management challenges
ELAN continues to solve problems with poor solubility which can be in corporate in to a Verity of dosage forms as well as customization release profile for oral dosage forms.
PRIALT® Ziconotide intrathecal infusion
Azactan® Aztreonam for injection, USP
MAXIpime® Cefepim hydrochloride for injection
Microchip technologies for delivery the insulin 8
Researchers are working hard to develop an implantable insulin pump that can major blood sugar levels and deliver the exact amount of insulin needed. This would make it possible to mimic the action of natural insulin delivery.
Scientists are making progress with an implantable capsule that continuously produces insulin and release it to the blood stream.
The capsules developers have also over come biocompatibility problems using microchip technologies they has succeeds in creating a capsule that won’t be a attacked an destroyers by bodies immune system.
OROS® push pull technology 9
Push pulls system compromise bilayer or trilayer tablet core consting of one push layer and 1 or more drug layer. The drug layer contains the poorly soluble drugs, Osmotic agents and suspending agent. The push layer contains among other things, osmotic agent water swellable polymers. Asemipermeable membrane surrounds the tablet core.
Product comerslize using the push pull system include Glucotrol Xl® and procardia XL both composed of a bilayer tablet core and Concerta® compose of a tilayer .
Fig.4 Bilayer and trilayer OROS Push pull technology
L– OROStm technology 9
To over come the drug solubility issue, Alza developed the L – OROS system where a lipid soft gel product containing drug in a dissolved state is initially manufactured and than coated with a barrier membrane, than osmotic push layer and than a semi preamble membrane, drilled with an exit orifice.
Fig.5 L – OROStm technolgoy
EN SO TROL Technology9
Shire laboratory use an integrated approach to drug delivery focusing on identification and incorporation of the identified enhancer into controlled release technologies to create optimized dosage form. Solubility enhancement of an order of magnitute or more can be achieved.
Fig.6 EN SO TROL Technology
DUROS technology 10
The Duros technology is the miniature drug dispensing system that opposite like a miniature syringe and reglious minute quantity of concentrated from in a continues and constistant from over months or year.
The system consists from a outer cylindrical titanium alloy reservoir. This reservoir high impact strength and protects the drug molecules from enzymes, body mostres, cellular components that might deactivate the drug prepare to deliver
Fig.7 Duros technology
Advanced application of DUROS technology
Ø Chronogesictm ( Sufentanil) pain therapy system
ØTargeted drug delivery with catheterized osmotic pump
ØSite-specific drug delivery using Duros with a precious miniature catheters
In recent years, considerable attention has been focused on the development of novel drug delivery system technology. The reason for third shift is relatively low development cost and time required for introducing a NDDS technology approximately doller 20-50 million and between 3- 4 years and these technology also reduces the side effect and easy etc patient compliance. In the form of NDDS technology, an existing drug molecule can get a new life. Thereby increasing its market value competitiveness and life.
Drug delivery, in general, will continue to se significant growth in the pharmaceutical industry. In corporation of drug delivery concepts such as bioavailability enhancement and controlled release into the development of NCEs is the next logical steps.
1.Aulton E. Micheal, Modified release per oral dosage forms, Pharmaceutics – The Science of Dosage form Design , Churchill LivingSton New York, Page no.575
2. Banker S. Gilbert , Rhodes T. Christopher , Mordern Pharmeceutics , Marcel Dekker , Inc., New York, Page no. 575
3.Lachman Leon ,Lieberman A. Herbert , Kanig L. Joseph , The Theory and practices of Industrial Pharmacy , Varghese publishing House , Bombay, ed 3rd 430-431
4.Bhatt, Padmanabh, Osmotic delivery system for poorly soluble drug, The Drug delivery companies Report Autumn/Winter 2004 ©PharmaVentures Ltd 2004
6.www. Flamel. technologies.com (info @flamel .com)
9. Bhatt, Padmanabh, Osmotic delivery system for poorly soluble drug, The Drug delivery companies
Lecturer, Deptt. of Pharmaceutical Technology,Noida Institute of engg. and technology, Greater Noida.
Lecturer,K.N. Modi Institute of Pharmaceutical Education and Research, Modinagar
Nanoparticles hold tremendous potential as an effective drug delivery system.
Controlled drug through diffusion and activation-based drug delivery devices have become commercially-feasible due to converging technologies and
Specialty pharmaceutical company Depomed, Inc., has developed a Gastric Retention (GR™) drug delivery system to provide oral, once-daily, control
During the past three decades significant advances have been made in the area of novel drug delivery.
Abstract : This study was designed to theoretically investigate the influence of drug release properties, characterized by the disi