Sustained-release parenteral formulations

During the past 30 years, there have been significant developments of parenteral disperse formulations. The use of parenteral emulsions can overcome the problems of low aqueous solubility and water hydrolysis of many drugs [184, 185]. Such formulations can avoid the use of conventional co-solvent systems and the undesirable effects caused by precipitation of drugs at the injection site. Recent developments of parenteral disperse formulations have the potential to provide sustained release and targeting of drugs [186-189],... 

Factors known to influence the clearance of drugs from interstitial sites, following extravasation or parenteral interstitial or transepithelial administration, include size and surface characteristics of particles, formulation medium, the composition and pH of the interstitial fluid, and disease within the interstitium. Studies indicate that soluble macromolecules smaller than 30 nm can enter the lymphatic system, whereas particulate materials larger than 50 nm are retained in the interstitial sites and serve as a sustained-release depot. The use of lipids or an oil in a formulation and the presence of a negative surface charge all appear to... 

Chaubal MY. Role of excipients in parenteral sustained-release formulations. Drug Deliv Tech 2003 3(7). 

Thus polymers serve as key excipients in oral and parenteral CR formulations. Other excipients used in sustained release dosage forms have been covered in other chapters within this book. For example, parenteral CR dosage forms involving polymers would still have other excipients as discussed in the chapter on injectable excipients (Chapter 16). Similarly oral dosage forms will require consideration of other excipients depending on the nature of the drug, as discussed in Chapter 12. This chapter reviews some of the promising polymers used in this application. 

Early development of polymers in injectable drug delivery primarily involved PLA and poly(lactic-co-glycolic) acid (PLGA) due to the prior use of these polymers in biomedical applications as sutures. Besides the safe and biocompatible nature of these polymers, their ease of availability made them ideal first candidates for screening parenteral CR formulations. Some of the early biodegradable polymer-based products for injectable sustained release used these polymers. However because... 

In the treatment of all types of glaucoma, acetazolamide is the most widely used orally administered CAI. Acetazolamide is commercially arailable as 125- and 250-mg tablets, 500-mg sustained-release capsules (Diamox Sequels), and a 500-mg vial formulated for parenteral administration. In glaucoma therapy in adults, acetazolamide is usually administered in doses of 250 mg every 6 hours or a single 500-mg sustained-release capsule twice daily. The recommended acetazolamide dose for children is 5 to 10 mg/kg body weight, administered every 4 to 6 hours. 

The bioavailability of molecules exclusively screened through in vitro assays can be low. Because of the polarity of the functional groups present in the molecule, they may be poorly absorbed or incorrectly distributed. They may also, as a result of their vulnerability, be the subject of early metabolic destructions, such as first-pass effects or any other kind of degradation leading to a short biological half-life. For such molecules, in vivo administration is limited to the parenteral route, and their clinical usefulness is thus restricted. Sometimes an adequate pharmaceutical formulation (micro-encapsulation, sustained-release or entero-soluble preparations) can overcome these drawbacks, but often the galenic formulation is inoperant, and a chemical... 

The chronic administration of molecules, which have a short biological half-life and cannot be given orally, presents a difficult challenge to formulators. One strategy which might be considered is the development of a sustained-release intramuscular or subcutaneous injection. Other non-parenteral options could include the inhalation or intranasal route, both of which have their own unique challenges. Sustained-release parenteral formulations might also be required in circumstances where patient compliance is likely to be poor. This consideration has led to the development of some antipsychotics and contraceptives as sustained-release injections. Table 9.6 lists some of the sustained-release parenteral products which are available on the U.S. market and their respective formulations. The typical approaches used in the formulation of sustained-release parenterals are summarised in this section. 

Table 9.6 Examples of sustained-release parenteral formulations. ...

This approach can be used to prolong the release of compounds with limited aqueous solubility. A suspension of a compound in its saturated solution can provide both immediate-release and sustained-release components of a dose (Madan 1985). A number of water-insoluble prodrugs are also formulated as suspensions, including hydrocortisone acetate and medroxyprogesterone acetate. As with any other type of suspension, excipients will usually be required to ensure the physical stability of the formulation. Strickley s (1999) article provides a table of parenteral suspension formulations the most popular excipient combinations are clearly polyethylene glycol/Tween 80 and carboxymethylcellulose/Tween 80. 

Drug delivery microspheres, in particular smart systems with controlled release, have been developed with PLA and its copolymers with glycolide to produce poly[(D,L-lactic acid)-co-(glycolic acid)]. Since the 80 s up until the present, many publications have reported on the various applications in the pharmaceutical field for using PLA and copolymers and polymers for their sustained release parenteral formulations and performance in drug release in a controlled manner from microspheres [200, 201]. 

Apart from the already established formulations, researchers are trying to develop novel oil-based formulations to combat the poor solubility and bioavailablity of NCE. Shevachman et al. developed novel U-type microemulsions to improve the percutaneous permeability of diclofenac. Shah et al.2 2 used microwave heating for the preparation of solid lipid nanoparticles by microemulsion techniques, which resulted in improved particle characteristics. Ki et al. reported sustained-release liquid crystal of injectable leuprolide using sorbitan monooleate. Recently, various novel oil-based drug delivery technologies are reported, which includes tocol emulsions, solid lipid nanopar-ticles, nanosuspensions, Upid microbubbles, sterically stabilized phospholipid micelles, and environmentally responsive drug delivery systems for parenteral administration.25 259... 

Table 20.6 lists FDA-approved PLGA-based parenteral microsphere products available on the US market. These formulations are based on the degradation of PLGA to achieve sustained release in vivo from 1 month to 3 months. According to the FDA dissolution method database, only Trelstar Depot has a standardized dissolution method listed using USP apparatus 2. FDA recommends using USP apparatus 2 or USP apparatus 4 to develop dissolution methods for four of the products, while for the other two products, there are no dissolution methods listed. Recent workshop reports have recommended the use of USP apparatus 4 for microsphere products [82]. 

Commercial Sustained Released Parenteral Formulations of Luteinizing Hormone-Releasing Hormone (LHRH) Agonists in PLGA Mierospheres"... 

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