Prolonged release systems

If the dmg is not broken down by the lytic enzymes of the lysosomes, it may be released in its active form from the lysosomal compartment into the cytoplasm and may even escape from the phagocyte, so causing a prolonged release systemic effect. Figure 5.2 depicts this macrophage mediated release of drags . 

Sesame oil may be used as a solvent in the preparation of subcutaneous injections, oral capsules, rectal suppositories, and ophthalmic preparations it may also be used in the formulation of suspensions and emulsions. Multiple-emulsion formulations, in which sesame oil was one of the oil phases incorporated, have been investigated as a prolonged-release system for rifampicin microemulsions containing sesame oil have been prepared for the transdermal delivery of ketoprofen. Sesame oil has also been used in the preparation of liniments, pastes, ointments, and soaps. A sesame paste... 

Occlusion of semi-solid preparations may be useful if systemic absorption is desired. A careful risk-benefit evaluation is then required. Transdermal patches are a more elegant alternative. Being virtually painless and easy to apply, if they achieve controlled delivery, they provide a formulation of choice for prolonged-release systemic uptake. They would have to be adapted to skin maturation, formulated with adhesives with low allergenic potential and be available in different strengths. Of course, the same inter- and intra-patient variability in relation to sites of administration and skin condition occurs in children as in adults. 

A prolonged action/controlled release system developed to deUver levonorgestrel for contraceptive therapy involves implantation of a set of flexible closed capsules made of demethylsiloxane—methylvinyl—sdoxane copolymer (see Contraceptives). Each capsule measures 2.4 mm in diameter and 34 mm in length. A set of six such capsules is surgically implanted beneath the skin of the upper arm. These capsules are intended to be removed by the end of the fifth year after implantation. 

Bovine growth hormone, a difficult protein for which to develop controlled release systems due to its propensity toward self-aggregation and inactivation, has successfully been incorporated into polyanhydride matrices (18). The growth hormone was colyophilized with sucrose, dry-mixed with finely powdered polyanhydride, and then compression molded into 1.4-cm-diaraeter wafers, 1 mm thick. As is shown in Fig. 15, release of bovine growth hormone was well controlled over a prolonged period of time. The assay for bovine... 

In the past, many of the terms used to refer to therapeutic systems of controlled and sustained release have been used in an inconsistent and confusing manner. Although descriptive terms such as timed release and prolonged release give excellent manufacturer identification, they can be confusing to health care practitioners. For the purposes of this chapter, sustained release and controlled release will represent separate delivery processes. Sustained release constitutes any dosage form that provides medication... 

The advantageous effects of liposomal carrier systems include protection of compounds from metabolism or degradation, as well as enhanced cellular uptake. Liposome-mediated delivery of cytotoxic drugs to cells in culture has resulted in improved potency [58,59]. Prolonged release of encapsulated cargo has also been demonstrated [60,61]. More recently, liposomes with extended circulation half-lives and dose-independent pharmacokinetics (Stealth liposomes) [62] have shown promise in delivery of drugs that are normally very rapidly degraded. 

Transdermal controlled-release systems can be used to deliver drugs with short biological half-lives and can maintain plasma levels of very potent drugs within a narrow therapeutic range for prolonged periods. Should problems occur with the system or a change in the status of the patient require modification of therapy, the system is readily accessible and easily removed. 

Sustained- and controlled-release devices for drug delivery in the vaginal and uterine areas are most often for the delivery of contraceptive steroid hormones. The advantages in administration by this route—prolonged release, minimal systemic side effects, and an increase in bioavailability—allow for less total drug than with an oral dose. First-pass metabolism that inactivates many steroid hormones can be avoided [183,184],... 

We include certain excipients in a formulation specifically because they interact with the physiological fluids and the bodily functions in a certain way. For example, as discussed above, we include disintegrants in immediate release tablet and capsule formulations, because we know that when they encounter the aqueous environment of the stomach, they will cause the tablet or capsule to disintegrate and thereby aid dissolution of the API. Another example is the general case of hydrophilic colloid matrices used as prolonged release drug delivery systems. We know that when these materials contact the aqueous environment of the GIT they swell and create a diffusion barrier that slows the rate of dissolution of the dissolved drug. 

Figure 6 Moraxen rectal delivery system. Comparative steady-state simulation of morphine plasma levels after single daily rectal administration of Moraxen with 100 mg morphine compared with twice-daily 50 mg morphine (OSRM) in an oral prolonged-release formulation. The simulation is based on the plasma levels from a single-dose study.

Loucas, S. P. and H. M. Haddad. 1972. Solid-state ophthalmic dosage systems in effecting prolonged release of pilocarpine in the cul-de-sad. Pharm. Sci61 985-986. 

Subcutaneous. Injecting medications directly beneath the skin is used when a local response is desired, such as in certain situations requiring local anesthesia. Also, a slower, more prolonged release of the medication into the systemic circulation can be achieved in situations where this is the desired effect. A primary example is insulin injection in a patient with diabetes mellitus. Subcutaneous administration provides a relatively easy route of parenteral injection that can be performed by patients themselves, providing they are properly trained. 

Intramuscular. The large quantity of skeletal muscle in the body allows this route to be an easily accessible site for parenteral administration. Intramuscular injections can be used to treat a problem located directly in the injected muscle. For example, botu-linum toxin and other substances can be injected directly into hyperexcitable muscles to control certain types of muscle spasms or spasticity (see Chapter 13).7,78 Alternatively, intramuscular injection can be used as a method for a relatively steady, prolonged release of the drug into the systemic circulation to control conditions such as psychosis,2 or to administer certain vaccines. 

As previously mentioned, degradable microspheres have gained attention as promising delivery vehicles for steroids in postmenopausal therapy. Copolymers of CL and d,l-LA were used to prepare microspheres for prolonged release of progesterone and [5-estradiol. The system offered a constant release for up to 40 days in vitro and 70 days in vivo [226]. Similarly, PCL copolymers have been considered useful for androgen replacement therapy in the treatment of aging men with a testosterone deficiency. Micelles of PCL-block-poly(ethylene oxide) released dihydrotestosterone in a controlled fashion over 30 days. The biocompatibility was confirmed in vitro in a HeLa cell culture [227]. 

It is estimated that 90% of all medicines usage is in oral forms and oral products consistently comprise more than half the annual drag delivery market. It is the preferred route of administration, being convenient, controlled by the patient and needs no skilled medical intervention. Considerable success has been achieved with various types of controlled-release systems for peroral delivery, which are used to prolong drag effects. 

In the small intestine, contact time with the absorptive epithelium is limited, and the small intestinel transit time is 3.5-4.5 h [32], The scintographic data show that many prolonged release products, particularly those intended for twice- or once-daily administration, actually release some of their drug contents in the colon where it may be absorbed into the systemic circulation for higher bioavailability. It is anticipated that conditions of dissolution, absorption, and metabolism in the distal portions of the intestine are different than in the proximal regions, due to differences in pH, lumen fluid, mucosal morphology, and motility. 

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