Parenteral depot formulation

Likelihood of compliance with an oral versus parenteral depot formulation Complications... 

Long-acting, parenteral, antipsychotic administration remains an important option in various clinical situations. Presently, only neuroleptics are available in this formulation, but it is anticipated that depot formulations of novel antipsychotics (e.g., risperidone, olanzapine) may soon be approved. The advent of such agents should significantly improve the efficacy and safety of this strategy. 

Pyrrolidones such as 2-pyrrolidone and N-methylpyrrolidone see Section 17) are mainly used as solvents in veterinary injections. They have also been suggested for use in human pharmaceutical formulations as solvents in parenteral, oral, and topical applications. In topical applications, pyrrolidones appear to be effective penetration enhancers. Pyrrolidones have also been investigated for their application in controlled-release depot formulations. ... 

Polymeric micropsheres, particularly those prepared from the biodegradable polylactide/ polyglycolide polymers, have been widely investigated as a means to achieve sustained parenteral drug delivery. The advantage of formulating the polymeric matrix as microspheres is the ability to administer them via a conventional needle and syringe as a suspension formulation, rather than as an implant (see below). Lupron depot formulations are available which can provide therapeutic blood levels of leuprolide acetate for up to four months. These products are presented as lyophilized polylactic acid microspheres which are reconstituted to form a suspension prior to administration. 

Improvement of the properties of a drug may be achieved by the chemical modification of the parent drug. The preparation of an ester, salt, or other modification of the parent structure may be employed with parenteral drugs to increase stability, alter drug solubility, enhance depot action, avoid formulation... 

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... 

Many drugs are administered as parenterals for speed of action because the patient is unable to take oral medication or because the drug is a macromolecule such as a protein that is unable to be orally absorbed intact due to stability and permeability issues. The U.S. Pharmacopoeia defines parenteral articles as preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal. They include intravenous, intramuscular, or subcutaneous injections. Intravenous injections are classified as small volume (<100 mL per container) or large volume (>100 mL per container) injections. The majority of parenteral dosage forms are supplied as ready-to-use solutions or reconstituted into solutions prior to administration. Suspension formulations may also be used,101 although their use is more limited to a subcutaneous (i.e., Novolin Penfill NOVO Nordisk) or intramuscular (i.e., Sandostatin LAR Depot Novartis) injection. Intravenous use of disperse systems is possible but limited (i.e., Doxil Injection Ortho Biotec). 

Huphenazine is a short acting agent. Eor the management of agitated and potentially violent patients its hydrochloride formulation is frequently used for parenteral administration. Fluphenazine decanoate is a widely used depot preparation. Although its principal pharmacological activities are similar to those of the other phenothiazines fluphenazine displays only weak sedative action and it shows little anticholinergic and hypotensive effect. 

Betamethasone is hardly ever used orally. It has a long duration of activity and can therefore also be used for alternate-day therapy. The parenteral formulation is also the sodium phosphate salt which when given IV or IM has a rapid onset of action. There are many similarities with dexamethasone such as their metabolic pathways and the indications for which both steroids are used, like the prevention of neonatal RDS and reduction of raised intracranial pressure. Combinations of betamethasone acetate and sodium phosphate have, when used for intra-articular and intra-lesional injections, the dual advantage of a rapid onset of action together with the long duration of action of a depot preparation. 

Unlike extended release parenteral formulations (depot suspensions), application of low-water-solubility salts in oral extended release forms is not used commonly. This probably is due to the fact that for oral delivery, coated and matrix-type systems are easy to design and can generate release profiles that are manipulated more easily than powder systems. Therefore, although it is not impossible, selecting a salt form with low water solubility to achieve a desired extended release profile has not been reported frequently. 

Parenteral formulations of certain antipsychotic drugs (e.g., fluphenazine, haioperidol) are available for rapid initiation of treatment and for maintenance therapy in noncompliant patients. Depot forms of both drugs exist. 

In recent years, the use of biomaterial as vaccine adjuvants has received considerable interest in oral and parenteral vaccine development. They have been formulated to elicit either mucosal or humoral immxmity via targeted phagocytosis in the Peyer s patches or as conventional subcutaneous depots. Golembek et al. were one of the first groups to apply microspheres for tumor immxmotherapy. GM-CSF or IFN-y was encapsulated in gelatin-chondroitin sulfate microspheres and mixed with irradiated B16/F10... 

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]. 

Another facet of parenteral drug delivery is the implanted device, and this is perhaps the most promising and most readily commercialised area for responsive and/or active polymers. For an implanted vehicle or depot, drag release rate is controlled by dissolution and/or diffusion in the formulation, or for solid polymer implants by diffusion and/or degradation of the polymer. For more complex polymer hydrogels, the release can be controlled by the linking chemistries, and these can be made responsive to a wide variety of stimuli such as enzymatic action, redox potential and so on, as well as those noted above for the oral route. 

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