Emulsion compositions for polyfunctional active ingredients

Details Emulsion compositions for polyfunctional active ingredients Emulsion compositions for polyfunctional active ingredients

1999-10-18

2004-04-13

Kim, Vickie (Department: 1614)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S450000, C424S456000, C424S400000

Reexamination Certificate

active

06720001

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to pharmaceutical delivery systems, and in particular to oil-in-water pharmaceutical emulsions for the improved delivery of polyfunctional active ingredients, such as pharmaceuticals, cosmeceuticals, nutritive agents, and diagnostic agents.
BACKGROUND
Polyfunctional active ingredients, i.e., active ingredients having at least some polar functionality, present difficult problems in formulating such compounds for effective administration to patients. A well-designed formulation should, at a minimum, be capable of presenting a therapeutically effective amount of the polyfunctional compound to the desired site of action, in a bioavailable form. Particularly when the polyfunctional active ingredient is hydrophobic, this minimal functionality has proven difficult to achieve. Delivery of a polyfunctional hydrophobic active ingredient requires interaction with aqueous physiological environments, such as blood, gastric fluids and intestinal fluids. Pharmaceutical compositions for delivery of such polyfunctional hydrophobic active ingredients should preferably carry the active ingredient through the aqueous environment, while maintaining the active ingredient compound in a bioavailable form, and avoiding or substantially reducing the use of physiologically harmful solvents or excipients.
A number of approaches to formulating polyfunctional hydrophobic active ingredients for oral or parenteral delivery are known. Several commercial formulations are available for parenteral dosage forms of polyfunctional active ingredients, based on organic cosolvent and/or synthetic surfactant solvent systems. For example, cyclosporin A (SANDIMMUNE®), paclitaxel (TAXOL®) and etoposide (VePesid®) are all commercially available in injectable dosage forms containing organic solvents and/or synthetic hydrophilic surfactants. See,
Physician's Desk Reference
, Medical Economics Co. (1999).
Solvent/hydrophilic surfactant formulations, however, suffer from a number of serious disadvantages. Hydrophilic polyethoxylated surfactants commonly used in such formulations, such as Cremophor® and Tween®, have a high toxicity potential. Pain at the injection site, thrombophlebitis, tissue necrosis and hypersensitivity reactions are commonly observed side effects of such formulations. Cremophor EL, for example, currently used in parenteral formulations of cyclosporin, paclitaxel and teniposide, has been found to be associated with severe anaphylactic/hypersensitive reactions. Cremophor EL has also been implicated at least partially responsible in the most significant side effect of cyclosporin concentrate for injection, acute nephrotoxicity. Besides being irritating and hemolytic, such formulations are potentially subject to active precipitation during storage, upon admixing prior to administration, or upon parenteral administration, leading to further safety challenges. In addition, some hydrophilic polyethoxylated surfactants, such as Cremophor EL, cause phthalate stripping and are incompatible with commonly used plasticized PVC infusion devices.
As an alternative to hydrophilic surfactant/cosolvent systems, oil-in-water (“o/w”) emulsion formulations have been used in polyfunctional hydrophobic active ingredient delivery. These formulations typically contain a long chain triglyceride oil phase dispersed in water and stabilized by an emulsifier layer of a phosphatide, such as soy or egg lecithin. Propofol, for example, is available commercially as Diprivan®, an o/w emulsion formulation using long chain triglycerides contained in vegetable oils, and an emulsifying agent. While such formulations may overcome some of the safety liabilities of hydrophilic surfactant/solvent based systems, the oil component may not be appropriately polar to effectively incorporate polyfunctional active ingredients at desirable therapeutic levels, without compromising product safety.
In an attempt to improve drug loading capacity in emulsions, some approaches incorporate additional stabilizers, or include undesirably high levels of compounds which hydrolyze to form medium chain fatty acids. Such approaches, however, present problems in processing, stability, and safety.
Several formulations have been developed based on medium chain triglyceride (“MCT”) oil phases, rather than (or in addition to) the more traditional long chain triglyceride (“LCT”) oil phases. U.S. Pat. No. 5,660,858 to Parikh et al. discloses cyclosporin oil-in-water emulsions with a synthetic MCT having predominantly C
8
-C
12
fatty acid chains. U.S. Pat. No. 5,364,632 to Benita et al. discloses an oil-in-water emulsion of a lipophilic drug having an MCT oil carrier and a combination of ionic and non-ionic surfactants.
Reportedly, such formulations enable better solubilization of polyfunctional active ingredients, compared to the less polar long chain triglycerides. See, e.g., Velazquez et al, “The scientific rationale and clinical application of short-chain fatty acids and medium-chain triglycerides,”
Proceedings of the Nutrition Society
, 55:49-78 (1996). However, the presence of predominantly medium chain (i.e., having fatty acids with carbon chain lengths of six to ten carbon atoms) triglycerides of higher polarity in the oil phase presents significant safety and stability issues that could limit the shelf live of MCT-based formulations, or place safety limits on the infusion rate. See, Velazquez et al., ibid, and Van de Velde et al., “Comparative hemodynamic effects of three different parenterally administered lipid emulsions in conscious dogs,”
Crit. Care Med
., 26:132-137 (1998).
The adverse effects of parenteral MCT-based emulsions reported in animals include poor growth and nitrogen balance, and increased energy expenditure. Some reports have indicated that medium chain triglycerides may not spare protein catabolism as well as do long chain triglycerides. More importantly, MCT-based emulsions do not seem to be well-tolerated by patients. Moderate to severe side effects have been reported, such as neurotoxicity, emesis, somnolence, coma, narcosis, essential fatty acid deficiency, and ketosis in susceptible patients. Since physical mixing of MCTs and LCTs does not alter the subsequent clearance kinetics, the corresponding triacyl glycerols are cleared from the blood and oxidized unaffected in the mixture. As a result, very rapid hydrolysis of MCTs and rapid uptake of the medium chain fatty acid hydrolysis products have been observed even in a one-to-one mixture of MCTs and LCTs administered parenterally. Some of the reported side effects have been attributed to uncoupling of oxidative phosphorylation resulting from the uncontrolled entry of medium chain fatty acids into the mitochondria, due to the rapid hydrolysis of MCTs.
As a specific example, caprylic acid, the hydrolysis product of an MCT containing the caprylic acid ester moiety, has been demonstrated to have neurological side effects. Caprylic acid infusion simultaneously produced alterations in the sodium-potassium-adenosinetriphosphatase activity in brain tissue, and resulted in hyperventilation, coma, seizure, hypotonia and electroencaphalographic changes in rabbits. (Velazquez et al.,
Proceedings of the Nutrition Society
, 55:49-78 (1996)). These events coincide with hemodynamic events, such as a decrease in cardiac output, stroke volume, and myocardial wall-thickening fraction, and an increase in aortic blood pressure and systemic vascular resistance when an MCT/LCT mixture is infused parentally in dogs. (Van de Velde et al.,
Crit. Care Med
., 26:132-137 (1998)). Thus, medium chain triglycerides and medium-chain-containing additives, such as medium chain mono- or diglycerides, which hydrolyze to medium chain fatty acids, present potentially severe safety problems in pharmaceutical emulsions.
Thus, there is a need for safe and effective pharmaceutical formulations of polyfunctional active ingredients that do not suffer from the foregoing disadvantages.
SUMMARY OF THE INVENTION
It is an object of the invention to provide pharmaceutical delivery s

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