In recent years, considerable attention has been focused on the development of new drugdelivery systems. There are a number of reasons for the intense interest in new systems. First, recognition of the possibility of repatenting successful drugs by applying the concepts and techniques of controlled release drugdelivery systems, coupled with the increasing expense in bringing new drug entities to market, has encouraged the development of new drugdelivery systems. Second, new systems are needed to deliver the novel, genetically engineered pharmaceuticals, i.e., peptides and proteins, to their site of action without incurring significant immunogenicity or biological inactivation. Third, treating enzyme deficient diseases and cancer therapies can be improved by better targeting.
Originally, polylactides and polyglycolides were used as absorbable suture material, and it was a natural step to work with these polymers in controlleddrugdelivery systems. The greatest advantage of these degradable polymers is that they are broken down into biologically acceptable molecules that are metabolized and removed from the body via normal metabolic pathways. However, biodegradable materials do produce degradation by- products that must be tolerated with little or no adverse reactions within the biological environment. These degradation products—both desirable and potentially nondesirable—must be tested thoroughly, since there are a number of factors that will affect the biodegradation of the original materials. The most important of these factors are shown below—a list that is by no means complete, but does provide an indication of the breadth of structural, chemical, and processing properties that can affect biodegradable drugdelivery systems [10-11].
INTRODUCTION: Earlier patients have been using conventional dosage forms like Tablet, Capsule to treat the acute and chronic diseases, but these conventional dosage forms have to be taken several times in a day for maintaining the peak plasma level concentration. Hence to overcome these problems controlled release drugdelivery system were developed. Controlleddrugdelivery system (Microspheres) releases the drug in controlled rate and overcome the problems of conventional drugdelivery system and enhances the therapeutic efficacy of a given drug 1 . The main purpose of Controlleddrugdelivery system is to ensure optimum plasma drug concentration, thus enhancing efficacy, safety and bioavailability of drug with improved patient compliances 2 .
Nanoparticles can be prepared by various techniques & are evaluated for parameters like: Particle size, Morphological properties, Thermal properties, surface chemistry & drug release etc. Nanoparticles can be converted into dry form & formulated in various dosage forms depending on the route of application. Several marketed formulation based on controlleddrugdelivery are also available which is the fruitful result of the development of biodegradable polymer, newer techniques for preparation, scale up procedure & better control over all the required manufacturing processes .
CDDS stands for osmotically controlleddrugdelivery systems. OCDDS is one of the most common and promising drugdelivery system that is done by using osmotic pressure as a driving force for the control delivery of active agent. The drugs which deliver through this system are not dependent on hydrodynamic and pH.conditions of the body. It is also possible to obtain higher release rates through these systems than through other diffusion-based systems. To fulfill patient’s need and requirement various type of osmotic pumps for different drugs are available in market. Recently research in field of pharmaceutical shows development of several novel drugdelivery systems. The main motive of newly develop drug product is to be therapeutically effective with some additional benefits such as:
ABSTRACT: Oral modified or controlled dosage forms have always proven to be more effective alternative to conventional or immediate release dosage forms.
Controlled or modified drugdelivery systems offer numerous advantages of delivering a drug to the body in a précised manner with an aim to minimize its unwanted side effects and maximize its benefits. Targeted drugdelivery systems target a particular site in the body to maximize the drug concentration in a specified tissue or organ of the body which improves therapeutic efficacy of the drug, decrease toxicity and with better patient compliance and convenience. In past few decades, microspheres have promised targeted or controlleddelivery of drugs in the body which has proved to be better than the conventional drugdelivery. Recently microspheres have been used to deliver drugs, vaccines, antibiotics and hormones in a controlled manner. The present study aims to review different aspects of the microparticulate drugdelivery system along with types of microspheres, methods of preparation and different applications as targeted or controlleddrugdelivery system.
The Physics of Membrane Emulsification and Applications for ControlledDrugDelivery
In many applications employing particles, the distribution of particle sizes has significant influence over the properties of the resultant material, and this holds especially true for many pharmaceutical products. In the case of depot formulations made of drug-loaded polymer microspheres, particle size significantly impacts the rate and duration of drug release. Thus, if particle size can be controlled, formulation characteristics can be engineered to better meet the needs of the specific situation. Cross-flow membrane emulsification (XME) is a method for manufacturing uniformly sized emulsion droplets which can be used for many applications, including production of drug-loaded polymer microspheres. In XME, a dispersed phase is forced through an orifice in a planar membrane into a simple shear flow set up by a second continuous phase flowing parallel to the membrane surface, thereby generating an emulsion. Though XME has become a popular technique for researchers generating monodisperse emulsions, there has been insufficient characterization of the physics of the XME process. This is true for both simple binary fluid systems, as well as the more complex fluid systems used for the generation of drug-loaded microspheres. In this work, we describe a unique XME system that allows for visualization of the process, providing access to details likely unseen by previous researchers. First employing our system for the study of pure fluids, we successfully show that a simple force balance can be used to model the size of emulsion droplets as a function of process conditions. We also show that the range of applicability of our model corresponds to the region of simple fluid dripping, and that the XME process undergoes a dripping-jetting transition much like the common household faucet. Extending the methods to a more complex case when dissolved polymers, drugs and surfactants are present, we find generally that our earlier results hold true, but only if dynamic interfacial tension is taken into account. Ultimately we show that drug-loaded polymer microspheres of uniform size can be reliably and predictably manufactured across a range of process conditions, and thus we conclude that XME has the potential to produce advanced controlled release formulations.
From the earliest times, people have found ways to introduce drugs into the body. This process began with the chewing of leaves and roots of medicinal plants. Throughout the history of medicine delivery of drugs to humans has evolved from primitive extracts and inhalants to more reliable dosages forms, such as injections, tablets and capsules. These drugdelivery systems are expected to be further optimized to increase drug activity and reduce toxicity. For instance, one of the most common ways of administering drugs to the body is via injection into the bloodstream. The injected material is circulated throughout the body and thus commonly termed systemic delivery. The drawbacks of this delivery method are that the concentration of the injected material is extremely diluted and the material acts on most tissues of the body and may be toxic to some of them. The problem could be solved by controlleddrugdelivery. In controlleddrugdelivery systems, the active agent is released in a predesigned manner. Drugdelivery systems can influence the performance of a drug by manipulating its concentration, location and duration of exposure.
Ion exchange resins(IER) recently used in the controlled release drugdelivery due to its properties, more efficient, accurate drug loading, control release and better stability. IER are the attractive carriers for the controlleddrugdelivery systems which suitable for drug-delivery technologies, including oral controlled release, reduction of toxicity, site specific, fast dissolving, iontophoretically assisted transdermal, nasal, ophthalmic, and taste masked systems. The present review is to focus, current technological developments like the factors affecting the nature and strength of the binding/loading of drug-sized model compounds into the ion-exchange resins. Also the practicability of ion exchange resins for delivery of drugs loading and IER applications and future potential.
Karan Jangra, Ravinder Verma and Deepak Kaushik *
Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak - 124001, Haryana, India.
ABSTRACT: The aim of the present study was to formulate an osmotically controlleddrugdelivery system (O-CDDS) of Metformin hydrochloride to reduce the frequency of multiple dosing in non-insulin dependent diabetes mellitus-II which is a lifelong disease. Metformin hydrochloride a BCS Class-III drug having a poor biological half-life of 6 h. O-CDDS of Metformin hydrochloride is a recent approach for the zero-order release profile. Different factors X1 (effect of percentage of plasticizer), X2 (effect of percentage of release modifier), X3 (effect of percentage of coating) were optimized using central composite design. The granules were prepared by wet granulation technique using PVP K90 as a binding agent. Evaluations of granules like bulk density, tapped density, Hausner's ratio, carr’s compressibility index, angle of repose was done. Then core tablets were prepared using 16 station tablet press and evaluated for hardness, friability, weight variation. For the preparation of a semi-permeable membrane, the coating of cellulose acetate using polyethylene glycol 400 as a plasticizer was done. Then drilling was done mechanically to create the delivery orifice.
Paliwal et al.: ControlledDrugDelivery of Ketorolac Tromethamine
The most common method for applying a drug in to the eye is to formulate the drug in the form of an eye drop, but this method is not considered ideal for ocular delivery of drug because of poor bioavailability arising from precorneal loss processes, this loss of drug from the precorneal area is a net effect of drainage, tear secretion and noncorneal absorption. Following the above lead we tried to improve the ocular bioavailability by increasing the corneal contact time and the feasible way was to formulate a drug with mucoadhesive/viscosity imparting agents. The adhesive strength of various polymers on corneal surface was studied with the help of self modifi ed Franz diffusion cell and freshly excised goat/bovine cornea. The polymers hydroxypropylmethylcellulose, carboxymethylcellulose sodium, Eudragit type E/RL/RS, Carbopol ETD 2020 and Carbopol 934 National Formulary were formulated with drug, ketorolac tromethamine. The adhesive strength of polymers on corneal surface and permeation characteristics of drug through cornea were investigated by using above said formulations. Eudragit type E/RL/RS did not show any improvement in mucoadhesion, but the formulations containing Carbopol ETD 2020 and Carbopol 934 national formulary showed good mucoadhesion on corneal surface in the concentration as low as 0.75%. The mucoadhesive strength was also evaluated using the combination of Carbopol acrylates/C 10-30 alkylacrylate with allylpentaerithrital and preservative benzalkonium chloride, which also resulted in good mucoadhesion with improved against S. aureus. Compounds 4b, 4c, 4d and 4j
A lot of work is being done to achieve pulsatile release so that the drug release can be delivered according to circadian rhythms of our body. Advancis Pharmaceutical Corp., German town, Maryland, USA has developed once-a-day pulsatile delivery system called Pulsys ® , which enables the delivery of antibiotic amoxicillin in regular concomitant pulses. The rationale behind designing such a system is that it has been reported that antibiotics are more effective against fast-growing bacteria. When an immediate release antibiotic is administered, bacteria respond to it by going into a dormant stage, while the administration of a pulsatile system in such a case is more effective because the regular release of increased pulses of antibiotic does not let defence system of the bacteria to go into a dormant stage. The preclinical studies have shown that pulsatile approach of delivering antibiotic is more effective. Advancis is developing Pulsysâ versions of three of the top five most prescribed antibiotics in the United States. Asthmatic patients suffer from lung discomfort more in early morning due to circadian changes 30 . Therefore, it is desirable to get maximum bronchodilating effect in the morning hours. One such example is of a bronchodilator “Uniphyl” (theophylline) 31 , which was developed by Purdue Pharmaceuticals Products L. P., Stamford, USA, and approved by FDA in 1989. It’s a once-a-day formulation. When taken in the evening, it reaches to peak blood levels in the morning hours, resulting in improved lung functioning and relief to the patient.
uncoated ODDS as they offer less fluctuation in drug plasma peak, low dose requirement, decrease in frequency of drug administration, less side effects because of low dose, and concentration of drug lies in therapeutic window, improved patient compliances etc. But there are disadvantages with CDDS like dose dumping. To overcome this, special requirements are required which give rise to new area of research called Pulsatile drugdelivery system (PDDS). There are some special conditions which require release of drug after a certain period of time called lag time to achieve optimum concentration at required time and required site. The release phase of drug is retarded in its initial phase but release is required after lag time. This type of drug formulations which have lag time and release drug after lag time are come under Pulsatile drugdelivery system(PDDS). Recent studies showed that diseases which are circadian rhythm follower are overcome if medication timing is proper or optimized. The explanations of biological clock are given by three rhythms in body which are set up by the natural biological clock of the body operated by SCN present in hypothalamus gland. The three types of rhythms are:
The main Single Chamber Osmotic Pump in use is Elementary Osmotic Pump (EOP). Elementary Osmotic Pump was developed by Theeuwes in 1975. EOP works on the most basic device and works on the principle of delivering the drug at a controlled rate by an osmotic process. EOP contains a drug of good aqueous solubility and can have an osmotic agent as well. It is surrounded by semi permeable membrane which is essentially rate controlling. The membrane is provided with an orifice for the controlled exposure of saturated solution of the drug which is the result of water imbibition by the fluid permeability of the membrane and the osmotic pressure of the compressed tablet when it is exposed to the aqueous environment.
Department of Pharmaceutics, Saraswati Institute of Pharmaceutical Sciences 1 , Gandhinagar, Gujarat, India Shree Sarvajanik Pharmacy College 2 , Mehsana, Gujarat, India
The parenteral administration route is the most effective and common form of delivery for active drug substances with poor bioavailability and the drugs with a narrow therapeutic index. Drugdelivery technology that can reduce the total number of injection throughout the drug therapy period will be truly advantageous not only in terms of compliance, but also to improve the quality of the therapy and also may reduce the dosage frequency. Such reduction in frequency of drug dosing is achieved by the use of specific formulation technologies that guarantee the release of the active drug substance in a slow and predictable manner. The development of new injectable drugdelivery system has received considerable attention over the past few years. A number of technological advances have been made in the area of parenteral drugdelivery leading to the development of sophisticated systems that allow drug targeting and the sustained or controlled release of parenteral medicines.
In non swelling matrix tablets the drug is embedded in a poorly soluble matrix such as Ethyl Cellulose or a Polymethacrylate. The combination of Ethyl Cellulose and a hydrophilic component such as Hydroxyl Propyl Methyl Cellulose offers a flexible system to tailor the drug release by changing the viscosity, substitution type and concentration of Hydroxyl Propyl Methyl Cellulose. 20 Ethyl Cellulose polymer coating is used for slow release of drug, the release is further slow down by the application of lipophillic plasticizer like Dibutyl sebacate. 21 Ethyl Cellulose produces hard tablet with low friability, tablet usually will disintegrate readily drug dissolution will be impaired due to the fact that Ethyl Cellulose acts as an inert, hydrophobic matrix, however this can be advantageous for delaying release of water soluble drugs. Lower viscosity Ethyl Cellulose displays the slowest drug release rate, as this grade is more compressible and therefore has a lower porosity. 21 Ethyl Cellulose is one of the most commonly used polymer for sustained release film coating. The polymer is insoluble, but permeable in water over the range of gastrointestinal pH, and thus can be utilized to produce semi-permeable membrane that controls the rate of drug release from coated substrate. 22
Cirrcadian rhythm are an adaptive phenomena relating to predictabe changes in environmental factors that regulate many body functions like metabolism, sleep pattern, hormone production and physiology. Synchronizing drugdelivery in a consistent manner with body’s circadian rhythm is the basic concept for chronotherapeutic drugdelivery system. The safety and efficacy of a drug can be improved by conducting the peak plasma concentration with the circadian rhythm of the body. The time controlled or pulsatile drugdelivery systems are the best approach for chemotherapy. It offers rapid and transient release of certain molecules within short period which is a time and site specific drugdelivery system. These systems delivers the drug at the right time in the right amount for patient suffering from circadian phase dependent disorders like asthma, myocardial infarction, angina pectoris, hypertension, arthritic, epilepsy etc. So various systems like osmotic and coated system are being made.
8 OROS liquid controlled release technology is intended to carry drug as a liquids formulation and unite the reimbursement of complete release with elevated bioavailability 11 . Figure 3 show the illustration for L-OROS SOFTCAPS drugdelivery technology before along with during procedure. So, these are the technologies were healthy for controlled drugs delivery of liquids preparations together with lipophilic self- emulsify formulation [SEF]. The liquid drugs preparation there in soft gelatin capsules, which was enclosed through the osmotic layers, the barrier coating, as well as release rates controlling membranes. A drugs delivery orifice is shaped from side to side these 3 layer. While these systems are in touch with the aqueous surroundings, water permeate transversely the rates controlling membranes and activate osmotic layers. Growth of the osmotic coat result in the expansion of hydrostatic pressures within the dosage form, thus force the liquid preparation to rupture from first to last hydrated gelatin capsule shells at the drugdelivery orifices. The drug liquid formulation is pumped through the delivery orifice. L-OROSE HARDCAPS is comparable to L- OROSE SOFTCAPS and consist of a liquid drugs coat, osmotic agent, and barrier layers, were enclosed in hard gelatin capsules and covered through SPM 12 . Release orifice is drill in the exterior at the ending of the drug layers; provide an opening for the drugs suspensions.
Compared with other routes, the oral route is the simplest, most convenient and safest means of drug administration. 1 The treatment of illness has been accomplished by administrating drug to the human body via various pharmaceutical dosage forms like tablet, capsule, and microspheres. To achieve and maintain the therapeutics range extensive effort have recently been focused on targeting a drug or drugdelivery system in a particular region of the body for extended period of time, not only for local targeting of drug but for better control of systemic drugdelivery. To achieve and maintain the drug concentration in the body within the therapeutics range required for medication, it is necessary to take this type of drugdelivery system several times a day this yield undesirable ‘seesaw’ drug level in body. A number of advancement has been made recently in the development of new technique for drugdelivery, the technique capable of regulating the rate of drugdelivery system 2