Established and Promising Drug Carriers for Parenteral Administration

Emulsions - established and promising drug carriers for parenteral administration

Emulsions are in general heterogeneous Over time, emulsions tend to revert to Emulsions – History systems in which one immiscible liquid the stable state of the phases comprising Lipid emulsions were developed after is dispersed as droplets in another liquid the emulsion. Surface active substances World War II to serve as an intravenous (simplified definition). (surfactants or emulsifiers) can increase the source of both calories and essential fatty kinetic stability of emulsions greatly so that, acids. The first approved IV-emulsion, once formed, the emulsion does not change Intralipid®, was developed more than 40 significantly over years of storage. years ago for parenteral nutrition. It consists of an O/W-emulsion of 10 or 20% soybean Emulsions – Fundamentals - oil droplets (70-400nm in size) stabilised Composition by a monolayer of egg yolk mixed with Normally one of the two immiscible phospholipids (1.2%) and glycerol (2.25%) as liquids is water, and the second is an oily an osmotic agent. substance, often a long chain triglyceride (e.g. soybean oil). The most frequent emulsifiers used in parenteral emulsion formulation are phospholipids (generally from egg yolk sources). The main functions of the emulsifiers are to form a thin film in the interface and lower the surface tension, Normally one of the two immiscible thus preventing flocculation and coalescence liquids is water, and the second is an oily of the dispersed phase. Additives are needed substance, often a long chain triglyceride to adjust to physiological pH and tonicity. (e.g. soybean oil). Hence, an emulsion Glycerol is most recommended as an isotonic in which the oil is dispersed as droplets agent, and can be found in almost every throughout the aqueous phase is termed parenteral emulsion. The pH is adjusted to an oil-in-water (O/W) emulsion. All the desired value with an aqueous solution pharmaceutical emulsions designed for of NaOH or HCL. The pH of an emulsion The wide and clinically well-accepted parenteral administration are of the O/W should generally be adjusted between 7 usage of this emulsion for parenteral type. Emulsions do not form spontaneously. and 8 to allow physiological compatibility nutrition later raised the possibility of using Energy input through shaking, stirring, and maintain emulsion physical integrity the internal oil core of this emulsion for homogenising or spray processes are by minimising hydrolysis reactions of the solubilising water-insoluble drugs. The needed to form an emulsion. components. past decade has seen enormous activity in drug delivery and targeting research using Reason Drug Sample emulsions as carriers of a wide variety of drugs. Solubilisation of low water-solubility Diazepam, vitamin A, vitamin drugst E, propofol, dexamethasone Emulsions – Relevance in today´s palmitate, progesterone medicine Intravenously administered emulsions Stabilisation of hydrolytically susceptible Lomustine, physostigmine salicylate are today excellent carriers for lipophilic compounds drugs which are often difficult to deliver (e.g. diazepam, vitamin A, vitamin E, propofol, Prevention of drug uptake by infusion sets Diazepam, Perilla Ketone dexamethasone palmitate, progesterone). Reduction of irritation, pain, or toxicity Amphotericine, diazepam, propofol of intravenously administered drugs

Potential for sustained release dosage Barbiturates, dexamethasone forms palmitate, physostigmine salicylate Possible directed drug delivery Cytotoxic agents to various organs Table 1: Reasons for using medicated emulsions.

62 INTERNATIONAL PHARMACEUTICAL INDUSTRY Winter 2009 / 2010 Type Pre-filled Ampoules Vials Bottles IV-bags Multi-chamber Speciality syringes bags Devices Size 1-50ml 1–20mL 1–100mL 50–1,000mL 40–5,000mL 100–5,000mL 1mL–200L

Material Glass Glass Glass Glass Non-PVC Non-PVC Various Plastic Plastic Plastic Plastic

Emulsions - Example: solution to some of the delivery problems container the production unit runs different Propofol (2,6 di-isopropylphenol) is not posed by new classes of active molecules, filling lines, which are adapted to a wide soluble in water. such as peptides, proteins, genes, and range of container types and formats. oligonucleotides. They may also extend the therapeutic potential of established drugs. Emulsions - Summary Emulsions are today well-established Emulsions – Manufacturing – The drug delivery systems of poorly water- Challenge soluble drugs. Fat emulsions are established Intravenous emulsions, like all and promising drug delivery systems which parenteral products, are required to meet can solubilise considerable amounts of pharmacopoeial requirements. The lipophilic drugs, control the in vivo disposition emulsion must be sterile, isotonic, non- of incorporated drugs, and deliver drugs pyrogenic, non-toxic, biodegradable and selectively to a target site. If emulsions stable. Furthermore, the particle size of the are carefully designed with respect to the It is presented as an oil-in-water- droplets has to be controlled accurately and target and route of administration, they emulsion with 1ml of emulsion containing needs to be within certain limits. To comply may provide one solution to some of the 10mg propofol (1%) or 1ml emulsion with these requirements, careful selection delivery problems posed by new classes containing 20mg propofol (2%), respectively. of the excipients and of the manufacturing of active molecules, such as peptides, Propofol is a highly effective short-acting process needs to be performed. proteins, genes, and oligonucleotides. They hypnotic without analgesic properties. It may also extend the therapeutic potential of is used for induction and maintenance of Emulsions – Manufacturing - Fresenius established drugs. general anaesthesia and for sedation of Kabi . mechanically-ventilated intensive care Intensive research efforts at Fresenius patients. Propofol emulsion appears as Kabi for more than 30 years have been a highly opaque white fluid due to the concentrated on the design of special scattering of light from the tiny (~150nm) oil injectable emulsion formulations that led droplets that it contains. It resembles milk, to sucessful marketed products such as the and is jocularly called “milk of amnesia” by emulsion of 1% propofol, a highly effective medical professionals. anaesthetic agent.

Emulsions – Relevance in medicine Emulsions – Manufacturing – Emulsions are able to control the in vivo Preparation process disposition of incorporated drugs, and deliver In Graz emulsions are produced in state- Copyright © Fresenius Kabi drugs selectively to a target site. Emulsions of-the-art equipment under full cGMP- are promising to improve the therapeutic conditions, utilising batch sizes ranging from index of drugs by increasing their efficacy 5 litres to 6000 litres and fully automated Anton and/or reducing their toxicity. Fat emulsion high pressure homogenisers. In the first step Gerdenitsch, drug delivery systems offer today a wide the drug substance is dissolved in the oily Master degree variety of possibilities for preparing better- component (e.g. soybean oil). This oily phase in Chemistry tolerated intravenous formulations of is then dispersed together with the emulsifier followed by selected drugs, while either maintaining (e.g. Lecithin) in water for injection using an Master degree the same characteristics concerning Ultra-turrax mixing device. The excipients in Economics. pharmacokinetics and tissue distribution, (e.g. Glycerol and sodium oleate) are added His main areas are Biotechnology or enhancing the site-specific delivery in under constant heating and stirring, forming and Biochemistry. Joined Fresenius targeted organs. the so called pre-emulsion.The pre- Kabi in 2008 as Director Contract emulsion is afterwards homogenised via Manufacturing, from Sanochemia Emulsions – Outlook high pressure homogenisers. Pharmazeutika AG where he was If emulsions are carefully designed Director Supply Chain Management with respect to the target and route of Emulsions – Manufacturing – Filling and Logistics. Email: anton. administration, they may provide one For filling the emulsions into the final [email protected]