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REVIEW ARTICLE
Year : 2006  |  Volume : 9  |  Issue : 4  |  Page : 207-216
 

Controlled release formulations in neurology practice


Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi - 221 005, India

Correspondence Address:
J K Pandit
Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi - 221 005
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-2327.29202

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   Abstract 

Recently, controlled release (CR) pharmaceutical products have become a very useful tool in medical practice, offering a wide range of actual and perceived advantages to the patient. A CR product requires numerous considerations, like drugs suitable for CR formulations, techniques of fabrication and evaluation, factors affecting bioavailability of the parent drug, before it can actually be claimed to provide the purported benefits. Such complex considerations fall under the domain of pharmaceutical experts and clinicians, naturally, are not sufficiently aware and updated about these products and their biological consequences. Various CR formulations used in neurological practice are discussed in the present review. The clinical studies of the conventional and CR dosage form of the drugs used in neurology practice reflect the advantages of prescribing CR formulations over the conventional dosage forms.


Keywords: Clinical studies, controlled release formulations, neurology practice, pharmaceutical evaluation


How to cite this article:
Pandit J K, Singh S, Muthu M S. Controlled release formulations in neurology practice. Ann Indian Acad Neurol 2006;9:207-16

How to cite this URL:
Pandit J K, Singh S, Muthu M S. Controlled release formulations in neurology practice. Ann Indian Acad Neurol [serial online] 2006 [cited 2017 May 1];9:207-16. Available from: http://www.annalsofian.org/text.asp?2006/9/4/207/29202


There had been an outpouring of controlled release (CR) formulations for several medicines in the last two decades. These delivery systems offer numerous advantages in comparison to conventional dosage forms, which include fewer doses per day or week, reduced adverse effects and improved patient compliance and convenience.[1],[2] CR products are designed to maintain constant therapeutic plasma concentration of the drug within the therapeutic range of the drug over prolonged periods [Figure - 1].[2]

In conventional oral dosage forms, which include capsules, solutions, suspensions and tablets, the drug is released by dissolution or diffusion. The resulting pattern of drug concentration in plasma can vary widely and may cause inconsistent and undesired clinical effects. The high-peak blood concentration reached soon after administration may result in adverse effects. An example is hypotension in patients taking rapid-release nifedipine products. The use of a CR product of nifedipine avoids the high initial blood concentration which causes the sudden hypotension and as reflex tachycardia. Another example is the transient nausea at sub-toxic concentrations which results from the local irritation caused by high intestinal concentrations of some conventional-release products such as theophylline.[2],[3]

With CR products the precise rate, extent or timing of drug entry into the blood stream is predetermined or achieved with an integral drug-specific composition, structure or mechanism.

The rate of dissolution or diffusion, especially of an orally administered drug in conventional dosage forms, is influenced by many patient-dependent factors.

Characteristically, all conventional dosage forms, except continuous IV infusion, release drugs largely according to first-order kinetics. This produces alternating high and low concentrations and the optimal therapeutic level is only briefly present. In contrast, the CR systems release the drug at a constant rate (zero order) or at a predictably constant declining rate (first order) for a certain time period. This results in uniform concentration of drug in plasma and tissue.[2]

Drugs with short half-life often need to be given at frequent intervals to maintain blood concentrations within the therapeutic range. There is an inverse correlation between the frequency of dosing and patient compliance. A reduction in the number of daily doses offered by CR products has the potential to improve patient compliance. However, this advantage probably only occurs when conventional formulations need to be given three or more times a day. Ideally, CR products are not significantly affected by the external environment, so that patient-to-patient variability is greatly reduced.[2],[4]

The clinicians are not sufficiently updated on the technologies behind these CR preparation and their biological consequences. Therefore, the aim in this review is to provide an update on the technologies of CR formulation and how they differ from the conventional or immediate release (IR) drug products.


   Drugs Suitable for CR Formulations Top


There are certain properties of the drug, which must be considered for the design of CR peroral dosage forms [Table - 1]. The aqueous solubility and intestinal permeability of drug compounds are of paramount importance. A drug that is highly soluble at intestinal pH and absorbed by passive diffusion has an ideal characteristic for fabrication of CR dosage forms. A drug with no site-specific absorption characteristic is preferred. A drug with low aqueous solubility (<1 mg ml -1) may already possess inherent sustained release (SR) potential.

Once the drug is dissolved in the gastro intestinal tract (GIT), its permeability across the GIT becomes important. More than 90% absorption in vivo may be expected for compounds with permeability coefficient P > 4 x 10 -6 mms -1, whereas less than 20% absorption is expected when P is < 0.5 x 10 -6 mms -1. Drug candidates with a permeability < 0.5 x 10 -6 mms -1 are likely to be unsuitable for formulation into a CR dosage form.

For drugs with short biological half-life (time for elimination of half of the amount of a substance that has been administered) and with a clear relationship between concentration and response (therapeutic activity of the drug molecule), it will be necessary to dose at regular, frequent intervals in order to maintain the concentration within the therapeutic range. Higher doses at less frequent intervals may result in higher-peak concentrations with the possibility of toxicity. For drugs with wide margins of safety, this approach may be satisfactory. For example amoxycillin has a half-life of approximately one hour, but a dosage frequency of eight hours. This means that very large fluctuations will occur within a dosing interval, but, in view of the low toxicity of this drug, no difficulty with this approach is encountered provided the concentrations are above the minimum effective concentration during the dosing interval.

A drug with biological half-life of between two and six hours is preferred for inclusion in CR dosage form to avoid accumulation in the body. CR formulation of drugs with long half-life does not offer any advantage. The pharmacological effect of some drugs with short half-life is sustained by various mechanisms:

  1. The drug binds to the tissues e.g. tissue-bound ACE inhibitors. For these drugs, less frequent dosing is needed even though the drug may have a short half-life.
  2. The drug has irreversible effects e.g., the inhibition of platelet cyclo-oxygenase by aspirin.
  3. The relationship between response and plasma/blood concentrations is relatively flat or if the dose given results in concentrations which are in the plateau region of the dose-response relationship e.g., thiazides in hypertension.
  4. The drug is metabolized to pharmacologically active metabolite(s), which are more slowly cleared than the parent drug e.g., quinapril, trandolapril and venlafaxine.


Drugs with dosage not exceeding 125-325 mg are more suited as CR products in order to limit the size of the delivery system. However in certain cases the dose may exceed.[2],[5],[6]


   Classification of CR Systems Based on Fabrication Techniques Top


The modulation of dissolution of the active drug component and diffusion of the dissolved or solubilized species are the basic mechanisms for controlling drug release. These mechanisms may operate independently, together or consecutively. The CR systems are classified on the basis of these mechanisms.

Diffusion-controlled products

Matrix diffusion controlled systems: The therapeutic agent is dispersed in an insoluble matrix of rigid non-swellable hydrophobic materials or swellable (soluble) hydrophilic substances. Materials used for rigid matrix are insoluble plastics such as poly vinyl chloride and fatty materials like stearic acid, bees wax, etc. Swellable matrix systems are generally composed of hydrophilic gums of natural (guar gum, tragacanth, karaya gum), semisynthetic (hydroxy propyl methyl cellulose, carboxy methyl cellulose, xanthan gum) and synthetic (polyacrylamides) origin. The drug and matrix materials are granulated together and compressed into CR tablets. Examples include Plendil ER (Felodipine), Agon SR (Felodipine), Kapanol (Morphine sulphate) and Slow-K (Potassium Chloride). TIMERx is a CR product based on agglomerated hydrophilic matrix consisting of xanthan gum and locust bean gum. Slofedipine XL (nifedipine) and Cystrin CR (oxybutynin) are other products developed using this technology. Drug release from insoluble matrices involves penetration of fluid, followed by dissolution of the drug particles and diffusion through fluid filled pores. In case of soluble matrix containing swellable hydrophilic substances the drug becomes available as the matrix swells or dissolves and the dissolved these matrix then undergoes surface erosion with little or no bulk erosion. The surface area of the matrix decreases with time, with a concomitant decrease in drug release. The diffusion depends on the solubility of the drug in the polymer. The drug may be either present below its solubility limit and dissolved in the polymer or present well above its solubility limit and dispersed in the polymer.[5],[7],[8],[9],[10]

Reservoir diffusion-controlled systems: A core of drug is coated with the water insoluble polymer. The polymer can be applied by coating or microencapsulation techniques. The drug release mechanism across the membrane involves diffusion of water through the membrane to the inside of the core, dissolution of the drug and then diffusion of the drug into the surrounding fluid. Materials used in such devices are hydroxy propyl cellulose, ethylcellulose and polyvinyl acetate. The reservoir diffusion products are Plateau CAPS capsules (nicotinic acid), Nio-bid (nitroglycerine), Nitrospan capsules (nitroglycerine), Brankadyl SR cap (theophylline).[10],[11],[12]

Dissolution-controlled products

Matrix dissolution controlled products: In these systems, the drug is homogeneously dispersed throughout a rate controlling membrane. The drugs, which are highly water-soluble can also be formulated as CR products by controlling their dissolution rate. Slowly soluble polymers control the rate of dissolution of the drug. Waxes such as beeswax, carnauba wax and hydrogenated castor oil have been used. The wax embedded drug is generally prepared by dispersing the drug in molten wax and congealing and granulating them.[5],[7],[10]

Reservoir dissolution-controlled systems: In reservoir dissolution control system the drug particles are coated or encapsulated by one of the several micro encapsulation techniques with slowly dissolving materials like cellulose derivatives, poly ethylene glycols, polymethacrylates, waxes etc. The resulting reservoirs (coated beads, multi-particulate systems, pellets) may be filled as such in hard gelatin capsules (spansules) or compressed into tablets.[13]

The common multi-particulate systems are microparticles (microspheres or microcapsules), nanoparticles (nanospheres or nanocapsules), liposomes etc.

The dissolution rate of the drug depends upon the solubility and the thickness of the coating. By varying the thicknesses of the coat and its composition, the rate of drug release can be controlled. These products should not be chewed as the coating may be damaged. One of the advantages of encapsulated reservoir products is that the onset of absorption is less sensitive to stomach emptying. The entrance of the reservoir into the small intestine is usually more uniform than with non-disintegrating CR tablet formulations. An example of this type of product is Fefol (Ferrous sulphate and folic acid).[5]

Erosion products

The release of a drug from these products is controlled by the rate of erosion of a carrier (polymer) matrix. The rate of release (amount of drug released from the dosage form per unit of time as defined by in vitro or in vivo testing) is determined by the rate of erosion.[14] An example of this formulation is Sinemet CR (Carbidopa/levodopa).[5]

Dissolution and diffusion controlled products (pore forming method)

In these systems, the drug core is coated with a partially soluble membrane. Pores are thus formed due to dissolution of parts of the membrane, which permit entry of aqueous medium into the core and release of dissolved drug by diffusion. Using a mixture of ethyl cellulose with poly vinyl pyrrolidone or methylcellulose, the latter material dissolves in water and forms pores in the insoluble ethyl cellulose membrane.[15]

Based on the above preparation techniques, CR trandermal therapeutic systems, buccal drug delivery systems, nasal drug delivery systems (inhalers) oral gastro retentive systems and ocular inserts etc, can

also be formulated.

Osmotic pump systems

Oral osmotic pump, popularly called as OROS®, works with the principle of osmotic pressure to release the drug at a constant rate. The rate of release of drug in these products is determined by the constant inflow of water across a semi-permeable membrane into a reservoir, which contains an osmotic agent. The drug is either mixed with the agent or is located in a reservoir. The dosage form contains a small hole from which the dissolved drug moves out at a rate determined by the rate of entrance of water due to osmotic pressure. The rate of release is constant and can be controlled within tight limits yielding relatively constant blood concentrations. The advantage of this type of product is that the release is unaltered by the environment of the GIT and relies simply on the passage of water into the dosage form. The rate of release can be modified by altering the osmotic agent and the size of the hole. An example of this type of product is Adalat Oros (Nifedipine).[16]

Ion exchange resins

Drugs can be bound to ion exchange resins and, when ingested, the release of drug is determined by the ionic environment within the GIT. The drug is released slowly by diffusion mechanism from the resin particle structure. Examples of this type of product are Duromine containing the basic drug phentermine complexed onto an anionic resin and MS Contin (Morphine sulfate) suspension which uses a polystyrene sulphonate resin.[5],[17]

Regulated systems

These devices are capable of releasing therapeutic agents by well-defined kinetics and have significant improvement over conventional CR systems. In these devices drug output is adjusted in response to a physiological need.

Regulated systems can be broadly grouped into externally regulated and self-regulated. Externally regulated devices can alter their drug output only in response to an external intervention (control of diabetes by delivering insulin in response to blood glucose levels) while self-regulated devices can do so without external intervention. In response to changes in temperature or pH in the system (self-regulated) leads to drug release. An example of this type of system is insulin release from pH-sensitive polymers. This approach utilizes pH changes resulting from the glucose oxidase conversion of glucose to gluconic acid. Erosion of polymer and insulin release in response to pH changes due to gluconic acid level in the blood. Self-regulated controlled delivery systems can release the drug in response to other drug level.[18],[19] Another example of this system is the release of narcotic antagonist naltrexone in response to morphine and is useful in treating narcotic addiction.[20]

Smart materials as drug delivery system

Stimuli-sensitive implant materials (SMART materials) and their techniques are expected to give numerous applications in drug delivery systems. It can deliver biological signals from biomaterials and tissue engineering scaffolds and a particular need for new delivery systems that can efficiently deliver biomolecules to intracellular targets. The biological drug delivery systems are reversible and not directly toxic. These delivery systems have the ability to change their structural and functional properties and thus display remarkable "smart" material properties.[21] An example of this type of delivery system is development of biosynthetic smart implants for repair of spinal cord injury.[22]

Transcutaneous needle-free delivery

Needle-free injection devices operate by using compressed gas to accelerate a small jet of liquid or powder at high speed, causing it to penetrate the skin for subcutaneous, intradermal or intramuscular adminstration.

Jet injectors for administration of liquids include the intraject, biojector and medijector systems, while solids are administered using powderjects technology.[23] Using dermal powderject device, dry powders formulations of microscopic solid particles are propelled across the skin into the target tissue layers. The particles are accelerated to supersonic speed within a helium gas jet, which is generated momentarily inside the device. Because the drug particles are so small, they enter cells without disrupting the cell membranes and do not trigger the pain receptors in the skin. Powderject is working on genetic vaccines in collaboration with Glaxo Wellcome and their hepatitis B prophylactic DNA vaccines have successfully completed clinical trials.[24]

Microfabrication and micro-elctromechanical systems technologies

Some therapeutic applications of micro-technology include microneedles for transdermal delivery, bioadhesive microdevice for oral delivery, microfluidic delivery systems, various implantable systems such as immunoisolating biocapsules and microchips for CR. Recent advances in micromachining and micro-elctromechanical systems technology have provided the opportunity to fabricate miniature biomedical devices. The progress of micro-fabrication technology has enabled the creation of entirely new class of drug delivery devices.[25],[26]

Implants

Implants have been used to deliver high drug concentrations to the immediate area surrounding the target tissue or to provide sustained drug release for systemic therapy. Clinically, implants are applied in situations of chronic therapy and chemical castration in the treatment of prostate cancer. Implants may be in the form of tiny rods impregnated with drug substances or a liquid which gels in situ (ReGel - Injectable gel depot).[27] Duros implantable osmotic pump is a miniature cylinder made from titanium alloy, which protects and stabilizes the drug inside using ALZA's formulation technology. It is designed for long-term delivery of proteins, peptides and macromolecules like leuprolide acetate.[28]

Zoladex implant is a subcutaneous rod-shaped implant made from biodegradable polymer PLGA. It is formulated for one-month delivery of peptide goserelin acetate.[29]


   Factors Affecting Biological Availability of CR Formulations Top


Biological availability or bioavailability in pharmacological parlance is defined as the fraction of a dose reaching the systemic circulation as unchanged drug following administration by any route other than intravenous. The term "absolute bioavailability" means that the bioavailability of a given dosage form is compared with the intravenous dose. Bioavailability of a drug may be affected by many factors, the most important of which are the components of the dosage form and physiochemical characteristics (like aqueous solubility and stability; pKa, partition coefficient {or more appropriately, permeability values} and salt forms) of the drug. A change in excipient can also affect the bioavailability of the formulations. For example, a phenytoin formulation lead to an outbreak of phenytoin toxicity due to increased bioavailability.[30] Different brands of the same drug may have different bioavailability profiles. Differences in bioavailability of carbamazepine brands are reported and a change of brand with good bioavailability to one with uncertain bioavailability can precipitate seizures in an otherwise controlled epileptic. It is necessary to have comparative bioavailability of conventional (IR) as well as SR formulations in case the innovator claims the product to be better than the IR product.[30],[31]

Drug absorption can also be influenced by a variety of gastrointestinal conditions. Rapid intestinal transit due to diarrhea (a common problem in India) may inhibit drug absorption. Pregnancy has occurred after the use of oral contraceptives during a period of diarrhea. Metoclopramide, which accelerates gastric emptying, has been shown to increase rate of absorption of aspirin, levodopa, lithium and tetracycline. In contrast, propantheline decreases the absorption rate of many drugs. Foods may affect the bioavailability of CR formulations. The changes in bioavailability after food may not be of clinical relevance when therapeutic effect is unaffected as with sulphadiazine.[30],[32] For drugs like chloroquine, increased bioavailability with food can improve compliance, by reducing gastric side-effects.[33] As food can also reduce or delay absorption, proper instructions regarding spacing of dose in relation to food are necessary for drugs like rifampicin and isoniazid. Other factors of food affect in vivo release and absorption. Temporal variations in drug absorption have been shown for benzodiazepines, e.g., triazolam.[30],[34] Bioavailability of nitroglycerine and propranolol is affected by hepatic first pass (biochemical conversion of drug mainly in liver), because of its high level of drug metabolizing enzymes, before reaching systemic circulation, results in decrease of bioavailability and is likely to increase in liver dysfunction. Sublingual nitroglycerine avoids the problem; however, the buccal absorption will be impaired if the mucosa is dry due to concomitant administration of imipramine or an anticholinergic. In addition to these factors, changing absorption, bioavailability, especially at steady state (plasma drug concentration during constant rate of drug administration) will be affected by factors influencing distribution, metabolism and excretion. The list of such interacting host and external factors is vast. Genetic factors, variations in vascular, cardiorenal, hepatic or endocrine disorders can affect bioavailability and bioequivalence (formulations are said to be bioequivalent if the nature and extent of therapeutic and toxic effects are equal following the administration of equal doses).[30],[35],[36],[37] One or more such factors may need to be considered while assessing bioavailability in individual patients. For many CR formulations, drug release rate can be altered by various factors including food and the rate of transit through the gut. CR products contain a higher drug load and thus any loss of integrity of the drug release characteristics of the dosage form may give rise to potential problems. Some CR products can be divided to provide half-doses [Table - 2], others should only be taken whole [Table - 3]. CR products should never be crushed or chewed as the slow-release characteristics may be lost and toxicity may result. These problems may lead to changes in bioavailability of CR products. This is particularly true in geriatric patients unable to swallow whole tablets.[5]


   Evaluation of CR Products Top


The absorption of an orally administered drug depends upon the dissolution of drug by GIT fluids and intestinal membrane permeation. Dissolution is defined as "taking up of substances by a liquid with the formation of homogeneous solution". In-vitro dissolution testing is one of the most popular tests in the quality control of dosage forms. These tests can assess the ability of the dosage form to release the drug completely and to simultaneously indicate how the product will perform in-vivo .

The in-vitro dissolution (drug release from a dosage form as measured in an in-vitro dissolution apparatus) testing is conducted using glass apparatus and conditions which mimic, to a certain extent, the conditions generally available in the GIT and helps in assessing the performance of the dosage form in actual "in use" conditions.

In-vitro drug release studies are focused on regulatory and compendial approaches, which could be modified appropriately for specific products as a given product may have specific requirements with respect to media, sampling interval or temperature.[38],[39],[40]

Apparatus

USP (United States Pharmacopeia) recommends seven different types of apparatus for in-vitro release testing. These apparatus are designed for oral and transdermal product. USP apparatus 1 (basket) and 2 (paddle) were designed for IR and modified release (MR) oral formulations (MR dosage forms are those whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional or an IR dosage form. MR solid oral dosage forms include both delayed and extended release (ER) drug products. ER dosage forms release drug slowly, so that plasma concentrations are maintained at a therapeutic level for a prolonged period of time (usually between eight and twelve hours). ER dosage forms allow a twofold reduction in dosing frequency and increase in patient compliance as well as therapeutic performance.[2],[39] USP apparatus 5 (paddle over disc), 6 (cylinder) and 7 (reciprocating holder) were designed for transdermal products. USP apparatus 3 (reciprocating cylinder) and 4 (flow through cell) were designed for ER oral formulations. The apparatus and media used should take into account the release mechanism and the physical properties of the product (e.g., size and stability). In addition, in-vitro release tests must also discriminate between the performances of different formulation variants and ideally should have biorelevance.[40],[41]

An important factor in the design of dissolution test is the composition of dissolution media. It is generally held that the medium should simulate the biological fluid found in-vivo and should provide sink conditions for drugs so as to improve the possibility of better in-vitro-in-vivo correlation line. Dissolution media usually containing hydrochloric acid (HCl), citrate, acetate, phosphate or Tris buffer in the pH range of 1-7.6 are used. Different medium are selected on the basis of the drug and formulation to simulate the biological fluid {gastric fluid (0.1 N HCl), intestinal fluid (pH 5.9-7) etc}.[40]


   In vivo Studies and IVIVC for CR Products Top


Pharmacokinetics (the time course of drug concentration in the body) of the CR dosage form should be compared with the IR product in healthy volunteers. Pharmacokinetic evaluation should be based on blood concentration data (parameters like Tmax, absorption rate constant, elimination rate constant, clearance, extent of absorption and mean residential time etc.) and the usefulness of the CR dosage form should be evaluated by comparing it with the reference product (a CR product which has already been approved). These in-vivo data are correlated with in-vitro property of CR products by in-vitro- in-vivo correlation (IVIVC) method.[6]

An IVIVC has been defined by the Food and Drug Administration of USA (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response. Generally, the in-vitro property is the rate or extent of drug dissolution or release while the in-vivo response is the plasma drug concentration or amount of drug absorbed.

The United States Pharmacopoeia also defines IVIVC as "the establishment of a relationship between a biological property or a parameter derived from a biological property produced from a dosage form and a physiochemical property of the same dosage form".

IVIVC plays an important role in product development to assist in quality control during manufacturing and selecting appropriate formulations and in establishing dissolution test as a surrogate for human studies.[40],[42]

Dosing regimen is established during Phase I and II clinical studies in which the blood concentrations are monitored during Phase II clinical trials to establish an appropriate dosing regimen.[6]


   CR Formulations in Neurological Practice Top


Drug delivery to central nervous system is a challenge in the treatment of neurological disorders. Oral, intramuscular and some newer MR formulations are available in the market.

In 2001, Organon filed a new drug application for gepirone ER. Gepirone has been assessed for use in the treatment of depressive and anxiety disorders. Initial placebo-controlled clinical trials demonstrated that gepirone IR product improved symptoms of depression; however, its short half-life necessitated frequent administration and high-peak plasma concentrations at higher doses were associated with an increased incidence of adverse events.[43]

More attention is now being paid to gepirone ER. Investigators concluded that gepirone ER "appears safe and effective in the short-term treatment of major depressive disorder and appears to be free of common side effects.[44] It was also reported that gepirone ER may have a positive effect on sexual function in patients with manic depressive disorder. Gepirone ER (40 mg/day to 80 mg/day) was effective in relapse prevention in patients with recurrent major depression.[45]

In one study, a CR formulation of levodopa and benserazide (Madopar CR) were evaluated in patients with Parkinson's disease exhibiting dose-related fluctuations in motor performance in response to conventional levodopa preparations. The effect of Madopar CR, with or without conventional levodopa/benserazide, on the proportion of time spent "on", "off" or "intermediate" was compared with that of previous conventional levodopa/decarboxylase inhibitor therapy. Madopar CR was judged to be advantageous in 83% and disadvantageous in 11% of patients. Madopar CR was found to be beneficial in a significant proportion of patients experiencing fluctuations in response to conventional levodopa.[46]

In another study, CR carbidopa/levodopa 50/200 (SINEMET CR) and standard carbidopa/levodopa (SINEMET 25/100) were compared in a crossover study involving 21 patients with chronic Parkinson's disease and motor response fluctuations. Daily dosage frequency was significantly reduced with SINEMET CR compared with SINEMET 25/100, while the daily amount of levodopa required with SINEMET CR was significantly greater. Parkinson's disease derived the greatest benefit from SINEMET CR.[47]

CR product of paroxetine delays the release of paroxetine until the tablet has passed through the stomach; the drug is then released over four to five hours. Paroxetine CR was generally well-tolerated in clinical trials, as patients felt significantly less nausea than recipients of IR paroxetine.[48]

Bupropion (Zyban-SR; GlaxoSmithKline, Ux-bridge, Middlesex, UK) has been used as a non-nicotine drug to aid in smoking cessation. Treatment with ZYBAN-SR reduced withdrawal symptoms compared to placebo. Depending on the study and the measure used, treatment with ZYBAN-SR showed evidence of reduction in craving for cigarettes or urge to smoke compared to placebo.[49]

Indiplon is a short-acting hypnotic that is currently being developed as a treatment for insomnia by Neurocrine Biosciences and Pfizer and is expected to be marketed in mid-2006. Responses that demonstrate clinical trials were carried out with an IR capsule and a MR tablet and the CR product demonstrated very positive efficacy and safety profiles.[50]

The effects of switching from IR carbamazepine formulations to an equal total daily dose of carbamazepine ER capsules (CBZ-ERC) in epilepsy is reported. The authors found that switching to CBZ-ERC significantly improved patients' adverse events and quality-of-life measures. Switching to CBZ-ERC also improved seizure control.[51]

Dl-Methylphenidate (MPH) remains the most widely used pharmacological agent in the treatment of attention-deficit/hyperactivity disorder (ADHD). Novel ER-MPH formulations now offer drug delivery options to overcome both, the short-term actions of IR-MPH and the acute tolerance associated with the first-generation ER-MPH products. These novel MPH products apply proprietary technologies such as OROS (Alza), Diffucaps (Eurand) and SODAS (Elan) to offer both the convenience of once-a-day administration and absorption profiles resembling, to varying degrees, the standard multiple dose schedules of IR-MPH.

OROS-Methylphenidate (OROS-MPH) is a once-daily CR formulation of MPH developed to overcome some of the limitations associated with IR-MPH and first-generation SR formulations. Once-daily OROS-MPH is significantly more effective than with IR-MPH. OROS-MPH and IR-MPH were both well-tolerated with a similar side effect profile.[52]

Long-acting compounds, also called "depot", are administered to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Risperidone is to date the only novel antipsychotic available as depot formulation. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.[53],[54],[55]

Thus far, long-acting antipsychotics have been delivered via intramuscular injection as depot formulations that utilize an oil-based vehicle and an esterified drug. Fluphenazine and haloperidol decanoate both use sesame seed oil as the vehicle, with the antipsychotic esterified at the drugs' benzylic ketone. The rate-limiting step in the kinetics of the depot product is the slow rate of absorption from the injection site. Hence, the observed terminal phase decline in plasma levels of fluphenazine decanoate corresponds to a half-life of 8 to 14 days, rather than the elimination half-life (time for elimination of one half of the total amount of drug) of 15 to 24 hours. Similarly, for haloperidol decanoate, the observed terminal half-life is 19 to 21 days rather than 15 to 24 hours. This pharmacokinetic action is called "flip-flop kinetics" and is the basis for understanding appropriate dosing with the older depot medications. Depot dosing can lower the rate of reversible motor side effects when compared with oral therapy by constraining the peak levels below the moderate-to-severe threshold of reversible motor side effects.[55],[56]

Depot preparations offer an advantage over oral medication for treating schizophrenia by reducing poor compliance. Randomized clinical controlled trials on fluphenazine decanoate or enanthate with placebo or oral anti-psychotics or other depot preparations showed little advantage of these depots over oral medications in terms of compliance.[53]

Unlike the traditional esterification of conventional antipsychotics to achieve a long-acting injectable formulation, long-acting risperidone is fabricated by a microsphere encapsulation process. Long-acting risperidone offers clinicians and patients the first atypical long-acting medication.[54]

Madopar HBS (hydrodynamically balanced system) is a commercially available product used in Europe and other countries but not available in US. It contains 100 mg levodopa and 25 mg benserzide. This CR formulation consists of a gelatin capsule that is designed to float on the gastric fluids. After the gelatin shell dissolves, a mucus body is formed that consists of active and other substance, from which the drug is slowly released to the gastric contents. The HBS system maximizes the dissolution of the drug by prolonging the gastric residence time (GRT).[57] Another example of this system is Valrelease CR (controlled release diazepam capsule).[58]

Morphine sulphate has been formulated into SR formulations. There are a number of MR formulations of morphine with recommended dosage intervals of either 12 or 24 hours, including tablets (MS Contin oramorph SR), capsules (Kapanol, Skenan), suspension and suppositories. Orally administered solid dosage forms are most popular but significant differences exist in the resultant pharmacokinetics and bioequivalence status of morphine after both single doses and at steady state.[59]

In a study comparing regular alprazolam tablet, given four times per day and extended release alprazolam (XR), given once in the morning, drowsiness occurred more frequently with CT alprazolam (86% of patients) than with the XR preparation (79%) or placebo (49%).[60]

In another study the efficacy, duration of action and tolerability of methylphenidate transdermal system (MTS) was evaluated. Time course and therapeutic effects of MTS suggest that this novel methylphenidate delivery system is an efficacious once-daily treatment for children with ADHD.[61]


   Conclusions Top


A wide range of drugs is now marketed in a variety of different CR products. However, only those, which result in a significant reduction in dose frequency and/or a reduction in dose related toxicity are likely to improve therapeutic outcomes. Presence of food, GI motility and concomitant diseases will influence the therapeutic response. The CR formulations extend the stay of drug molecule in the body and hence with some drugs it may show exacerbation of the undesirable effects. In addition, the termination of a response in case of an eventuality is also difficult. These should not be chewed and/or crushed. Hence the physicians must be cautious in prescribing them.

 
   References Top

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[Figure - 1]

    Tables

[Table - 1], [Table - 2], [Table - 3]


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