US 20030077297A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0077297 A1 Chen et al. (43) Pub. Date: Apr. 24, 2003

(54) PHARMACEUTICAL FORMULATIONS AND 09/345,615, ?led on Jun. 30, 1999, noW Pat. No. SYSTEMS FOR IMPROVED ABSORPTION 6,267,985. Continuation-in-part of application No. AND MULTISTAGE RELEASE OF ACTIVE 09/800,593, ?led on Mar. 6, 2001, Which is a division AGENTS of application No. 09/447,690, ?led on Nov. 23, 1999, noW Pat. No. 6,248,363. (76) Inventors: Feng-Jing Chen, Salt Lake City, UT (US); Srinivasan Venkateshwaran, Publication Classi?cation Salt Lake City, UT (US); Steven L. Krill, Park City, UT (US); Mahesh V. (51) Patel, Salt Lake City, UT (US) (52) Correspondence Address: REED & ASSOCIATES (57) ABSTRACT 800 MENLO AVENUE SUITE 210 The present invention pertains to pharmaceutical formula MENLO PARK, CA 94025 (US) tions and systems for delivery of active agents, Wherein a ?rst fraction of an active agent is suspended in a vehicle and (21) Appl. No.: 10/074,687 a second fraction of active agent is solubiliZed in the vehicle, With the suspended fraction representing about 5 Wt. % to (22) Filed: Feb. 11, 2002 about 80 Wt. % of the active agent and the second fraction representing about 20 Wt. % to about 95 Wt. % of the active Related US. Application Data agent. One or more additional active agents, Which may be fully solubiliZed, partially solubiliZed, or suspended, may (60) Continuation-in-part of application No. 09/898,553, also be present. The ?rst and second fractions of the active ?led on Jul. 2, 2001, Which is a continuation of agent may or may not have different release pro?les. Gen application No. 09/258,654, ?led on Feb. 26, 1999, erally, a signi?cant fraction of the solubiliZed drug Will noW Pat. No. 6,294,192. Continuation-in-part of release rapidly, providing for rapid onset, While the sus application No. 09/877,541, ?led on Jun. 8, 2001, pended drug may be formulated for delayed and/or sustained Which is a continuation-in-part of application No. release. Patent Application Publication Apr. 24, 2003 Sheet 1 0f 7 US 2003/0077297 Al Patent Application Publication Apr. 24, 2003 Sheet 2 0f 7 US 2003/0077297 A1 Patent Application Publication Apr. 24, 2003 Sheet 3 0f 7 US 2003/0077297 A1 A ///, % L)

FIG. 3A FIG. 35

FIG. 4A FIG. 45 Q Q Q

FIG. 5A FIG. 58 FIG. 5C Patent Application Publication Apr. 24, 2003 Sheet 4 of 7 US 2003/0077297 A1

0-20 - —.— Formulation of Example 13

0_ 16 _ —-I— Accutane®

BloodConc.inlsotretinoin 0.12 (lug/mll/[mg/kgl) 0.08

0.04 -

0.00 0 3O 6O 90 120 150 Time (min)

FIG. 6

1 100 C 1 .9 ‘5 . 8 so 1 1 .2U l‘ l 2 A i l *5‘ 5 6O - i l 2 E l 5 9.2 : I 1 _Q ‘U E l ‘a ‘D 40 - x o E “E2 ‘ _ ® ‘I I s ‘_ ;—.—Tr|cor \ 1 3 20- ,-' ‘§---o--FormulationofExample14(n=3) ‘ 2 g ‘I i l i g - l l 1 0 | | | l l | l 1 0 2o 40 Time60 (min) so 100 120 i l FIG. 7 Patent Application Publication Apr. 24, 2003 Sheet 5 0f 7 US 2003/0077297 A1

120 7 100 ------"g

i ‘,9. . so { :Q' a ',

6O ' 1 40 4 1} i—l—--—Tricor® a! 20 [ Formulation of Example 15(n=2)

0 S ‘ ‘ { O 20 4O 60 80 100 120 Time (min)

FIG. 8

—O— Formulation of Example 15, one capsule containing 134 mg feno?brate (n=3) —I— Reference, 2 capsules each containing 67 mg solubilized feno?brate (n=2)

2 4 6 8 10 l2 14 16 18 20 22 24 Time(h)

FIG. 9 Patent Application Publication Apr. 24, 2003 Sheet 6 0f 7 US 2003/0077297 A1

Dissolution of Progesterone from Capsule Dosage Forms USP Apparatus 100 rpm; 1000 ml SGF+12.5 mM SLS I‘ MeaniSD fié?gbieié?é é'fizgai'ééi'e 3i T60 rHQérOQ‘ESt'émne’rEé" 100% ' ' ‘Prometrium(SoIvay), 100 mg Progesterone, n=3

845% 834% 80%‘

70%

60% 4 %Released 50%

20%

10%

FIG. 10 Patent Application Publication Apr. 24, 2003 Sheet 7 0f 7 US 2003/0077297 A1

Single Dose Progesterone; Randomized 2X2 Cross-Over MeaniSEM, n=l2 subjects

!

3025 l + Formulation of Example 37, 50 mg Progesterone, 50 mg (Example 49) Concentration(ng/ml)Serum + Prometrium®, 100 mg

l l l l l l l l l 4 O 2 4 6 8 l0 l2 l4 l6 18 2O 22 24 Time (h)

i e 35 1 Fe E E, 30 1 l i . /®\ l-O-Formulation of Example 37 E l 2 25 ‘ i ‘ 8'1: 20 \ —9—Pr0metrium®

Q m2 15 \ 2e 10 // \ i B #5 “EN

c : 9-1 0 I l l l l I l l 0 60 120 180 240 300 360 420 480 Time (min)

FIG. 11B US 2003/0077297 A1 Apr. 24, 2003

PHARMACEUTICAL FORMULATIONS AND hydrophobic therapeutic agents, the loading capacity of SYSTEMS FOR IMPROVED ABSORPTION AND conventional micelle formulations is limited by the solubil MULTISTAGE RELEASE OF ACTIVE AGENTS ity of the therapeutic agent in the micelle surfactant. For many therapeutic agents, such solubility is too loW to offer CROSS-REFERENCE TO RELATED formulations that can deliver therapeutically effective doses. APPLICATIONS [0005] Another conventional approach takes advantage of [0001] This application is a continuation-in-part of US. the increased solubility of hydrophobic therapeutic agents in patent application Ser. No. 09/898,553, ?led Jul. 20, 2001, lipids, particularly oils, i.e., triglycerides. HoWever, tradi Which is a continuation of US. patent application Ser. Nos. tional lipid-based formulations are generally limited by a 09/258,654, 09/258,654, ?led Feb. 26, 1999, Which issued loW drug loading capacity, Which in turn precludes delivery on Sep. 25, 2001 as US. Pat. No. 6,294,192. This applica of a therapeutically effective amount of an active agent in a tion is also a continuation-in-part of US. patent application single unit dosage form, a signi?cant draWback in terms of Ser. No. 09/877,541, ?led Jun. 8, 2001, Which is a continu patient compliance. For eXample, the administration of ation-in-part of US. patent application Ser. No. 09/345,615, vitamins typically requires multiple dosage units, as does the ?led Jun. 30, 1999, issued on Jul. 31, 2001 as US. Pat. No. administration of a number of pharmacologically active 6,297,985. This application is also a continuation-in-part of agents (e.g., ritonavir and various other antiviral agents). US. patent application Ser. No. 09/800,593, ?led Mar. 6, Furthermore, the properties of oil-based formulations are 2001, Which is a divisional of US. patent application Ser. determined by such factors as the siZe of the triglyceride/ No. 09/447,690, ?led Nov. 23, 1999, issued on Jun. 19, 2001 therapeutic agent colloidal particles and the presence or as US. Pat. No. 6,248,363. The disclosures of the afore absence of surfactant additives. Although triglyceride-based mentioned patent applications are incorporated by reference pharmaceutical compositions are useful in solubiliZing and herein. delivering some hydrophobic therapeutic agents, such com positions are subject to a number of signi?cant limitations TECHNICAL FIELD and disadvantages. Emulsions are thermodynamically unstable, and colloidal emulsion particles Will spontane [0002] The present invention relates generally to the ?eld ously agglomerate, eventually leading to complete phase of drug delivery. More speci?cally, the invention relates to separation. The tendency to agglomerate and phase separate novel pharmaceutical compositions for administration of presents problems of storage and handling, and increases the active agents to patients, Wherein the compositions provide likelihood that pharmaceutical emulsions initially properly for multi-stage drug release. The invention additionally prepared Will be in a less optimal, less effective, and relates to processes for preparing the suspensions and meth poorly-characteriZed state upon ultimate administration to a ods of using the suspensions to administer an active agent to patient. UncharacteriZed degradation is particularly disad a patient. The invention has utility in the ?elds of pharma vantageous, since increased particle siZe sloWs the rate of ceutical formulation, pharmacology, and medicine. transport of the colloidal particle and digestion of the oil component, and hence the rate and eXtent of absorption of BACKGROUND the therapeutic agent. These problems lead to poorly-char acteriZed and potentially harmful changes in the effective [0003] Those Working in the ?elds of pharmaceutical dosage received by the patient. Moreover, changes in col formulation and drug delivery continue to be limited by a loidal emulsion particle siZe are also believed to render number of difficulties presented by different active agents. It absorption more sensitive to and dependent upon conditions has proved particularly problematic to provide therapeuti in the gastrointestinal tract, such as pH, enZyme activity, bile cally effective formulations for administration of drugs components, and stomach contents. Such uncertainty in the exhibiting loW bioavailability and absorption. A Well-de rate and eXtent of ultimate absorption of the therapeutic signed formulation must, at a minimum, be capable of agent severely compromises the medical professional’s abil presenting a therapeutically effective amount of the active ity to safely administer therapeutically effective dosages. A agent to the desired absorption site, in an absorbable form. further disadvantage of triglyceride-containing composi Even this minimal functionality can be dif?cult to achieve, tions is the dependence of therapeutic agent absorption on hoWever, e.g., When delivery of a hydrophobic active agent the rate and eXtent of lipolysis. Although colloidal emulsion requires interaction With aqueous physiological environ particles can transport hydrophobic therapeutic agents ments, such as gastric ?uids and intestinal ?uids. through the aqueous environment of the gastrointestinal [0004] A number of approaches to formulating active tract, ultimately the triglyceride must be digested and the agents having loW aqueous solubility are knoWn. One Well therapeutic agent must be released in order to be absorbed knoWn approach uses surfactant micelles to solubiliZe and through the intestinal mucosa. The triglyceride carrier is transport the therapeutic agent. Micelles are agglomerates of emulsi?ed by bile salts and hydrolyZed, primarily by pan colloidal dimensions formed by amphiphilic compounds creatic lipase. The rate and eXtent of lipolysis, hoWever, are under certain conditions. Micelles, and pharmaceutical com dependent upon several factors that are dif?cult to positions containing micelles, have been extensively studied adequately control. and are described in detail in the literature; see, e.g., Rem [0006] Hydrophilic active agents, hoWever, also present ington: The Science and Practice of Pharmacy, Nineteenth formulation problems, and although readily dissolved in the Ed. (Easton, Pa.: Mack Publishing Company, 1995). In gastrointestinal environment, simple dissolution is not suf aqueous solution, micelles can incorporate hydrophobic ?cient to provide ef?cient bioabsorption of the therapeutic therapeutic agents in the hydrocarbon core of the micelle, or agent. Barriers to absorption are presented by the mucous entangled at various positions Within the micelle Walls. layer, the intestinal epithelial cell membrane, and the junc Although micellar formulations can solubiliZe a variety of tional structure such as tight junctions betWeen the epithelial US 2003/0077297 A1 Apr. 24, 2003

cells. Due to the presence of the negatively charged mucosal [0010] With fundamental limitations presenting such enor layer, signi?cant electrostatic binding or repulsion of mous challenges for those attempting to formulate effective charged molecules can be encountered. The epithelial cell drug delivery systems, more complex formulation aspects membranes are composed of phospholipid bilayers in Which have largely been ignored. For example, it Would be highly proteins are embedded via the hydrophobic segments. These desirable to provide a drug delivery system that not only bilayers at the apical and/or basolateral cell surface represent provides for enhanced bioavailability and absorption of an very strong barriers for transport of hydrophilic substances, active agent, but also exhibits long-term chemical and including peptides and proteins. Frequently, hydrophilic physical stability, and that, furthermore, may be readily therapeutic agents are also subject to enZymatic attack and tailored during manufacture to provide any of a number of are degraded before they can be presented to the absorption unique drug release pro?les, e.g., immediate release com bined With delayed and/or sustained release, pulsatile site. release, targeted release, and the like. [0007] Much effort has been expended to develop methods of overcoming these absorption barriers, in order to enhance SUMMARY OF THE INVENTION the bioavailability of hydrophilic active agents. For [0011] The present invention is addressed to the afore example, the enZymatic barrier can be attacked by admin mentioned need in the art, and provides pharmaceutical istering enZyme inhibitors to prevent or at least lessen the formulations and drug delivery systems exhibiting numer extent of presystemic degradation in the gastrointestinal ous advantages relative to prior formulations and systems, tract (see, e.g., Bernkop-Schnurch (1998), “The use of including, but not limited to, the folloWing: (1) signi?cantly inhibitory agents to overcome the enZymatic barrier to enhanced rate and extent of absorption, substantially perorally administered therapeutic peptides and proteins, increasing the bioavailability of both hydrophilic and hydro ”J0urnal of Controlled Release 5211-16). Other efforts have phobic active agents; (2) as a result of (1), the capability of focused on, for example, the use of absorption promoters to administering a therapeutically sufficient amount of drug enhance epithelial permeability (e.g., LeCluyse and Sutton using feWer dosage units than previously possible, Without (1997), “In vitro models for selection of development can compromising pharmacokinetic/pharmacodynamic proper didates. Permeability studies to de?ne mechanisms of ties; (3) reduced interpatient variability; (4) reduced impact absorption enhancement,”Advanced Drug Delivery Reviews of food on drug absorption; and (5) the capability of pro 231163-183). HoWever, the effectiveness of absorption viding any of a variety of drug release pro?les, e.g., rapid enhancers such as permeability enhancers or enZyme inhibi onset coupled With rapid apparent elimination, and rapid tors depends upon the ability of a pharmaceutical carrier to onset coupled With a longer duration of action. effectively present the absorption enhancers and the hydro philic therapeutic agent to the absorption site, and prior [0012] In one aspect of the invention, a pharmaceutical efforts have not provided carriers Which can do so ef?ciently. formulation is provided in Which a ?rst fraction of an active Moreover, maintaining effective carrier concentrations at the agent is suspended in a vehicle, and the remaining, second epithelium is not easily controlled in vivo. Too little carrier, fraction of the active agent is solubiliZed in the vehicle. The or carrier concentrations only brie?y maintained, may be ?rst fraction of the active agent, i.e., the suspended fraction, ineffective. Too much carrier, or carrier concentrations is comprised of a plurality of solid particles and represents maintained for too long, may result in compromised safety. about 5 Wt. % to about 80 Wt. % of the total active agent in the formulation, such that the second fraction, i.e., the [0008] Traditional pharmaceutical suspensions of drugs solubiliZed fraction, represents approximately 20 Wt. % to are primarily composed of an aqueous continuous phase about 95 Wt. % of the total active agent. The vehicle is With little or no solubiliZed fraction. HoWever, there are a comprised of at least one compound selected from the group feW nonaqueous compositions on the market, e.g., consisting of a hydrophilic surfactant, a lipophilic surfactant, Prometrium® (Solvay), an encapsulated formulation of a triglyceride and a solubiliZer, and is preferably comprised microniZed progesterone for oral administration, Accutane® of at least tWo such compounds. The solid particles repre (Roche), an encapsulated formulation of isotretinoin (cis senting the second fraction of the active agent, generally retinoic acid, indicated for treatment of severe nodular although not necessarily having a mean diameter in the acne), also for oral administration, and Depo Provera® range of about 0.1 pm to about 100 pm, may be suspended (Pharmacia), an injectable medroxyprogesterone acetate in particulate form, or they may associate so as to form one suspension. These nonaqueous dispersions have a very small or more larger dosage units such as a granule, pellet, bead or fraction of drug in the dissolved state, typically far less than tablet, Which dosage unit or units are then suspended in the 10% of the total drug in the formulation. Moreover, because vehicle. Alternatively, the solid particles representing the these traditional compositions lack any therapeutically sig second fraction of the active agent may be contained Within ni?cant solubiliZed fraction of drug, they are incapable of a capsule, Which is in turn suspended in the vehicle. either enhancing the rate and extent of absorption or rapidly providing a therapeutically effective blood level of drug. For [0013] The ?rst and second fractions of the active agent many types of drugs, these are signi?cant limitations. may or may not have different release pro?les. Generally, hoWever, a signi?cant fraction of the solubiliZed drug Will [0009] Current sustained release dosage forms provide a release rapidly, providing for rapid onset, While the sus longer duration of action; hoWever, their therapeutic utility pended drug Will be released from the formulation and/or is limited by the failure to provide any rapid onset, in turn absorbed someWhat more sloWly. Accordingly, the formu a result of sloW dissolution, loW solubility, and the lack of lation provides for “multistage release,” meaning that not all any signi?cant fraction of predissolved drug. For many of the active agent in the formulation is released at once. If therapeutic indications, such as pain, there is a need for both a sufficiently substantial fraction of active agent is solubi rapid onset of action and a longer duration of action. liZed and the suspended fraction is not speci?cally formu US 2003/0077297 A1 Apr. 24, 2003

lated for delayed or extended release (e.g., With an enteric Wherein the second fraction represents about 20 Wt. % to and/or sustained release coating), the release pro?le pro about 95 Wt. % of the total active agent in the formulation. vided by the formulation as a Whole Will involve rapid onset The active agent, the vehicle, and the at least one compound as Well as rapid apparent elimination. Alternatively, an may be administered simultaneously, in a single formulation overall release pro?le that involves rapid onset coupled With or in tWo or more formulations, or at least tWo of the active an extended release period and/or duration of action may be agent, the vehicle, and the at least one compound are not provided by formulating the suspended fraction of drug so as administered simultaneously, in Which case they may or may to have desired extended and/or delayed release character not be housed in different dosage forms. istics. [0018] In contrast to prior formulations, the present inven [0014] In the aforementioned embodiment, the ?rst and tion provides a pharmaceutical suspension in Which a sig second fractions of the active agent may be physically ni?cant fraction of the active agent, on the order of 20 Wt. segregated such that they are not in contact. In such a case, % to 95 Wt. %, is solubiliZed in the vehicle. The vehicle is the formulation further includes a means for physically highly Water-dispersible so that the solubiliZed fraction of segregating the ?rst and second fractions so as to prevent the active agent can be dispersed and available for absorp contact therebetWeen, Which can be, by Way of example, a tion immediately. vehicle-impermeable coating on the second fraction of BRIEF DESCRIPTION OF THE DRAWINGS active agent, i.e., a coating on the individual solid particles [0019] FIG. 1 schematically various embodiments of the When the second fraction is in particulate form, a coating on invention Wherein the pharmaceutical formulation, includ the one or more larger dosage units When the solid particles ing both the suspended and solubiliZed fractions of active are associated With each other to form such dosage units, agent, are included in a single dosage form. The shaded e.g., granules, pellets, beads, or tablets, or a coating on a regions represent the solubiliZed fractions of the formula capsule When the solid particles of the second fraction are encapsulated and suspended in capsule form. As another tion, Wherein the active agent is solubiliZed in the vehicle. example, the formulation may be housed Within a dosage [0020] FIGS. 2A through 2D schematically alternative form such as a capsule, and the means for physically embodiments of the invention Wherein the solubiliZed frac segregating the ?rst and second fractions comprises a Wall, tion of the drug and the remainder of the drug are incorpo a plug, or a septum dividing the dosage form into a ?rst rated into different dosage forms. Again, the shaded regions region that contains the ?rst fraction and a second region that represent the solubiliZed fractions of the formulation, contains the second fraction. Wherein the active agent is solubiliZed in the vehicle. [0015] In a further aspect of the invention, a method is [0021] FIGS. 3A and 3B schematically illustrate, in provided for administering an active agent to a mammalian cross-sectional vieW, capsules having an internal septum patient, generally although not necessarily a human patient, dividing the capsule interior into tWo regions, one of Which Wherein the method involves administering an amount of the may contain solubiliZed drug and the other of Which may aforementioned formulation that is suf?cient to deliver a contain suspended drug. therapeutically effective amount of the active agent to the [0022] FIGS. 4A and 4B schematically illustrate, in patient. Preferably, the formulation is orally administered. cross-sectional vieW, one-piece capsules having an internal [0016] In another aspect of the invention, a pharmaceuti Wall separating the capsule interior into tWo regions, one of Which may contain solubiliZed drug and the other of Which cal system is provided for administration of an active agent, Wherein the system is comprised of an active agent and a may contain suspended drug. vehicle as above, i.e., a vehicle comprising at least one [0023] FIGS. 5A, 5B, and 5C schematically illustrate compound selected from the group consisting of a hydro various Ways that dosage forms can be prepared so that an philic surfactant, a lipophilic surfactant, a triglyceride and a outer capsule encapsulates and inner capsule, alloWing one solubiliZer, Wherein the relative amounts of the active agent fraction of a formulation to be encapsulated in the inner and the vehicle are such that upon admixture thereof, a ?rst capsule, and a second fraction of a formulation to be fraction of the active agent becomes suspended in the encapsulated in the outer capsule along With the sealed inner vehicle, and a second fraction of the active agent becomes capsule. solubiliZed in the vehicle, Wherein the second fraction [0024] FIG. 6 is a graph comparing the absorption of represents about 20 Wt. % to about 95 Wt. % of the total isotretinoin in rats from a formulation of the invention and active agent in the formulation. from Accutane®, a commercially available isotretinoin [0017] In a related aspect of the invention, a method is product, as evaluated in Example 13. provided for administering an active agent to a mammalian [0025] FIG. 7 is a graph illustrating the results of the patient, generally although not necessarily a human patient, dissolution tests described in Example 35, With respect to a Wherein the method involves administering to the patient a comparison of the feno?brate formulation of Example 14 pharmaceutical system of a) a therapeutically effective and a commercially available feno?brate product, Tricor®. amount of an active agent; and (b) a pharmaceutically acceptable vehicle comprising at least one compound [0026] FIG. 8 is a graph illustrating the results of the selected from the group consisting of a hydrophilic surfac dissolution tests described in Example 35, With respect to a tant, a lipophilic surfactant, a triglyceride and a solubiliZer, comparison of the feno?brate formulation of Example 15 Wherein the relative amounts of the active agent and the and a commercially available feno?brate product, Tricor®. vehicle are such that upon admixture thereof, a ?rst fraction [0027] FIG. 9 is a graph illustrating the results of the in of the active agent is suspended in the vehicle, and a second vivo absorption tests described in Example 36 for the fraction of the active agent is solubiliZed in the vehicle, feno?brate formulation of Example 15. US 2003/0077297 A1 Apr. 24, 2003

[0028] FIG. 10 is a graph illustrating the results of the symptoms, elimination of symptoms and/or underlying dissolution tests described in Example 49, With respect to a cause, prevention of the occurrence of symptoms and/or comparison of the progesterone formulation of Example 37 their underlying cause, and improvement or remediation of and a commercially available progesterone suspension, damage. Thus, for example, “treating” a patient involves Prometrium®. prevention of a particular disorder or adverse physiological event in a susceptible individual as Well as treatment of a [0029] FIGS. 11A and 11B are graphs illustrating the clinically symptomatic individual by inhibiting or causing results of the in vivo absorption tests described in Example regression of a disorder or disease. 50 for the progesterone formulation of Example 37 and a commercially available progesterone suspension, [0037] By an “effective” amount or a “therapeutically Prometrium®. effective amount” of an active agent is meant a nontoxic but suf?cient amount of the agent to provide the desired effect. DETAILED DESCRIPTION OF THE The amount of active agent that is “effective” Will vary from INVENTION subject to subject, depending on the age and general con dition of the individual, the particular active agent or agents, [0030] I. De?nitions and Overview: and the like. Thus, it is not alWays possible to specify an exact “effective amount.” HoWever, an appropriate “effec [0031] It is to be understood that unless otherWise indi tive” amount in any individual case may be determined by cated, this invention is not limited to speci?c active agents, one of ordinary skill in the art using routine experimentation vehicles, excipients, dosage forms, or the like, as such may vary. It is also to be understood that the terminology used [0038] By “pharmaceutically acceptable,” such as in the herein is for the purpose of describing particular embodi recitation of a “pharmaceutically acceptable excipient,” or a ments only, and is not intended to be limiting. “pharmaceutically acceptable additive,” is meant a material that is not biologically or otherWise undesirable, i.e., the [0032] As used in this speci?cation and the appended material may be incorporated into a pharmaceutical compo claims, the singular forms “a,”“an” and “the” include plural sition administered to a patient Without causing any unde referents unless the context clearly dictates otherWise. Thus, sirable biological effects or interacting in a deleterious for example, reference to “an active agent” includes a single manner With any of the other components of the composition active agent as Well a tWo or more different active agents in in Which it is contained. “Pharmacologically active” (or combination, reference to “an excipient” includes mixtures simply “active”), as in a “pharmacologically active” deriva of tWo or more excipients as Well as a single excipient, and tive of an active agent, refers to a derivative having the same the like. type of pharmacological activity as the parent compound [0033] In describing and claiming the present invention, and approximately equivalent in degree. When the term the folloWing terminology Will be used in accordance With “pharmaceutically acceptable” is used to refer to a derivative the de?nitions set out beloW. (e.g., a salt) of an active agent, it is to be understood that the compound is pharmacologically active as Well. When the [0034] The terms “active agent, pharmacologically term “pharmaceutically acceptable” is used to refer to an active agent,” and “drug” are used interchangeably herein to excipient, it implies that the excipient has met the required refer to any chemical compound, complex or composition standards of toxicological and manufacturing testing or that that has a bene?cial biological effect, preferably a therapeu it is on the Inactive Ingredient Guide prepared by the FDA. tic effect in the treatment of a disease or abnormal physi [0039] The term “multistage release” refers to a drug ological condition. The terms also encompass pharmaceu tically acceptable, pharmacologically active derivatives of containing formulation or system Wherein some of the drug those active agents speci?cally mentioned herein, including, is released according to a ?rst release pro?le (e.g., imme diate release), and the remainder of the drug is released but not limited to, salts, esters, amides, prodrugs, active according to one or more different release pro?les (e.g., metabolites, isomers, fragments, analogs, and the like. When the terms “active agent,”“pharmacologically active agent” sustained release and/or delayed release as de?ned beloW). “Pulsatile release” is a form of multistage release Wherein and “drug” are used, then, or When a particular active agent discrete pulses of drug are released over an extended time is speci?cally identi?ed, it is to be understood that applicants period. intend to include the active agent per se as Well as pharma ceutically acceptable, pharmacologically active salts, esters, [0040] The term “controlled release” refers to a drug amides, prodrugs, active metabolites, isomers, fragments, containing formulation or fraction thereof in Which release analogs, etc. of the drug is not immediate, i.e., With a “controlled release” formulation, administration does not result in immediate [0035] The term “dosage form” denotes any form of a release of the drug into an absorption pool. The term is used pharmaceutical composition that contains an amount of interchangeably With “nonimmediate release” as de?ned in active agent suf?cient to achieve a therapeutic effect With a Remington." The Science and Practice of Pharmacy, Nine single administration. When the formulation is a tablet or teenth Ea'. (Easton, Pa.: Mack Publishing Company, 1995). capsule, the dosage form is usually one such tablet or In general, the term “controlled release” as used herein capsule. The frequency of administration that Will provide includes sustained release and delayed release formulations. the most effective results in an ef?cient manner Without overdosing Will vary With the characteristics of the particular [0041] The term “sustained release” (synonymous With active agent, including both its pharmacological character “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a istics and its physical characteristics, such as hydrophilicity. drug over an extended period of time, and that preferably, [0036] The terms “treating” and “treatment” as used although not necessarily, results in substantially constant herein refer to reduction in severity and/or frequency of blood levels of a drug over an extended time period. US 2003/0077297 A1 Apr. 24, 2003

[0042] The term “delayed release” is used in its conven teroids, COX-2 inhibitors, decongestants, diuretics, gas tional sense to refer to a drug formulation in Which there is trointestinal agents, genetic materials, histamine receptor a time delay provided betWeen oral administration of a drug antagonists, hormonolytics, hypnotics, hypoglycemic dosage form and the release of the drug therefrom. “Delayed agents, immunosuppressants, keratolytics, leukotriene release” may or may not involve gradual release of drug over inhibitors, lipid-regulating agents, macrolides, mitotic an eXtended period of time, and thus may or may not be inhibitors, muscle relaXants, narcotic antagonists, neurolep “sustained release.” Preferred “delayed release” formula tic agents, nicotine, nutritional oils, parasympatholytic tions are enterically coated compositions. agents, sedatives, seX hormones, sympathomimetic agents, tranquilizers, vasodilators, vitamins, and combinations [0043] The term “polymer” as used herein refers to a thereof. Active agents that may be administered according to molecule containing a plurality of covalently attached the invention also include nutrients, cosmeceuticals, diag monomer units, and includes branched, dendrimeric and star nostic agents, and nutritional agents. Some agents, as Will be polymers as Well as linear polymers. The term also includes both homopolymers and copolymers, e.g., random copoly appreciated by those of ordinary skill in the art, and as may be deduced from the discussion beloW, are encompassed by mers, block copolymers and graft copolymers, as Well as uncrosslinked polymers and slightly to moderately to sub tWo or more of the aforementioned groups. stantially crosslinked polymers. [0048] The active agent can be hydrophobic, amphiphilic, [0044] “Vehicles” refer to conventional pharmaceutically or hydrophilic. The intrinsic Water solubility of those active acceptable carrier materials suitable for drug administration, agents referred to as “hydrophobic” herein, i.e., the aqueous and include any such materials knoWn in the art that are solubility of the active agent in electronically neutral, non nontoXic and do not interact With other components of a ioniZed form, is generally less than 1% by Weight, and pharmaceutical formulation or drug delivery system in a typically less than 0.1% or 0.01% by Weight. Hydrophilic deleterious manner. and amphiphilic active agents herein (Which, unless other Wise indicated, are collectively referred to herein as “hydro [0045] Accordingly, the invention pertains to a novel philic” active agents) have apparent Water solubilities of at pharmaceutical formulation that provides for increased least 0.1% by Weight, and typically at least 1% by Weight. absorption and bioavailability of active agents, particularly Both hydrophobic active agents and hydrophilic active active agents that are administered orally. In a ?rst embodi agents may be selected from any of the active agent classes ment, the formulation is comprised of an active agent having enumerated earlier in this section. a ?rst fraction suspended in a vehicle, and the remaining, second fraction solubiliZed in the vehicle. The ?rst fraction [0049] Among the various active agent categories, pre of the active agent, i.e., the suspended fraction, is comprised ferred classes of active agents for administration using the of a plurality of solid particles and represents about 5 Wt. % present method and formulations are lipid regulating agents, to about 80 Wt. % of the total active agent in the formulation. seX hormones, anti-hypertensive agents, anti-diabetic The vehicle is comprised of at least one compound selected agents, anti-viral agents (including protease inhibitors), pep from the group consisting of a hydrophilic surfactant, a tidyl drugs, genetic materials, and combinations of any of lipophilic surfactant, a triglyceride and a solubiliZer. The the foregoing. individual components of the formulation are described in [0050] Lipid-regulating agents that are generally classi?ed detail beloW. as hydrophobic include HMG CoA reductase inhibitors such [0046] II. The Active Agent: as atorvastatin, simvastatin, ?uvastatin, pravastatin, lovas tatin, cerivastatin, rosuvastatin, and pitavastatin, as Well as [0047] The active agents that may be administered using other lipid-loWering (“antihyperlipidemic”) agents such as the formulations, systems and methods of the invention are beZa?brate, beclobrate, bini?brate, cipro?brate, clino?brate, not limited, as the invention enables the effective delivery of clo?brate, clo?bric acid, eZetimibe, eto?brate, feno?brate, a Wide variety of active agents. Therefore, the active agent feno?bric acid, gem?broZil, nico?brate, piri?brate, probu administered may be selected from any of the various col, roni?brate, sim?brate, and theo?brate. A particularly classes of such agents including, but not limited to, analgesic preferred lipid-regulating agent that may be administered agents, anesthetic agents, anti-anginal agents, antiarthritic using the methods and formulations of the invention is agents, anti-arrhythmic agents, antiasthmatic agents, anti feno?brate. bacterial agents, anti-BPH agents, anticancer agents, anti cholinergic agents, anticoagulants, anticonvulsants, antide [0051] Preferred seX hormones for administration using pressants, antidiabetic agents, antidiarrheals, anti-epileptic according to the invention include progestins (progesto agents, antifungal agents, antigout agents, antihelminthic gens), estrogens, and combinations thereof. Progestins agents, antihistamines, antihypertensive agents, antiin?am include acetoXypregnenolone, allylestrenol, anagestone matory agents, antimalarial agents, antimigraine agents, acetate, chlormadinone acetate, cyproterone, cyproterone antimuscarinic agents, antinauseants, antineoplastic agents, acetate, desogestrel, dihydrogesterone, dimethisterone, anti-obesity agents, antiosteoporosis agents, antiparkin ethisterone (17(x-ethinyltestosterone), ethynodiol diacetate, sonism agents, antiprotoZoal agents, antipruritics, antipsy ?urogestone acetate, gestadene, hydroXyprogesterone, chotic agents, antipyretics, antispasmodics, antithyroid hydroXyprogesterone acetate, hydroXyprogesterone agents, antitubercular agents, antiulcer agents, anti-urinary caproate, hydroXymethylprogesterone, hydroXymethyl incontinence agents, antiviral agents, anXiolytics, appetite progesterone acetate, 3-ketodesogestrel, levonorgestrel, suppressants, attention de?cit disorder (ADD) and attention lynestrenol, medrogestone, medroXyprogesterone acetate, de?cit hyperactivity disorder (ADHD) drugs, calcium chan megestrol, megestrol acetate, melengestrol acetate, nore nel blockers, cardiac inotropic agents, beta-blockers, central thindrone, norethindrone acetate, norethisterone, norethis nervous system stimulants, cognition enhancers, corticos terone acetate, norethynodrel, norgestimate, norgestrel, US 2003/0077297 A1 Apr. 24, 2003

norgestrienone, norrnethisterone, progesterone, and trirnge interferon alpha, larnivudine, nel?navir, nevirapine, ribavi stone. Also included Within this general class are estrogens, rin, rirnantadine, ritonavir, saquinavir, stavudine, tipranavir, e.g.: estradiol (i.e., 1,3,5-estratriene-3,17[3-diol, or “176 valganciclovir, Zalcitabine, and Zidovudine; and other anti estradiol”) and its esters, including estradiol benZoate, val viral agents such as abacavir, indinavir, interferon alpha, erate, cypionate, heptanoate, decanoate, acetate and diac nel?navir, ribavirin, rirnantadine, tipranavir, ursodeoXy etate; 17a-estradiol; ethinylestradiol (i.e., 170. cholic acid, and valganciclovir. ethinylestradiol) and esters and ethers thereof, including [0056] Peptidyl drugs include therapeutic peptides and ethinylestradiol 3-acetate and ethinylestradiol 3-benZoate; proteins per se, Whether naturally occurring, chemically estriol and estriol succinate; polyestrol phosphate; estrone synthesized, recornbinantly produced, and/or produced by and its esters and derivatives, including estrone acetate, biochernical (e.g., enZyrnatic) fragmentation of larger mol estrone sulfate, and piperaZine estrone sulfate; quinestrol; ecules, and may contain the native sequence or an active rnestranol; and conjugated equine estrogens. In many con fragment thereof. Speci?c peptidyl drugs include, without teXts, e.g., in female contraception and in horrnone replace limitation, the peptidyl horrnones activin, arnylin, angio rnent therapy (HRT), a combination of a progestin and tensin, atrial natriuretic peptide (AN P), calcitonin, calcitonin estrogen is used, e.g., progesterone and 17 [3-estradiol. For gene-related peptide, calcitonin N-terrninal ?anking peptide, HRT, an androgenic agent may be advantageously included ciliary neurotrophic factor (CNTF), corticotropin (adreno as Well. Androgenic agents for this purpose include, for corticotropin horrnone, ACTH), corticotropin-releasing fac example, dehydroepiandrosterone (DHEA; also termed tor (CRF or CRH), epidermal growth factor (EGF), follicle “prasterone”), sodiurn dehydroepiandrosterone sulfate, 4-di stirnulating hormone (FSH), gastrin, gastrin inhibitory hydrotestosterone (DHT; also termed “stanolone”), and tes peptide (GIP), gastrin-releasing peptide, gonadotropin-re tosterone, and pharrnaceutically acceptable esters of test leasing factor (GnRF or GNRH), growth hormone releasing osterone and 4-dihydrotestosterone, typically esters formed factor (GRF, GRH), human chorionic gonadotropin (hCH), from the hydroXyl group present at the C-17 position, inhibin A, inhibin B, insulin, luteinizing hormone (LH), including, but not limited to, the enanthate, propionate, luteinizing hormone-releasing hormone (LHRH), a-rnelano cypionate, phenylacetate, acetate, isobutyrate, buciclate, cyte-stirnulating horrnone, [3-rnelanocyte-stirnulating hor heptanoate, decanoate, undecanoate, caprate and isocaprate rnone, y-rnelanocyte-stirnulating horrnone, rnelatonin, rnoti esters. lin, oXytocin (pitocin), pancreatic polypeptide, parathyroid [0052] Androgenic agents may also be administered for hormone (PTH), placental lactogen, prolactin (PRL), pro other purposes Well knoWn in the art. In addition to the lactin-release inhibiting factor (PIF), prolactin-releasing fac androgenic agents enumerated above, other androgenic tor (PRF), secretin, sornatotropin (growth hormone, GH), agents include, but are not limited to, androsterone, andros sornatostatin (SIF, groWth horrnone-release inhibiting factor, terone acetate, androsterone propionate, androsterone ben GIF), thyrotropin (thyroid-stimulating hormone, TSH), thy Zoate, androstenediol, androstenediol-3-acetate, androstene rotropin-releasing factor (TRH or TRF), thyroXine, vasoac diol-17-acetate, androstenediol-3,17-diacetate, tive intestinal peptide (VIP),and vasopressin. Other peptidyl androstenediol-17-benZoate, androstenediol-3-acetate-17 drugs are the cytokines, e.g., colony stimulating factor 4, benZoate, androstenedione, ethylestrenol, oXandrolone, nan heparin binding neurotrophic factor (HBNF), interferon-a, drolone phenpropionate, nandrolone decanoate, nandrolone interferon ot-Za, interferon ot-Zb, interferon ot-n3, interferon furylpropionate, nandrolone cycloheXane-propionate, nan [3, etc., interleukin-1, interleukin-2, interleukin-3, interleu drolone benZoate, nandrolone cycloheXanecarboXylate, kin-4, interleukin-5, interleukin-6, etc., tumor necrosis fac stanoZolol, drornostanolone, and drornostanolone propi tor, tumor necrosis factor-0t, granuloycte colony-stimulating onate. factor (G-CSF), granulocyte-rnacrophage colony-stirnulat ing factor (GM-CSF), rnacrophage colony-stirnulating fac [0053] Antihypertensive agents include, Without lirnita tor, rnidkine (MD), and thyrnopoietin. Still other peptidyl tion, arnlodipine, benaZepril, benidipine, candesartan, cap drugs that can be advantageously delivered using the meth topril, carvedilol, darodipine, dilitaZern, diaZoXide, doX odology and formulations of the present invention include aZosin, enalapril, epleronone, eposartan, felodipine, endorphins (e.g., derrnorphin, dynorphin, ot-endorphin, fenoldoparn, fosinopril, guanabenZ, iloprost, irbesartan, isra [3-endorphin, y-endorphin, o-endorphin, [Leu5]enkephalin, dipine, lercardinipine, lisinopril, losartan, rninoXidil, nebiv [Met5]enkephalin, substance P), kinins (e.g., bradykinin, olol, nicardipine, nifedipine, nirnodipine, nisoldipine, orna potentiator B, bradykinin potentiator C, kallidin), LHRH patrilat, phenoXybenZarnine, praZosin, quinapril, reserpine, analogues (e.g., buserelin, deslorelin, fertirelin, goserelin, sernotiadil, sitaXsentan, teraZosin, telrnisartan, and valsartan. histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), and the coagulation factors, such as otl-antitrypsin, (x2-rnacroglobu [0054] Anti-diabetic agents include, by Way of example, lin, antithrornbin III, factor I (?brinogen), factor II (pro acetoheXarnide, chlorproparnide, ciglitaZone, farglitaZar, thrornbin), factor III (tissue prothrornbin), factor V (proac glibenclarnide, gliclaZide, glipiZide, glucagon, glyburide, celerin), factor VII (proconvertin), factor VIII glyrnepiride, rniglitol, pioglitaZone, nateglinide, pirnage (antihernophilic globulin or AHG), factor IX (Christrnas dine, repaglinide, rosiglitaZone, tolaZarnide, tolbutarnide, factor, plasrna thrornboplastin component or PTC), factor X triarnpterine, and troglitaZone. (Stuart-Power factor), factor XI (plasrna thrornboplastin [0055] Antiviral agents that can be delivered using the antecedent or PTA), factor XII (Hagernan factor), heparin present methods and dosage forms include the antiherpes cofactor II, kallikrein, plasrnin, plasrninogen, prekallikrein, agents acyclovir, farnciclovir, foscarnet, ganciclovir, idoXu protein C, protein S, and thrornbornodulin and combinations ridine, sorivudine, tri?uridine, valacyclovir, and vidarabine, thereof. and otherantiviral agents such as abacavir, arnantadine, [0057] Genetic material may also be delivered using the arnprenavir, delviridine, didanosine, efavirenZ, indinavir, present methods and formulations, including, for example, US 2003/0077297 A1 Apr. 24, 2003

nucleic acids, RNA, DNA, recombinant RNA, recombinant tirapaZarnine, topotecan, torernifene citrate, vitamin A, vita DNA, antisense RNA, antisense DNA, riboZyrnes, ribooli min A derivatives, and Zacopride; gonucleotides, deoXyribonucleotides, antisense ribooligo nucleotides, and antisense deoXyribooligonucleotides. Rep [0066] anti-coagulants and other agents for preventing and resentative genes include those encoding for vascular treating stroke, such as cilostaZol, citicoline, clopidogrel, endothelial groWth factor, ?broblast groWth factor, Bcl-2, crorna?ban, deXanabinol, dicurnarol, dipyridarnole, nicou cystic ?brosis transrnernbrane regulator, nerve groWth fac rnalone, oprelvekin, perindopril erburnine, phenindione, tor, human growth factor, erythropoietin, tumor necrosis rarnipril, repinotan, ticlopidine, tiro?ban, and heparin, factor, and interleukin-2, as Well as histocornpatibility genes including heparin salts formed with organic or inorganic such as HLA-B7. bases, and low molecular Weight heparin, i.e., heparin frag rnents generally having a Weight average molecular Weight [0058] Other therapeutic agents that can be delivered in the range of about 1000 to about 10,000 D and eXernpli using the present methods and formulations include the ?ed by enoXaparin, dalteparin, danaproid, garnrnaparin, folloWing representative cornpounds: nadroparin, ardeparin, tinZaparin, certoparin, and reviparin; [0059] anti-in?ammatory agents and non-opioid analge [0067] anti-diabetics, such as acetoheXarnide, chlorpropa sics, such as aloXiprin, aurano?n, aZapropaZone, aZathio rnide, farglitaZar, glibenclarnide, gliclaZide, glipiZide, glirne prine, benorylate, butorphenol, capsaicin, celecoXib, piride, rniglitol, nateglinide, pirnagedine, pioglitaZone, repa diclofenac, di?unisal, esonarirnod, etodolac, fenbufen, feno glinide, rosiglitaZone, tolaZarnide, tolbutarnide, troglitaZone, profen calciurn, ?urbiprofen, ibuprofen, indornethacin, keto and voglibose; profen, ketorolac, le?unornide, rneclofenarnic acid, rnefe [0068] anti-epileptics, such as beclarnide, carbarnaZepine, narnic acid, naburnetone, naproXen, novantrone, oXaproZin, clonaZeparn, ethotoin, felbarnate, fosphenytoin, larnotrigine, oXyphenbutaZone, parecoXib, phenylbutaZone, piclarnilast, rnethoin, rnethsuXirnide, rnethylphenobarbitone, oXcarba piroXicarn, rofecoXib, ropivacaine, sulindac, tetrahydrocan Zepine, pararnethadione, phenacernide, phenobarbitone, nabinol, trarnadol, trornetharnine, valdecoXib, and phenytoin, phensuXirnide, prirnidone, sulthiarne, tiagabine, Ziconotide, as Well as the urinary analgesics phenaZopyri topirarnate, valproic acid, and vigabatrin; dine and tolterodine; [0069] anti-fungal agents, such as arnphotericin, buten [0060] anti-angina agents, such as rnibefradil, re?udan, a?ne, butoconaZole nitrate, clotrirnaZole, econaZole nitrate, nahnefene, carvedilol, crorna?ban, larni?ban, fasudil, rano ?uconaZole, ?ucytosine, griseofulvin, itraconaZole, keto laZine, tedisarnil, nisoldipine, and tiZanidine; conaZole, rniconaZole, natarnycin, nystatin, sulconaZole [0061] antihelrninthics, such as albendaZole, bepheniurn nitrate, oXiconaZole, terbina?ne, terconaZole, tioconaZole hydroXynaphthoate, carnbendaZole, dichlorophen, iverrnec and undecenoic acid; tin, rnebendaZole, oXarnniquine, oXfendaZole, oXantel [0070] anti-gout agents, such as allopurinol, probenecid ernbonate, praZiquantel, pyrantel ernbonate and thiabenda and sulphin-pyraZone; Zole; [0071] antihistamines and allergy medications, such as [0062] anti-arrhythrnic agents, such as arniodarone, dis acrivastine, asterniZole, chlorphenirarnine, cinnariZine, ceti opyrarnide, ?ecainide acetate and quinidine sulfate; riZine, clernastine, cycliZine, cyproheptadine, desloratadine, deXchlorphenirarnine, dirnenhydrinate, diphenhydrarnine, [0063] anti-asthrna agents, such as Zileuton, Za?rlukast, terbutaline sulfate, rnontelukast, and albuterol; epinastine, feXofenadine, ?unariZine, loratadine, rnecliZine, rniZolastine, oXatornide, and terfenadine; [0064] anti-bacterial agents, such as alatro?oXacin, [0072] anti-rnalarials, such as arnodiaquine, chloroquine, aZithrornycin, baclofen, benetharnine penicillin, cinoXacin, chlorproguanil, halofantrine, rne?oquine, proguanil, cipro?oXacin, clarithrornycin, clofaZirnine, cloXacillin, derneclocycline, dirithrornycin, doXycycline, erythrornycin, pyrirnetharnine and quinine sulfate; ethionarnide, furaZolidone, grepa?oXacin, irnipenern, levof [0073] agents for treating headaches, including anti-rni loXacin, lore?oXacin, rnoXi?oXacin, nalidiXic acid, nitro graine agents, such as alrnotriptan, butorphanol, dihydroer furantoin, nor?oXacin, o?oXacin, rifarnpicin, rifabutine, rifa gotarnine, dihydroergotarnine rnesylate, eletriptan, ergota pentine, spar?oXacin, spirarnycin, sulphabenZarnide, rnine, frovatriptan, rnethysergide, naratriptan, piZotyline, sulphadoXine, sulpharneraZine, sulphacetarnide, sulphadiaZ riZatriptan, surnatriptan, tonaberstat, and Zolrnitriptan; ine, sulphafuraZole, sulpharnethoXaZole, sulphapyridine, tet racycline, trirnethoprirn, trova?oXacin, and vancornycin; [0074] anti-rnuscarinic agents, such as atropine, ben ZheXol, biperiden, ethopropaZine, hyoscyarnine, rnepen [0065] anti-cancer agents and irnrnunosuppressants, such Zolate brornide, oXyphencyclirnine, scopolarnine, and tropi as alitretinoin, arninoglutethirnide, arnsacrine, anastroZole, carnide; aZathioprine, beXarotene, bicalutarnide, biricodar, bisant rene, busulfan, carnptothecin, candoXatril, capecitabine, cyt [0075] anti-protoZoal agents, such as atovaquone, ben arabine, chlorarnbucil, cyclosporin, dacarbaZine, decitabine, ZnidaZole, clioquinol, decoquinate, diiodohydroXyquinoline, ellipticine, estrarnustine, etoposide, gerncitabine, irinotecan, diloXanide furoate, dinitolrnide, furaZolidone, rnetronida lasofoXifene, letroZole, lornustine, rnelphalan, rnercaptopu Zole, nirnoraZole, nitro?raZone, ornidaZole and tinidaZole; rine, rnethotreXate, rnitornycin, rnitotane, rnitoXantrone, [0076] anti-thyroid agents, such as carbirnaZole, parical rnofetil, rnycophenolate, nebivolol, nilutarnide, paclitaXel, citol, and propylthiouracil; palonosetron, procarbaZine, rarnipril, rubitecan, sirolirnus, tacrolirnus, tarnoXifen, teniposide, testolactone, thalidornide, [0077] anti-tussives, such as benZonatate; US 2003/0077297 A1 Apr. 24, 2003

[0078] anXiolytics, sedatives, and hypnotics, such as alpra [0084] keratolytics, such as such as acetretin, calcipot Zolam, amylobarbitone, barbitone, bentaZepam, bro riene, calcifediol, calcitriol, cholecalciferol, ergocalciferol, maZepam, bromperidol, brotiZolam, butobarbitone, carbro etretinate, retinoids, targretin, and taZarotene; mal, chlordiaZepoXide, chlormethiaZole, chlorpromaZine, [0085] lipid regulating agents, such as atorvastatin, beZa? chlorprothiXene, clonaZepam, clobaZam, clotiaZepam, brate, cerivastatin, cipro?brate, clo?brate, eZetimibe, feno? cloZapine, deXmethylphenidate (d-threo-methylphenidate) brate, ?uvastatin, gem?broZil, pitavastatin, pravastatin, diaZepam, droperidol, ethinamate, ?unanisone, ?uni traZepam, tri?upromaZine, ?upenthiXol decanoate, probucol, rosuvastatin, and simvastatin; ?uphenaZine, ?uraZepam, gabapentin, gaboXadol, y-hy [0086] muscle relaXants, such as cyclobenZaprine, dant droXybutyrate, haloperidol, lamotrigine, loraZepam, rolene sodium and tiZanidine HCl; lormetaZepam, medaZepam, meprobamate, mesoridaZine, [0087] agents to treat neurodegenerative diseases, includ methaqualone, methylphenidate, midaZolam, moda?nil, ing active agents for treating AlZheimer’s disease such as molindone, nitraZepam, olanZapine, oXaZepam, pentobarbi akatinol, doneZepil, donepeZil hydrochloride, dronabinol, tone, perphenaZine pimoZide, pregabalin, prochlorperaZine, galantamine, neotro?n, rasagiline, physostigmine, physos pseudoephedrine, quetiapine, rispiridone, sertindole, sir tigmine salicylate, propentoffyline, quetiapine, rivastigmine, amesine, sulpiride, sunepitron, temaZepam, thioridaZine, tacrine, tacrine hydrochloride, thalidomide, and Xaliproden; triaZolam, Zaleplon, Zolpidem, and Zopiclone; active agents for treating Huntington’s Disease, such as [0079] appetite suppressants, anti-obesity drugs and drugs ?uoXetine and carbamaZepine; anti-parkinsonism drugs use for treatment of eating disorders, such as amphetamine, ful herein include amantadine, apomorphine, bromocriptine, bromocriptine, deXtroamphetamine, diethylpropion, lint entacapone, levodopa (particularly a levodopa/carbidopa itript, maZindol, methamphetamine, orlistat, phentermine, combination), lysuride, pergolide, pramipeXole, rasagiline, and topiramate; riluZole, ropinirole, selegiline, sumanirole, tolcapone, tri heXyphenidyl, and triheXyphenidyl hydrochloride; and [0080] cardiovascular drugs, including: angiotensin con active agents for treating ALS such as the anti-spastic agents verting enZyme (ACE) inhibitors such as enalapril, ramipril, baclofen, diaZemine, and tiZanidine; perindopril erbumine, 1-carboXymethyl-3-1-carboXy-3-phe nyl-(l S)-propylamino-2,3,4,5-tetrahydro-1H-(3S)-1-benZa [0088] nitrates and other anti-anginal agents, such as amyl Zepine-2-one, 3-(5-amino-1-carboXy-1S-pentyl)amino-2,3, nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide 4,5-tetrahydro-2-oXo-3S-1H-1-benZaZepine-1acetic acid or mononitrate and pentaerythritol tetranitrate; 3-(1-ethoXycarbonyl-3-phenyl-(1S)-propylamino)-2,3,4,5 [0089] neuroleptic drugs, including antidepressant drugs, tetrahydro-2-oXo-(3S)-benZaZepine-1-acetic acid monohy antimanic drugs, and antipsychotic agents, Wherein antide drochloride; cardiac glycosides and cardiac inotropes such pressant drugs include (a) the tricyclic antidepressants such as amrinone, digoXin, digitoXin, enoXimone, lanatoside C, as amoXapine, amitriptyline, clomipramine, desipramine, medigoXin, and milrinone; calcium channel blockers such as doXepin, imipramine, maprotiline, nortriptyline, protrip verapamil, nifedipine, nicardipene, felodipine, isradipine, tyline, and trimipramine, (b) the serotonin reuptake inhibi nimodipine, amlodipine and diltiaZem; beta-blockers such as tors citalopram, ?uoXetine, ?uvoXamine, paroXetine, sertra acebutolol, alprenolol, atenolol, labetalol, metoprolol, nad line, and venlafaXine, (c) monoamine oXidase inhibitors olol, oXyprenolol, pindolol, propafenone, propranolol, such as phenelZine, tranylcypromine, and (—)-selegiline, and esmolol, sotalol, timolol, and acebutolol; antiarrhythmics (d) other antidepressants such as aprepitant, bupropion, such as moriciZine, dofetilide, ibutilide, nesiritide, procaina duloXetine, gepirone, igmesine, lamotrigine, maprotiline, mide, quinidine, disopyramide, lidocaine, phenytoin, tocain mianserin, mirtaZapine, nefaZodone, rabalZotan, sunepitron, ide, meXiletine, ?ecainide, encainide, bretylium and amio traZodone and venlafaXine, and Wherein antimanic and darone; cardioprotective agents such as deXraZoXane and antipsychotic agents include (a) phenothiaZines such as leucovorin; vasodilators such as nitroglycerin; diuretic acetophenaZine, acetophenaZine maleate, chlorpromaZine, agents such as aZetaZolamide, amiloride, bendro?umethiaZ chlorpromaZine hydrochloride, ?uphenaZine, ?uphenaZine ide, bumetanide, chlorothiaZide, chlorthalidone, ethacrynic hydrochloride, ?uphenaZine enanthate, ?uphenaZine acid, furosemide, hydrochlorothiaZide, metolaZone, nesir decanoate, mesoridaZine, mesoridaZine besylate, perphena itide, spironolactone, and triamterine; and miscellaneous Zine, thioridaZine, thioridaZine hydrochloride, tri?uopera cardiovascular drugs such as monteplase and corlopam; Zine, and tri?uoperaZine hydrochloride, (b) thioXanthenes such as chlorprothiXene, thiothiXene, and thiothiXene hydro [0081] corticosteroids, such as beclomethasone, chloride, and (c) other heterocyclic drugs such as carbam betamethasone, budesonide, cortisone, desoXymethasone, aZepine, cloZapine, droperidol, haloperidol, haloperidol deXamethasone, ?udrocortisone, ?unisolide, ?uocortolone, decanoate, loXapine succinate, molindone, molindone ?uticasone propionate, hydrocortisone, methylprednisolone, hydrochloride, olanZapine, pimoZide, quetiapine, risperi prednisolone, prednisone and triamcinolone; done, and sertindole. [0082] erectile dysfunction drugs, such as apomorphine, [0090] nutritional agents, such as calcitriol, carotenes, phentolamine, and vardena?l; dihydrotachysterol, essential fatty acids, non-essential fatty acids, phytonadiol, vitamin A, vitamin B2, vitamin D, vita [0083] gastrointestinal agents, such as alosetron, bisa codyl, cilansetron, cimetidine, cisapride, diphenoXylate, min E and vitamin K. domperidone, esomepraZole, famotidine, granisetron, lanso [0091] opioid analgesics, such as alfentanil, apomorphine, praZole, loperamide, mesalaZine, niZatidine, omepraZole, buprenorphine, butorphanol, codeine, deXtropropoXyphene, ondansetron, prantopraZole, rabepraZole sodium, ranitidine, diamorphine, dihydrocodeine, fentanyl, hydrocodone, risperidone, sulphasalaZine, and tegaserod; hydromorphone, levorphanol, meperidine, meptaZinol, US 2003/0077297 A1 Apr. 24, 2003

methadone, morphine, nalbuphine, oXycodone, oXymor acid, amphotericin B, antihemophilic factor (human), anti phone, pentaZocine, propoXyphene, sufentanil, and trama hemophilic factor (porcine), antihemophilic factor (recom dol; binant), aprotinin, asparaginase, atenolol, atracurium besy [0092] stimulants, including active agents for treating nar late, atropine, aZithromycin, aZtreonam, BCG vaccine, colepsy, attention de?cit disorder (ADD) and attention de? bacitracin, becaplermin, belladona, bepridil hydrochloride, cit hyperactivity disorder (ADHD), such as amphetamine, bleomycin sulfate, calcitonin human, calcitonin salmon, deXamphetamine, deXfen?uramine, fen?uramine, maZindol, carboplatin, capecitabine, capreomycin sulfate, cefamandole methylphenidate (including d-threo-methylphenidate, or nafate, cefaZolin sodium, cefepime hydrochloride, ce?Xime, “deXmethylphenidate,” as Well as racemic d,l-threo-meth cefonicid sodium, cefoperaZone, cefotetan disodium, cefo ylphenidate), moda?nil, pemoline, and sibutramine. taXime, cefoXitin sodium, ceftiZoXime, ceftriaXone, cefuroXime aXetil, cephaleXin, cephapirin sodium, cholera [0093] Preferred hydrophobic active agents include, but vaccine, chorionic gonadotropin, cidofovir, cisplatin, are not limited to, acetretin, acetyl coenZyme Q, albenda Zole, albuterol, aminoglutethimide, amiodarone, amlo cladribine, clidinium bromide, clindamycin and clindamycin dipine, amphetamine, amphotericin B, atorvastatin, atova derivatives, cipro?oXacin, clodronate, colistimethate quone, aZithromycin, baclofen, beclomethasone, benaZepril, sodium, colistin sulfate, corticotropin, cosyntropin, cro benZonatate, betamethasone, bicalutanide, budesonide, molyn sodium, cytarabine, dalteparin sodium, danaparoid, bupropion, busulfan, butena?ne, calcifediol, calcipotriene, deferoXamine, denileukin diftitoX, desmopressin, diatriZoate calcitriol, camptothecin, candesartan, capsaicin, carbam meglumine and diatriZoate sodium, dicyclomine, eZepine, carotenes, celecoXib, cerivastatin, cetiriZine, chlo didanosine, dirithromycin, dopamine hydrochloride, dor rpheniramine, cholecalciferol, cilostaZol, cimetidine, cin nase alpha, doXacurium chloride, doXorubicin, etidronate nariZine, cipro?oXacin, cisapride, clarithromycin, disodium, enalaprilat, enkephalin, enoXaparin, enoXaprin clemastine, clomiphene, clomipramine, clopidogrel, sodium, ephedrine, epinephrine, epoetin alpha, erythromy codeine, coenZyme Q10, cyclobenZaprine, cyclosporin, cin, esmolol hydrochloride, factor IX, famciclovir, ?udara danaZol, dantrolene, deXchlorpheniramine, diclofenac, dicu bine, ?uoXetine, foscamet sodium, ganciclovir, granulocyte marol, digoXin, dehydroepiandrosterone, dihydroergota colony stimulating factor, granulocyte-macrophage stimu lating factor, recombinant human groWth hormone, bovine mine, dihydrotachysterol, dirithromycin, doneZepil, groWth hormine, gentamycin, glucagon, glycopyrolate, efavirenZ, eposartan, ergocalciferol, ergotamine, essential gonadotropin releasing hormone and synthetic analogs fatty acid sources, estradiol, etodolac, etoposide, famotidine, feno?brate, fentanyl, feXofenadine, ?nasteride, ?uconaZole, thereof, gonadorelin, grepa?oXacin, haemophilus B conju ?urbiprofen, ?uvastatin, fosphenytoin, frovatriptan, fura gate vaccine, hepatitis Avirus vaccine inactivated, hepatitis Zolidone, gabapentin, gem?broZil, glibenclamide, glipiZide, B virus vaccine inactivated, heparin sodium, indinavir sul glyburide, glimepiride, griseofulvin, halofantrine, ibupro fate, in?uenza virus vaccine, interleukin-2, interleukin-3, fen, irbesartan, irinotecan, isosorbide dinitrate, isotretinoin, insulin-human, insulin lispro, insulin procine, insulin NPH, itraconaZole, ivermectin, ketoconaZole, ketorolac, lamot insulin aspart, insulin glargine, insulin detemir, interferon rigine, lansopraZole, le?unomide, lisinopril, loperamide, alpha, interferon beta, ipratropium bromide, ifosfamide, loratadine, lovastatin, L-thyroXine, lutein, lycopene, Japanese encephalitis virus vaccine, lamivudine, leucovorin medroXyprogesterone, mifepristone, me?oquine, megestrol calcium, leuprolide acetate, levo?oXacin, lincomycin and acetate, methadone, methoXsalen, metronidaZole, micona lincomycin derivatives, lobucavir, lome?oXacin, loracarbef, Zole, midaZolam, miglitol, minoxidil, mitoXantrone, mon mannitol, measles virus vaccine, meningococcal vaccine, telukast, nabumetone, nalbuphine, naratriptan, nel?navir, menotropins, mepenZolate bromide, mesalamine, meth nifedipine, nisoldipine, nilutanide, nitro furantoin, niZati enamine, methotreXate, methscopolamine, metformin dine, omepraZole, oprevelkin, oXaproZin, paclitaXel, para hydrochloride, metoprolol, meZlocillin sodium, mivacurium calcitol, paroXetine, pentaZocine, pioglitaZone, piZofetin, chloride, mumps viral vaccine, nedocromil sodium, neostig pravastatin, prednisolone, probucol, progesterone, pseu mine bromide, neostigmine methyl sulfate, neurontin, nor doephedrine, pyridostigmine, rabepraZole, raloXifene, repa ?oXacin, octreotide acetate, o?oXacin, olpadronate, oXyto glinide, rifabutine, rifapentine, rimeXolone, ritanovir, riZa cin, pamidronate disodium, pancuronium bromide, triptan, rofecoXib, rosiglitaZone, saquinavir, sertraline, paroXetine, per?oXacin, pentamidine isethionate, pentosta sibutramine, sildena?l citrate, simvastatin, sirolimus, tin, pentoXifylline, penciclovir, pentagastrin, phentolamine spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, mesylate, phenylalanine, physostigmine salicylate, plague tamsulosin, targretin, taZarotene, telmisartan, teniposide, vaccine, piperacillin sodium, platelet derived groWth factor, terbina?ne, teraZosin, tetrahydrocannabinol, tiagabine, ticlo pneumococcal vaccine polyvalent, poliovirus vaccine (inac pidine, tiro?ban, tiZanidine, topiramate, topotecan, tivated), poliovirus vaccine live (OPV), polymyXin B sul toremifene, tramadol, tretinoin, troglitaZone, trova?oXacin, fate, pralidoXime chloride, pramlintide, pregabalin, pro ubidecarenone, valsartan, venlafaXine, vertepor?n, pafenone, propenthaline bromide, pyridostigmine bromide, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, rabies vaccine, risedronate, ribavirin, rimantadine hydro Za?rlukast, Zileuton, Zolmitriptan, Zolpidem, Zopiclone, and chloride, rotavirus vaccine, salmeterol Xinafoate, sincalide, combinations thereof. smallpox vaccine, solatol, somatostatin, spar?oXacin, spec tinomycin, stavudine, streptokinase, streptoZocin, suXam [0094] Preferred hydrophilic active agents that may be ethonium chloride, tacrine hydrochloride, terbutaline sul delivered using the method and formulations of the present fate, thiopeta, ticarcillin, tiludronate, timolol, tissue type invention include, Without limitation, acarbose, acyclovir, plasminogen activator, TNFRzFc, TNK-tPA, trandolapril, acetyl cysteine, acetylcholine chloride, alatro?oXacin, alen trimetreXate gluconate, trospectomycin, trova?oXacin, tub dronate, alglucerase, amantadine hydrochloride, ambeno ocurarine chloride, tumor necrosis factor, typhoid vaccine mium, amifostine, amiloride hydrochloride, aminocaproic live, urea, urokinase, vancomycin, valacyclovir, valsartan, US 2003/0077297 A1 Apr. 24, 2003

varicella virus vaccine live, vasopressin and vasopressin [0104] (8) combinations of anticoagulants, e.g., (a) a derivatives, vecuronium bromide, vinblastine, vincristine, salicylate and a platelet receptor binding inhibitor, vinorelbine, vitamin B12, Warfarin sodium, yellow fever such as aspirin and clopidogrel, (b) a salicylate and vaccine, Zalcitabine, Zanamivir, Zolendronate, Zidovudine, a loW molecular Weight heparin, such as aspirin and and combinations thereof. dalteparin, and (c) a platelet receptor binding inhibi tor and a loW molecular Weight heparin, such as [0095] Of course, certain active agents indicated as hydro clopidogrel and enoXaparin; phobic may be readily converted to and commercially available in hydrophilic form, e.g., by ionizing a non-ioniZed [0105] (9) combinations of antidiabetics, e.g., (a) an active agent so as to form a pharmaceutically acceptable, insulin sensitiZer and an insulin stimulant, such as pharmacologically active salt. Conversely, certain active a thiaZolidinedione such as glitaZone or pioglitaZone agents indicated as hydrophilic may be readily converted to and a sulfonylurea such as glimepiride, and (ii) a and commercially available in hydrophobic form, e.g., by biguanide such as metformin and a meglitinide such neutralization, esteri?cation, or the like. Thus, it should be as repaglinide, (b) an insulin sensitiZer and an ot-glu understood that the above categoriZation of certain active cosidase inhibitor, such as metformin and acarbose, agents as hydrophilic or hydrophobic is not intended to be (c) an insulin stimulant and an ot-glucosidase inhibi limiting. tor, such as a sulfonylurea such as glyburide [0096] Any of the aforementioned active agents may also combined With acarbose, (ii) acarbose and a megli be administered in combination using the present formula tinide such as repaglinide, (iii) miglitol and a sulfo tions. Active agents administered in combination may be nylurea such as glipiZide, or (iv) acarbose and a from the same therapeutic class (e.g., lipid-regulating agents thiaZolidinedione such as pioglitaZone; or anticoagulants) or from different therapeutic classes (e.g., [0106] (10) combinations of cardiovascular drugs, a lipid-regulating agent and an anticoagulant). Examples of such as combinations of ACE inhibitors, e.g., lisi particularly important drug combination products include, nopril and candesartan; a combination of an ACE but are not limited to: inhibitor With a diuretic agent such as losartan and [0097] (1) female contraceptive compositions con hydrochlorothiaZide; a combination of a calcium taining both a progestogen and an estrogen; channel blocker and a [3-blocker such as nifedipine and atenolol; and a combination of a calcium channel [0098] female HRT compositions containing a blocker and an ACE inhibitor such as felodipine and progestogen, an estrogen, and an androgen; ramipril; [0099] (3) combinations of lipid-regulating agents, e.g., (a) a ?brate and a statin, such as feno?brate and [0107] (11) combinations of an antihypertensive atorvastatin, feno?brate and simvastatin, feno?brate agent and an antidiabetic agent, such as an ACE and lovastatin, or feno?brate and pravastatin; (b) a inhibitor and a sulfonylurea, e.g., irbesartan and ?brate and nicotinic acid, such feno?brate and nia glipiZide; cin; and (c) a statin and a nicotinic acid, such as [0108] (12) combinations of antihistamines and anti lovastatin and niacin; asthmatic agents, e.g., an antihistamine and a leu [0100] (4) combinations of a lipid-regulating agent kotriene receptor antagonist such as loratadine and and an antiviral agent, e.g., a ?brate and a protease Za?rlukast, desloratidine and Za?rlukast, and cetira inhibitor, such as feno?brate and ritonavir; Zine and montelukast; [0101] (5) combinations of a lipid-regulating agent [0109] (13) combinations of antiin?ammatory agents and an anticoagulant, e.g., (a) a ?brate and a salicy and analgesics, e.g., a COX-2 inhibitor and a non late, such as feno?brate and aspirin, (b) a ?brate and steroidal antiin?ammatory agent (NSAID) such as another anticoagulant, such as feno?brate and clo rofecoXib and naproXen, or a COX-2 inhibitor and a pidogrel, (c) a statin and a salicylate, such as simv salicylate such as celecoXib and aspirin; astatin and aspirin, and (d) a statin and another anticoagulant such as pravastatin and clopidogrel; [0110] (14) combinations of an anti-obesity drug and an antidiabetic agent, e.g., a lipase inhibitor such as [0102] (6) combinations of a lipid-regulating agent orlistat in combination With metformin; and an antidiabetic agent, including (a) a ?brate and a insulin sensitiZer such as a thiaZolidinedione, e.g., [0111] (15) combinations of a lipid-regulating agent feno?brate and pioglitaZone, or feno?brate and and a drug for treating coronary artery disease, e.g., rosiglitaZone, (b) a ?brate and an insulin stimulant feno?brate and eZetimibe, or lovastatin and such as a sulfonylurea, e.g., feno?brate and glime eZetimibe; and piride, or feno?brate and glipiZide, a statin and and insulin sensitiZer such as a thiaZolidinedione, e.g., [0112] other combinations, such as docetaXel and lovastatin and pioglitaZone, simvastatin and rosigli cisplatin, tirapaZamine and cisplatin, metoclopra taZone, pravastatin and pioglitaZone, or the like; mide and naproXen sodium, an opioid analgesic such as oXycodone and an anti-in?ammatory agent, an [0103] (7) combinations of a lipid regulating agent agent for treating erectile dysfunction, such as and a cardiovascular drug, e.g., (a) a ?brate and a alprostadil, With an antihypertensive/vasodilator calcium channel blocker, such as feno?brate and such as praZosin. amlodipine, or feno?brate and irbesartan, or (b) a statin and a calcium channel blocker, such as fosi [0113] The aforementioned eXamples are merely illustra nopril and pravastatin; tive, and it must be emphasiZed that any given drug iden US 2003/0077297 A1 Apr. 24, 2003

ti?ed by structural or functional class may be replaced With [0118] III. Vehicle: another drug of the same structural or functional class. [0119] The vehicle of the present formulations and sys [0114] It should also be emphasized that When the formu tems is comprised of at least one compound selected from lations and systems of the invention contain more than one the group consisting of a hydrophilic surfactant, a lipophilic active agent, the requirement of the preferred embodiment surfactant, a triglyceride, and a solubiliZer. Such compounds herein that at least 20% of the active agent be solubiliZed provide the formulations and systems With any of several means, in this case, that at least 20% of only one active agent advantageous characteristics, including, but not limited to, need be solubiliZed. Additional active agent(s) present may (1) an increased amount of solubiliZed active agent available or may not be solubiliZed, i.e., they may be entirely con for immediate release, (2) improved physical and/or chemi tained in a suspended fraction of the formulation or system. cal stability of the active agent and/or formulation, (3) [0115] Any of the active agents may be administered in the enhanced in?ux of the active agent at the site of absorption by inhibition of the efflux pump, and (4) enhanced transport form of a salt, ester, amide, prodrug, active metabolite, isomer, analog, fragment, or the like, provided that the salt, of the active agent across membranes (e.g., cell membranes) ester, amide, prodrug, active metabolite, isomer, analog or or other transport barriers, i.e., an increased rate of transport, fragment, is pharmaceutically acceptable and pharmacologi an increase in the amount of active agent transported, or cally active in the present context. Salts, esters, amides, both, relative to formulations in Which less than 20 Wt. % of prodrugs, metabolites, analogs, fragments, and other deriva an active agent to be delivered is solubiliZed in a vehicle. tives of the active agents may be prepared using standard Additional advantages include improved dissolution of an procedures knoWn to those skilled in the art of synthetic active agent With respect to the extent and/or rate of disso organic chemistry and described, for example, by J. March, lution under a given condition (e.g., pH, temperature, etc.), Advanced Organic Chemistry: Reactions, Mechanisms and e.g., physiological conditions, and improved solubiliZation Structure, 4th Edition (NeW York: Wiley-Interscience, of the active agent released from the formulation upon dispersion in an aqueous medium, e.g., gastrointestinal ?uid 1992). (With respect to the equilibrium solubility and/or the degree [0116] For example, acid addition salts are prepared from of supersaturation in such aqueous media). a drug in the form of a free base using conventional [0120] The vehicle preferably exists as at least one liquid methodology involving reaction of the free base With an acid. Suitable acids for preparing acid addition salts include at a temperature of about 40° C. The liquid can be a monotropic solution or it can have a biphasic structure both organic acids, e.g., acetic acid, propionic acid, glycolic comprised of, for example, lamellar, cubic, hexagonal, acid, pyruvic acid, oxalic acid, malic acid, malonic acid, reversed hexagonal, micellar, and/or reversed micellar succinic acid, maleic acid, fumaric acid, tartaric acid, citric phases. When the vehicle is comprised of tWo or more acid, benZoic acid, cinnamic acid, mandelic acid, methane liquids, the liquids can be completely miscible, forming a sulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, single phase, or they can be partially miscible or completely salicylic acid, and the like, as Well as inorganic acids, e.g., immiscible, in Which case the vehicle is comprised of more hydrochloric acid, hydrobromic acid, sulfuric acid, nitric than tWo distinct phases. The liquid phase(s) in the vehicle acid, phosphoric acid, and the like. An acid addition salt may may consist entirely of the at least one compound noted be reconverted to the free base by treatment With a suitable base. Conversely, preparation of basic salts of acid moieties above, i.e., a hydrophilic surfactant, a lipophilic surfactant, a triglyceride, and/or a solubiliZer, or a liquid carrier may be that may be present on an active agent may be carried out in added to the aforementioned compound(s) to form the a similar manner using a pharmaceutically acceptable base vehicle. Any pharmaceutically acceptable liquid carrier may such as sodium hydroxide, potassium hydroxide, ammo nium hydroxide, calcium hydroxide, trimethylamine, or the be added, providing that in all cases, the vehicle is capable of solubiliZing a signi?cant fraction of the active agent in the like. Preparation of esters involves transformation of a formulation, i.e., at least 20 Wt. % of the total active agent. carboxylic acid group via a conventional esteri?cation reac tion involving nucleophilic attack of an R0‘ moiety at the [0121] A. Surfactants: carbonyl carbon. Esteri?cation may also be carried out by [0122] Hydrophilic surfactants can be used to provide any reaction of a hydroxyl group With an esteri?cation reagent of several advantageous characteristics to the compositions, such as an acid chloride. Esters can be reconverted to the including: increased solubility of the active agent in the free acids, if desired, by using conventional hydrogenolysis vehicle; improved dissolution of the suspended active agent; or hydrolysis procedures. Amides may be prepared from improved solubiliZation of the active agent upon dissolution; esters, using suitable amine reactants, or they may be enhanced absorption and/or bioavailability of the active prepared from an anhydride or an acid chloride by reaction agent; and improved stability, both physical and chemical, of With ammonia or a loWer alkyl amine. Prodrugs and active the active agent. The hydrophilic surfactant can be a single metabolites may also be prepared using techniques knoWn to hydrophilic surfactant or a mixture of hydrophilic surfac those skilled in the art or described in the pertinent literature. tants, and can be ionic or non-ionic. Prodrugs are typically prepared by covalent attachment of a [0123] LikeWise, various embodiments of the invention moiety that results in a compound that is therapeutically include a lipophilic component, Which can be a lipophilic inactive until modi?ed by an individual’s metabolic system. surfactant, a triglyceride, or a mixture thereof. The lipophilic [0117] Other derivatives and analogs of the active agents surfactant and triglyceride can provide any of the advanta may be prepared using standard techniques knoWn to those geous characteristics listed above for hydrophilic surfac skilled in the art of synthetic organic chemistry, or may be tants. These various embodiments are described in more deduced by reference to the pertinent literature. In addition, detail beloW. For convenience, the surfactants are described chiral active agents may be in isomerically pure form, or in this section, and the triglycerides in the section that they may be administered as a racemic mixture of isomers. folloWs. US 2003/0077297 A1 Apr. 24, 2003

[0124] As is Well known in the art, the terms “hydrophilic” typically do, have different HLB values. In addition, a and “lipophilic” are relative terms. To function as a surfac certain amount of lot-to-lot variability is expected, even for tant, a compound must necessarily include polar or charged a single commercial surfactant product. Keeping these hydrophilic moieties as Well as non-polar hydrophobic (lipo inherent difficulties in mind, and using HLB values as a philic) moieties; i.e., a surfactant compound must be guide, one skilled in the art can readily identify surfactants amphiphilic. An empirical parameter commonly used to having suitable hydrophilicity or lipophilicity for use in the characteriZe the relative hydrophilicity and lipophilicity of present invention, as described herein. non-ionic amphiphilic compounds is the hydrophilic-lipo [0127] Surfactants can be any surfactant suitable for use in philic balance (the “HLB” value). Surfactants With loWer pharmaceutical compositions. Suitable surfactants can be HLB values are more lipophilic, and have greater solubility in oils, Whereas surfactants With higher HLB values are anionic, cationic, ZWitterionic, or non-ionic. Such surfac tants can be grouped into the folloWing general chemical more hydrophilic, and have greater solubility in aqueous classes detailed in the Tables herein. The HLB values given solutions. in the Tables beloW generally represent the HLB value as [0125] Using HLB values as a rough guide, hydrophilic reported by the manufacturer of the corresponding commer surfactants are generally considered to be those compounds cial product. In cases Where more than one commercial having an HLB value greater than about 10, as Well as product is listed, the HLB value in the Tables is the value as anionic, cationic, or ZWitterionic compounds for Which the reported for one of the commercial products, a rough aver HLB scale is not generally applicable. Similarly, lipophilic age of the reported values, or a value that, in the judgment surfactants are compounds having an HLB value less than of the present inventors, is more reliable. about 10. [0128] It should be emphasiZed that the invention is not [0126] It should be appreciated that the HLB value of a limited to the surfactants in the Tables, Which shoW repre surfactant is merely a rough guide used to enable the sentative, but not exclusive, lists of available surfactants. In formulation of industrial, pharmaceutical, and cosmetic addition, re?ned, distilled, or fractionated surfactants, puri emulsions. For many important surfactants, including sev ?ed fractions thereof, or re-esteri?ed fractions, are also eral polyethoxylated surfactants, it has been reported that Within the scope of the invention, although not speci?cally HLB values can differ by as much as about 8 HLB units, listed in the Tables. depending upon the empirical method chosen to determine [0129] Polyethoxylated Fatty Acids: the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Likewise, for certain polypropylene oxide contain [0130] Although polyethylene glycol (PEG) itself does not ing block copolymers (poloxamers, available commercially function as a surfactant, a variety of PEG-fatty acid esters as PLURONIC® surfactants, BASF Corp.), the HLB values have useful surfactant properties. Among the PEG-fatty acid may not accurately re?ect the true physical and chemical monoesters, esters of lauric acid, oleic acid, and stearic acid nature of the compounds. Finally, commercial surfactant are especially useful. Among the surfactants of Table 2, products are generally not pure compounds, but are often preferred hydrophilic surfactants include PEG-8 laurate, complex mixtures of compounds, and the HLB value PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 lau reported for a particular compound may more accurately be rate, PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG characteristic of the commercial product of Which the com 15 oleate, PEG-20 laurate and PEG-20 oleate. Examples of pound is a major component. Different commercial products polyethoxylated fatty acid monoester surfactants commer having the same primary surfactant component can, and cially available are shoWn in Table 1.

TABLE 1

PEG-Fatty Acid Monoester Surfactants

COMPOUND COMMERCIAL PRODUCT (Supplier) HLB

PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG 4-100 monooleate Crodet O series (Croda) >8 PEG 4-100 monostearate Crodet S series (Croda), Myrj Series (Atlas/ICI) >6 PEG 400 distearate Cithrol 4DS series (Croda) >10 PEG 100,200,300 Cithrol ML series (Croda) >10 monolaurate PEG 100,200,300 Cithrol MO series (Croda) >10 monooleate PEG 400 dioleate Cithrol 4DO series (Croda) >10 PEG 400-1000 Cithrol MS series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster K1 (Condea) 2 PEG-2 stearate Nikkol MYS-Z (Nikko) 4 PEG-2 oleate Nikkol MYO-Z (Nikko) 4.5 PEG-4 laurate Mapeg ® 200 ML (PPG), Kessco ® PEG 200 ML (Stepan), LIPOPEG 2L 9.3 (Lipo Chem.) PEG-4 oleate Mapeg ® 200 MO (PPG), Kessco ® PEG200 MO (Stepan), 8.3 PEG-4 stearate Kessco ® PEG 200 MS (Stepan), Hodag 20 S (Calgene), Nikkol MYS-4 6.5 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleate Nikkol TMGO-S (Nikko) 9.5