Conventional Matrix System for Selected Soluble Insoluble Drug Products and Their Corresponding Release Modifiers

Drugs that are sparingly soluble or insoluble in water Clarithromycin (antibiotic) Carbamazepine (anticonvulsant) Zolpidem tartartae (Insomnia) Alprazolam (Panic disorder) Fluvoxamine (Anxiety disorder) combination (Abbott) Simcor - a niacin combination (Abbott) Biaxin XL (Abbott) Tegretol XR (Novartis) Ambien CR (Sanofi) Xanax XR (Pharmacia) Luvox CR (Elan) povidone3 Hypromellose, povidoneb Cellulosic polymers0 Cellulose compounds'1 Hypromellose, PEG, sodium starch glycolatee Hypromellosef...

Advantages and Disadvantages

From an engineering and operational perspective, injection molding technology can be low cost, highly precise (ensuring accurate drug content), and provide a wide range of product geometries. Scale-up can be less of an issue because the unit operation remains unchanged. It can also facilitate a largely continuous rather than batch mode of manufacture. Disadvantages are high initial set-up costs, with Fig. 12.7 MiniJet injection molder (left) and MiniLab-compounder. Courtesy Thermo Scientific...

Coating as a Means to Control Drug Release

Figure 1.6 summarises the many ways in which control of drug release has been achieved by enveloping drugs as opposed to modifying the form of the drug as discussed later. 1.1.3.1 Early Enteric Coating Materials The use of keratin-coated pills is reported in a Lancet paper in 1893 20 . Although the process is credited to the German dermatologist, Dr Paul Unna, who first marketed such products 21 , he himself did not claim to have originated the idea of enteric coating. The early alternative to...

References

Rajilic-Stojanovic M, Smidt H, de Vos WM (2007) Diversity of the human gastrointestinal tract microbiota revisited. Environ Microbiol 9 2125-2136 2. Sousa T, Paterson R, Moore V, Carlsson A, Abrahamsson B, Basit AW (2008) The gastrointestinal microbiota as a site for the biotransformation of drugs. Int J Pharm 363 1-25 3. Wilding I (2001) The enterion capsule a novel technology for understanding the biopharma-ceutical complexity of new molecular entities (NMEs). Drug Deliv Technol 1 8-11 4....

Commercial Products and Their Corresponding Release Mechanisms

Ambien CRm Depakote ERn Budeprion XLo Asacolp Esomeprazole magnesium Venlafaxine HCl Duloxetine HCl Dextroamphetamine sulfate, dextroamphet-amine saccharate, amphetamine aspartate H2O, and amphetamine sulfate Tamsulosin HCl Tolterodine tartarate Dexmethylphenidate HCl Morphine sulfate Morphine sulfate Tramadol HCl Zolpidem tartrate Divalproex sodium Bupropion HCl Mesalamine pseudoephedrine HCl Darifenacin Oxymorphone HCl pseudoephedrine HCl Methylphenidate HCl Multiparticulate Multiparticulate...

Buccal Drug Delivery Systems

Table 16.6 lists commercially available products for oral TMD. Most are conventional dosage forms adapted for oral mucosal delivery (e.g., tablets, sprays) but there is an increasing presence of novel systems for delivery of traditional drugs, proteins, peptides, and vaccines. Combinations of unifunctional and multifunctional materials may decrease previous limitations for product design. Indeed, new excipients, including a new polymer specifically designed for melt extrusion, Soluplus , may...

Regulating Gastric Emptying

Gastric Motility

The duodenum regulates the supply of material from the stomach to the small intestine. Fat, high salinity and highly acid solutions cause the duodenal wall pressure to increase and slow down the exit of the gastric contents. Because the gastroduodenal system regulates the exit of the slurried contents from the stomach, the transit time from duodenum to the caecum is relatively constant. The diameter of the pyloric opening varies according to the nature of the gastric contents. When taken with...

The Gastrocolic Reflex

It has been noted in scintigraphic studies that ingestion of food whilst a tablet was in the ascending colon tended to move the unit into the transverse colon, or if the tablet was in the transverse colon, it moved it further along 31 . This provided a good illustration of the propulsive ileocolic reflex, sometimes mistakenly termed the gastrocolic reflex. Misiewicz, in a classical paper on colonic motility, referred to his earlier study 32, 33 and pointed out that this phenomenon occurs in...

Introduction and General Principles

Interaction between a drug and a polymeric material generally forms the basis of controlled oral drug delivery. Drug in solution exhibits random Brownian motion to equilibrate concentration, where concentration gradients exist. A polymer at certain concentration in such a solution imposes mandatory pathways for drug diffusion. Thus, polymers that dissolve in or otherwise hydrate in aqueous media can alter the drug diffusion process in a time-dependent manner. For example, hydroxypropyl...

Mechanics of Injection Molding

This section gives an account of the injection molding, process, particularly those aspects that are important in a drug delivery dosage form design context. The reader is encouraged to consult engineering textbooks on injection molding for more comprehensive accounts. The following sequence of operations comprises the manufacturing cycle (Fig. 12.3) Materials are fed from a hopper (funnel) into a heated barrel with a reciprocating screw (extruder). Materials are melted, mixed, and advanced...

Inert Matrices

Table 7.4 lists water insoluble and lipidic materials commonly used for fabrication of inert matrices, along with their FDA listed maximum use level in designing oral formulations 34 . Ethylcellulose is prepared by reacting alkali cellulose with ethyl chloride It is characterized by degree of ethoxy substitution and associated molecular weight and is available in different molecular weights with varying viscosities in organic solvents. Multiple particle size grades are also available. It is...

Lipids and Lipid Self Assembly in Oral Drug Delivery

Schematic Diagrams Fat Absorption

There are a number of considerations associated with the use of lipids in dosage form design. In particular, the following properties and behaviors can play key roles, as well as forming the basis for lipid classifications Lipids can act as solvents, leading to drug being present in the gastrointestinal tract (GIT) (at least initially) in solution thereby overcoming the drug dissolution step 1 . Lipids may have amphiphilic structures that determine their capability to self-assemble in aqueous...

Geomatrix Partially Coated Swellable Matrices

There have been many attempts to control release kinetics in hydrophilic matrices by manipulating and balancing diffusion and relaxation mechanisms. Zero-order release from a matrix was obtained by designing an appropriate matrix shape 1 or nonuniform drug distribution 2 , by using ionic-exchange resins, hydrophobic porous materials 3, 4 , hydrophilic soluble polymers capable of modifying the effective diffusivity of drug 5 , or by surface cross-linking of the matrix 6 and others. Geometric...

Capsule Based Devices

Colon Drug Delivery

A range of lag-times can be selected, to enable an increased range of temporal targeting from a single capsule device. Capsules can be coated with a semipermeable or water impervious layer. A semipermeable coat provides the basis for osmotically driven release. The pressure caused by internal swelling forces the capsule open or ruptures the body to deliver drug. A water-impervious, low-density capsule might also float on the gastric contents, prolonging residence time in the GI tract before...

Enteric Coatings

Enteric coats are used to obviate gastric irritation, drug degradation at low pH, or to delay release until the unit reaches the small intestine or even the colon, possibly to evince a local effect or to ensure better absorption. They usually comprise acidic polymers as film formers. The pH at which the coat dissolves is determined by Table 13.1 Fast dissolving coating polymers 22 Table 13.2 Commercial formulations for fast dissolution 22 Commercial product (selection) Polymer PVA polyvinyl...

Introduction Of Oral Drug Delivery

An ion-exchange resin (IER) comprises an insoluble, commonly synthetic matrix possessing ionizable groups capable of exchanging ions with those in bulk solution with which it is in contact. Thus, under appropriate conditions it can deliver to or sequester chemical species from an aqueous environment. The process is reversible, exchange capability being regenerated by washing the resin with an excess of the originally bound ions. The technology is utilized in many industrial applications such as...

Drug and Disease Candidates for Colonic Delivery

Drug delivery systems described so far have focused on delivery for IBD. The primary drug candidates in use or under investigation are the mesalamine derivatives and the steroids prednisolone, budesonide, and beclometasone. Many other drugs and diseases are postulated as candidates for colonic delivery, whether these be local treatment or are aiming to achieve systemic delivery. Cytotoxic agents are of great interest. Colon cancer is the third most common form of cancer and is prevalent in the...

Physical Stabilization of Amorphous and Molecularly Dispersed Drugs

The large numbers of poorly soluble compounds emanating from drug discovery pipelines has stimulated growing interest in formulation approaches to overcome solubility dissolution-limited oral absorption. In such a context, amorphous drug forms have been widely investigated. The high internal energy of the amorphous state, relative to the crystalline state can provide increased apparent solubility and dissolution rate, which may translate to increased bioavailability. However, the amorphous...

Processing Characteristics 751 Hydrophilic Matrices

Hydrophilic matrix tablets can be manufactured by DC, wet granulation, dry granulation (roller compaction or slugging), or hot melt granulation extrusion, depending on the drug, the formulation, and available equipment. HPMC polymers generally have very good compressibility, producing tablets with high mechanical strength 56 . High molecular weight grades may exhibit less plastic flow, requiring higher compaction pressures for deformation 54 . Wet (aqueous) granulation of hydrophilic matrices...

Geomatrix Technology

Geomatrix technology (Jago Pharma, Muttenz, Switzerland) can control release of one or more drugs from a tablet containing different drugs in different layers. Different layers in the tablet with different swelling, gelling, and erosion behaviors can provide separate drug release modes (http www.skyepharma.com In general, hydro-philic polymers progressively swell on encountering aqueous media thereby increasing gastric residence time, core surface area, and diffusivity for release. Thus, as...

Introductory Remarks and Historical Development

Traditionally, the clinical applications of oral colonic drug delivery have been limited to the local treatment of inflammatory bowel disease (IBD). Enteric coatings, sustained release systems, and bacterially triggered treatments have all been used to deliver anti-inflammatory molecules to the colon to treat this debilitating condition. However, for many years the treatment of colonic cancer has been postulated as an ideal candidate for colonic drug delivery but little has been delivered in...

Polymers for Modifying Release 741 Hydrophilic Matrices

This section describes the critical quality attributes of polymers used in hydrophilic matrix systems. These are listed in Table 7.3 along with FDA-recommended maximum use levels 34 . 7.4.1.1 Hypromellose Hydroxypropyl methylcellulose Hydroxypropyl methylcellulose HPMC is widely used in matrix applications. Key advantages include global regulatory acceptance, stability, nonionic nature resulting in pH-independent release of drugs , and ease of processing by direct compression DC or granulation....

Capsules as a Technology Platform 1421 Capsule Sizes Materials and Properties

Different design options exist for HC capsules, depending on the active ingredient API and fill composition. They may accommodate solids such as powder, granules, pellets, mini-tablets, or combinations thereof in standard two-piece capsules e.g. ConiSnap capsules Fig. 14.1 . Liquid, semisolid, or formulations comprising liquid and solid e.g. pellets, capsules can be contained using capsules designed for liquid fillings e.g. Licaps capsule and readily sealed by microspray technology e.g. LEMS...

Fast Dissolving Film Strip

A dissolvable oral strip is a pliable film, applied lingually that quickly disintegrates dissolves to release drug into the oral cavity. Good wettability, large surface, and low thickness less than 100 mm facilitate fast release. The physicochemical properties of drugs and polymers used to fabricate the film can influence whether the drug is absorbed via the oral mucosa or is swallowed, which would lead to absorption of the bioactive from the GI tract. Advantages of the thin film strip format,...

Preparation of Resinates

The process for drug-resin complex manufacture is relatively simple. An ionizable active pharmaceutical ingredient API is loaded on to the resin by exchanging with the resin functional group's native ion, forming a drug-resin complex or resinate also referred to as Polistirex in some literature . Drug structure and biological activity is not affected but bound drug is essentially inert and not available to the environment. Binding energy is determined by the ionic attractions between the resin...

The Butterfly Effect in Swellable Matrices

The butterfly effect was first observed when hypromellose-based matrix compacts partially separated as two wings during dissolution studies. Such splitting was pH-independent and the halves so generated remained attached to each other. Figure 11.12 illustrates such changes. Such a phenomenon, if reproducible, has potential applications for modifying drug release due to the changed release area consequent to splitting. Fig. 11.12 Progression of events during disk matrix swelling leading to the...

Gastric Retentive Strategies Mucoadhesion Bioadhesives

Polymer Nanofibers

The concept of mucoadhesion is based on the formulation first making good contact with the mucus layer of the stomach, followed by its adhesion to the mucus layer. Thus the formulation remains in the stomach until the mucus layer sloughs off or the formulation no longer adheres to the mucus. There are several challenges with this approach the first is the challenge to make good contact with the mucus layer. In the fed state, nonspecific adhesion could occur with food. In both the fed and fasted...

Formulation Factors

16.5.3.1 Bioadhesion and Bioadhesive Polymers Bioadhesion is a phenomenon related to the ability of biological or synthetic material to adhere to a biological substrate. Oral mucosal drug delivery necessitates the use of mucoadhesive polymers as dosage forms should ideally adhere to the mucosa and withstand salivation, tongue movement, and swallowing for a predetermined period of time. Mucoadhesion has received considerable attention due its importance in drug delivery. A widely used approach...

Gastric Retentive Strategies Buoyancy Floating and High Density

The concept of buoyancy has been studied extensively and reported in the literature 22-24 . Floating products that have been marketed include Madopar HBS, Valrelease HBS, Gaviscon, and TUMS Lasting Effects. Floating systems have received considerably more attention than high-density formulations, possibly because high-density products have not reported consistent success at any stage of development except possibly in some veterinary applications . Floating formulations have proven to be...