Examples of customized release particles How it works One or more functional polymer membranes are applied to a drug core granulated or layered onto a neutral surface through either aqueous or organic solvent-based drug solutions or suspensions. This results in a small, multi-layered bead. Depending on drug pH levels of solubility, either an organic acid or an alkaline buffer layer is incorporated to create an optimal pH. The organic acid layer is placed underneath the drug layer, while the alkaline buffer is placed over the drug layer.

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Acute coronary syndrome sudden death Vasospastic angina Morning surge Morning Early Morning Morning Morning Afternoon Ischemic heart disease: Ischemic heart disease IHD is the generic designation for a group of closely related syndromes resulting from ischemia, an imbalance between the supply and demand of the heart for oxygenated blood.

There are four overlapping ischemic syndrome, differing in rate of onset and severity of ischemia. They are myocardial infarction, angina pectoris, chronic IHD with heart failure and sudden cardiac death.

There is an accumulation of ischemic cardiac events such as unstable angina and acute myocardial infarction within the first few hours after waking and assuming activity.

The risk of these events is relatively lower during the rest of the day, especially during the sleep period. Most ischemic episodes occurred during the morning hours, beginning around a. The peak frequency of such events usually occurs between 10 a. This timing is consistent with the timing of surge in a series of physiological parameters: heart rate, blood pressure, blood concentration of epinephrine and nor-epinephrine, angiotensin II level, and platelet agreeability.

During this time, myocardial oxygen demand increases, while its supply may decrease. Also, coagulation activity is increased, and fibrinolytic activity is decreased. Together, these phenomena can account for the increased risk of ischemic events in the morning hours. In variant angina there appears to be a very early morning peak between 5 and 6 a. This is a time when ischemia occurs least frequently in patients who have a stable coronary artery disease.

The hour pattern in MI is also a result of the predictable timing of environmental triggers, change in posture and physical and mental loading occurring in the morning. These are largely responsible for the rapid increase in blood pressure, heart rate, and myocardial oxygen demand. Cardiovascular BP is at its lowest during the sleep cycle and rises Nitroglycerin,Calcium diseases steeply during the early morning A wakening channel Blocker,ACE period.

Arthritis Pain in the morning and more pain at night. HMG CoA reductase Inhibitors, Insulin, Chronopharmaceutical Drug Delivery system Pulsatile system is amongst one of them and gaining a lot of interest as it is increasing patient compliance by means of providing time- and site specific drug delivery system, thus providing special and temporal delivery.

Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period.

Recent studies show that diseased have predictable cyclic rhythms and the timing of medication regimens can improve outcome in selected chronic conditions.

Numerous studies conducted, suggest that pharmacokinetics, drug efficacy and side effects can be modified by following therapy matching the biological rhythm.

Specificity in delivering higher amount of drug in a burst at circadian timings correlated with specific pathological disorder is a key factor to achieve maximum drug effect. Ideally, Chronopharmaceutical drug delivery systems ChrDDS should represent time- controlled and site-specific drug delivery systems. First pass metabolism: Some drugs, such as beta blockers and salicylamide undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize presystemic metabolism.

Biological tolerance: Drugs that produce biological tolerance demand a system that will prevent their continuous presence at the biophase, as this tends to reduce their therapeutic effect.

The lag time is essential for drugs that undergo degradation in gastric acidic medium e. Targeting a drug to a distal organ of gastrointestinal tract GIT , like the colon, requires that the release is prevented in the two-third portion of the GIT.

Special Chronopharmacological needs: Circadian rhythms in certain physiological functions are well established. It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24 hour day, e. Local therapeutic need: For the treatment of local disorders such as inflammatory bowel disease, the delivery of compounds to the site of inflammation with no loss due to absorption in the small intestine is [26] highly desirable to achieve the therapeutic effect and to minimize side effects.

Gastric irritation or drug instability in gastric fluid: Protection from gastric environment is essential for the drugs that undergo degradation in gastric acidic medium eg, peptide drugs , irritate the gastric mucosa [27] NSAIDS or induce nausea and vomiting. Drug absorption differences in various gastro-intestinal segments: In general, drug absorption is moderately slow in the stomach, rapid in the small intestine, and sharply declining in the large intestine.

Compensation for changing absorption characteristics in the gastrointestinal tract may be important for some drugs. For example, it is rational for a delivery system to pump out the drug much faster when the [25] system reaches the distal segment of the intestine, to avoid the entombment of the drug in the feces. Predictable, reproducible and short gastric residence time 2. Less inter- and intra-subject variability 3.

Improve bioavailability 4. Limited risk of local irritation 5. No risk of dose dumping 6. Flexibility in design 7. Improve stability. Lack of manufacturing reproducibility and efficacy 2. Large number of process variables 3. Batch manufacturing process 4. The core is placed between two layers of polymer and directly compressed by flat punches of tablet machine. Drugs that treat cardiovascular disease nifedipine, nitrendipine, amlodipine, diltiazem etc and asthma theophylline, budesonide had been attempted to formulate such dosage forms.

Swada et al. Core in cup tablets: It is a novel oral pulsatile release drug delivery system based on a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and circumference wall with inactive material. The system consists of three different parts, a core tablet, containing active ingredient, an impermeable outer shell and a top cover layer- barrier of a soluble polymer.

The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic swellable materials such as polyethylene oxide, sodium alginate or sodium carboxy methyl cellulose. The system releases the drug after a certain lag time generally due to the erosion of top cover layer. The quantity of material, its characteristics viscosity, swelling, gel layer thickness and the drug solubility was found to modify lag time and drug release.

The lag [37,38] time increases when quantity of top layer increases, whereas drug release decreases. Drug formulation is contained within the insoluble capsule body which is sealed by means of a hydrogel plug. On oral administration the water soluble capsule cap dissolves in the gastric juices and hydrogel plug swells.

At a controlled and predetermined time point after the ingestion, the swollen plug is ejected from the pulsincap dosage form after which the encapsulated dosage formulation is then released.

To simplify this technology, the hydrogel plug has been replaced by an erodible tablet, which has a tight fit in capsule to prevent the entry of fluid. During the release process it erodes away from the mouth of capsule. The effect of various parameters such as type and weight of swellable polymer, type of hydrophilic polymers used in erodible tablet formulation and erodible tablet weight was investigated in [,45] order to characterize the lag time and drug release profiles.

First is placed into the capsule cap while the second dose is released from an insoluble capsule body. The capsules are filled with active pharmaceutical ingredient either for single pulse or multi-pulse release in form of multiparticulates and coated with a swelling layer followed by an external water insoluble semipermeable polymeric coating. Upon water ingress the swelling layer swells to attain a threshold hydrodynamic pressure required to rupture the outer coating and allowing the release of contents in surrounding medium.

The time required by swelling layer to rupture outer coating surves the purpose of desired lag time required in chrono therapy of disease. The tablets are manufactured and coated on the same [42] principle as that of double coated gelatin capsules. Pulsatile release muliparticulate systems: These systems have been developed on the basis of various approaches of designing pulsatile drug delivery system discussed later like time controlled, stimuli induced or externally regulated pulsatile drug delivery systems.

In recent pharmaceutical applications involving pulsatile drug delivery, multiparticulate dosage forms are gaining much favour over single unit dosage forms. The potential benefits include increased bioavailability, predictable, reproducible, and generally short gastric residence time; no risk of dose dumping; reduced risk of local irritation; and flexibility to blend pellets with different compositions or release patterns.

Because of their smaller particle size, these systems are capable of passing through gastrointestinal tract easily, leading to less inter- and intra-subject variability. For instance, colonic delivery of theophylline in form of microspheres and coated pellets for nocturnal asthma, formulation of indomethacin, ibuprofen, flurbiprofen, meloxicam, aceclofenac, diclophenac pellets and microspheres for chronotherapy of rheumatoid arthritis and floating beads of alginates encapsulating the active drug component in core, have been attempted to deliver many of the drugs which are absorbed in upper gastrointestinal tract.

Numerous advanced technologies have been developed in designing of pulsatile release [43,44] multiparticulate dosage forms and many of them are FDA approved and being marketed.

Chronomodulating infusion pumps: Externally and internally controlled systems across a range of technologies including pre-programmed systems, as well as systems that are sensitive to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, ultrasound, electric fields, temperature, light and mechanical stimulation.

To our knowledge infusion pumps on the market that have been referred to as chronomodulating for drug delivery application include the Melodie, programmable Synchromed, Panomat V5 infusion, and the Rhythmic pumps.

The portable pumps are usually characterized by a light weight g for easy portability and precision in drug delivery. For example portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the chronotherapy principle in a sufficiently large patient population. In case of insulin therapy, implantable infusion pumps containing a reservoir of insulin may be surgically placed within the subcutaneous tissue of the abdomen in the left upper or lower quadrant above or below the belt.

A catheter leads from the pump through the muscle layers into the peritoneal cavity, where it floats freely, and insulin delivery is by the intraperitoneal route. Doses adjustments are made by the patient within ranges established by the physician using radiotelemetry and an electronic device that is held over the pump. Their advantages include the fact that the peritoneum provides a large, well-vascularized surface area, and absorption is faster by this route than after subcutaneous injection better insulin gradient , improved glycemic control and a reduction in the frequency of hypoglycemic episodes.

Possible drawbacks of this approach include eventual formation of fibrous tissue pocket and local skin erosion. Catheter blockade which can reduce insulin delivery, are the most common problems with implantable pumps. However, these pumps [46,47] have been effectively used in the chronotherapy of several diseases such as cancer and diabetes.

Controlled-release microchip: An alternative method to achieve pulsatile or chronopharmaceutical drug release involves using microfabrication technology. Santini et al. The release mechanism was based on the electrochemical dissolution of thin anode membranes covering microreservoirs filled with [48] chemicals in solid, liquid or gel form. Approaches for Chronopharmaceutical DDS: Various approaches of pulsatile drug: Pulsatile drug delivery system can be broadly classified into three classes.

Time controlled pulsatile drug delivery II. Stimuli induced pulsatile drug delivery III. Externally regulated pulsatile drug delivery I. Time controlled pulsatile release: These time-controlled systems can be classified as single unit e. Single Unit Systems: Single-unit systems are mostly developed in capsule form. Capsular system: Single-unit systems are mostly developed in capsule form. The system that comprises of a water-insoluble capsule enclosing the drug reservoir.

A Swellable hydrogel plug was used to seal the drug contents into the capsule body. When this capsule came in contact with the dissolution fluid, it swelled; and after a lag time, the plug pushed itself outside the capsule and rapidly released the drug.

Polymers used for designing of the hydro gel plug were various viscosity grades of hydroxyl propyl methyl cellulose, poly methyl methacrylate, poly vinyl acetate and poly ethylene oxide. The length of the plug and its point of insertion into the capsule [49] controlled the lag time.

Tablets system: Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. This barrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly. This coat erodes or emulsifies in the aqueous environment in a time proportional to the thickness of the film, and the core is then available for dispersion.


review article - BOPAMS




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