USOO6638537B2 (12) United States Patent (10) Patent No.: US 6,638,537 B2 Dennis et al. (45) Date of Patent: *Oct. 28, 2003 (54) MICROEMULSION AND MICELLE (56) References Cited SYSTEMS FOR SOLUBLIZING DRUGS U.S. PATENT DOCUMENTS (75) Inventors: Donn M. Dennis, Gainesville, FL (US); 5,478.860 A 12/1995 Wheeler Nikolaus Gravenstein, Gainesville, FL 5,560.931. A 10/1996 Eickhoff (US); Jerome H. Modell, Gainesville, 5,637.625 A 6/1997 Haynes FL (US); Timothy E. Morey, 5,726,164 A 3/1998 Weder Gainesville, FL (US); Dinesh Shah, 5,750,142 A 5/1998 Friedman .................... 424/450 Gainesville, FL (US) 5,858.410 A 1/1999 Muller 5,908,619 A 6/1999 Scholz (73) Assignee: University of Florida, Gainesville, FL 5,908.825 A 6/1999 Fasano et al. (US) 5,908,869 A 6/1999 Jones 5,916,596. A 6/1999 Desai 5,925,684 A 7/1999 Schweikert ................. 574/941 (*) Notice: Subject to any disclaimer, the term of this 5,952.004 A * 9/1999 Rudnic et al. .............. 424/455 patent is extended or adjusted under 35 6,197,323 B1 * 3/2001 Georgieff .................... 424/423 U.S.C. 154(b) by 0 days. 6,451,339 B2 * 9/2002 Patel et al. ................. 424/451 This patent is Subject to a terminal dis FOREIGN PATENT DOCUMENTS claimer. WO PCTUS93/09916 4/1994 (21) Appl. No.: 09/924,290 WO PCT/IB96/0O868 3/1997 (22) Filed: Aug. 8, 2001 * cited by examiner (65) Prior Publication Data Primary Examiner Thurman K. Page ASSistant Examiner-Liliana Di Nola-Baron US 2002/0120015 A1 Aug. 29, 2002 (74) Attorney, Agent, or Firm-Brinks Hofer Gilson & Related U.S. Application Data Lione (63) Continuation-in-part of application No. 09/630.237, filed on (57) ABSTRACT Aug. 1, 2000. A microemulsion delivery system for water insoluble or (51) Int. Cl. .................................................. A61K 9/50 sparingly water Soluble drugs that comprises a long polymer (52) U.S. Cl. ....................... 424/502; 424/400; 424/484; chain Surfactant component and a short fatty acid Surfactant 424/486; 424/489: 424/501; 424/500 component, with the amount of each being Selected to (58) Field of Search ................................. 424/455, 400, provide Stable microemulsion or micellar Systems. 424/484, 486, 489, 501, 502,500; 514/772, 772.1 20 Claims, 2 Drawing Sheets A6 A. A2 Es -0- A g -- 6 2. - -- A 3 (6 2 A. (), () W W SN) AW SSA U.S. Patent Oct. 28, 2003 Sheet 1 of 2 US 6,638,537 B2 YS & g a 22 ad ad -e 2yo 22. 2 2 CN2 2. ad ad - ad al o ed - cN2 ad se s: : d d ad ad SaeoNeoAQOSQN U.S. Patent Oct. 28, 2003 Sheet 2 of 2 US 6,638,537 B2 33.2 3 2. 2 o ca - cN2 ad ad ad ad SaeoNeol\eqQSQN US 6,638,537 B2 1 2 MICROEMULSION AND MICELLE all three types of microemulsions, the interface is SYSTEMS FOR SOLUBLIZING DRUGS Stabilized by an appropriate combination of Surfactants and/or co-Surfactants. CROSS REFERENCED TO ARELATED It can be seen from the above description that there is a APPLICATION 5 real and continuing need for the development of new and This application is a continuation-in-part of Dennis et al., effective drug delivery Systems for water insoluble or spar Ser. No. 09/630,237 filed Aug. 1, 2000. ingly Soluble drugs. One Such approach might be pharma ceutical microemulsions. However, one must choose mate FIELD OF THE INVENTION rials that are biocompatible, non-toxic, clinically acceptable, This invention relates to compositions and a method for and use emulsifiers in an appropriate concentration range, making microemulsion delivery Systems for water insoluble and form stable microemulsions. This invention has as its or sparingly Soluble drugs. objective the formation of Safe and effective pharmaceutical microemulsion delivery Systems. BACKGROUND OF THE INVENTION The delivery system described herein has been found Dissolving water insoluble agents into acqueous Solutions 15 particularly useful for propofol, but is not exclusively lim appropriate for human use (e.g., oral, topical application, ited thereto. It is presented here as an example of a State of intravenous injection, intramuscular injection, Subcutaneous the art drug, normally poorly Soluble in its present delivery injection) represents a major technological hurdle for phar form, but when properly delivered in a pharmaceutical maceutical delivery Systems. Previous attempts have microemulsion carrier, the current problems can be Solved. resulted in a number of Serious Side effects caused not by the Such current problems in the case of propofol Stem directly drugs, but by the carrier agents used to dissolve the drug. from its poor Solubility in water. These include significant These complications include Significant hypotension during pain during injection, and post-operative infections in Some intravenous injection (e.g., amiodarone), painful injection patients who, for example, receive a macroemulsion of with Subsequent phlebitis (e.g., valium), anaphylaxis (e.g., propofol for Surgery or Sedation. propofol in Cremaphor), postoperative infections (e.g., pro 25 In an attempt to lower health care costs, there has been an pofol in Intralipid), and others. Clearly, an approach aimed explosive growth in the number of Surgical procedures being at improving the Solubilization of these drugs and avoiding done on an outpatient basis in the United States. In the the complications of Solubilizing agents would enhance the outpatient Setting, the use of Short acting anesthetics allows quality of health care to patients. For many drugs, a major for prompt emergence from anesthesia and provides expe technological barrier for their routine clinical use is very ditious discharge of patients to their home. Propofol (2,6- poor Solubility in the aqueous phase. For Such drugs, oil/ diisopropylphenol, molecular weight 178.27) is an organic water macroemulsions have been commonly used in the liquid Similar to oil, has very little Solubility in the aqueous pharmaceutical industry to “dissolve' a drug to its desired phase (octanol/water partition coefficient 6761:1 at a pH concentration. For example, the anesthetic propofol is Sup 6.0-8.5), and is a short-acting intravenous anesthetic that plied to the health care industry as Baxter PPI propofol 35 meets the criteria of rapid anesthetic emergence with mini (Gensia Sicor, Inc.) or Diprivan (AstraZeneca mal side effects. Currently, propofol is Supplied as a Pharmaceuticals, Inc.), as a macroemulsion of propofol in macroemulsion, an opaque dispersion using biocompatible Soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg emulsifierS Such as phospholipids, cholesterol, and others. In lecithin (12 mg/mL), and disodium edetate (0.005%) or addition, a number of other drawbacks cause significant metabisulfite; with sodium hydroxide to adjust pH to 40 limitations and risk to Some patients. 7.0-8.5. However, the stability of such macroemulsions is Most of the disadvantages of propofol relate to its com relatively poor, and the oil and water components Separate mercial formulation and physical properties. That is, propo into distinct phases over time. In addition, the droplet Size of fol is a liquid at room temperature and is extremely insoluble the macroemulsion increases with time. Macroemulsions are in water. The inherent lipophilicity of propofol makes dis 45 Solution in Saline or phosphate buffer problematic. In the defined as formed by high shear mixing and normally having early 1980's, Cremaphor was used as a solvent, but Subse particles of 1 micron to 10 microns in size. quently abandoned because of its propensity to cause life In contrast to macroemulsion Systems, microemulsion threatening anaphylactic reactions. Since that time, propofol Systems consisting of oil, water, and appropriate emulsifiers is Suspended in a macroemulsion consisting of 10% can form Spontaneously and are therefore thermodynami 50 Intralipid, a milky white solution of soybean oil and other cally stable. For this reason, microemulsion Systems theo additives as Specified previously. The current commercial retically have an infinite shelf life under normal conditions formulation of propofol has Several major disadvantages. in contrast to the limited life of macroemulsions (e.g., two First, use of propofol in Intralipid has been implicated as the years for Baxter PPI propofol). In addition, the size of the causative agent contributing to Several cases of postopera droplets in Such microemulsions remains constant and 55 tive infection in human patients as detailed by the Center for ranges from 100-1000 angstroms (10-100 nm), and has Disease Control and Prevention. The cause of the infections very low oil/water interfacial tension. Because the droplet and death was attributed to extrinsically contaminated Dipri size is less than 25% of the wavelength of visible light, van (i.e., propofol in Intralipid) used as an anesthetic during microemulsions are transparent. Three distinct microemul the Surgical procedures. To address the propensity of bac Sion Solubilization Systems that can be used for drugs are as 60 terial growth, manufacturers added the preservatives EDTA follows: (0.05 mg/ml) to Diprivan and sodium metabisulfite (0.25 1. oil in water microemulsions wherein oil droplets are mg/ml) to Baxter PPI propofol. Unfortunately, both of these dispersed in the continuous aqueous phase, preservatives may potentially cause adverse reactions in 2. Water in oil microemulsions wherein water droplets are humans. Whereas Sodium metabisulfite may cause allergic dispersed in the continuous oil phase, 65 type reactions in Susceptible patients, the chelating proper 3. bi-continuous microemulsions wherein microdomains ties of EDTA were of concern to the FDA because of their of oil and water are interdispersed within the System. In effects on cardiac conduction and renal function. Thus, use US 6,638,537 B2 3 4 of a Solvent that does not Support bacterial growth would Sion Systems consisting of biocompatible Surfactants and Significantly enhance the therapeutic Safety of propofol not co-Surfactants will work.