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Canada,European Union. 2. Drugs with unknown formula or composition shall not be admitted to the hospital formulary. Fixed dosage form combinations of two. of Health are pleased to offer a tool for the drug sellers and Health Center staff, .. In case of severe infections, doses be increased and given 3 times daily. Provided by the Academic Center for Excellence 1. How to Solve Drug Dosage Problems. Reviewed August How to Solve Drug Dosage Problems.

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For ease of use and to avoid having to make calculations, doses are given according to the body weight of the child. As errors in calculating drug doses are . Jun 23, essential medicines, certain drugs have been added, others have been For certain symptomatic drugs, dosage is expressed in milligrams per. 50 DRUGS EVERY EMERGENCY PHYSICIAN SHOULD KNOW IV Dose: mg/kg in ml D5W over 1 hour, 50 mg/kg in ml D5W over 4 hours.

Manufacturing of Mini-tablets Despite the increasing importance of mini-tablets for its advantages as pediatric formulations and in modified-release applications, its popularity is limited due to the lack of formulation and processing knowledge in developing such dosage forms. The development of minitablets as a Drug Product DP is mainly dictated by the type of dosage form required, physico-chemical properties of the active ingredient, and other excipients and factors related to the manufacturing process. Depending on the nature of the active ingredient, the most common manufacturing process for mini-tablets includes blending operations, compression of the final blend into mini-tablet cores, coating minitablet cores and finally packaging of the coated mini-tablets into appropriate packaging configuration. Physical properties of blend The current drug development pipeline has many molecules with poorly aqueous solubility. These drug candidates are typically developed into their different salt forms or processed as Amorphous Solid Dispersion ASD. Some challenges observed during pre-formulation with such salt and crystalline forms include poor flow properties, electrostatic effects and low densities due to very fine particle size. When a high drug load is required, challenges related to flow is magnified.

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Population pharmacokinetic analysis of circadian rhythms in hepatic CYP3A activity using midazolam. J Clin Pharmacol. CrossRef Google Scholar 9. McInnes GT. The value of therapeutic drug monitoring to the practising physician — an hypothesis in need of testing. Brit J Clin Pharmacol.

CrossRef Google Scholar The value of therapeutic drug monitoring to the practicing physician — an hypothesis needing sensible application. Therapeutic drug monitoring — an hypothesis still in need of testing. An agenda for UK clinical pharmacology. Monitoring drug therapy.

A randomized trial of genotype-guided dosing of warfarin. A pharmacogenetics versus a clinical algorithm for warfarin dosing. Cost-effectiveness of pharmacogenetics-guided dosing of warfarin in the United Kingdom and Sweden. Pharmacogenomics J. Polymorphic hydroxylation of debrisoquine in man. Polymorphic hydroxylation of debrisoquine. Google Scholar Defective N-oxidation of sparteine in man. Eur J Clin Pharmacol. Why hypertensive patients vary in their response to oral debrisoquine.

Br Med J. Prescribing aids for gentamicin. Br J Clin Pharmacol. Target-controlled infusion devices: are we missing much? Can J Anaesth. Algorithms to rapidly achieve and maintain stable drug concentrations at the site of drug effect with a computer controlled infusion pump.

J Pharmacokin Biopharm. General derivation of the ideal intravenous drug input required to achieve and maintain a constant plasma drug concentration.

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Schwilden H. A general method for calculating the dosage scheme in linear pharmacokinetics. Dashboard systems: implementing pharmacokinetics from bench to bedside. AAPS J. Clinical decision support tools: the evolution of a revolution.

Clin Pharmacol Ther. Physiologically-based pharmacokinetics in drug development and regulatory science. Drug-drug interactions: computational approaches. Royal Society of Chemistry, ; pp Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.

J Pharmacokin Pharmacodyn. Challenges in CYP2D6 phenotype assignment from genotype data: A critical assessment and call for standardization.

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Curr Drug Metab. Interindividual variability of CYP2Ccatalyzed drug metabolism due to differences in gene diplotypes and cytochrome P oxidoreductase content.

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Influence of genetic polymorphisms in cytochrome P oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese. Zhing X, Leeder JS. Epigenetic regulation of ADME-related genes: focus on drug metabolism and transport. Drug Metab Dispos. Geneva cocktail for cytochrome P and P-glycoprotein activity assessment using dried blood spots.

Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin.

A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions. A comparison of 4 beta-hydroxycholesterol: cholesterol and 6 beta-hydroxycortisol: cortisol as markers of CYP3A4 induction.

Li Y, Chiang JY. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Metabolism of 4 beta-hydroxycholesterol in humans. J Biol Chem. Stability and half-life of elimination after induction with rifampicin. Renard M. Implantable closed-loop glucose sensing and insulin delivery: the future for insulin pump therapy.

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Anaesthetic Pharmacol. Closed loop anesthesia: are we getting close to finding the Holy grail. Anesth Analg. Closed-loop control of anesthesia. It has been noticed that higher press speeds can contribute to higher friability or fragmented mini-tablets.

Typically, the optimum ratio of particle-to die diameter to minimize weight variability in tablet compression is between to A large proportion of particles larger than the optimum ratio in mini-tablet manufacturing can lead to increased tablet weight variability. The tolerance for weight variability in mini-tablets is smaller than for larger tablets.

Small absolute weight variations will lead to more significant relative variations in potency. Additionally, hardness and thickness needs to be measured as in-process controls during compression process. The tablet press has to be equipped with force feeder as compared to gravity feeder to reduce weight variability. These challenges to monitor and control physico-mechanical attributes, sensitive characterization techniques and thus the specialized equipment needed for these measurements results in an increases manufacturing cost.

Coating of mini-tablets Film coatings are frequently applied when it comes to solid oral dosage pharmaceutical drug delivery. The purpose for coating can vary including altering properties range from cosmetic considerations color, gloss , improving the stability light protection and moisture , taste masking. Moreover, functional coatings can be used to modify the drug release behavior of the dosage form. It is possible to delay the release of the drug such as in enteric coatings or sustain the release of the drug over an extended periods of time, depending on the polymers used.

The drug can also be layered as functional coating material to produce immediate release effect of the same drug or a different drug for a combination of drugs. The equipment used to employ coating on the surface of the tablet cores are pan coaters and fluid beds. Many believe that pan coating is mainly designed to coat regular-sized tablets because of the large opening in pans which are not suitable for minitablets. However mini-tablet pans are available with smaller openings.

Thus, both pan coating and fluidized bed coating are suitable methods. Fluid-bed coating of mini-tablets: The coating of mini-tablets is typically carried out by fluid-bed technology where materials are in fluidized state and spraying gun position dictates different ways of coating.

A number of design modifications on the conventional fluidized bed have been adopted to improve the coating process for mini-tablets. A careful evaluation of an appropriate fluid bed critical processing parameters such as fluidizing air flow, bed temperature, spray rate, atomization pressure and filter bag mesh size used are imperative to the mini-tablet coating process. The processing parameter values will differ depending on the equipment, batch size, and the type of coating formulation used.

Fluid bed technology is used as an alternative approach to pan coatings as it helps in achieving a fast and uniform coating using air to mix, coat, and dry the substrate at the same time.

A major concern during fluid bed mini-tablet coating is high friability and compromise in core tablet appearance due to physical stress including frequent collisions, high friction, increased moisture and high temperature which occurs during the fluidization process.

Pan coating is a much gentler process. Hence, mini-tablet coating by fluidized-bed technology requires higher strength for minitablet cores, and a high standard for tablet formulation design. Neha et al. Moreover, lower fluidization with respect to bed load, led to non-uniform coating and formation of doublets during process [ 21 ].

Vuong et al. For both types of equipment, good enteric coating efficiency was obtained and the results were comparable [ 22 ]. However, the main benefit of using the perforated pan instead of a fluid-bed was a shorter process time [ 23 , 24 ]. Figure 3: D-Plate for coating of mini-tablets in fluid bed coating.

Pan coating of mini-tablets: The main challenge for perforated pan coating of mini-tablets is fabrication of the pan to prevent minitablets falling through the perforations in the coating pan. A simple and economical way to pan coat mini-tablets is to use a mesh insert [ 24 ]. It was also noticed that due to the small size of mini-tablets they tend to jump out of the coating pan increasing residual loss. A Perspex shield plate can be placed at the front of the pan to prevent jumping.

The coating of mini-tablets was found to be faster and more reproducible due to uniform shape, size, smooth surface, low porosity, and high attainable strength.

It was found that one third reductions of functional coating of mini-tablets was needed compared to coating of granules because of lower surface to volume ratio [ 25 ]. Mini-tablets has also been successfully coated in a solid wall pan machine, GS IMA coating equipment where drying air was delivered to the core tablet bed by means of two immersed perforated swords. From a commercial stand point, coating of mini-tablets in a perforated pan can be more efficient due to higher production volumes, lower waste of coating material, and faster equipment cleaning time compared to the conducting the process in a fluid bed [ 26 ].

Other coating technology for mini-tablets: Even though pan coating and fluid bed coating technology for mini-tablets are better understood, these conventional coating methods are considered laborious, expensive, and require technical expertise for material selection and process development.

Thus, formulation scientists are continuously searching for new, effective, inexpensive, and simple coating approaches.

Oral Dosage Forms That Should Not Be Crushed

Recently, Atomic Layer Deposition ALD was investigated as a novel technique for thin coating of mini-tablets, and for masking the bitter taste of the drug substances. ALD is a surface controlled, self-limiting layer-by-layer proceeding coating method for depositing ultra-thin, high quality, and conformal thin films.

The concept of ALD seems attractive, as ALD coatings are not only continuous, ultra-thin, dense, and smooth, but also most importantly pinhole-free, very conformal to the substrate, and provide good diffusion barriers with low gas and moisture permeability. As compared to the conventional pan or fluid bed coating, ALD process is very different and it does not involve certain limitations as tablet cores are stationary, and are coated during separate surface saturation deposition cycles involving chemical interactions in reactor [ 27 , 28 ].

Packaging of Mini-Tablets The packaging configuration of mini-tablets is mainly dictated by the target product profile or product design requirements.

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The selection of correct packaging configuration also depends on drug product performance in a particular packaging configuration during long term storage. There are number of ways to deliver mini-tablets to the patients, these include encapsulation in capsule shells, packaged into unit-dose packaging such as stick-packs or sachets, or prefilling a container for disintegration Figure 1.

Encapsulation of mini-tablets Among the possible packaging configurations, encapsulation of mini-tablets is preferred option. The encapsulation machines are capable to fill mini-tablets, pellets, powder, and granules with direct or indirect filling operation mechanism.

In the case of direct filling operation, the mini-tablets are fed into the body until it is completely full. An encapsulator such as the Qualifill TM Pellet filler works on direct filling operation mechanism.

For indirect filling, operation the encapsulates have modified d osators that use either suction to hold the material in the tube during transfer or are pushed through the material bed as seen in Zanasi 40 E encapsulator. However, most advanced encapsulation equipment currently on the market is units such as Bosch GKF Figure 4. These machines offer filling of minitablets based on number of individual mini-tablets per capsule. Table 2 represents number of mini-tablets of 2 mm size can be filled in different capsule size.

Custom designed dosing discs with cavities deliberate to be filled with mini-tablets are used. Each dosing disc is designed to accommodate the specific size of the mini-tablets and count required per capsule.

A variable thickness dosing disc can slide underneath to hold the material prior to transfer to allow only one mini-tablet per cavity. The mini-tablets are held in position on the wheel by vacuum, and this is electronically monitored by a webcam sensor which checks the disc for the presence of mini-tablets.

All insufficiently filled capsules are automatically rejected in the finished product discharge chute.

Personalized Drug Dosage – Closing the Loop

The dosing discs are intended to count mini-tablets in an accurate manner across a wide range of target fills. A pilot scale encapsulator such as the Zanasi 40 E is capable of filling capsules at relatively moderate speed of around 40, capsules per hour whereas the Bosch GKF can be used for commercial scale and is capable of filling capsules at speeds of , capsules or more per hour.

Moreover, modern encapsulators are capable of filling combination products, such as mini-tablets with different release profiles ER component and IR component of same drug, or different types of mini-tablets, or mini-tablets combined with pellets or powder. Lopes et al. A recent study by Mitra et al. Hence, the ability to accurately dispense varying mini-tablet quantities using different encapsulators can cover a wide dose range and such dosing flexibility is beneficial in clinical trials [ 30 ].

Unit-dose packing of mini-tablets Unit-dose packaging of mini-tablets has been receiving attention recently, especially for pediatric formulations. The unit-dose packaging can be referred to as stick-packs or sachets depending on the fill volume: stick-packs have smaller fill volumes, whereas sachets have larger fill volumes. The main advantage of unit-dose packaging is that it is suitable for packaging relatively large numbers of mini-tablets which can be beneficial for high dose drugs.

With increasing complexity, more options can be included, such as an increased number of minitablets per dose, or the possibility of dispensing two or more products simultaneously. Stick packing requires specific equipment and there are a number of stick packing machines available. They usually work on same vertical intermittent-motion principle.

During stick packing, the machine processes flexible composite films often including foil from the flat laminate reel, cut lengthwise, formed to a tube during transportation and sealed lengthwise.

Oral Dosage Forms That Should Not Be Crushed | Institute For Safe Medication Practices

It is then filled, sealed transversally, and cut. At the same time, photocell control assures the exact positioning of the print. The critical process parameters related to stick packing are sealing temperature, sealing pressure; sealing dwell time and size of the stick pack which depends on fill volume. There is change parts required depending on the selection of products meaning powder dosing vs.

In case of mini-tablets dosing, specifically fabricated dosing disk selected based on number of count of mini-tablets per stick packs.