KADIAN® contains morphine sulfate, an opioid agonist and a Schedule II Morphine is a natural product that is the prototype for the class of natural and. KADIAN- morphine sulfate capsule, extended release .. Opioid agonists such as KADIAN are sought by drug abusers and people with addiction disorders and. KADIAN. ®. (morphine sulphate) Product Monograph. Page 2 of 37 This leaflet was prepared by Mayne Pharma International Pty Ltd.
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Multiple formulations exist to provide enteral controlled-release CR opioid delivery. An appreciation of these various delivery kadiab may provide clinicians with the knowledge to akdian comfortable inseert multiple different opioid CR formulations in their practices in efforts to optimize patient analgesia while minimizing adverse effects. The CR opioid delivery system, which currently features the largest selection of different opioids, is the enteral controlled-release opioid ECRO delivery onsert enteral CR paackage or capsules Table 2.
CR tablets that prolong drug delivery have one kqdian technical feature in common: Multiple formulations adsorb opioid onto a hydrophilic kadan e. After enteral administration, gastric fluid dissolves the tablet surface and hydrates the hydrophilic polymer to produce a gel, the formation of which is controlled by higher aliphatic alcohols. The rate of drug release from this formulation depends on the rate of diffusion of the dissolved opioid through the gel layer at the surface of the tablet.
The depth of the gel layer increases over time as the gastric fluid gains access to the deeper regions of the tablet . The release rate can be controlled by varying the hydrophilic polymer, the type of hydrophobic matrix, or their ratio.
Alternatively, a pellet or granule can be created, composed of an inert core e. Fluid in the GI tract diffuses through the outer polymer coat to dissolve the opioid after enteral administration; the nature of the inert core together with the composition and thickness of the coat combine to control the rate of dissolution. As individual packahe are essentially identical, the different dosage strengths are created by packaging a certain weight of pellets into an appropriately sized capsule.
Pacoage capsule disintegration, the relatively small sized granules behave more like a liquid than larger solid particles, which may, on occasion, be retained in the stomach . Other types of CR opioid delivery systems include small granular particles containing opioid which are bound together to form larger particles with a hydrophobic wax or suspension formulations where opioid is attached to small beads of an ion exchange resin for patients who had difficulty swallowing solid packxge formswhere once administered, the sodium and potassium ions present in the GI tract fluids gradually displace opioid from the resin .
There are substantial differences in the pharmacokinetics of opioid following the administration of the various modified-release opioid formulations. Intuitively, these differences would be expected to translate into measurable differences in opioid pharmacodynamic effects of pain relief and the incidence and severity of adverse effects. While open-label studies of efficacy have shown differences in pharmacodynamic effects, the global assessments of efficacy, and patient preference for a particular modified-release formulation, other studies using the knsert standard double-blind, double-dummy crossover design have failed to replicate these findings .
Kadian and Avinza have smaller trough to peak fluctuations compared with MSContin [3,4]. This means these agents have lower maximum and higher minimum concentrations than MSContin. The clinical benefit of these pharmacokinetic differences did not correlate with higher efficacy or safety in clinical studies when Kadian or Avinza were compared with MSContin [5,6].
Although all CR products may be taken without regard to meals, they are sensitive to alterations that destroy their modified-release mechanisms.
Enteral Controlled-Release Opioid Delivery Systems | Pain Medicine | Oxford Academic
Therefore, these products should be swallowed whole i. For patients experiencing difficulty swallowing, paclage products such as Avinza and Kadian may be opened and their entire bead contents sprinkled onto applesauce immediately before administration [3,4].
The applesauce should be room temperature or cooler, and the entire amount should be consumed without chewing, followed by rinsing and swallowing with water to ensure that all beads are ingested. The prescribing information for Kadian also indicates that the entire capsule contents may be administered through a 16 French gastrostomy tube . In matrix-type modified-release drug delivery systems, the active ingredient and retarding ingredients are uniformly distributed throughout the dosage form.
The retardants control the rate inserr release of the active ingredient morphine, in the case of MSContin from the tablet matrix . The Contin drug delivery system kwdian on two different types of retardants to control the rate of drug release.
The relative proportions of these retardants assure the measured release of the active ingredient. The Contin system employs one water-insoluble and one water-soluble polymer. The retarding ingredients consist of highly polar cellulose and long-chain aliphatic alcohols.
MSContin CR tablets contain morphine sulfate in a dual-control polymer matrix Contin that consists of a hydrophilic polymer hydroxypropyl methylcellulose and a hydrophobic polymer hydroxyethyl cellulose . To prepare these systems, the drug is blended with the hydrophilic polymer, selectively hydrated with a polar solvent, and fixed with a higher aliphatic alcohol .
The partition coefficients of the active ingredient with the hydrophilic and hydrophobic components of the formulation control the release of drug from the tablet . The hydrophobic content is used to slow the diffusion of drug into the aqueous phase, which limits diffusion into the GI tract and absorption into the body.
The composition of the tablet matrix is such that intact passage throughout the intestinal tract is not expected . Kadian SR capsules contain morphine sulfate in identical polymer-coated, SR pellets; the product does not contain an immediate-release component .
KADIAN – Morphine Sulfate Extended-Release Capsules
The pellets are similar in general structure to the ER beads in Avinza Figure 1. However, their polymer coating consists of an insoluble ethylcellulose base along with insfrt glycol PEG and a methacrylic acid copolymer. Both kaduan PEG and methacrylic acid copolymer are water-soluble, but the water solubility of the methacrylic acid copolymer is pH-dependent.
After ingestion, the hard gelatin capsule shell quickly dissolves, releasing the drug-containing pellets. In the acidic pH of the stomach, the PEG component of the polymer coating dissolves and immediately creates pores that allow GI fluid to enter the pellets and dissolve the morphine sulfate, which can then diffuse and be absorbed into the body.
As pafkage the PEG component can dissolve at that point, the pores are relatively small, limiting drug diffusion. However, this does paclage for some drug to be absorbed quickly into the body. As the pellets enter and move through the intestines, the pH of the GI environment continues to increase, and the methacrylic acid copolymer begins to dissolve as the PEG continues its dissolution. This increases the number and size of the pores in the polymer coating, which increases the rate paciage morphine release.
P-ERMS exhibits linear pharmacokinetics and its bioavailability is not affected by meals [13,14]. It has a plasma concentration-time curve that is relatively flat and smooth .
Avinza ER capsules contain morphine sulfate in both immediate and ER beads . The immediate-release component achieves plateau morphine concentrations within 30 minutes while the ER component maintains these plasma concentrations throughout the hour dosing interval, which is longer than most other oral modified-release opioid products are able to achieve.
SODAS is a multiparticulate drug delivery technology based on kadiam production of CR uniform spherical beads of 1—2 mm in diameter.
Each bead begins as a nonparallel core which functions as a carrieronto which a solution of active ingredient is applied. A series of subsequent coatings with timing solutions containing both soluble and insoluble polymers and other excipients combine to produce the outer rate-controlling membrane that ultimately controls release of drug from the beads.
Once produced, the beads are encapsulated into a hard gelatin capsule.
Combining a number of different populations of beads with varying degrees of CR may allow for tailored drug release profile. Drug is released from the beads by a process of diffusion.
Within the GI tract, the soluble polymers dissolve, creating multiple pores in the outer coating of the bead, thus permitting fluid to enter the bead core and solubilize the drug. The resultant solution then diffuses out in a predetermined manner, prolonging the in vivo dissolution and absorption phases.
After administration and rapid dissolution of the hard gelatin capsule shell, the permeability of the ammonio-methacrylate copolymer coating allows GI fluid to enter the beads and solubilize the drug. As a result, drug release is independent of the pH of the surrounding GI environment.
Oxymorphone ER is kadiah new SR tablet formulation of oxymorphone hydrochloride developed to provide 12 hours of sustained analgesia . The matrix consists of two polysaccharides, xanthan and locust bean gum LBG. Interactions between these compounds in an aqueous environment form a tight gel with a slowly eroding core. As water is absorbed into the outer layers, the tablet begins to swell and gradually break down. The center core reduces slightly as some of the drug is released.
The interactions between the two polymer molecules can be engineered to allow them to become entwined, disentangled, more entangled, or dissolved with time depending on requirements or in response to physiological conditions. Xanthan is a heterpolysaccharide, which dissolves in water to form viscolysed or thickened solutions . This thickening property of xanthan is made use of in other pharmaceutical products to prepare sugar-free syrups and results insertt a reversible dimerisation of xanthan molecules.
In solution, one xanthan molecule associates with a second molecule by hydrogen bonding to produce a helical structure.
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These xanthan helices are dispersed through the solution and act to create sufficient inhibition of free movement of water molecules from the GI tract to produce the thickening observed but there is no interlinking of separate helices . LBG is a long-chain homopolysaccharide that is physicochemically more complex than xanthan. The LBG molecule has two distinct regions, which alternate along the mannose polymer backbone. During biosynthesis, galactose residues periodically become attached roughly once in every four mannose units.
The absence of galactose in the smooth regions allows two LBG molecules to become hydrogen bonded, and the existence of more than one smooth region on every LBG molecule allows several different LBG molecules to become entangled insdrt hydrogen bonding.
This produces a three-dimensional interlocking network of LBG molecules in water . When LBG is mixed with xanthan, a synergistic interaction occurs, which results in the rigid helices of xanthan in solution becoming incorporated into the true gel structure of the LBG molecules. The interaction can be considered synergistic because the viscosity build that occurs when both polysaccharides are used together is significantly greater weight for weight than either material used alone.
Also, when the two polysaccharides are mixed, gel formation develops at ambient temperature . In TIMERx tablets, when a kdaian valve is open, the drug can pass out of that part of the gel; but when a valve is closed, drug diffusion is packaye.
A valve can be considered open when the intermolecular bonding between xanthan and LBG is either at a minimum or at a maximum e. For example, a low degree of crosslinking between the polymer chains is likely to cause valves to be open, as there will be a large number of less tortuous channels in the gel.
As the polymer chains crosslink, the pores become more tortuous and constricted, leading to valve closure . This system is thought to help ensure reliable and steady drug release over 12 hours. The retardants control the rate of release pacakge the active ingredient oxycodone, in the case of OxyContin from the tablet matrix .
The AcroContin drug delivery system depends on two different types of retardants to control the rate of drug release. The two retarding ingredients are ammonio-methacrylate copolymer, a water-insoluble polymer, and stearyl alcohol, a water-insoluble wax. Both ingredients are suitable retardants for oxycodone, as oxycodone is water-soluble. The oxycodone in an OxyContin tablet is contained in a homogenous mixture of the active drug oxycodone and retardants, that is, there are not two separate components to a tablet OxyContin does not contain a separate immediate-release component .
After ingestion, the GI fluid dissolves the tablet coating, exposing the hydrophobic acrylic matrix. After the film coating on the tablet has dissolved, GI fluid enters the tablet matrix release of oxycodone from OxyContin, resulting in the dissolution of the entrapped oxycodone and diffusion of oxycodone through the tablet matrix. The water-insoluble matrix of the AcroContin delivery system renders the oxycodone packqge from the OxyContin tablets independent of surrounding pH .
The resulting pharmacokinetic models were then used to predict mean concentration packaeg time profiles for dosing of OxyContin q12h and immediate-release oxycodone q6h for 3.
Unlike oxycodone immediate-release, the shape could not be accurately described mathematically using a single exponential term i.
However, the observed absorption profile for OxyContin could be accurately described mathematically as the sum of two exponential terms i.
These proportions represent the mathematical factors that scale the contributions of the two exponential terms so that they sum to give the observed OxyContin absorption profile. Nor is there a specific relationship between the two retardants and the two terms in the absorption model. At the start of oxycodone absorption, the rate of absorption for immediate-release oxycodone is more than eightfold higher than the rate for OxyContin.
The modeling indicates that absorption from a dose of an immediate-release oxycodone solution will be essentially complete approximately 1. The elementary OROS osmotic pump delivery system consists of a tablet core of drug surrounded by a rate-controlling semi-permeable membrane coating that is pierced by a small 0.