Parenteral formulations administration

Due to particle sizes in the micrometer range, parenteral suspensions are generally limited to either subcutaneous or intramuscular routes of administration. However, ultrafine suspensions can be approached by high-pressure homogenization [200]. The particle size obtained from this technique is in the 100 500 nm range, thus intravenous administration is possible [201]. General information on parenteral formulations is given in Chapter 12. 

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

Benzoic acids substituted with a basic side chain also are also of interest as pro-moieties whose physicochemical properties and rates of enzymatic hydrolysis can readily be modulated. A number of drugs have been converted to prodrugs with this type of pro-moiety, e.g., hydrocortisone, prednisolone, acyclovir, chloramphenicol, and paracetamol [148] [149], These prodrugs appear well suited as parenteral formulations, being water-soluble, stable in slightly acidic solution, and readily hydrolyzed enzymatically. As examples, we consider here the hydrolysis in human plasma of a number of (aminomethyl)ben-zoates of metronidazole (8.109-8.115, Sect. 8.5.5.1, Table 8.9) [138], These prodrugs are very rapidly activated, which may be beneficial for parenteral administration. However, this type of pro-moiety may be cleaved too rapidly after oral administration to be of interest for poorly absorbed drugs. 

Gupta, P.K., Patel, J.P., and Hahn, K.R., Evaluation of pain and irritation following local administration of parenteral formulations using the rat paw lick model, /. Pharm. Sci. Technol., 48, 159, 1994. 

The antimykotie amphotericine is eneapsulated in liposomes and marketed as Am-Bisome" against severe systemic mycosis. The liposomal encapsulation reduces the toxicity of amphotericine while increasing the half-life of the drug and plasma level peaks [31], For stability reasons, the parenteral formulation is a lyophilized powder whieh has to be reeonstituted by adding the solvent just before administration. 

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. 

The usual dosage of chloramphenicol is 50-100 mg/kg/d. After oral administration, crystalline chloramphenicol is rapidly and completely absorbed. A 1-g oral dose produces blood levels between 10 and 15 mcg/mL. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. The parenteral formulation is a prodrug, chloramphenicol succinate, which hydrolyzes to yield free chloramphenicol, giving blood levels somewhat lower than those achieved with orally administered drug. Chloramphenicol is widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid, such that the concentration of chloramphenicol in brain tissue may be equal to that in serum. The drug penetrates cell membranes readily. 

The hypericin constituent of St. John s wort is photolabile and can be activated by exposure to certain wavelengths of visible or UVA light. Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given... 

Most peptides and proteins are currently formulated as parenteral formulations because of their poor oral bioavailability. Nevertheless, oral delivery of peptides and proteins would be the preferred route of administration if bioavailability issues could be overcome, as it offers the advantages of convenient, pain-free administration. Although various factors such as permeability, chemical and metabolic stability and gastrointestinal transit time can affect the rate and extent of absorption of orally administered peptides and proteins, molecular size is generally considered the ultimate obstacle [36]. 

Routine parenteral administration by injection serves to deliver drugs to specific body tissues. The most important routes of injection of these sterile products are intramuscular (im), intravenous (iv) and subcutaneous (sc). Basic parenteral formulation involves the selection of appropriate bases (e.g. aqueous, oily and emulsions) to achieve the desired bioavailability following injection. The detailed description of... 

The parenteral route of administration is associated with several major disadvantages (see Section 3.5.2). Parenteral administration is invasive and may require the intervention of trained medical professionals. Strict regulations for parenteral formulations govern their use and generally dictate that they are as simple as possible and the inclusion of excipients in the formulation is kept to an absolute minimum. Furthermore, developing a DDTS requires an enormous amount of R D investment in terms of cost, effort and time,... 

It is eliminated via both renal and hepatic routes (t/ 6h) with 30-55% excreted in the urine as the active drug. Oral and parenteral formulations are available, and doses range from 400 to 600 mg 12-hourly by both routes absorption after oral administration is rapid, little affected by food, and approaches 100%. 

The use of cosolvents in small-volume parenteral preparations is often critical due to the limited volume of solution that can be administered by a single injection. Thus, the required dose of drug must often be incorporated in 1 or 2mL of solution. Table 6 lists parenteral products containing cosolvents. The cosolvents most often used include ethanol, propylene glycol, glycerin, PEG 400, and, sometimes, dimethylacetamide. Other cosolvents, such as DMSO, have been used as solvents for parenteral formulations of experimental anticancer agents however, their use is restricted due to toxicity and potential incompatibilities with plastic administration devices. ... 

Several new excipients are being evaluated in order to increase the solubility or improve the stability of parenteral drugs. Cyclodextrins have been tried for the above reasons. Currently, there are two FDA approved parenteral products that have utilized a and y-cyclodextrins. p-cyclodextrin is unsuitable for parenteral administration because it causes necrosis of the proximal kidney tubules upon IV and subcutaneous administration. Hydroxypropyl p-cyclodextrin (HPpCD) and sulfobutylether p-cyclodextrin (SBE-7-p-CD) have shown the most promise. Captisol is the trade name of SBE-7-p-CD and is anionic. Currently, two CaptisoF based small molecule IV and IM drug formulations are in Phase III clinical trials in the United States. One parenteral formulation that utilizes HPpCD (Cavitron ) is in Phase II/III clinical trials, and another (Sporanox) has been approved by... 

The microparticle system has become an indispensable part of the controlled drug delivery fields for the past few decades since it can readily be adapted for various administration methods. In particular, biodegradable polymeric microparticles can provide a number of advantages over conventional parenteral formulations ... 

Polysorbate 80 is a surfactant commonly used in protein parenteral formulations to minimize denaturation at the air-water interface. Polysorbate 80 is also sometimes used in injectable solution formulations of small molecules for the purpose of solubility enhancement owing to micelle formation. Docetaxel, a first-line therapeutic to treat breast and small cell lung cancer, is practically insoluble in water and is solubilized in Taxotere to 40mg/ml in 100% polysorbate 80, and is diluted four-fold with the supplied diluent of 13% ethanol in water, then further diluted to 0.3-0.74mg/ml with saline or dextrose 5% prior to administration by rV infusion. The dose of Taxotere is up to 5 ml of polysorbate 80 per dose, representing the estimated maximum amount administered intravenously. 

A transdermal delivery system has been developed for prevention of motion sickness and vomiting, using an adhesive patch for postauricular application the drug is released at a uniform rate for 72 hours. The adverse effects of this formulation are qualitatively typical of those reported for the oral and parenteral formulations of hyoscine and its congeners, although comparative studies suggest that the incidence is reduced with transdermal administration. Nevertheless, adverse effects involving the central nervous system, vision, bladder, and skin have been described, as have withdrawal symptoms after the patch is removed. 

In parenteral formulations, medium-chain triglycerides have similarly been used in the production of emulsions, solutions, or suspensions intended for intravenous administration. Medium-chain triglycerides have been particularly investigated for their use in total parenteral nutrition (TPN) regimens in combination with long-chain triglycerides. ... 

Ingestion is the most common route of both accidental and intentional exposures to cimetidine. The drug is available as a parenteral formulation for intravenous administration and with improper dosing may result in acute toxicides. 

A choice of salts can also expand the formulation options for a material. The antimalarial agent a-(2-piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrene-methanol hydrochloride (Fig. 9) exhibited poor solubility, was delivered as an oral formulation, and required a single dosing of 750 mg (13). Seven salts and the free base were evaluated. The lactate salt was found to be 200 times as soluble as the hydrochloride salt (Table 3). This enhanced solubility would make it possible to reduce the oral dose to achieve the same therapeutic response as well as develop a parenteral formulation for the treatment of malaria. However, the case of lidocaine hydrochloride (Fig. 14) demonstrates that a compound limited to parenteral and topical formulations can be expanded to oral administration by changing to a salt form with acceptable physical properties (16). The hydrochloride salt was hygroscopic, difficult to prepare, and hard to handle. Six salts were evaluated for salt formation, solubility, and hygroscopicity. Other salts, such as phosphate, exhibited properties acceptable for dry pharmaceutical dosage forms. 

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. 

Terbutaline is a p2-selective bronchodilator that contains a resorcinol ring and thus is not a substrate for COMT. It is effective when taken orally, subcutaneously, or by inhalation. Effects are observed rapidly after inhalation or parenteral administration after inhalation, its action may persist for 3-6 hours. With oral administration, the onset of effect may be delayed for 1—2 hours. Terbutaline (brethine, others) is used for the long-term treatment of obstructive airway diseases and acute bronchospasm a parenteral formulation is used for the emergency treatment of status asthmaticus (see Chapter 27). 

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