Immediate release or slow release?

The regulated release drug delivery system can achieve special clinical purposes that cannot be achieved by conventional preparations by regulating the absorption of the drug or changing the release site
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The therapeutic advantages of properly designed modified release formulations include: Improve drug efficacy and reduce toxic and side effects; Ease of use, improve patient compliance; Optimize performance; Screen new active drugs or develop new clinical indications
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Modified release drug is a technology or method that can change the delivery mode of therapeutic drug, through physical, chemical and biological modification of therapeutic drug components, to obtain the expected blood drug concentration determined by clinical pharmacological experiments
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Oral modified release formulations include: extended-release (ER) and delayed-release (DR) products
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Delayed release dosage forms can release the drug continuously over a period of time, thus reducing the frequency of dosing compared to conventional dosage forms such as solutions or immediate release formulations
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The design goal of oral modified-release drug formulations is to alter the rate of drug input (dissolution/absorption) in the gastrointestinal tract to obtain a predetermined plasma concentration profile
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① Delayed-release: such as enteric coating; ② site-specific or timed release: such as colon administration; ③ extended-release: such as zero-, first-, Two-stage release, etc.
; ④ programmed release: such as pulsed, delayed, sustained release, etc.

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Here are some examples of drug regulated release products that have achieved clinical and commercial success: ① Procardia® XL is a zero-order nifedipine release tablet, which not only reduces the three-time-a-day medication method to once-a-day, but also Significantly improved the ratio of efficacy and safety; ② Asacol® and Lialda™ are mesalazine delayed-release tablets, which can release mesalazine in the ileum or colon end for the treatment of ulcerative colitis
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Let's take a look at what are the common oral sustained-release drug delivery systems? 1 Matrix-type preparations In matrix-type preparations, active drugs (such as crystalline, amorphous, and a few in the form of molecular dispersions) are uniformly mixed with rate-controlling materials and other inert ingredients
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The drug in matrix formulations is released by diffusion or erosion
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According to the characteristics of the rate-controlling material, skeleton-type preparations can be divided into the following two categories: a.
Hydrophilic type; b.
Hydrophobic type
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From the application point of view, the controlled-release material in the former matrix formulation is composed of water-insoluble and/or water-swellable materials, and the latter is composed of water-insoluble and low-swellable materials
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a Hydrophilic matrix formulation A polymer-based drug delivery system in which drug release involves two competing mechanisms, Fickian diffusion release and free diffusion release
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The main rate-controlling material is a hydrophilic polymer, which swells rapidly after absorbing water and can form a gel layer on the surface of the formulation
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Diffusion through the viscous gel layer is not the only way of drug release, and the relaxation of polymer chains leads to matrix erosion that contributes to the overall drug release
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Which release mode plays a major role in drug release is determined by the nature and matrix composition of the specific drug
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b Hydrophobic matrix preparation is the earliest clinically used modified release preparation
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However, hydrophobic matrix formulations are not suitable as carriers for poorly soluble drugs because the drug concentration gradient in the matrix is ​​too low to allow drug release within the expected gastrointestinal transit time
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2 Depot polymer preparations Typical depot preparations are prepared by coating the tablet cores containing solid drugs or high-concentration drug solutions with film coatings with controlled release materials
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In this dosage form, the only construct that can effectively limit drug release is the polymer coating that surrounds the drug reservoir
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Common modified-release depot oral formulations include polymer-coated pellets or tablets, capsules (microparticles, microspheres or nanoparticles) with various contents
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The polymer coating film usually includes a hydrophilic agent or an additive (for example, a second polymer material, a surfactant or a plasticizer, etc.
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This polymer coating film is a porous coating film, which is used for drug storage.
The library provides a predetermined resistance to diffusion of the external solvent
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This resistance varies depending on the thickness of the membrane, as well as the properties of the membrane and soluble species in a particular environment
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In practical applications, the mechanism of drug release from coated dosage forms can be summarized as: ① drug transport through the capillary network filled with dissolution medium (K=1) ② drug transport through hydration and swelling membrane layer ③ drug transport through coating Release from cracks, pores, etc.
in the membrane (K=1) The preferred depot formulations often consist of a number of coating units such as pellets, microspheres and minitablets
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3 Osmotic pump-type controlled-release formulations Osmotic pump-type controlled-release formulations are similar to reservoir-type formulations, but contain a permeation enhancer that absorbs moisture in the surrounding medium and allows it to pass through a semipermeable membrane
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This dosage form is also known as a primary (single chamber) osmotic pump
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The release of the active substance in this formulation is controlled by a semipermeable membrane through which moisture can freely pass
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The drug is released from the small pores in the preparation driven by the osmotic pressure generated inside the preparation
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The size of the drug release hole should be within a range to prevent the drug from being released too quickly, and at the same time, it can reduce the hydrostatic pressure in the system, which can reduce the osmotic pressure and change the volume of the preparation
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In the process of oral formulation development, two common osmotic pump formulations are single-chamber primary osmotic pump formulations and dual-chamber osmotic pumps (such as push-pull osmotic pump (Push-Pull®) and push-rod osmotic pump (Push-Pull®) -Stick®))
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1 Enteral drug release Enteral drug release refers to the delayed release of the drug until the drug preparation passes through the stomach and enters the gastrointestinal tract
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A range of formulation processes have been successfully used to delay drug release, including single- or multi-unit coating formulations, capsule formulations, or osmotic pumps
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The earliest physicochemical method for delayed drug release is to coat the preparation with enteric coating, which can act as a barrier layer to control the localized release of drugs in the digestive system
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Enteric coating materials that can prevent drug release in the stomach are mostly acidic polymers, so they are stable or insoluble under acidic conditions
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After the formulation reached the small intestine, the enteric coating was able to dissolve rapidly under the pH conditions of the gastrointestinal tract, as shown in Figure 4
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For example, the drug aspirin, which is irritating to the stomach, is enteric-coated, and the drug is only released when it reaches the small intestine
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2 The colon-targeted drug delivery system in the gastrointestinal tract for colonic drug delivery has attracted attention, and has obvious therapeutic advantages for certain drugs, such as reducing the incidence of systemic drug side effects and lowering the dose of drugs, for local lesions of the colon (such as ulcers).
colitis, irritable bowel syndrome) for effective treatment
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Colonic delivery systems are essentially delayed-delivery formulations that release drugs immediately or slowly in the large intestine
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For optimal colonic administration formulations, the active drug is not released in the upper environment of the gastrointestinal tract until the drug is released at the site closest to the colon
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Considering the unique delivery environment of the colon (pH, transit time, pressure, or microbes), various methods and techniques have been used in the study of colon-targeted drug delivery formulations
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These include the use of pH-sensitive or slowly eroding polymer-coated formulations, swellable or osmotic pump-type delayed-release formulations, and the use of drug carriers that can be degraded by colonic flora
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3 Pulsed drug release Pulsed drug release in general is the sudden release of a portion of the total drug load at a specified time, followed by a period of time with no or little drug release (lag period), alternating with and without drug release A mode of administration performed
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Oral pulsed-release preparations are preparations that are administered in bursts after oral administration in a certain pattern
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In the field of modified release formulations, such non-single release and multi-drug loading formulations have been recognized and proven to bring specific clinical benefits: ① Optimization of chronotherapy; ② Simulation of endocrine physiological models; ③ For the production of Tolerable drugs provide the best treatment regimen, and constant drug concentrations result in receptor downregulation
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4 Biphasic drug release In non-single sustained-release formulations, the biphasic drug release mode is most commonly used to avoid maintaining a constant plasma concentration
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The conventional basis for this design includes: ① The rapid onset of action by adding an immediate-release portion to a sustained-release preparation; ② For chronotherapy drugs, the sustained-release preparation is combined with a delayed-release portion to optimize the dosing schedule; ③ Blood production Fluctuations in drug concentration to avoid or attenuate apparent tolerance due to continuous exposure of the drug to the receptor site; ④ Overcome problems related to non-linear pharmacokinetic first-pass effects, specific pharmacokinetics, or pharmacodynamics, which Can result in reduced bioavailability or alter the ratio of drug to metabolite
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For example, the biphasic drug release formulations currently on the market include verapamil, diltiazem?, nifedipine, and leadide
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Utilizing modified release technologies is the most critical factor in achieving desired clinical outcomes, including establishing clinical evidence and understanding drug properties
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The successful design of a commercially viable modified-release formulation depends on the physicochemical, biopharmaceutical, pharmacokinetic, and biological properties of the candidate drug, independent of specific delivery techniques
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However, there is no one-size-fits-all drug release technology.
For compounds with properties suitable for the preparation of modified release formulations, different drug release technologies can usually be used
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Therefore, it is more important to choose drug release technology according to technical conditions, actual conditions, development and commercial value
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References [1] Qiu, Y(2007).
Design and evaluation of Oral Modified-Release Dosage Forms based on Drug Property and Delivery Technology.
[2] Eichel, HJ, Massmann, BD & Cobb, Jr.
, JE Delayed, sustained -released diltiazem pharmaceutical preparation.
US Patent 5 529 790.
[3] Development of solid oral preparations-pharmaceutical theory and practice