(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`7 February 2002 (07.02.2002)
`
`(10) International Publication Number
`WO 02/09671 A2
`
`(51) International Patent Classificationlz
`
`A61K 9/107
`
`(21) International Application Number:
`
`PCT/US01/24167
`
`(22) International Filing Date:
`
`31 July 2001 (31.07.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`09/630,237
`
`1 August 2000 (01.08.2000)
`
`US
`
`(71) Applicant (for all designated States except I/.9: UNI-
`VERSITY OF FLORIDA [US/US]; P.O. Box 115500,
`Gainesville, FL 32611-5500 (US).
`
`Box 115500, Gainesville, FL 32611-5500 (US). SHAH,
`Dinesh [US/US]; P.O. Box 115500, Gainesville, FL
`32611-5500 (US).
`
`Agent: SEASE, Edmund, J.; Zarley, McKee, Thomte,
`Voorhees & Sease, Suite 3200, 801 Grand Avenue, Des
`Moines, IA 50309-2721 (US).
`
`Designated States (national): AE, AL, AM, AT, AU, AZ,
`BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM,
`TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): DENNIS, Donn, M.
`[US/US]; PO. Box 115500, Gainesville, FL 32611-5500
`(US). GRAVENSTEIN, Nikolaus [US/US]; PO. Box
`115500, Gainesville, FL 32611-5500 (US). MODELL,
`Jerome, H. [US/US]; PO. Box 115500, Gainesville, FL
`32611-5500 (US). MOREY, Timothy, E. [US/US]; P.O.
`
`Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD,
`TG).
`
`[Continued on next page]
`
`(54) Title: NOVEL MICROEMULSION AND MICELLE SYSTEMS FOR SOLUBILIZING DRUGS
`
`1.6
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`\A
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`1.2
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`llbsorbance{llicelles
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`WO02/09671A2
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`200
`
`\SOS\n\l
`
`(57) Abstract: A microemulsion delivery system for water insoluble or sparingly water soluble drugs that comprise a long polymer
`chain surfactant component and a short fatty acid sufractant component, with the amount of each being selected to provide stable
`microemulsion or micellar systems.
`
`Page 1 of 32
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`LUPIN EX 1067
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`LUPIN EX 1067
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`WO 02/09671 A2
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`Published:
`— without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
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`TITLE:
`
`NOVEL MICROEMULSION AND MICELLE SYSTEMS FOR
`
`SOLUBILIZING DRUGS
`
`FIELD OF THE INVENTION
`
`This invention relates to compositions and a method for making
`
`microemulsion delivery systems for Water insoluble or sparingly soluble drugs.
`
`BACKGROUND OF THE INVENTION
`
`Dissolving Water insoluble agents into aqueous solutions appropriate for
`
`human use (e.g., oral, topical application, intravenous injection, intramuscular
`
`injection, subcutaneous injection) represents a major technological hurdle for
`
`pharmaceutical delivery systems. Previous attempts have resulted in a
`
`number of serious side effects caused not by the drugs, but by the carrier
`
`agents used to dissolve the drug. These complications include significant
`
`hypotension during intravenous injection (e.g., amiodarone), painful injection
`
`with subsequent phlebitis (e.g., Valium), anaphylaxis (e.g., propofol in
`
`Cremaphor), postoperative infections (e.g., propofol in Intralipid), and others.
`
`Clearly, an approach aimed at improving the solubilization of these drugs and
`
`avoiding the complications of solubilizing agents would enhance the quality of
`
`health care to patients. For many drugs, a major technological barrier for
`
`their routine clinical use is very poor solubility in the aqueous phase. For such
`
`drugs, oil/water macroemulsions have been commonly used in the
`
`pharmaceutical industry to "dissolve" a drug to its desired concentration. For
`
`example, the anesthetic propofol is supplied to the health care industry as
`
`Baxter PPI propofol (Gensia Sicor, Inc.) or Diprivan (AstraZeneca
`
`Pharmaceuticals, Inc.), as a macroemulsion of propofol in soybean oil (100
`
`mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL), and disodium edetate
`
`(0.005%) or metabisulfite; with sodium hydroxide to adjust pH to 7.0-8.5.
`
`However, the stability of such macroemulsions is relatively poor, and the oil
`
`and water components separate into distinct phases over time. In addition,
`
`the droplet size of the macroemulsion increases with time. Macroemulsions
`
`1
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`are defined as formed by high shear mixing and normally having particles of 1
`
`micron to 10 microns in size.
`
`In contrast to macroemulsion systems, microemulsion systems
`
`consisting of oil, water, and appropriate emulsifiers can form spontaneously
`
`and are therefore thermodynamically stable. For this reason, microemulsion
`
`systems theoretically have an infinite shelf life under normal conditions in
`
`contrast to the limited life of macroemulsions (e.g., two years for Baxter PPI
`
`propofol). In addition, the size of the droplets in such microemulsions remains
`
`constant and ranges from 100-1000 angstroms (10—100 nm), and has very low
`
`oil/water interfacial tension. Because the droplet size is less than 25% of the
`
`wavelength of visible light, microemulsions are transparent. Three distinct
`
`microemulsion solubilization systems that can be used for drugs are as follows:
`
`1.
`
`oil in water microemulsions wherein oil droplets are dispersed in
`
`the continuous aqueous phase;
`
`2.
`
`water in oil microemulsions wherein water droplets are dispersed
`
`in the continuous oil phase;
`
`3.
`
`bi-continuous microemulsions wherein microdomains of oil and
`
`water are interdispersed within the system. In all three types of
`
`microemulsions, the interface is stabilized by an appropriate combination of
`
`surfactants and/or co—surfactants.
`
`It can be seen fi'om the above description that there is a real and
`
`continuing need for the development of new and effective drug delivery
`
`systems for water insoluble or sparingly soluble drugs. One such approach
`
`might be pharmaceutical microemulsions. However, one must choose
`
`materials that are biocompatible, non-toxic, clinically acceptable, and use
`
`emulsifiers in an appropriate concentration range, and form stable
`
`microemulsions. This invention has as its objective the formation of safe and
`
`effective pharmaceutical microemulsion delivery systems.
`
`The delivery system described herein has been found particularly useful
`
`for propofol, but is not exclusively limited thereto. It is presented here as an
`
`example of a state of the art drug, normally poorly soluble in its present
`
`2
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`delivery form, but when properly delivered in a pharmaceutical microemulsion
`
`carrier, the current problems can be solved. Such current problems in the case
`
`of propofol stem directly from its poor solubility in water. These include
`
`significant pain during injection, and post-operative infections in some
`
`patients who, for example, receive a macroemulsion of propofol for surgery or
`
`sedation.
`
`In an attempt to lower health care costs, there has been an explosive
`
`growth in the number of surgical procedures being done on an outpatient basis
`
`in the United States. In the outpatient setting, the use of short acting
`
`anesthetics allows for prompt emergence from anesthesia and provides
`
`expeditious discharge of patients to their home. Propofol (2,6-
`
`diisopropylphenol, molecular weight 178.27) is an organic liquid similar to oil,
`
`has very little solubility in the aqueous phase (octanol/water partition
`
`coefficient 6761:1 at a pH 6.0-8.5), and is a short-acting intravenous anesthetic
`
`that meets the criteria of rapid anesthetic emergence with minimal side
`
`effects. Currently, propofol is supplied as a macroemulsion, an opaque
`
`dispersion using biocompatible emulsifiers such as phospholipids, cholesterol,
`
`and others. In addition, a number of other drawbacks cause significant
`
`limitations and risk to some patients.
`
`Most of the disadvantages of propofol relate to its commercial
`
`formulation and physical properties. That is, propofol is a liquid at room
`
`temperature and is extremely insoluble in water. The inherent lipophilicity of
`
`propofol makes dissolution in saline or phosphate buffer problematic. In the
`
`early 1980's, Cremaphor was used as a solvent, but subsequently abandoned
`
`because of its propensity to cause life threatening anaphylactic reactions.
`
`Since that time, propofol is suspended in a macroemulsion consisting of 10%
`
`Intralipid, a milky white solution of soybean oil and other additives as
`
`specified previously. The current commercial formulation of propofol has
`
`several major disadvantages. First, use of propofol in Intralipid has been
`
`implicated as the causative agent contributing to several cases of postoperative
`
`infection in human patients as detailed by the Center for Disease Control and
`
`3
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`Prevention. The cause of the infections and death was attributed to
`
`extrinsically contaminated Diprivan (i.e., propofol in Intralipid) used as an
`
`anesthetic during the surgical procedures. To address the propensity of
`
`bacterial growth, manufacturers added the preservatives EDTA (0.05 mg/ml)
`
`to Diprivan and sodium metabisulfite (0.25 mg/ml) to Baxter PPI propofol.
`
`Unfortunately, both of these preservatives may potentially cause adverse
`
`reactions in humans. Whereas sodium metabisulfite may cause allergic-type
`
`reactions in susceptible patients, the chelating properties of EDTA were of
`
`concern to the FDA because of their effects on cardiac conduction and renal
`
`function. Thus, use of a solvent that does not support bacterialgrowth Would
`
`significantly enhance the therapeutic safety of propofol not only by preventing
`
`intravenous injection of microbes, but also by obviating the need for
`
`preservatives and possible adverse effects of these agents.
`
`Second, the cost of Intralipid substantially adds to the expense of
`
`manufacturing a propofol macroemulsion. This vehicle is produced by Clinitec,
`
`licensed to the pharmaceutical corporations for the purpose of solubilizing
`
`propofol, and constitutes a major fraction of the cost of producing Diprivan
`
`(propofol in 10% Intralipid).
`
`A third major disadvantage of the current preparation of propofol
`
`relates to its free, aqueous concentrations. Propofol is a phenol derivative (2,6-
`
`diisopropylphenol) and causes pain on injection. This effect is the single
`
`greatest complaint of anesthesiologists and patients regarding propofol and
`
`may on occasion necessitate discontinuation of the drug for sedative purposes.
`
`Most authorities believe that the stinging relates to the concentration of
`
`propofol in free, aqueous solution.
`
`A solvent that completely emulsifies or partitions propofol into the non-
`
`aqueous phase would preclude (or markedly reduce) stinging and allow
`
`painless injection similar to thiopental sodium (another widely used
`
`intravenous anesthetic). The formulations of the present invention address
`
`and overcome these three disadvantages.
`
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`BRIEF DESCRIPTION OF THE DRAWINGS
`
`Figure 1 shows release of active drug from microemulsions or micelles to
`
`I-Ieptane phase.
`
`Figure 2 shows similar experimental results.
`
`SUMMARY OF THE INVENTION
`
`A microemulsion delivery system for normally water insoluble or
`
`sparingly soluble drugs, such as propofol. The drug is microemulsified with an
`
`emulsifier combination of a long chain polymer surfactant component and a
`
`short chain fatty acid surfactant component. These are selected to reduce
`
`surface tension to absorption between the two phases to thereby allow the
`
`formation of thermodynamically stable microemulsions or micelles. The
`
`system is particularly useful for propofol, but is not limited to propofol.
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`Microemulsion drug delivery systems of this invention are hereinafter
`
`described in conjunction with microemulsions with the pharmaceutically
`
`active anesthetic propofol. However, it should be understood that the use of
`
`propofol as the active water insoluble or sparingly soluble drug in the
`
`description is exemplary only of the generally described class of normally
`
`poorly water soluble drugs. Microemulsion systems of the present invention,
`
`particularly oil and water, can be used to dissolve substantial concentrations
`
`of oil—soluble drugs such as propofol, and they can thereafter be injected
`
`intravenously into human patients or animals with less, or even without pain
`
`caused by the delivery system.
`
`Many water soluble drugs such as cyclosporine, insulin, and others can
`
`be dissolved in water-in-oil microemulsions and can be taken orally (e.g.,
`
`gelatin capsule) or injected. These microemulsions spread over the intestinal
`
`surface wherein nanometer-sized water droplets with drugs dissolved therein
`
`permeate and diffuse across the intestinal brush border. The delivery of
`
`various drugs (i.e., oil-soluble, water-soluble, and interphase soluble drugs) in
`
`5
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`patients using the previously-mentioned three types of microemulsion systems
`
`consisting of biocompatible surfactants and co-surfactants will Work. Such
`solutions can be especially valuable to patients with abdominal disorders that
`
`inhibit absorption such as short gut syndrome and for better oral delivery of
`
`expensive drugs that are otherwise poorly absorbed.
`
`Substantially Water insoluble pharmacologically active agents
`
`contemplated for use in the practice of the present invention include
`
`pharmaceutically active agents, not limited in class, except to say they are
`
`normally difficultly soluble in aqueous systems. Examples of
`
`pharmaceutically active drug agents include: analgesics/antipyretics (e.g.,
`
`aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine
`
`hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate,
`
`meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate,
`
`oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate,
`
`pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate,
`
`diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid,
`butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate,
`
`diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride,
`
`meprobamate, and the like); anesthetics (e.g., halothane, isoflurane,
`
`methoxyflurane, propofol, thiobarbiturates and the like); antiasthmatics (e.g.,
`
`Azelastine, Ketotifen, Traxanox, and the like); antibiotics (e.g., neomycin,
`
`streptomycin, chloramphenicol, cephalosporin, ampicillin, penicillin,
`
`tetracycline, and the like); antidepressants (e.g., nefopam, oxypertine, doxepin
`
`hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline
`
`hydrochloride, maprotiline hydrochloride, phenelzine sulfate, desipramine
`
`hydrochloride, nortriptyline hydrochloride, tranylcypromine sulfate, fluoxetine
`
`hydrochloride, doxepin hydrochloride, imipramine hydrochloride, imipramine
`
`pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxazid,
`
`desipramine hydrochloride, trimipramine maleate, protriptyline hydrochloride,
`
`and the like); antidiabetics (e.g., biguanides, hormones, sulfonylurea
`
`derivatives, and the like); antifungal agents (e.g., griseofulvin, keoconazole,
`
`6
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`amphotericin B, Nystatin, candicidin, and the like); antihypertensive agents
`
`(e.g., propanolol, propafenone, oxyprenolol, nifedipine, reserpine,
`
`trimethaphan camsylate, phenoxybenzamine hydrochloride, pargyline
`
`hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil,
`
`rescinamine, sodium nitroprusside, rauwolfia serpentina, alseroxylon,
`
`phentolamine mesylate, reserpine, and the like); anti-inflammatories (e.g.,
`
`(non-steroidal) indomethacin, naproxen, ibuprofen, ramifenazone, piroxicam,
`
`(steroidal) cortisone, dexamethasone, fluazacort, hydrocortisone, prednisolone,
`
`prednisone, and the like); antineoplastics (e.g., adriamycin, cyclophosphamide,
`
`actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin,
`
`methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU,
`
`cisplatin, etoposide, interferons, camptothecin and derivatives thereof,
`
`phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof,
`
`vinblastine, vincristine, tamoxifen, etoposide, piposulfan, and the like);
`
`antianxiety agents (e.g., lorazepam, buspirone hydrochloride, prazepam,
`
`chlordiazepoxide hydrochloride, oxazepam, clorazepate dipotassium, diazepam,
`
`hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol,
`
`halazepam, chlormezanone, dantrolene, and the like); immunosuppressive
`
`agents (e.g., cyclosporine, azathioprine, mizoribine, FK506 (tacrolimus), and
`
`the like); antimigraine agents (e.g., ergotamine tartrate, propanolol
`
`hydrochloride, isometheptene mucate, dichloralphenazone, and the like);
`
`sedatives/hypnotics (e.g., barbiturates (e.g., pentobarbital, pentobarbital
`
`sodium, secobarbital sodium), benzodiazapines (e.g., flurazepam hydrochloride,
`
`triazolam, tomazeparm, midazolam hydrochloride, and the like); antianginal
`
`agents (e.g., beta-adrenergic blockers, calcium channel blockers (e.g.,
`
`nifedipine, diltiazem hydrochloride, and the like), nitrates (e.g., nitroglycerin,
`
`isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, and
`
`the like)); antipsychotic agents (e.g., haloperidol, loxapine succinate, loxapine
`
`hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene,
`
`fluphenazine hydrochloride, fluphenazine decanoate, fluphenazine enanthate,
`
`trifluoperazine hydrochloride, chlorpromazine hydrochloride, perphenazine,
`
`7
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`lithium citrate, prochlorperazine, and the like); antimanic agents (e.g., lithium
`
`carbonate); antiarrhythmics (e.g., amiodarone, related derivatives of
`
`amiodarone, bretylium tosylate, esmolol hydrochloride, Verapamil
`
`hydrochloride, encainide hydrochloride, digoxin, digitoxin, mexiletine
`
`hydrochloride, disopyramide phosphate, procainamide hydrochloride,
`
`quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide
`
`acetate, tocainide hydrochloride, lidocaine hydrochloride, and the like);
`
`antiarthritic agents (e.g., phenylbutazone, sulindac, penicillamine, salsalate,
`
`piroxicam, azathioprine, indomethacin, meclofenamate sodium, gold sodium
`
`thiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium, and the
`
`like); antigout agents (e.g., colchicine, allopurinol, and the like);
`
`anticoagulants (e.g., heparin, heparin sodium, Warfarin sodium, and the like);
`
`thrombolytic agents (e.g., urokinase, streptokinase, altoplase, and the like);
`
`antifibrinolytic agents (e.g., aminocaproic acid); hemorheologic agents (e.g.,
`
`pentoxifylline); antiplatelet agents (e.g., aspirin, empirin, ascriptin, and the
`
`like); anticonvulsants (e.g., valproic acid, divalproate sodium, phenytoin,
`
`phenytoin sodium, clonazepam, primidone, phenobarbitol, phenobarbital
`
`sodium, carbamazepine, amobarbital sodium, methsuximide, metharbital,
`
`mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin,
`
`phenacemide, secobarbitol sodium, clorazepate dipotassium, trimethadione,
`
`and the like); antiparkinson agents (e.g., ethosuximide, and the like);
`
`antihistamines/antipruritics (e.g., hydroxyzine hydrochloride,
`
`diphenhydramine hydrochloride, chlorpheniramine maleate, brompheniramine
`
`maleate, cyproheptadine hydrochloride, terfenadine, clemastine fumarate,
`
`triprolidine hydrochloride, carbinoxamine maleate, diphenylpyraline
`
`hydrochloride, phenindamine tartrate, azatadine maleate, tripelennamine
`
`hydrochloride, dexchlorpheniramine maleate, methdilazine hydrochloride,
`
`trimprazine tartrate and the like); agents useful for calcium regulation (e.g.,
`
`calcitonin, parathyroid hormone, and the like); antibacterial agents (e.g.,
`
`amikacin sulfate, aztreonam, chloramphenicol, chloramphenicol palmitate,
`
`chloramphenicol sodium succinate, ciprofloxacin hydrochloride, clindamycin
`
`8
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`hydrochloride, clindamycin palmitate, clindamycin phosphate, metronidazole,
`metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride,
`
`tobramycin sulfate, vancomycin hydrochloride, polymyxin B sulfate,
`
`colistimethate sodium, colistin sulfate, and the like); antiviral agents (e.g.,
`
`interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir,
`
`and the like); antimicrobials (e.g., cephalosporins (e.g., cefazolin sodium,
`
`cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone
`
`sodium, cefotetan disodium, cefutoxime azotil, cefotaxime sodium, cefadroxil
`
`monohydrate, ceftazidime, cephalexin, cephalothin sodium, cephalexin
`
`hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid
`
`sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine,
`
`cefuroxime sodium, and the like), prythronycins, penicillins (e_.g., ampicillin,
`
`amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin G
`
`potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium,
`
`bacampicillin hydrochloride, cloxacillin sodium, ticarcillin disodium, azlocillin
`
`sodium, carbenicillin indanyl sodium, penicillin G potassium, penicillin G
`
`procaine, methicillin sodium, nafcillin sodium, and the like), erythromycins
`
`(e.g., erythromycin ethylsuccinate, erythromycin, erythromycin estolate,
`
`erythromycin lactobionate, erythromycin siearate, erythromycin
`
`ethylsuccinate, and the like), tetracyclines (e.g., tetracycline hydrochloride,
`
`doxycycline hyclate, minocycline hydrochloride, and the like), and the like);
`
`anti-infectives (e.g., GM-CSF); bronchodilators (e.g., sympathomimetics (e.g.,
`
`epinephrine hydrochloride, metaproterenol sulfate, terbutaline sulfate,
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`isoetharine, isoetharine mesylate, isoetharine hydrochloride, albuterol sulfate,
`
`albuterol, bitolterol, mesylate isoproterenol hydrochloride, terbutaline sulfate,
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`epinephrine bitartrate, metaproterenol sulfate, epinephrine, epinephrine
`
`bitartrate), anticholinergic agents (e.g., ipratropium bromide), xanthines (e.g.,
`
`aminophylline, dyphylline, metaproterenol sulfate, aminophylline), mast cell
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`stabilizers (e.g., cromolyn sodium), inhalant corticosteroids (e.g.,
`
`flurisolidebeclomethasone dipropionate, beclomethasone dipropionate
`
`monohydrate), salbutamol, beclomethasone dipropionate (BDP), ipratropium
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`bromide, budesonide, ketotifen, salmeterol, xinafoate, terbutaline sulfate,
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`triamcinolone, theophylline, nedocromil sodium, metaproterenol sulfate,
`
`albuterol, flunisolide, and the like); hormones (e.g., androgens (e.g., danazol,
`
`testosterone cypionate, fluoxymesterone, Iethyltostosterone, testosterone
`
`enanihate, methyltestosterone, fluoxymesterone, testosterone cypionate),
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`estrogens (e.g., estradiol, estropipate, conjugated estrogens), progestins (e.g.,
`
`methoxyprogesterone acetate, norethindrone acetate), corticosteroids (e.g.,
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`triamcinolone, betamethasone, betamethasone sodium phosphate,
`
`dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate,
`
`prednisone, methylprednisolone acetate suspension, triamcinolone acetonide,
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`methylprednisolone, prednisolone sodium phosphate methylprednisolone
`
`sodium succinate, hydrocortisone sodium succinate, methylprednisolone
`
`sodium succinate, triamcinolone hexacatonide, hydrocortisone, hydrocortisone
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`cypionate, prednisolone, fluorocortisone acetate, paramethasone acetate,
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`prednisolone tebulate, prednisolone acetate, prednisolone sodium phosphate,
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`hydrocortisone sodium succinate, and the like), thyroid hormones (e.g.,
`
`levothyroxine sodium) and the like), and the like; hypoglycemic agents (e.g.,
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`human insulin, purified beef insulin, purified pork insulin, glyburide,
`
`chlorpropamide, glipizide, tolbutamide, tolazamide, and the like);
`
`hypolipidemic agents (e.g., clofibrate, dextrothyroxine sodium, probucol,
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`lovastatin, niacin, and the like); proteins (e.g., DNase, alginase, superoxide
`
`dismutase, lipase, and the like); nucleic acids (e.g., sense or anti-sense nucleic
`
`acids encoding any therapeutically useful protein, including any of the
`
`proteins described herein, and the like); agents useful for erythropoiesis
`
`stimulation (e.g., erythropoietin); antiulcer/antireflux agents (e.g., famotidine,
`
`cimetidine, ranitidine hydrochloride, and the like); antinauseants/antiemetics
`
`(e.g., meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate,
`
`promethazine hydrochloride, thiethylperazine, scopolamine, and the like);
`
`oil-soluble Vitamins (e.g., vitamins A, D, E, K, and the like); as Well as other
`
`drugs such as mitotane, Visadine, halonitrosoureas, anthrocyclines, ellipticine,
`
`and the like.
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`As Well, the microemulsion systems of the present invention may be
`
`used in brain chemotherapy and gene chemotherapy, since the nature of the
`
`surface of Virus particles is an important determinant of the transfer rate of
`
`viruses across the blood/brain barrier or into another protected compartment
`
`(e.g., intraocular cerebrospinal fluid).
`
`Likewise, many chemotherapeutic agents dissolved in an oil in Water
`
`microemulsion might be more readily delivered to a tumor site in the brain.
`
`For example, pediatric patients With brain tumors may frequently require
`
`general anesthesia so that chemotherapeutic agents can be safely injected i11to
`
`the cerebrospinal fluid by puncture of the lumbar cistern. Use of
`
`microemulsions to target brain tumors might obviate the need for anesthesia
`
`and/or lumbar puncture in adult and pediatric patients.
`
`The solubility of nonpolar drugs can be significantly increased if
`
`dissolved in mixed solvents such as Water and alcohol or propylene glycol by
`
`influencing the hydrophobic forces existing in the system. This approach Will
`
`also be compared with microemulsion and selective micelle release systems.
`
`The mixed solvent system may be the simplest method to solve problems of
`
`drug solubilization.
`
`In preparation of the pharmaceutically active drug such as propofol
`
`useful in highly bioavailable form in accordance with the present invention,
`
`the first step is to select the normally difficultly soluble drug, such as propofol,
`
`which is similar to an oil. In order to make a homogeneous microemulsion of
`
`the pharmaceutically active component such as propofol, one needs to mix it
`
`with the appropriate emulsifier combination for formation of the
`
`microemulsion.
`
`Surprisingly, it has been found that in accordance with the present
`
`invention, the appropriate combination of surfactants is the combination of a
`
`long chain polymer surfactant component such as’ a poloxamer with a short
`
`chain fatty acid surfactant component. The ratio of long chain polymer
`
`surfactant to short chain fatty acid surfactant should be from 10 to 100,
`
`preferably from 25 to 80 (Wt./wt.).
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`Suitable long chain surfactants can be selected from the group known as
`
`organic or inorganic surfactant pharmaceutical excipients. Preferred
`
`surfactants include nonionic and anionic surfactants.
`
`Representative examples of long chain or high molecular weight (>1000)
`
`surfactants include gelatin, casein, lecithin (phosphatides), gum acacia,
`
`cholesterol, tragacanth, polyoxyethylene alkyl ethers, e.g., macrogol ethers
`
`such as cetomacrogol 1000, polyoxyethylene castor oil derivatives,
`
`polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available
`
`Tweens, polyethylene glycols, polyoxyethylene stearates, colloidal silicon
`
`dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,
`
`carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
`
`hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,
`
`microcrystalline cellulose, magnesium aluminum silicate, triethanolamine,
`
`polyvinyl alcohol, and polyvinylpyrrolidene (PVP). The low molecular Weight
`
`(<1000) include stearic acid, benzalkonium chloride, calcium stearate, glycerol
`
`monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, and sorbitan
`
`esters. Most of these surface modifiers are known pharmaceutical excipients
`
`and are described in detail in the Handbook of Pharmaceutical Excipients,
`
`published jointly by the American Pharmaceutical Association and The
`
`Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.
`
`Particularly preferred long chain surfactants include
`
`polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronic F68, F77, and
`
`F108, which are block copolymers of ethylene oxide and propylene oxide, and
`
`polyxamines such as Tetronic 908 (also known as Poloxamine 908), which is a
`
`tetrafunctional block copolymer derived from sequential addition of propylene
`
`oxide and ethylene oxide to ethylenediamine, available from BASF, dextran,
`
`lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, which
`
`is a dioctyl ester of sodium sulfosuccinic acid, available from American
`
`Cyanamid, Duponol P, which is a sodium lauryl sulfate, available from
`
`DuPont, Triton X-200, which is an alkyl aryl polyether sulfonate, available
`
`from Rohm and Haas, Tween 20 and Tween 80, which are polyoxyethylene
`
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`sorbitan fatty acid esters, available from ICI Specialty Chemicals; Carbowax
`
`3550 and 934, which are polyethylene glycols available from Union Carbide;
`
`Crodesta F-110, Which is a mixture of sucrose stearate and sucrose distearate,
`
`available from Croda Inc., Crodesta SL-40, which is available from Croda, Inc.,
`
`and SA90I-ICO, which is C.sub.18 H.sub.37 -
`
`CH.sub.2(CON(CH.sub.3)CH.sub.2 (CHOH).sub.4 CH.sub.2 OH).sub.2.
`
`Surface modifiers which have been found to be particularly useful include
`
`Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. Other
`
`useful surface modifiers include: decanoyl-N-methylglucamide; n-decyl.beta-
`
`D-glucsopyranoside; n-decyl.beta-D-maltopyranoside; n-dodecyl.beta-D-
`
`glucopyranoside; n-dodecylbeta.-D-maltoside; heptanoyl-N-methylglucamide;
`
`n-heptyl-.beta.-D-glucopyranoside; n-heptyl.beta.-D-thioglucoside; n-
`
`heXyl.beta.-D-glucopyranoside; nonanoyl~N-methylglucamide; n-noyl.beta.-D-
`
`glucopyranoside; octanoyl-N-methylglucamide; 11—octyl-.beta.-D-
`
`glucopyranoside; octyl.beta.—D-thioglucopyranoside; and the like.
`
`Another useful long chain surfactant is tyloxapol (a nonionic liquid
`
`polymer of the alkyl aryl polyether alcohol type; also known as superinone or
`
`triton). This surfactant is commercially available and/or can be prepared by
`
`techniques known in the art.
`
`Another preferred surfactant p-isononylphenoxypoly (glycidol) also
`
`known as Olin-10G or Surfactant 10-G, is commercially available as 10G from
`
`Olin Chemicals, Stamford, Conn.
`
`One preferred long chain surfactant is a block copolymer linked to at
`
`least one anionic group. The polymers contain at least one, and preferably
`
`two, three, four or more anionic groups per molecule. Preferred anionic groups
`
`include sulfate, sulfonate, phosphonate, phosphate and carboxylate groups.
`
`The anionic groups are covalently attached to the nonionic block copolymer.
`
`The nonionic sulfated polymeric surfactant has a molecular weight of 1,000-
`
`50,000, preferably 2,000-40,000, and more preferably 3,000-30,000. In
`
`preferred embodiments, the polymer comprises at least about 50%, and more
`
`preferably, at least about 60% by weight of hydrophilic units, e.g., alkylene
`
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`oxide units. The reason for this is that the presence of a major weight
`
`proportion of hydrophilic units confers aqueous solubility to the polymer.
`
`A preferred class of block copolymers useful as surface modifiers herein
`
`includes block copolymers of ethylene oxide and propylene oxide. These block
`
`copolymers are commercially ava