US 2003OO77297A1 (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, filed 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, filed on Mar. 6, 2001, which is a division AGENTS of application No. 09/447,690, filed on Nov. 23, 1999, now Pat. No. 6,248,363. (76) Inventors: Feng-Jing Chen, Salt Lake City, UT (US); Srinivasan Venkateshwaran, Publication Classification Salt Lake City, UT (US); Steven L. (51) Int. CI.7. A61K 9/00 Krill, Park City, UT (US); Mahesh V. Patel, Salt Lake City, UT (US) (52) U.S. Cl...... 424/400 Correspondence Address: REED & ASSOCATES (57) ABSTRACT 800 MENLO AVENUE The present invention pertains to pharmaceutical formula SUTE 210 tions and Systems for delivery of active agents, wherein a MENLO PARK, CA 94025 (US) first 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 U.S. 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 first and Second fractions of the active filed on Jul. 2, 2001, which is a continuation of agent may or may not have different release profiles. Gen application No. 09/258,654, filed on Feb. 26, 1999, erally, a significant 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, filed 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 of 7

Patent Application Publication Apr. 24, 2003. Sheet 2 of 7 US 2003/0077297 A1

Patent Application Publication Apr. 24, 2003. Sheet 3 of 7 US 2003/0077297 A1

FIG. 3A FIG. 3B

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

0.20 -O-Formulation of Example 13

0.16 -- Accutane"

0.2

0.08

0.04

0.00 O 30 60 90 120 150 Time (min) FIG. 6

-o-Tricor” ... O -- Formulation of Example 14 (n=3)

O 20 40 60 8O 100 120 Time (min)

FIG. 7

Patent Application Publication Apr. 24, 2003 Sheet 6 of 7 US 2003/0077297 A1

Dissolution of from Capsule Dosage Forms USP Apparatus 100 rpm, 1000 ml SGF+12.5 mMSLS, -Suspension of Example 37, 100 mg Progesterone, n=2 100% Prometrium(Solvay), 100 mg Progesterone, n=3

90%

80% 845% 8.34%

70%

60%

50%

40%

30%

20%

10%

-44%. ------28% 15 Timehr)

F.G. 10 Patent Application Publication Apr. 24, 2003 Sheet 7 of 7 US 2003/0077297 A1

Single Dose Progesterone; Randomized 2X2 Cross-Over Mean-SEM, n=12 subjects

3 5

O O 23. A -o-Formulation of Example 37, 50 mg Progesterone, 50 mg (Example 49) \ —e - Prometrium', 100 mg 2 15 10 - 5 0 de -— - E ===== 0 2 4 6 8 0 1 2 4 16 18 20 22 24 Time (h)

FIG. 11A

-O-Formulation of Example 37 -e-Prometrium

1 O

O 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 . 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 U.S. the increased Solubility of hydrophobic therapeutic agents in patent application Ser. No. 09/898,553, filed Jul. 20, 2001, lipids, particularly oils, i.e., triglycerides. However, tradi which is a continuation of U.S. patent application Ser. NoS. tional lipid-based formulations are generally limited by a 09/258,654, 09/258,654, filed Feb. 26, 1999, which issued low drug loading capacity, which in turn precludes delivery on Sep. 25, 2001 as U.S. 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 U.S. patent application Single unit dosage form, a significant drawback in terms of Ser. No. 09/877,541, filed Jun. 8, 2001, which is a continu patient compliance. For example, the administration of ation-in-part of U.S. patent application Ser. No. 09/345,615, Vitamins typically requires multiple dosage units, as does the filed Jun. 30, 1999, issued on Jul. 31, 2001 as U.S. Pat. No. administration of a number of pharmacologically active 6,297,985. This application is also a continuation-in-part of agents (e.g., and various other antiviral agents). Furthermore, the properties of oil-based formulations are U.S. patent application Ser. No. 09/800,593, filed Mar. 6, determined by Such factors as the size of the triglyceride/ 2001, which is a divisional of U.S. patent application Ser. therapeutic agent colloidal particles and the presence or No. 09/447,690, filed Nov. 23, 1999, issued on Jun. 19, 2001 absence of Surfactant additives. Although triglyceride-based as U.S. Pat. No. 6,248,363. The disclosures of the afore pharmaceutical compositions are useful in Solubilizing and mentioned patent applications are incorporated by reference delivering Some hydrophobic therapeutic agents, Such com herein. positions are Subject to a number of Significant limitations and disadvantages. Emulsions are thermodynamically TECHNICAL FIELD unstable, and colloidal emulsion particles will Spontane 0002 The present invention relates generally to the field ously agglomerate, eventually leading to complete phase of drug delivery. More Specifically, 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 fields 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 fields 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 professionals 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 difficult 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 fluids and intestinal fluids. 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 emulsified 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 difficult 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 ficient to provide efficient 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, Significant 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 unique drug release profiles, e.g., immediate release com are degraded before they can be presented to the absorption 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) Significantly 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 ''Journal of Controlled Release 52:1-16). 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 define 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 23:163-183). However, the effectiveness of absorption Viding any of a variety of drug release profiles, e.g., rapid enhancerS Such as permeability enhancers or enzyme inhibi tors depends upon the ability of a pharmaceutical carrier to onset coupled with rapid apparent elimination, and rapid effectively present the absorption enhancers and the hydro onset coupled with a longer duration of action. 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 efficiently. formulation is provided in which a first 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 briefly maintained, may be first 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(R) (Solvay), an encapsulated formulation of a triglyceride and a Solubilizer, and is preferably comprised micronized progesterone for oral administration, Accutane(R) 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 Proverace range of about 0.1 um to about 100 um, 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 nificant 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 first and second fractions of the active agent many types of drugs, these are significant limitations. may or may not have different release profiles. Generally, however, a significant 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 Significant 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 specifically 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 profile 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 profile 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 0.014. In the aforementioned embodiment, the first and tion provides a pharmaceutical Suspension in which a Sig Second fractions of the active agent may be physically nificant 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 first 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 when the Second fraction is in particulate form, a coating on 0019 FIG. 1 schematically various embodiments of the the one or more larger dosage units when the Solid particles invention wherein the pharmaceutical formulation, includ are associated with each other to form Such dosage units, ing both the Suspended and Solubilized fractions of active e.g., granules, pellets, beads, or tablets, or a coating on a agent, are included in a single dosage form. The Shaded capsule when the Solid particles of the Second fraction are regions represent the Solubilized fractions of the formula 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 first 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 first rated into different dosage forms. Again, the Shaded regions region that contains the first 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. 0.015. 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 Sufficient 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 cal System is provided for administration of an active agent, which may contain solubilized drug and the other of which 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 first 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(E), a commercially available isotretinoin 0.017. 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 fenofibrate formulation of Example 14 pharmaceutical System of a) a therapeutically effective and a commercially available fenofibrate product, Tricor(R). 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 fenofibrate formulation of Example 15 wherein the relative amounts of the active agent and the and a commercially available fenofibrate product, Tricor(R). vehicle are Such that upon admixture thereof, a first 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, fenofibrate 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(E). prevention of a particular disorder or adverse physiological 0029 FIGS. 11A and 11B are graphs illustrating the event in a Susceptible individual as well as treatment of a results of the in vivo absorption tests described in Example clinically Symptomatic individual by inhibiting or causing 50 for the progesterone formulation of Example 37 and a regression of a disorder or disease. commercially available progesterone Suspension, 0037. By an “effective” amount or a “therapeutically Prometrium(E). effective amount of an active agent is meant a nontoxic but Sufficient 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. Definitions and Overview: and the like. Thus, it is not always possible to specify an 0031. It is to be understood that unless otherwise indi exact “effective amount.” However, an appropriate “effec cated, this invention is not limited to specific active agents, tive” amount in any individual case may be determined by vehicles, excipients, dosage forms, or the like, as Such may one of ordinary skill in the art using routine experimentation 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 specification 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 definitions 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 beneficial 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 ological condition. The terms also encompass pharmaceu 0039 The term “multistage release” refers to a drug tically acceptable, pharmacologically active derivatives of containing formulation or System wherein Some of the drug those active agents Specifically mentioned herein, including, is released according to a first release profile (e.g., imme but not limited to, Salts, esters, amides, prodrugs, active diate release), and the remainder of the drug is released metabolites, isomers, fragments, analogs, and the like. When according to one or more different release profiles (e.g., the terms “active agent,”“pharmacologically active agent' Sustained release and/or delayed release as defined below). and "drug” are used, then, or when a particular active agent “Pulsatile release” is a form of multistage release wherein is specifically identified, it is to be understood that applicants discrete pulses of drug are released over an extended time intend to include the active agent perse as well as pharma period. 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 defined in active agent Sufficient 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 Ed. (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 efficient manner without 0041) The term “sustained release” (synonymous with Overdosing will vary with the characteristics of the particular “extended release”) is used in its conventional Sense to refer active agent, including both its pharmacological character 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, 0.036 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 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, macrollides, 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, , nutritional oils, parasympatholytic tions are enterically coated compositions. agents, Sedatives, SeX hormones, Sympathomimetic agents, 0043. The term “polymer” as used herein refers to a tranquilizers, vasodilators, Vitamins, and combinations molecule containing a plurality of covalently attached thereof. Active agents that may be administered according to monomer units, and includes branched, dendrimeric and Star the invention also include nutrients, cosmeceuticals, diag polymers as well as linear polymers. The term also includes nostic agents, and nutritional agents. Some agents, as will be both homopolymers and copolymers, e.g., random copoly appreciated by those of ordinary skill in the art, and as may mers, block copolymers and graft copolymers, as well as be deduced from the discussion below, are encompassed by 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 0.045 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 first 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 first fraction Suspended in a vehicle, and the remaining, Second fraction Solubilized in the vehicle. The first 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 classified detail below. as hydrophobic include HMG CoA reductase inhibitors such 0046 II. The Active Agent: as atorvastatin, , fluvastatin, 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 bezafibrate, beclobrate, binifibrate, ciprofibrate, clinofibrate, not limited, as the invention enables the effective delivery of clofibrate, clofibric acid, eZetimibe, etofibrate, fenofibrate, a wide variety of active agents. Therefore, the active agent fenofibric acid, gemfibrozil, nicofibrate, pirifibrate, probu administered may be selected from any of the various col, ronifibrate, Simfibrate, and theofibrate. 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 fenofibrate. 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, agents, antigout agents, antihelminthic gens), estrogens, and combinations thereof. Progestins agents, antihistamines, antihypertensive agents, antiinflam 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 (17O-ethinyl testosterone), ethynodiol diacetate, Sonism agents, antiprotozoal agents, antipruritics, antipsy flurogestone 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 deficit disorder (ADD) and attention lynestrenol, medrogestone, medroxyprogesterone acetate, deficit 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, normethisterone, progesterone, and trimge interferon alpha, lamivudine, nelfinavir, , ribavi Stone. Also included within this general class are estrogens, rin, rimantadine, ritonavir, Saquinavir, Stavudine, tipranavir, e.g.: estradiol (i.e., 1,3,5-estratriene-3,17B-diol, or “17B Valganciclovir, Zalcitabine, and Zidovudine, and other anti estradiol) and its esters, including estradiol benzoate, val Viral agents Such as abacavir, , interferon alpha, erate, cypionate, heptanoate, decanoate, acetate and diac nelfinavir, ribavirin, rimantadine, tipranavir, urSOdeoxy etate, 17a-estradiol; (i.e., 17o 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, recombinantly produced, and/or produced by and its esters and derivatives, including estrone acetate, biochemical (e.g., enzymatic) fragmentation of larger mol estrone Sulfate, and piperazine estrone Sulfate; quinestrol; ecules, and may contain the native Sequence or an active meStranol; and conjugated equine estrogens. In many con fragment thereof. Specific peptidyl drugs include, without texts, e.g., in female contraception and in hormone replace limitation, the peptidyl hormones activin, amylin, angio ment therapy (HRT), a combination of a progestin and tensin, atrial natriuretic peptide (ANP), calcitonin, calcitonin estrogen is used, e.g., progesterone and 17 B-estradiol. For gene-related peptide, calcitonin N-terminal flanking 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 hormone, ACTH), corticotropin-releasing fac example, (DHEA, also termed tor (CRF or CRH), epidermal growth factor (EGF), follicle “'), Sodium dehydroepiandrosterone Sulfate, 4-di Stimulating hormone (FSH), gastrin, gastrin inhibitory hydrotestosterone (DHT; also termed “stanolone”), and tes peptide (GIP), gastrin-releasing peptide, gonadotropin-re tosterone, and pharmaceutically 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-melano cypionate, phenylacetate, acetate, isobutyrate, buciclate, cyte-Stimulating hormone, B-melanocyte-stimulating hor heptanoate, decanoate, undecanoate, caprate and isocaprate mone, Y-melanocyte-stimulating hormone, melatonin, moti eSterS. lin, oxytocin (pitocin), pancreatic polypeptide, parathyroid 0.052 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, somatotropin (growth hormone, GH), agents include, but are not limited to, androsterone, andros Somatostatin (SIF, growth hormone-release inhibiting factor, terone acetate, androsterone propionate, androsterone ben GIF), thyrotropin (thyroid-stimulating hormone, TSH), thy Zoate, , 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, , ethyleStrenol, Oxandrolone, nan heparin binding neurotrophic factor (HBNF), interferon-a, drolone phenpropionate, nandrolone decanoate, nandrolone interferon C-2a, interferon C-2b, interferon C.-n3, interferon furylpropionate, nandrolone cyclohexane-propionate, nan B, etc., interleukin-1, interleukin-2, interleukin-3, interleu drolone benzoate, nandrolone cyclohexanecarboxylate, kin-4, interleukin-5, interleukin-6, etc., tumor necrosis fac tor, tumor necrosis factor-O, granuloycte colony-stimulating Stanozolol, dromoStanolone, and dromoStanolone propi factor (G-CSF), granulocyte-macrophage colony-stimulat Onate. ing factor (GM-CSF), macrophage colony-stimulating fac 0.053 Antihypertensive agents include, without limita tor, midkine (MD), and thymopoietin. Still other peptidyl tion, , benazepril, benidipine, candesartan, cap drugs that can be advantageously delivered using the meth topril, , darodipine, dilitaZem, diaZOxide, dox odology and formulations of the present invention include aZosin, enalapril, epleronone, epoSartan, , endorphins (e.g., dermorphin, dynorphin, C.-endorphin, fenoldopam, fosinopril, guanabenz, iloprost, irbesartan, isra f-endorphin, Y-endorphin, O-endorphin, Leulenkephalin, dipine, lercardinipine, lisinopril, losartan, minoxidil, nebiv Metlenkephalin, Substance P), kinins (e.g., bradykinin, olol, , , nimodipine, , Oma potentiator B, bradykinin potentiator C, kallidin), LHRH patrilat, phenoxybenzamine, praZosin, quinapril, , analogues (e.g., buserelin, deslorelin, fertirelin, goserelin, Semotiadil, SitaXSentan, teraZosin, , and Valsartan. histrelin, leuprolide, lutrelin, nafarelin, tryptorelin), and the coagulation factors, Such as C.-antitrypsin, C-macroglobu 0.054 Anti-diabetic agents include, by way of example, lin, antithrombin III, factor I (fibrinogen), factor II (pro acetohexamide, chlorpropamide, , farglitazar, thrombin), factor III (tissue prothrombin), factor V (proac glibenclamide, gliclazide, glipizide, glucagon, glyburide, celerin), factor VII (proconvertin), factor VIII glymepiride, miglitol, pioglitaZone, nateglinide, pimage (antihemophilic globulin or AHG), factor IX (Christmas dine, repaglinide, rosiglitaZone, tolaZamide, tolbutamide, factor, plasma thromboplastin component or PTC), factor X triampterine, and . (Stuart-Power factor), factor XI (plasma thromboplastin 0.055 Antiviral agents that can be delivered using the antecedent or PTA), factor XII (Hageman factor), heparin present methods and dosage forms include the antiherpes cofactor II, kallikrein, plasmin, plasminogen, prekallikrein, agents acyclovir, famciclovir, foScarnet, ganciclovir, idoxu protein C, protein S, and thrombomodulin and combinations ridine, Sorivudine, trifluridine, Valacyclovir, and Vidarabine, thereof. and otherantiviral agents Such as abacavir, amantadine, 0057 Genetic material may also be delivered using the amprenavir, delviridine, didanosine, , indinavir, present methods and formulations, including, for example, US 2003/0077297 A1 Apr. 24, 2003

nucleic acids, RNA, DNA, recombinant RNA, recombinant tirapazamine, topotecan, toremifene citrate, Vitamin A, Vita DNA, antisense RNA, antisense DNA, ribozymes, ribooli min A derivatives, and Zacopride; gonucleotides, deoxyribonucleotides, antisense ribooligo nucleotides, and antisense deoxyribooligonucleotides. Rep 0066 anti-coagulants and other agents for preventing and treating Stroke, Such as ciloStaZol, citicoline, clopidogrel, resentative genes include those encoding for Vascular cromafiban, deXanabinol, dicumarol, dipyridamole, nicou endothelial growth factor, fibroblast growth factor, Bcl-2, malone, oprelvekin, perindopril erbumine, phenindione, cystic fibrosis transmembrane regulator, nerve growth fac ramipril, repinotan, ticlopidine, tirofiban, and heparin, tor, human growth factor, erythropoietin, tumor necrosis including heparin Salts formed with organic or inorganic factor, and interleukin-2, as well as histocompatibility genes bases, and low molecular weight heparin, i.e., heparin frag Such as HLA-B7. ments generally having a weight average molecular weight 0.058 Other therapeutic agents that can be delivered in the range of about 1000 to about 10,000 D and exempli using the present methods and formulations include the fied by enoxaparin, dalteparin, danaproid, gammaparin, following representative compounds: nadroparin, ardeparin, tinzaparin, certoparin, and reviparin; 0059 anti-inflammatory agents and non- analge 0067 anti-diabetics, such as acetohexamide, chlorpropa Sics, Such as aloxiprin, auranofin, azapropaZone, azathio mide, farglitazar, glibenclamide, gliclazide, glipizide, glime prine, benorylate, butorphenol, capsaicin, celecoxib, piride, miglitol, nateglinide, pimagedine, pioglitaZone, repa diclofenac, diflunisal, eSonarimod, etodolac, fenbufen, feno glinide, rosiglitaZone, tolaZamide, tolbutamide, troglitaZone, profen calcium, flurbiprofen, ibuprofen, indomethacin, keto and Voglibose, profen, ketorolac, leflunomide, meclofenamic acid, mefe 0068 anti-epileptics, Such as beclamide, , namic acid, nabumetone, naproxen, novantrone, Oxaprozin, , ethotoin, felbamate, foSphenytoin, lamotrigine, OxyphenbutaZone, parecoxib, phenylbutaZone, piclamilast, methoin, methSuximide, methylphenobarbitone, Oxcarba piroXicam, rofecoxib, ropivacaine, Sulindac, tetrahydrocan Zepine, paramethadione, phenacemide, phenobarbitone, nabinol, tramadol, tromethamine, Valdecoxib, and , phensuXimide, primidone, Sulthiame, tiagabine, Ziconotide, as well as the urinary analgesics phenaZopyri topiramate, Valproic acid, and vigabatrin; dine and tolterodine, 0069 anti-fungal agents, such as amphotericin, buten 0060 anti-angina agents, such as mibefradil, refludan, afine, butoconazole nitrate, , econazole nitrate, nahnefene, carvedilol, cromafiban, lamifiban, fasudil, rano fluconazole, flucytosine, , itraconazole, keto lazine, tedisamil, nisoldipine, and tizanidine, conazole, miconazole, natamycin, nystatin, Sulconazole 0061 antihelminthics, such as albendazole, bephenium nitrate, Oxiconazole, terbinafine, , tioconazole hydroxynaphthoate, cambendazole, dichlorophen, ivermec and undecenoic acid; tin, mebendazole, oxaminiquine, Oxfendazole, OXantel 0070 anti-gout agents, such as allopurinol, probenecid embonate, praziquantel, pyrantel embonate and thiabenda and Sulphin-pyrazone, Zole; 0071 antihistamines and allergy medications, such as 0.062 anti-arrhythmic agents, Such as , dis acrivastine, astemizole, chlorpheniramine, cinnarizine, ceti opyramide, flecainide acetate and quinidine Sulfate; rizine, clemastine, cyclizine, cyproheptadine, desloratadine, deXchlorpheniramine, dimenhydrinate, diphenhydramine, 0.063 anti-asthma agents, such as Zileuton, , epinastine, feXofenadine, flunarizine, , , terbutaline Sulfate, montelukast, and albuterol; mizolastine, , and terfenadine, 0.064 anti-bacterial agents, Such as alatrofloxacin, azithromycin, baclofen, benethamine penicillin, cinoxacin, 0072 anti-malarials, Such as amodiaquine, chloroquine, ciprofloxacin, clarithromycin, clofazimine, cloxacillin, chlorproguanil, halofantrine, mefloquine, proguanil, demeclocycline, dirithromycin, doxycycline, , pyrimethamine and quinine Sulfate; ethionamide, furazolidone, grepafloxacin, imipenem, leVof 0073 agents for treating headaches, including anti-mi loxacin, lorefloxacin, moxifloxacin, nalidixic acid, nitro graine agents, Such as almotriptan, butorphanol, dihydroer furantoin, norfloxacin, ofloxacin, , rifabutine, rifa gotamine, dihydroergotamine meSylate, eletriptan, ergota pentine, Sparfloxacin, Spiramycin, Sulphabenzamide, mine, froVatriptan, methySergide, naratriptan, pizotyline, Sulphadoxine, Sulphamerazine, Sulphacetamide, Sulphadiaz rizatriptan, Sumatriptan, tonaberstat, and Zolmitriptan; ine, Sulphafurazole, Sulphamethoxazole, Sulphapyridine, tet racycline, trimethoprim, trovafloxacin, and Vancomycin; 0074 anti-muscarinic agents, Such as , ben ZheXol, biperiden, ethopropazine, hyoscyamine, mepen 0065 anti-cancer agents and immunosuppressants, Such Zolate bromide, oxyphencyclimine, Scopolamine, and tropi as alitretinoin, aminoglutethimide, amsacrine, anastrozole, camide; aZathioprine, beXaroteine, bicalutamide, biricodar, bisant rene, buSulfan, camptothecin, candoXatril, capecitabine, cyt 0075 anti-protozoal agents, such as atovaquone, ben arabine, chlorambucil, cycloSporin, dacarbazine, decitabine, Znidazole, clioquinol, decoquinate, diiodohydroxyquinoline, ellipticine, estramustine, etoposide, gemcitabine, irinotecan, diloxanide furoate, dinitolmide, furazolidone, metronida lasofoXifene, letrozole, lomustine, melphalan, mercaptopu Zole, nimorazole, nitrofiraZone, ornidazole and tinidazole; rine, methotrexate, mitomycin, mitotane, mitoxantrone, 0076 anti-thyroid agents, such as carbimazole, parical mofetil, mycophenolate, nebivolol, nilutamide, , citol, and propylthiouracil; palonosetron, procarbazine, ramipril, rubitecan, , , , tenipoSide, testolactone, thalidomide, 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 tazaroteine; mal, chlordiazepoxide, chlormethiazole, , 0085 lipid regulating agents, Such as atorvastatin, beZafi chlorprothixene, clonazepam, clobazam, clotiazepam, brate, cerivastatin, ciprofibrate, clofibrate, eZetimibe, fenofi clozapine, dexmethylphenidate (d-threo-methylphenidate) brate, fluvastatin, gemfibrozil, pitavastatin, pravastatin, , droperidol, ethinamate, flunanisone, fluni trazepam, triflu promazine, flupenthixol decanoate, probucol, rosuvastatin, and Simvastatin; fluphenazine, , gabapentin, , 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, modafinil, 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, neotrofin, 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 fluoxetine 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, , phentermine, combination), lysuride, pergolide, pramipexole, rasagiline, and topiramate; , 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-(1S)-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-1 acetic 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 , amitriptyline, clomipramine, desipramine, medigoxin, and milrinone, calcium channel blockerS Such as doxepin, , maprotiline, nortriptyline, protrip , nifedipine, nicardipene, felodipine, isradipine, tyline, and trimipramine, (b) the Serotonin reuptake inhibi nimodipine, amlodipine and diltiazem; beta-blockerS Such as tors citalopram, fluoxetine, fluvoxamine, 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, dolfetilide, ibutilide, neSiritide, procaina dulloxetine, gepirone, igmesine, lamotrigine, maprotiline, mide, quinidine, disopyramide, lidocaine, phenytoin, tocain mianserin, mirtazapine, , rabalzotan, Sunepitron, ide, mexiletine, flecainide, 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, , bendroflumethiaz chlorpromazine hydrochloride, fluphenazine, fluphenazine ide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic hydrochloride, fluphenazine enanthate, fluphenazine acid, , hydrochlorothiazide, metolaZone, neSir decanoate, mesoridazine, mesoridazine beSylate, perphena itide, , and triamterine; and miscellaneous Zine, thioridazine, thioridazine hydrochloride, trifluopera cardiovascular drugs. Such as monteplase and corlopam, Zine, and trifluoperazine hydrochloride, (b) thioxanthenes Such as chlorprothixene, thiothixene, and thiothixene hydro 0.081 corticosteroids, such as beclomethasone, chloride, and (c) other heterocyclic drugs. Such as carbam betamethasone, budeSonide, cortisone, desoxymethasone, aZepine, clozapine, droperidol, haloperidol, haloperidol , fludrocortisone, flunisolide, fluocortolone, decanoate, loxapine Succinate, molindone, molindone fluticasone propionate, hydrocortisone, , hydrochloride, olanzapine, pimozide, quetiapine, risperi , prednisone and triamcinolone, done, and Sertindole. 0082) erectile dysfunction drugs, such as apomorphine, 0090 nutritional agents, such as calcitriol, carotenes, phentolamine, and Vardenafil; dihydrotachysterol, essential fatty acids, non-essential fatty 0.083 gastrointestinal agents, Such as alosetron, bisa acids, phytonadiol, Vitamin A, Vitamin B, Vitamin D, Vita 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, , buprenorphine, butorphanol, , dextropropoxyphene, Ondansetron, prantoprazole, rabeprazole Sodium, ranitidine, diamorphine, dihydrocodeine, , hydrocodone, risperidone, SulphaSalazine, and tegaSerod; hydromorphone, , meperidine, meptaZinol, US 2003/0077297 A1 Apr. 24, 2003 methadone, , 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 deficit disorder (ADD) and attention defi bacitracin, becaplermin, belladona, bepridil hydrochloride, cit hyperactivity disorder (ADHD), Such as amphetamine, bleomycin Sulfate, calcitonin human, calcitonin Salmon, deXamphetamine, dexfenfluramine, fenfluramine, mazindol, carboplatin, capecitabine, capreomycin Sulfate, cefamandole methylphenidate (including d-threo-methylphenidate, or nafate, cefazolin Sodium, cefepime hydrochloride, cefixime, “dexmethylphenidate,” as well as racemic d.l-threo-meth cefonicid Sodium, cefoperaZone, cefotetan disodium, cefo ylphenidate), modafinil, pemoline, and Sibutramine. taxime, cefoXitin Sodium, ceftizoxime, ceftriaxone, 0.093 Preferred hydrophobic active agents include, but cefuroxime axetil, cephalexin, cephapirin Sodium, cholera are not limited to, acetretin, acetyl coenzyme Q, albenda vaccine, chorionic gonadotropin, cidofovir, cisplatin, Zole, albuterol, aminoglutethimide, amiodarone, amlo cladribine, clidinium bromide, and clindamycin dipine, amphetamine, amphotericin B, atorvastatin, atova derivatives, ciprofloxacin, 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, butenafine, 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, ciprofloxacin, 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, fludara danazol, dantrolene, dexchlorpheniramine, diclofenac, dicu bine, fluoxetine, foScamet Sodium, ganciclovir, granulocyte marol, digoxin, dehydroepiandrosterone, dihydroergota colony Stimulating factor, granulocyte-macrophage Stimu mine, dihydrotachysterol, dirithromycin, doneZepil, lating factor, recombinant human growth hormone, bovine efavirenz, epoSartan, ergocalciferol, ergotamine, essential growth hormine, gentamycin, glucagon, glycopyrolate, fatty acid Sources, estradiol, etodolac, etoposide, famotidine, gonadotropin releasing hormone and Synthetic analogs fenofibrate, fentanyl, feXofenadine, finasteride, fluconazole, thereof, gonadorelin, grepafloxacin, haemophilus B conju flurbiprofen, fluvastatin, foSphenytoin, froVatriptan, fura gate Vaccine, hepatitis A Virus Vaccine inactivated, hepatitis Zolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, B virus Vaccine inactivated, heparin Sodium, indinavir Sul glyburide, glimepiride, griseofulvin, halofantrine, ibupro fate, influenza virus Vaccine, interleukin-2, interleukin-3, fen, irbeSartan, irinotecan, isosorbide dinitrate, isotretinoin, insulin-human, insulin lispro, insulin procine, insulin NPH, itraconazole, , , ketorolac, lamot insulin aspart, insulin glargine, insulin detemir, interferon rigine, lanSoprazole, leflunomide, lisinopril, loperamide, alpha, interferon beta, ipratropium bromide, ifosfamide, loratadine, , L-thyroXine, lutein, lycopene, Japanese encephalitis virus Vaccine, lamivudine, leucovorin medroxyprogesterone, , mefloquine, megestrol calcium, leuprolide acetate, levofloxacin, lincomycin and acetate, methadone, methoXSalen, metronidazole, micona lincomycin derivatives, lobucavir, lomefloxacin, loracarbef, Zole, midazolam, miglitol, minoxidil, mitoxantrone, mon mannitol, measles virus Vaccine, meningococcal vaccine, telukast, nabumetone, nalbuphine, naratriptan, nelfinavir, 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 floxacin, Octreotide acetate, ofloxacin, olpadronate, oxyto doephedrine, pyridoStigmine, rabeprazole, raloxifene, repa cin, pamidronate disodium, pancuronium bromide, glinide, rifabutine, rifapentine, , ritanovir, riza paroxetine, perfloxacin, pentamidine isethionate, pentosta triptan, rofecoxib, rosiglitaZone, Saquinavir, Sertraline, tin, pentoxifylline, penciclovir, pentagastrin, phentolamine Sibutramine, Sildenafil citrate, Simvastatin, Sirolimus, meSylate, phenylalanine, phySoStigmine Salicylate, plague Spironolactone, Sumatriptan, tacrine, tacrolimus, tamoxifen, vaccine, piperacillin Sodium, platelet derived growth factor, tamsulosin, targretin, tazarotene, telmisartan, teniposide, pneumococcal vaccine polyvalent, poliovirus vaccine (inac terbinafine, teraZosin, , tiagabine, ticlo tivated), poliovirus vaccine live (OPV), polymyxin B sul pidine, tirofiban, tizanidine, topiramate, topotecan, fate, pralidoxime chloride, pramlintide, pregabalin, pro toremifene, tramadol, tretinoin, troglitaZone, trovafloxacin, pafenone, propenthaline bromide, pyridoStigmine bromide, ubidecarenone, Valsartan, Venlafaxine, Verteporfin, rabies vaccine, risedronate, ribavirin, rimantadine hydro vigabatrin, Vitamin A, Vitamin D, Vitamin E, Vitamin K, chloride, rotavirus Vaccine, Salmeterol Xinafoate, Sincalide, Zafirlukast, Zileuton, Zolmitriptan, Zolpidem, Zopiclone, and Smallpox vaccine, Solatol, Somatostatin, Sparfloxacin, Spec combinations thereof. 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, TNFR:Fc, TNK-tPA, trandolapril, acetyl cysteine, acetylcholine chloride, alatrofloxacin, allen trimetrexate gluconate, trospectomycin, trovafloxacin, 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 0.095. Of course, certain active agents indicated as hydro tor and a low molecular weight heparin, Such as phobic may be readily converted to and commercially clopidogrel and enoxaparin; 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 (i) 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, esterification, or the like. Thus, it should be as repaglinide, (b) an insulin Sensitizer and an O-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 O-glucosidase inhibi limiting. tor, Such as (i) a Sulfonylurea Such as glyburide 0.096 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 fibrate and a statin, Such as fenofibrate and 0107 (11) combinations of an antihypertensive atorvastatin, fenofibrate and Simvastatin, fenofibrate agent and an antidiabetic agent, Such as an ACE and lovastatin, or fenofibrate and pravastatin; (b) a inhibitor and a Sulfonylurea, e.g., irbesartan and fibrate and nicotinic acid, Such fenofibrate 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 fibrate and a protease Zafirlukast, desloratidine and Zafirlukast, and cetira inhibitor, Such as fenofibrate and ritonavir, Zine and montelukast, 0101 (5) combinations of a lipid-regulating agent 0109 (13) combinations of antiinflammatory agents and an anticoagulant, e.g., (a) a fibrate and a Salicy and analgesics, e.g., a COX-2 inhibitor and a non late, Such as fenofibrate and aspirin, (b) a fibrate and steroidal antiinflammatory agent (NSAID) such as another anticoagulant, Such as fenofibrate 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 0102 (6) combinations of a lipid-regulating agent an antidiabetic agent, e.g., a lipase inhibitor Such as and an antidiabetic agent, including (a) a fibrate and orlistat in combination with metformin; a insulin Sensitizer Such as a thiazolidinedione, e.g., 0111 (15) combinations of a lipid-regulating agent fenofibrate and pioglitaZone, or fenofibrate and and a drug for treating coronary artery disease, e.g., rosiglitaZone, (b) a fibrate and an insulin Stimulant fenofibrate and eZetimibe, or lovastatin and Such as a Sulfonylurea, e.g., fenofibrate and glime eZetimibe; and piride, or fenofibrate and glipizide, a Statin and and insulin Sensitizer Such as a thiazolidinedione, e.g., 0112 other combinations, such as 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-inflammatory 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 fibrate and a alproStadil, with an antihypertensive/vasodilator calcium channel blocker, Such as fenofibrate and Such as prazosin. amlodipine, or fenofibrate 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 tified 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 influx of the active agent at the site of absorption form of a Salt, ester, amide, prodrug, active metabolite, by inhibition of the efflux pump, and (4) enhanced transport 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 both, relative to formulations in which less than 20 wt.% of cally active in the present context. Salts, esters, amides, an active agent to be delivered is Solubilized in a vehicle. prodrugs, metabolites, analogs, fragments, and other deriva Additional advantages include improved dissolution of an tives of the active agents may be prepared using Standard active agent with respect to the extent and/or rate of disso procedures known to those skilled in the art of Synthetic lution under a given condition (e.g., pH, temperature, etc.), organic chemistry and described, for example, by J. March, e.g., physiological conditions, and improved Solubilization Advanced Organic Chemistry: Reactions, Mechanisms and of the active agent released from the formulation upon Structure, 4th Edition (New York: Wiley-Interscience, dispersion in an aqueous medium, e.g., gastrointestinal fluid 1992). (with respect to the equilibrium Solubility and/or the degree 0116 For example, acid addition salts are prepared from of SuperSaturation in Such acqueous media). a drug in the form of a free base using conventional methodology involving reaction of the free base with an 0120) The vehicle preferably exists as at least one liquid acid. Suitable acids for preparing acid addition Salts include at a temperature of about 40 C. The liquid can be a both organic acids, e.g., acetic acid, propionic acid, glycolic monotropic Solution or it can have a biphasic structure acid, pyruvic acid, Oxalic acid, malic acid, malonic acid, comprised of, for example, lamellar, cubic, hexagonal, Succinic acid, maleic acid, fumaric acid, tartaric acid, citric reversed hexagonal, micellar, and/or reversed micellar acid, benzoic acid, cinnamic acid, mandelic acid, methane phases. When the vehicle is comprised of two or more , ethaneSulfonic acid, p-toluenesulfonic acid, liquids, the liquids can be completely miscible, forming a Salicylic acid, and the like, as well as inorganic acids, e.g., Single phase, or they can be partially miscible or completely hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric immiscible, in which case the vehicle is comprised of more acid, phosphoric acid, and the like. An acid addition Salt may than two distinct phases. The liquid phase(s) in the vehicle be reconverted to the free base by treatment with a suitable may consist entirely of the at least one compound noted base. Conversely, preparation of basic Salts of acid moieties above, i.e., a hydrophilic Surfactant, a lipophilic Surfactant, that may be present on an active agent may be carried out in a triglyceride, and/or a Solubilizer, or a liquid carrier may be a similar manner using a pharmaceutically acceptable base added to the aforementioned compound(s) to form the Such as , potassium hydroxide, ammo vehicle. Any pharmaceutically acceptable liquid carrier may nium hydroxide, calcium hydroxide, trimethylamine, or the be added, providing that in all cases, the vehicle is capable like. Preparation of esters involves transformation of a of Solubilizing a significant fraction of the active agent in the carboxylic acid group via a conventional esterification reac formulation, i.e., at least 20 wt.% of the total active agent. tion involving nucleophilic attack of an RO moiety at the 0121 A. : carbonyl carbon. Esterification may also be carried out by 0.122 Hydrophilic surfactants can be used to provide any reaction of a hydroxyl group with an esterification 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 modified 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

0.124 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 philic balance (the “HLB' value). Surfactants with lower 0127 Surfactants can be any surfactant suitable for use in HLB values are more lipophilic, and have greater Solubility pharmaceutical compositions. Suitable Surfactants can be in oils, whereas surfactants with higher HLB values are anionic, cationic, Zwitterionic, or non-ionic. Such Surfac more hydrophilic, and have greater Solubility in aqueous tants can be grouped into the following general chemical classes detailed in the Tables herein. The HLB values given Solutions. in the Tables below generally represent the HLB value as 0.125 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, refined, distilled, or fractionated Surfactants, puri emulsions. For many important Surfactants, including Sev fied fractions thereof, or re-esterified fractions, are also eral polyethoxylated Surfactants, it has been reported that within the Scope of the invention, although not specifically HLB values can differ by as much as about 8 HLB units, listed in the Tables. depending upon the empirical method chosen to determine the HLB value (Schott, J. Pharm. Sciences, 79(1), 87-88 0129 Polyethoxylated Fatty Acids: (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 PLURONICE) surfactants, BASF Corp.), the HLB values have useful Surfactant properties. Among the PEG-fatty acid may not accurately reflect 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), Myri Series (Atlas/ICI) >6 PEG 400 distearate Cithrol 4DS series (Croda) >10 PEG 100,200,300 Cithrol ML series (Croda) >10 monoaurate PEG 100,200,300 Cithrol MO series (Croda) >10 monooleate PEG 400 dioleate Cithrol 4DO series (Croda) >10 PEG 4OO-1OOO Cithrol MS series (Croda) >10 mOnOStearate PEG-1 stearate Nikkol MYS-1EX (Nikko), Coster K1 (Condea) 2 PEG-2 stearate Nikkol MYS-2 (Nikko) 4 PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate Mapeg (R) 200 ML (PPG), Kessco (R) PEG 200 ML (Stepan), LIPOPEG 2L 9.3 (Lipo Chem.) PEG-4 oleate Mapeg (R) 200 MO (PPG), Kessco (R) PEG200 MO (Stepan), 8.3 PEG-4 stearate Kessco (R) 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-5 (Nikko) 9.5 US 2003/0077297 A1 Apr. 24, 2003 13

TABLE 1-continued PEG-Fatty Acid Monoester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-6 oleate Algon OL 60 (Auschem SpA), Kessco (R) PEG 300 MO Stepan), Nikkol 8.5 A6 (Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) PEG-6 laurate Kessco (R) PEG300 ML (Stepan) PEG-7 laurate Lauridac 7 (Condea) PEG-6 stearate Kessco (R) PEG300 MS (Stepan) 7 PEG-8 laurate Mapeg (R) 400 ML (PPG), LIPOPEG 4DL (Lipo Chem.) PEG-8 oleate Mapeg (R) 400 MO (PPG), Emulgante A8 (Condea) PEG-8 stearate Mapeg (R) 400 MS (PPG), Myri 45 PEG-9 oleate Emulgante A9 (Condea) PEG-9 Stearate Cremophor S9 (BASF) PEG-10 laurate Nikkol MYL-10 (Nikko), Lauridac 10 (Croda) PEG-10 oleate Nikkol MYO-10 (Nikko) PEG-10 Stearate Nikkol MYS-10 (Nikko), Coster K100 (Condea) PEG-12 laurate Kessco (R) PEG 600 ML (Stepan) PEG-12 oleate Kessco (R) PEG 600 MO (Stepan) PEG-12 ricinoleate (CAS #9004-97-1) PEG-12 stearate Mapeg (R) 600 MS (PPG), Kessco (R) PEG 600 MS (Stepan) PEG-15 stearate Nikkol TMGS-15 (Nikko), Koster K15 (Condea) PEG-15 oleate Nikkol TMGO-15 (Nikko) PEG-20 laurate Kessco (R) PEG 1000 ML (Stepan) PEG-20 oleate Kessco (R) PEG 1000 MO (Stepan) PEG-2O Stearate Mapeg (R) 1000 MS (PPG), Kessco (R) PEG 1000 MS Stepan), Myri 49 PEG-25 stearate Nikkol MYS-25 (Nikko) PEG-32 laurate Kessco (R) PEG 1540 ML (Stepan) PEG-32 oleate Kessco (R) PEG 1540 MO (Stepan) PEG-32 Stearate Kessco (R) PEG 1540 MS (Stepan) PEG-30 Stearate Myri 51 PEG-40 laurate Crodet L40 (Croda) PEG-40 oleate Crodet O40 (Croda) PEG-40 steara Myri 52, Emerest (E 2715 (Henkel), Nikkol MYS-40 (Nikko) PEG-45 steara Nikkol MYS-45 (Nikko) PEG-50 steara Myri 53 PEG-55 steara Nikkol MYS-55 (Nikko) PEG-100 oleate Crodet O-100 (Croda) 8 PEG-1OO Stearate Myri 59, Arlacel 165 (ICI) PEG-200 oleate Albunol 200 MO (Taiwan Surf.) PEG-400 oleate LACTOMUL (Henkel), Albunol 400 MO (Taiwan Surf) > PEG-600 oleate Albunol 600 MO (Taiwan Surf.)

0131 PEG-Fatty Acid Diesters: ferred hydrophilic surfactants include PEG-20 dilaurate, 0132 Polyethylene glycol (PEG) fatty acid diesters are PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate, and also Suitable for use as Surfactants in the compositions of the PEG-32 dioleate. Representative PEG-fatty acid diesters are present invention. Among the Surfactants in Table 2, pre shown in Table 2.

TABLE 2 PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-4 dilaurate Mapeg (R) 200 DL (PPG), Kessco (R) PEG 200 DL (Stepan), LIPOPEG 2-DL (Lipo Chem.) PEG-4 dioleate Mapeg (R) 200 DO (PPG), PEG-4 distearate Kessco (R) 200 DS (Stepan) PEG-6 dilaurate Kessco (R) PEG 300 DL (Stepan) 9.8 PEG-6 dioleate Kessco (R) PEG 300 DO (Stepan) 7.2 PEG-6 distearate Kessco (R) PEG 300 DS (Stepan) 6.5 PEG-8 dilaurate Mapeg (R) 400 DL (PPG), Kessco (R) PEG 400 DL (Stepan), LIPOPEG 4 DL 11 (Lipo Chem.) PEG-8 dioleate Mapeg (R) 400 DO (PPG), Kessco (R) PEG 400 DO (Stepan), LIPOPEG 4 O 8.8 (Lipo Chem.) PEG-8 distearate Mapeg (R) 400 DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10 PEG-12 dilaurate Kessco (R) PEG 600 DL (Stepan) 11.7 PEG-12 distearate Kessco (R) PEG 600 DS (Stepan) 10.7 PEG-12 dioleate Mapeg (R) 600 DO (PPG), Kessco (R) 600 DO(Stepan) 1O US 2003/0077297 A1 Apr. 24, 2003 14

TABLE 2-continued

PEG-Fatty Acid Diester Surfactants

COMPOUND COMMERCIAL PRODUCT (Supplier) HLB

PEG-20 dilaurate Kessco (R) PEG 1000 DL (Stepan) 15 PEG-20 dioleate Kessco (R) PEG 1000 DO (Stepan) 13 PEG-20 distearate Kessco (R) PEG 1000 DS (Stepan) 12 PEG-32 dilaurate Kessco (R) PEG 1540 DL (Stepan) 16 PEG-32 dioleate Kessco (R) PEG 1540 DO (Stepan) 15 PEG-32 distearate Kessco (R) PEG 1540 DS (Stepan) 15 PEG-400 dioleate Cithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series (Croda) >10

0133) PEG-Fatty Acid Mono- and Di-Ester Mixtures: oil Such as corn oil, olive oil, peanut oil, palm kernel oil, 0134. In general, mixtures of Surfactants are also useful in apricot kernel oil, or almond oil. Preferred include the present invention. Several PEG-fatty acid esters are glycerol, propylene glycol, ethylene glycol, polyethylene marketed commercially as mixtures of mono- and diesters. glycol, Sorbitol, and pentaerythritol. Among these Representative surfactant mixtures are shown in Table 3. oil transesterified Surfactants, preferred hydrophilic Surfac tants are PEG-35 castor oil (Incrocas(R)-35), PEG-40 hydro TABLE 3 genated castor oil (Cremophor(R) RH 40), PEG-25 trioleate (TAGATE TO), PEG-60 corn glycerides (Crovol(R) M70), PEG-Fatty Acid Mono- and Diester Mixtures PEG-60 almond oil (Crovol(R) A70), PEG-40 palm kernel oil (Crovol(R) PK70), PEG-50 castor oil (Emalex(R) C-50), PEG COMPOUND COMMERCIAL PRODUCT (Supplier) 50 hydrogenated castor oil (Emalex(R) HC-50), PEG-8 PEG 4-150 mono, dilaurate Kessco (R) PEG 200-6000 mono, dilaurate (Stepan) caprylic/capric glycerides (Labrasolf), and PEG-6 caprylic/ PEG 4-150 mono, dioleate Kessco (R) PEG 200-6000 mono, dioleate capric glycerides (Softigen(R 767). Preferred lipophilic Sur (Stepan) factants in this class include PEG-5 hydrogenated castor oil, PEG 4-150 mono, distearate Kessco (E) 200-6000 mono, distearate PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor (Stepan) oil, PEG-6 corn oil (Labrafile M 2125 CS), PEG-6 almond oil (Labrafil(R) M 1966 CS), PEG-6 apricot kernel oil (Labra fil(R) M 1944 CS), PEG-6 olive oil (Labrafil(R) M 1980 CS), 0135 Polyethylene Glycol Glycerol Fatty Acid Esters: PEG-6 peanut oil (Labrafil(R) M 1969 CS), PEG-6 hydroge 0.136 Suitable PEG glycerol fatty acid esters are shown nated palm kernel oil (Labrafil(R) M 2130 BS), PEG-6 palm in Table 4. Among the surfactants in the Table, preferred kernel oil (Labrafil(RM 2130 CS), PEG-6 triolein (Labrafilg) hydrophilic surfactants are PEG-20 glyceryl laurate, PEG M 2735 CS), PEG-8 corn oil (Labrafil(R) WL 2609 BS), 30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyc PEG-20 corn glycerides (Crovol(R) M40), and PEG-20 eryl oleate, and PEG-30 glyceryl oleate. almond glycerides (Crovol(R) A40). The latter two surfac

TABLE 4 PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-20 glyceryl laurate Tagat (R. L. (Goldschmidt) 16 PEG-30 glyceryl laurate Tagat (R) L2 (Goldschmidt) 16 PEG-15 glyceryl laurate Glycerox L series (Croda) 15 PEG-40 glyceryl laurate Glycerox L series (Croda) 15 PEG-20 glyceryl stearate Capmul (R) EMG (ABITEC), Aldo (R) MS-20 KFG (Lonza) 13 PEG-20 glyceryl oleate Tagat (R) O (Goldschmidt) >10 PEG-30 glyceryl oleate Tagat (R) O2 (Goldschmidt) >10

0.137 Alcohol-Oil Transesterification Products: tants are reported to have HLB values of 10, which is generally considered to be the approximate border line 0138 A large number of surfactants of different degrees between hydrophilic and lipophilic Surfactants. For purposes of hydrophobicity or hydrophilicity can be prepared by of the present invention, these two Surfactants are considered reaction of alcohols or polyalcohols with a variety of natural to be lipophilic. Representative Surfactants of this class and/or hydrogenated oils. Most commonly, the oils used are suitable for use in the present invention are shown in Table castor oil or hydrogenated castor oil, or an edible vegetable 5. US 2003/0077297 A1 Apr. 24, 2003 15

TABLE 5

Transesterification Products of Oils and Alcohols COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-3 castor oil Nikkol CO-3 (Nikko) 3 PEG-5, 9, and 16 castor oil ACCONON CA series (ABITEC) 6-7 PEG-20 castor oil Emalex C-20 (Nihon Emulsion), Nikkol CO-20 TX (Nikko) 11 PEG-23 castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (Nihon Emulsion), Alkamuls (R EL 620 (Rhone- 11 Poulenc), Incrocas 30 (Croda) PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35 (Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65 (Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), Alkamuls (R EL 719 (Rhone 3 Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion) PEG-56 castor oil Eumulgin (R) PRT 56 (Pulcra SA) > PEG-60 castor oil Nikkol CO-6OTX (Nikko) PEG-100 castor oil Thornley > PEG-200 castor oil Eumulgin (R) PRT 200 (Pulcra SA) > PEG-5 hydrogenated castor oil Nikkol HCO-5 (Nikko) PEG-7 hydrogenated castor oil Simusol (R) 989 (Seppic), Cremophor WO7 (BASF) PEG-10 hydrogenated castor oil Nikkol HCO-10 (Nikko) PEG-20 hydrogenated castor oil Nikkol HCO-20 (Nikko) PEG-25 hydrogenated castor oil Simulsol (R) 1292 (Seppic), Cerex ELS 250 (Auschem SpA) PEG-30 hydrogenated castor oil Nikkol HCO-30 (Nikko) PEG-40 hydrogenated castor oil Cremophor RH 40 (BASF), Croduret (Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated castor oil Cerex ELS 450 (Auschem Spa) PEG-50 hydrogenated castor oil Emalex HC-50 (Nihon Emulsion) PEG-60 hydrogenated castor oil Nikkol HCO-60 (Nikko); Cremophor RH 60 (BASF) PEG-80 hydrogenated castor oil Nikkol HCO-80 (Nikko) PEG-100 hydrogenated castor oil Nikkol HCO-100 (Nikko) PEG-6 corn oil Labrafil (R) M 2125 CS (Gatefosse) PEG-6 almond oil Labrafil (R) M 1966 CS (Gatefosse) PEG-6 apricot kernel oil Labrafil (R) M 1944 CS (Gatefosse) PEG-6 Olive oil Labrafil (R) M 1980 CS (Gatefosse) PEG-6 peanut oil Labrafil (R) M 1969 CS (Gatefosse) PEG-6 hydrogenated palm kernel oil Labrafil (R) M 2130 BS (Gatefosse) PEG-6 palm kernel oil Labrafil (R) M 2130 CS (Gatefosse) PEG-6 triolein Labrafil (R) M 2735 CS (Gatefosse) PEG-8 corn oil Labrafil (R) WL 2609 BS (Gatefosse) 67 PEG-20 corn glycerides Crovol M40 (Croda) PEG-20 almond glycerides Crovol A40 (Croda) PEG-25 trioleate TAGAT (R) TO (Goldschmidt) PEG-40 palm kernel oil Crowo PK-70 > PEG-60 corn glycerides Crovol M70 (Croda) PEG-60 almond glycerides Crovol A70 (Croda) PEG-4 caprylic?capric triglyceride Labrafiac (R) Hydro (Gattefosse), 4 PEG-8 caprylic?capric glycerides Labrasol (Gattefosse), Labrafac CM 10 (Gattefosse) > PEG-6 caprylic?capric glycerides SOFTIGEN (R) 767 (Huls), Glycerox 767 (Croda) Lauroyl macrogol-32 glyceride GELUCIRE 44/14 (Gatefosse) Stearoyl macrogol glyceride GELUCIRE 50/13 (Gatefosse) Mono, di, tri, tetra esters of vegetable SorbitOGlyceride (Gattefosse) 3. oils and sorbitol Pentaerythrityl tetraisostearate Crodamol PTIS (Croda) Pentaerythrityl distearate Albunol DS (Taiwan Surf.) Pentaerythrityl tetraoleate Liponate PO-4 (Lipo Chem.) Pentaerythrityl tetrastearate Liponate PS-4 (Lipo Chem.) Pentaerythrityl Liponate PE-810 (Lipo Chem.), Crodamol PTC (Croda) tetracaprylate?tetracaprate Pentaerythrityl tetraoctanoate Nikkol Pentarate 408 (Nikko)

0.139. Also included as oils in this category of surfactants various molecular weights of the PEG moiety, such as PEG are oil-soluble vitamin Substances. The oil-soluble vitamin 100-8000, are also Suitable Surfactants. Substances include Vitamins A, D, E, K, and isomers, ana 0140 Polyglycerized Fatty Acids: logues, and derivatives thereof. The derivatives include 0141 Polyglycerol esters of fatty acids are also suitable organic acid esters of these oil-Soluble vitamin Substances, Surfactants for the present invention. Among the polyglyc Such as the esters of Vitamin E or Vitamin A with Succinic eryl fatty acid esters, preferred lipophilic Surfactants include acid. Thus, derivatives of these vitamins, Such as tocopheryl polyglyceryl oleate (Plurol Oleicque(E), polyglyceryl-2 PEG-1000 succinate (Vitamin ETPGS, available from East dioleate (Nikkol DGDO), and polyglyceryl-10 trioleate. man) and other tocopheryl PEG succinate derivatives with Preferred hydrophilic surfactants include polyglyceryl-10 US 2003/0077297 A1 Apr. 24, 2003 16 laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate Surfactant class, preferred lipophilic Surfactants include pro (Nikkol Decaglyn 1-O), and polyglyceryl-10 mono dioleate pylene glycol monocaprylate (Capryol(E90), propylene gly (Caprol(R) PEG 860). Polyglyceryl polyricinoleates (Polymuls) are also preferred hydrophilic and hydrophobic col monolaurate (Lauroglycol FCC), propylene glycol rici Surfactants. Examples of Suitable polyglyceryl esters are noleate (Propymuls(E), propylene glycol monooleate shown in Table 6. (Myverol(R) P-06), propylene glycol dicaprylate/dicaprate

TABLE 6 Polyglycerized Fatty Acids COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7 Polyglyceryl-2 isostearate Nikkol DGMIS (Nikko) 5-7 Polyglyceryl-3 oleate Caprol(R) 3GO (ABITEC), Drewpol 3-1-O (Stepan) 6.5 Polyglyceryl-4 oleate Nikkol Tetraglyn 1-O (Nikko) 5-7 Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S (Nikko) 5-6 Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), Nikkol Hexaglyn 1-O (Nikko) 9 Polyglyceryl-10 laurate Nikkol Decaglyn 1-L (Nikko) 15 Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14 Polyglyceryl-10 stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleate Nikkol Hexaglyn PR-15 (Nikko) >8 Polyglyceryl-10 linoleate Nikkol Decaglyn 1-LN (Nikko) 12 Polyglyceryl-6 pentaoleate Nikkol Hexaglyn 5-O (Nikko) &10 Polyglyceryl-3 dioleate Cremophor GO32 (BASF) &10 Polyglyceryl-3 distearate Cremophor GS32 (BASF) &10 Polyglyceryl-4 pentaoleate Nikkol Tetraglyn 5-O (Nikko) &10 Polyglyceryl-6 dioleate Caprol(R) 6G20 (ABITEC); Hodag PGO-62 (Calgene), PLUROL 8.5 OLEIQUE CC 497 (Gatefosse) Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 trioleate Nikkol Decaglyn 3-O (Nikko) 7 Polyglyceryl-10 pentaoleate Nikkol Decaglyn 5-O (Nikko) 3.5 Polyglyceryl-10 septaoleate Nikkol Decaglyn 7-O (Nikko) 3 Polyglyceryl-10 tetraoleate Caprol(R) 10G4O (ABITEC); Hodag PGO-62 (CALGENE), 6.2 Drewpol 10-4-O (Stepan) Polyglyceryl-10 decaisostearate Nikkol Decaglyn. 10-IS (Nikko) &10 Polyglyceryl-101 decaoleate Drewpol 10-10-O (Stepan), Caprol 10G10O (ABITEC), Nikkol 3.5 Decaglyn. 10-O Polyglyceryl-10 mono, dioleate Caprol (R) PGE 860 (ABITEC) 11 Polyglyceryl polyricinoleate Polymuls (Henkel) 3-2O

0142 Propylene Glycol Fatty Acid Esters: (Captex(R) 200; Miglylol(R) 840), and propylene glycol dio 0143 Esters of propylene glycol and fatty acids are ctanoate (Captex(R 800). Examples of Surfactants of this Suitable Surfactants for use in the present invention. In this class are given in Table 7.

TABLE 7 Propylene Glycol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Propylene glycol monocaprylate Capryol 90 (Gattefosse), Nikkol Sefsol 218 (Nikko) &10 Propylene glycol monolaurate Lauroglycol 90 (Gattefosse), Lauroglycol FCC (Gattefosse) &10 Propy eneg yco oleate Lutrol OP2000 (BASF) &10 Propy eneg yco myristate Mirpyl &10 Propy eneg yco mOnOStearate ADM PGME-03 (ADM), LIPO PGMS (Lipo Chem.), Aldo (R) 3-4 PGHMS (Lonza) Propy eneg yco hydroxy stearate &10 Propy eneg yco ricinoleate PROPYMULS (Henkel) &10 Propy eneg yco isostearate &10 Propy eneg yco monooleate Myverol P-O6 (Eastman) &10 Propy eneg yco dicaprylate/dicaprate Captex (R) 200 (ABITEC), Miglyol (R) 840 (Huls), Neobee (R) M-20 >6 Propy eneg yco dioctanoate Captex (R) 800 (ABITEC) >6 Propy eneg yco caprylate/caprate LABRAFAC PG (Gatefosse) >6 Propy eneg yco dilaurate >6 Propy eneg yco distearate Kessco (R) PGDS (Stepan) >6 Propy eneg yco dicaprylate Nikkol Sefsol 228 (Nikko) >6 Propy eneg yco dicaprate Nikkol PDD (Nikko) >6 US 2003/0077297 A1 Apr. 24, 2003

0144) Mixtures of Propylene Glycol Esters-Glycerol 0146 Mono- and Diglycerides: Esters: 0145. In general, mixtures of Surfactants are also suitable for use in the present invention. In particular, mixtures of 0147 A particularly important class of surfactants is the propylene glycol fatty acid esters and glycerol fatty acid class of mono- and diglycerides. These Surfactants are esters are Suitable and are commercially available. One preferred mixture is composed of the oleic acid esters of generally hydrophobic. Preferred lipophilic Surfactants in propylene glycol and glycerol (Arlacel(R) 186). Examples of this class of compounds include glyceryl monooleate these Surfactants are shown in Table 8. (Peceol), glyceryl ricinoleate, glyceryl laurate, glyceryl dilaurate (Capmul(R) GDL), glyceryl dioleate (Capmul(R) TABLE 8 GDO), glyceryl mono- and di-oleate (Capmul(R) GMO-K), Glycerol/Propylene Glycol Fatty Acid Esters glyceryl caprylate/caprate (CapmulE MCM), caprylic acid COMPOUND COMMERCIAL PRODUCT (Supplier) HLB mono- and di-glycerides (Imwitor(R) 988), and mono- and diacetylated monoglycerides (My vacet(R) 9-45). Examples of Oleic ATMOS 3.00, ARLACEL 186 (ICI) 3-4 Stearic ATMOS 150 3-4 these Surfactants are given in Table 9.

TABLE 9 Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Monopalmitolein (C16:1) (Larodan) &10 Monoelaidin (C18:1) (Larodan) &10 Monocaproin (C6) (Larodan) &10 Monocaprylin (Larodan) &10 Monocaprin (Larodan) &10 Monolaurin (Larodan) &10 Glyceryl monomyristate (C14) Nikkol MGM (Nikko) 3-4 Glyceryl monooleate (C18:1) PECEOL (Gatefosse), Hodag GMO-D, Nikkol MGO (Nikko) 3-4 Glyceryl monooleate RYLO series (Danisco), DIMODAN series (Danisco), EMULDAN 3-4 (Danisco), ALDO (R) MO FG (Lonza), Kessco GMO (Stepan), MONOMULS (R) series (Henkel), TEGINO, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80 (Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman) Glycerol monooleate/linoleate OLICINE (Gattefosse) 3-4 Glycerol monolinoleate Maisine (Gattefosse), Myverol 18-92, Myverol 18-06 (Eastman) 3-4 Glyceryl ricinoleate Softigen (R 701 (Huls), HODAG GMR-D (Calgene), ALDO (R) MR 6 Glyceryl monolaurate ALDO (R) MLD (Lonza), Hodag GML (Calgene) 6.8 Glycerol monopalmitate Emalex GMS-P (Nihon) 4 Glycerol monostearate Capmul (R) GMS (ABITEC), Myvaplex (Eastman), Imwitor (R) 191 (Huls), 5-9 CUTINA (R) GMS, Aldo (R) MS (Lonza), Nikkol MGS series (Nikko) Glyceryl mono-, dioleate Capmul (R) GMO-K (ABITEC) &10 Glyceryl palmitic?stearic CUTINA MD-A, ESTAGEL-G 18 &10 Glyceryl acetate Lamegin (R) EE (Grunau GmbH) &10 Glyceryl laurate Imwitor (R 312 (Huls), Monomuls (R) 90-45 (Grunau GmbH), Aldo (R) 4 (Lonza) Glyceryl citrate/lactatefoleate? Imwitor (R) 375 (Huls) &10 linoleate Glyceryl caprylate Imwitor (R) 308 (Huls), Capmul (R) MCMC8 (ABITEC) 5-6 Glyceryl caprylate/caprate Capmul (R) MCM (ABITEC) 5-6 Caprylic acid mono/diglycerides Imwitor (R) 988 (Huls) 5-6 Caprylic?capric glycerides Imwitor (R 742 (Huls) &10 Mono-and diacetylated Myvacet (R) 9-45, Myvacet (R) 9-40, Myvacet (R) 9-08 (Eastman), Lamegin (R) 3.8-4 monoglycerides (Grunau) Glyceryl monostearate Aldo (R) MS, Arlacel 129 (ICI), LIPO GMS (Lipo Chem.), Imwitor (R) 191 4.4 (Huls), Myvaplex (Eastman) Lactic acid esters of LAMEGIN GLP (Henkel) &10 mono, diglycerides Dicaproin (C6) (Larodan) &10 Dicaprin (C10) (Larodan) &10 Dioctanoin (C8) (Larodan) &10 Dimyristin (C14) (Larodan) &10 Dipalmitin (C16) (Larodan) &10 Distearin (Larodan) &10 Glyceryl dilaurate (C12) Capmul (R) GDL (ABITEC) 3-4 Glyceryl dioleate Capmul (R) GDO (ABITEC) 3-4 Glycerol esters of fatty acids GELUCIRE 39/01 (Gatefosse), GELUCIRE 43/01 (Gatefosse) 1. GELUCIRE 37/06 (Gatefosse) 6 US 2003/0077297 A1 Apr. 24, 2003 18

TABLE 9-continued Mono- and Diglyceride Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Dipalmitolein (C16:1) (Larodan) 1, 2 and 1,3-diolein (C18:1) (Larodan) Dielaidin (C18:1) (Larodan) Dilinolein (C18:2) (Larodan)

0148 Sterol and Sterol Derivatives: TABLE 10-continued 0149 Sterols and derivatives of sterols are suitable Sur factants for use in the present invention. These Surfactants can be hydrophilic or lipophilic. A preferred Sterol in this Sterol and Sterol Derivative Surfactants class is cholesterol or the esters of cholesterol with an organic acid, Such cholesteryl Succinate. Preferred deriva COMPOUND COMMERCIAL PRODUCT (Supplier) HLB tives include the polyethylene glycol derivatives. These derivatives could be esters and ethers depending upon the PEG-5 soya sterol Nikkol BPS-5 (Nikko) &10 chemical bonds formed between the polyethylene glycol PEG-10 soya sterol Nikkol BPS-10 (Nikko) &10 moiety and the sterol moiety. Preferred hydrophilic Surfac tants in this class include PEG-24 cholesterol ether (Solulan PEG-20 soya sterol Nikkol BPS-20 (Nikko) &10 C-24) and cholesteryl polyethylene glycol Succinate, con PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10 taining various molecular weights of the polyethylene glycol moeity. Examples of Surfactants in this class are shown in Table 10. 0150 Polyethylene Glycol Sorbitan Fatty Acid Esters: TABLE 10 0151. A variety of PEG-Sorbitan fatty acid esters are commercially available and are Suitable for use as Surfac Sterol and Sterol Derivative Surfactants tants in the present invention. In general, these Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB are hydrophilic, although Several lipophilic Surfactants of Cholesterol, sitosterol, &10 this class can be used. Among the PEG-Sorbitan fatty acid lanosterol esters, preferred hydrophilic Surfactants include PEG-20 PEG-24 cholesterol ether Solulan C-24 (Americhol) >10 sorbitan monolaurate (Tween-20), PEG-Sorbitan mono PEG-30 cholestanol Nikkol DHC (Nikko) >10 Phytosterol GENEROL series (Henkel) &10 palmitate (Tween-40), PEG-20 sorbitan monostearate PEG-25 phytosterol Nikkol BPSH-25 (Nikko) >10 (Tween-60), and PEG-20 sorbitan monooleate (Tween-80). Examples of these surfactants are shown in Table 11.

TABLE 11

PEG-Sorbitan Fatty Acid Esters

COMPOUND COMMERCIAL PRODUCT (Supplier) H L B PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) > PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), Crillet 1 (Croda), DACOL MLS 20 (Condea) PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI), Crillet 11 (Croda) PEG-80 sorbitan monolaurate Hodag PSML-80 (Calgene); T-Maz. 28 > PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko) PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI), Crillet 2 (Croda) PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), Crillet 3 (Croda) PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), Crillet 31 (Croda) PEG-8 sorbitan monostearate DACOL MSS (Condea) > PEG-6 sorbitan monostearate Nikkol TS106 (Nikko) PEG-20 sorbitan tristearate Tween-65 (Atlas/ICI), Crillet 35 (Croda) PEG-6 sorbitan tetrastearate Nikkol GS-6 (Nikko) PEG-60 sorbitan tetrastearate Nikkol GS-460 (Nikko) PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), Crillet 41 (Croda) PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), Crillet 4 (Croda) PEG-40 sorbitan oleate Emalex ET 8040 (Nihon Emulsion) PEG-20 sorbitan trioleate Tween-85 (Atlas/ICI), Crillet 45 (Croda) US 2003/0077297 A1 Apr. 24, 2003 19

TABLE 11-continued

PEG-Sorbitan Fatty Acid Esters

COMPOUND COMMERCIAL PRODUCT (Supplier) HLB

PEG-6 sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleate Nikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440 (Nikko) 13 PEG-20 sorbitan monoisostearate Tween-120 (Atlas/ICI), Crillet 6 (Croda) >10 PEG sorbitol hexaoleate Atlas G-1086 (ICI) 1O PEG-6 sorbitol hexastearate Nikkol GS-6 (Nikko)

0152 Polyethylene Glycol Alkyl Ethers: 0154) Sugar Esters: 0153 Ethers of polyethylene glycol and alkyl alcohols O155 Esters of Sugars are suitable surfactants for use in are Suitable Surfactants for use in the present invention. Preferred lipophilic ethers include PEG-3 oleyl ether the present invention. Preferred hydrophilic surfactants in (Volpo(R3) and PEG-4 lauryl ether (Brij(R 30). Examples of this class include Sucrose monopalmitate and Sucrose mono these Surfactants are shown in Table 12. laurate. Examples of Such Surfactants are shown in Table 13.

TABLE 12 TABLE 13 Polyethylene Glycol Alkyl Ethers Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supplier) HLB COMPOUND COMMERCIAL PRODUCT (Supplier) HLB PEG-2 oleyl ether, Brij92/93 (Atlas/ICI) 4.9 oleth-2 PEG-3 Oleyl ether, Volpo 3 (Croda) &10 Sucrose distearate SUCRO ESTER 7 (Gatefosse), 3 oleth-3 Crodesta F-10 (Croda) PEG-5 oleyl ether, Volpo 5 (Croda) &10 Sucrose SUCRO ESTER 11 (Gatefosse), 12 Oleth-5 PEG-10 oleyl ether, Volpo 10 (Croda), Brij 96/97 (Atlas/ICI) 2 distearate/monostearate (Croda) Crodesta F-110 oleth-10 Sucrose dipalmitate 7.4 PEG-20 oleyl ether, Volpo 20 (Croda), Brij98/99 (Atlas/ICI) 5 Sucrose monostearate Crodesta F-160 (Croda) 15 oleth-20 PEG-4 lauryl ether, Brij 30 (Atlas/ICI) 9.7 Sucrose monopalmitate SUCRO ESTER 15 (Gattefosse) >10 laureth-4 Sucrose monolaurate Saccharose monolaurate 1695 15 PEG-9 lauryl ether >10 PEG-23 lauryl ether, Brij 35 (Atlas/ICI) 7 (Mitsubishi-Kasei) laureth-23 PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10 cetyl ether Brij 56 (ICI) 3 PEG-20 cetyl ether Brij 58 (ICI) 6 0156 Polyethylene Glycol Alkyl Phenols: PEG-2 stearyl ether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 2 O157 Several hydrophilic PEG-alkyl phenol surfactants PEG-20 stearyl ether Brij 78 (ICI) 5 PEG-100 stearyl ether Brij 700 (ICI) >10 are commercially available, and are Suitable for use in the present invention. Examples of these Surfactants are shown in Table 14.

TABLE 1.4

Polyethylene Glycol Alkyl Phenol Surfactants

COMPOUND COMMERCIAL PRODUCT (Supplier) HLB

PEG-10-100 nonyl phenol Triton X series (Rohm & Haas), Igepal CA series (GAF, >10 USA), Antarox CA series (GAF, UK) PEG-15-100 octyl phenol ether Triton N-series (Rohm & Haas), Igepal CO series (GAF, >10 USA), Antarox CO series (GAF, UK) US 2003/0077297 A1 Apr. 24, 2003 20

0158 Polyoxyethylene-Polyoxypropylene Block Copolymers: The POE-POP block copolymers are a unique TABLE 15-continued class of polymeric Surfactants. The unique Structure of the surfactants, with hydrophilic POE and hydrophobic POP POE-POP Block Copolymers moieties in well-defined ratioS and positions, allows for a wide variety of Surfactants Suitable for use in the present COMPOUND a, b values in HO(CHO), (CHO)(CHO), H HLB invention. These Surfactants are available under various Poloxamer 235 a = 27 b = 39 Poloxamer 237 a = 62 b = 39 24 trade names, including Symperoni(Rc PE series (ICI); Plu Poloxamer 238 a = 97 b = 39 ronic(R) series (BASF), Emkalyx(R), Lutrol(R) (BASF), Poloxamer 282 a = 10 b = 47 Supronic(R), MonolanE, Pluracare(R), and Plurodac(R). The Poloxamer 284 a = 21 b = 47 generic term for these polymers is “poloxamer” (CAS Poloxamer 288 a = 122 b = 47 >10 Poloxamer 331 a = 7 b = 54 0.5 9003-11-6). These polymers have the formula Poloxamer 333 a = 20 b = 54 Poloxamer 334 a = 31 b = 54 HO(CHO) (CHO)(CHO).H Poloxamer 335 a = 38 b = 54 0159) wherein “a” and “b” denote the number of poly Poloxamer 338 a = 128 b = 54 oxyethylene and polyoxypropylene units, respectively. Poloxamer 401 a = 6 b = 67 Poloxamer 402 a = 13 b = 67 0160 Preferred hydrophilic Surfactants of this class Poloxamer 403 a = 21 b = 67 include Poloxamers 108, 188, 217, 238,288,338, and 407. Poloxamer 407 a = 98 b = 67 Preferred lipophilic Surfactants in this class include Polox amers 124, 182, 183, 212, 331, and 335. 0162. Other block co-polymers are also suitable for the 0.161 Examples of suitable surfactants of this class are present invention. The block co-polymers can be made of shown in Table 15. Since the compounds are widely avail various block components in different combination and able, commercial sources are not listed in the Table. The sequences, such as BA diblock, ABA triblock, BAB triblock, compounds are listed by generic name, with the correspond and other more complex combinations and Sequences ing “a” and “b' values. involving three or more block components. The block com ponents can be any poly(alkylene oxide), poly(lactic acid), TABLE 1.5 poly(glycolic acid), poly(lactic-co-glycolic acid), poly(Vi nylpyrrolidone) and poly(e-caprolactone). The molecular POE-POP Block Copolymers weights of Suitable block co-polymers can range from a few COMPOUND a, b values in HO(CHO), (CHO)(CHO), H HLB thouthand to a few million Daltons. These block co-poly mers can be either hydrophilic or lipophilic depending on Poloxamer 105 a = 11 b = 16 8 Poloxamer 108 a = 46 b = 16 >10 the distribution and ratios of different block components. Poloxamer 122 a = 5 b = 21 3 Other co-polymers, not necessarily block co-polymers, are Poloxamer 123 a = 7 b = 21 7 also Suitable for the present invention. The co-polymers can Poloxamer 124 a = 11 b = 21 >7 Poloxamer 181 a = 3 b = 30 be made of monomers of any combinations. The monomer Poloxamer 182 a = 8 b = 30 2 component can be any alkylene oxide, lactic acid, glycolic Poloxamer 183 a = 10 b = 30 acid, Vinylpyrrolidone, or e-caprolactone. Poloxamer 184 a = 13 b = 30 Poloxamer 185 a = 19 b = 30 0163 Sorbitan Fatty Acid Esters: Sorbitan esters of fatty Poloxamer 188 a = 75 b = 30 29 acids are Suitable Surfactants for use in the present invention. Poloxamer 212 a = 8 b = 35 Among these esters, preferred hydrophobic Surfactants Poloxamer 215 a = 24 b = 35 Poloxamer 217 a = 52 b = 35 include Sorbitan monolaurate (Arlacel(R) 20), sorbitan mono Poloxamer 231 a = 16 b = 39 palmitate (Span-40(R), sorbitan monooleate (Span-80(R), Poloxamer 234 a = 22 b = 39 Sorbitan monoStearate, and Sorbitan tristearate. Examples of these Surfactants are shown in Table 16.

TABLE 16

Sorbitan Fatty Acid Ester Surfactants

COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1 (Croda), Arlacel 20 (ICI) 8.6 Sorbitan monopalmitate Span-40 (Atlas/ICI), Crill 2 (Croda), Nikkol SP-10 (Nikko) 6.7 Sorbitan monooleate Span-80 (Atlas/ICI), Crill 4 (Croda), Crill 50 (Croda) 4.3 Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), Nikkol SS-10 (Nikko) 4.7 Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda), Nikkol SO-30 (Nikko) 4.3 Sorbitan sesquioleate Arlacel-C (ICI), Crill 43 (Croda), Nikkol SO-15 (Nikko) 3.7 Sorbitan tristearate Span-65 (Atlas/ICI) Crill 35 (Croda), Nikkol SS-30 (Nikko) 2.1 Sorbitan monoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7 Sorbitan sesquistearate Nikkol SS-15 (Nikko) 4.2 US 2003/0077297 A1 Apr. 24, 2003

0164. Lower Alcohol Fatty Acid Esters: 0165 Esters of lower alcohols (C. to C) and fatty acids TABLE 18-continued (Cs to Cs) are Suitable for use in the present invention. Ionic Surfactants Among these esters, preferred lipophilic Surfactants include ethyl oleate (Crodamol(R) EO), isopropyl myristate COMPOUND HLB (Crodamol(R) IPM), and isopropy palmitate (Crodamol(R) BILE SALTS >10 IPP). Examples of these surfactants are shown in Table 17. Sodium cholate Sodium taurocholate Sodium glycocholate TABLE 1.7 Sodium deoxycholate Sodium taurodeoxycholate Lower Alcohol Fatty Acid Ester Surfactants Sodium glycodeoxycholate Sodium ursodeoxycholate COMPOUND COMMERCIAL PRODUCT (Supplier) HLB Sodium chenodeoxycholate Sodium taurochenodeoxycholate Ethyl oleate Crodamol EO (Croda), Nikkol EOO (Nikko) <10 Sodium glyco chenodeoxycholate Isopropyl myristate Crodamol IPM (Croda) &10 Sodium cholylsarcosinate Isopropyl palmitate Crodamol IPP (Croda) &10 Sodium N-methyl taurocholate Ethyl linoleate Nikkol VF-E (Nikko) &10 PHOSPHOLIPIDS Isopropyl linoleate Nikkol VF-IP (Nikko) &10 Egg/Soy lecithin Epikuron (R) (Lucas Meyer), Ovothin1 (R) (Lucas Meyer) Cardiolipin Ionic Surfactants: Sphingomyelin 0166) Phosphatidylcholine Phosphatidyl ethanolamine 0167 Ionic Surfactants, including cationic, anionic, and Phosphatidic acid Zwitterionic Surfactants, are Suitable hydrophilic Surfactants Phosphatidylglycerol for use in the present invention. Preferred anionic Surfactants Phosphatidyl include fatty acid salts and bile salts. Preferred cationic PHOSPHORIC ACID ESTERS Surfactants include carnitines. Specifically, preferred ionic Diethanolammonium polyoxyethylene-10 oleyl ether phosphate Esterification products of fatty alcohols or fatty alcohol ethoxylates Surfactants include Sodium oleate, Sodium lauryl Sulfate, with phosphoric acid or anhydride Sodium lauryl Sarcosinate, Sodium dioctyl SulfoSuccinate, CARBOXYLATES Sodium cholate, Sodium taurocholate, lauroyl camitine, Ether carboxylates (by Oxidation of terminal OH group of palmitoyl carnitine, and myristoyl carnitine. Examples of fatty alcohol ethoxylates) Succinylated monoglycerides LAMEGIN ZE (Henkel) such surfactants are shown in Table 18. For simplicity, Sodium stearyl fumarate typical counterions are shown in the entries in the Table. It Stearoyl propylene glycol hydrogen succinate will be appreciated by one skilled in the art, however, that Monofcdiacetylated tartaric acid esters of mono-and diglycerides any bioacceptable counterion may be used. For example, Citric acid esters of mono-, diglycerides Glyceryl-lacto esters of fatty acids (CFR ref. 172.852) although the fatty acids are shown as Sodium Salts, other Acyl lactylates: cation counterions can also be used, Such as alkali metal lactylic esters of fatty acids cations or ammonium. Unlike typical non-ionic Surfactants, calcium/sodium stearoyl-2-lactylate calcium/sodium stearoyl lactylate these ionic Surfactants are generally available as pure com Alginate salts pounds, rather than as commercial (proprietary) mixtures. Propylene glycol alginate Because these compounds are readily available from a SULFATES AND variety of commercial Suppliers, Such as Aldrich, Sigma, and Ethoxylated alkyl sulfates the like, commercial Sources are not generally listed in the Alkyl sulfones Table. C-olefin sulfonates Acyl isethionates Acyl taurates TABLE 1.8 Alkyl glyceryl ether sulfonates Octyl sulfosuccinate disodium Ionic Surfactants Disodium undecylenamideo-MEA-sulfosuccinate CATIONIC Surfactants >10 COMPOUND HLB Hexadecyl triammonium bromide Dodecyl ammonium chloride FATTY ACID SALTS >10 Alkyl benzyldimethylammonium salts Sodium caproate Diisobutyl phenoxyethoxydimethyl benzylammonium salts Sodium caprylate Alkylpyridinium salts Sodium caprate Betaines (trialkylglycine): Sodium laurate Lauryl betaine (N-lauryl,N,N-dimethylglycine) Sodium myristate Ethoxylated amines: Sodium myristolate Polyoxyethylene-15 coconut amine Sodium palmitate Sodium palmitoleate Sodium oleate 18 Sodium ricinoleate 0.168. Non-Ionized Ionizable Surfactants: Sodium linoleate Sodium linolenate 0169. Ionizable surfactants, when present in their non Sodium stearate Sodium lauryl sulfate (dodecyl) 40 ionized (neutral, non-salt) form, are lipophilic Surfactants Sodium tetradecyl sulfate Suitable for use in the compositions and methods of the Sodium lauryl sarcosinate present invention. Particular examples of Such Surfactants Sodium dioctyl sulfosuccinate sodium (Cytec) include free fatty acids, particularly C-C fatty acids, and bile acids. More specifically, Suitable non-ionized ionizable US 2003/0077297 A1 Apr. 24, 2003 22 surfactants include the free fatty acid and forms of 0.174 Among these preferred surfactants, more preferred any of the fatty acid salts and bile salts shown in Table 18. are PEG-20 laurate, PEG-20 oleate, PEG-35 castor oil, 0170 Among the above-listed Surfactants, several com PEG-40 palm kernel oil, PEG-40 hydrogenated castor oil, binations are preferred. In Some of the preferred combina PEG-60 corn oil, PEG-25 glyceryl trioleate, polyglyceryl-10 tions, the vehicle includes at least one hydrophilic Surfac laurate, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/ tant. Preferred non-ionic hydrophilic Surfactants include caprylate glycerides, PEG-30 cholesterol, polysorbate 20 alkylglucosides, alkylmaltosides, alkylthioglucosides; lau polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, ryl macrogolglycerides, polyoxyethylene alkyl ethers, poly POE-10 oleyl ether, PEG-24 cholesterol, Sucrose monostear oxyethylene alkylphenols, polyethylene glycol fatty acids ate, Sucrose monolaurate, and poloxamers. Most preferred esters, polyethylene glycol glycerol fatty acid esters, poly are PEG-35 castor oil, PEG-40 hydrogenated castor oil, oxyethylene Sorbitan fatty acid esters, polyoxyethylene PEG-60 corn oil, PEG-25 glyceryl trioleate, PEG-6 caprate/ polyoxypropylene block copolymers, polyglycerol fatty acid caprylate glycerides, PEG-8 caprate/caprylate glycerides, esters, polyoxyethylene glycerides, polyoxyethylene Sterols, polysorbate 20, polysorbate 80, tocopheryl PEG-1000 suc derivatives, and analogues thereof; polyoxyethylene Veg cinate, PEG-24 cholesterol, and hydrophilic poloxamers. etable oils, polyoxyethylene hydrogenated vegetable oils, 0.175. The hydrophilic Surfactant can also be, or can reaction mixtures of polyols with fatty acids, glycerides, include as a component, an ionic Surfactant. Preferred ionic vegetable oils, hydrogenated vegetable oils, and Sterols, Surfactants include alkyl ammonium Salts, bile acids and Sugar esters, Sugar ethers, Sucroglycerides, and mixtures Salts, analogues, and derivatives thereof, fusidic acid and thereof. derivatives thereof, fatty acid derivatives of amino acids, 0171 More preferably, the non-ionic hydrophilic surfac oligopeptides, and polypeptides, glyceride derivatives of tant is Selected from the group consisting of polvoxyethyl amino acids oligopeptides, and polypeptides, acyl lactylates, ene alkylethers, polyethylene glycol fatty acid esters, poly mono-and di-acetylated tartaric acid esters of mono- and ethylene glycol glycerol fatty acid esters, polyoxyethylene di-glycerides; Succinylated monoglycerides, citric acid Sorbitan fatty acid esters, polyoxyethylene-polyoxypropy esters of mono- and di-glycerides, alginate Salts, propylene lene block copolymers, polyglyceryl fatty acid esters, poly glycol alginate, lecithins and hydrogenated lecithins; lyso oxyethylene glycerides, polyoxyethylene vegetable oils, and lecithin and hydrogenated lySolecithins; lysophospholipids polyoxyethylene hydrogenated vegetable oils. The glyceride and derivatives thereof; phospholipids and derivatives can be a monoglyceride, diglyceride, triglyceride, or a thereof; Salts of alkylsulfates, Salts of fatty acids, Sodium mixture. docusate; carnitines, and mixtures thereof. 0172 Also preferred are non-ionic hydrophilic surfac 0176 More preferable ionic Surfactants include bile acids tants that are reaction mixtures of polyols and fatty acids, and Salts, analogues, and derivatives thereof, lecithins, lyso glycerides, vegetable oils, hydrogenated vegetable oils, or lecithin, phospholipids, lySophospholipids and derivatives Sterols. These reaction mixtures are largely composed of the thereof; Salts of alkylsulfates, Salts of fatty acids, Sodium transesterification products of the reaction, along with com docusate; acyl lactylates, mono- and di-acetylated tartaril monly complex mixtures of other reaction products. The acid esters of mono- and di-glycerides; Succinylated polyol is preferably glycerol, ethylene glycol, polyethylene monoglycerides, citric acid esters of mono- and di-glycer glycol, Sorbitol, propylene glycol, pentaerythritol, or a sac ides, carnitines, and mixtures thereof. charide. 0177 More specifically, preferred ionic Surfactants are 0173 Several particularly preferred compositions are lecithin, lySolecithin, phosphatidylcholine, phosphatidyle those that include as a non-ionic hydrophilic Surfactant Such thanolamine, phosphatidylglycerol, phosphatidic acid, phos as PEG-10 laurate, PEG-12 laurate, IIEG-20 laurate, PEG phatidylserine, lySophosphatidylcholine, lySophosphatidyle 32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 ole thanolamine, lySophosphatidylglycerol, lySophosphatidic ate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG acid, lysophosphatidylserine, PEG-phosphatidylethanola 200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 mine, PVP-phosphatidylethanolamine, lactylic esters of distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 fatty acids, Stearoyl-2-lactylate, Stearoyl lactylate, Succiny dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG lated monoglycerides, mono- and di-acetylated tartaric acid 20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyc esters of mono- and di-glycerides, citric acid esters of mono eryl Stearate, PEG-glyceryl oleate, PEG-30 glyceryl oleate, and di-glycerides, cholate, taurocholate, glycocholate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 deoxycholate, taurodeoxycholate, chenodeoxycholate, gly palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 codeoxycholate, glycochenodeoxycholate, taurochenode castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 Oxycholate, urSodeoxycholate, taurourSodeoxycholate, gly hydrogenated castor oil, PEG-60 hydrogenated castor oil, courSodeoxycholate, cholylsarcosine, N-methyl PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, taurocholate, caproate, caprylate, caprate, laurate, myristate, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 lau palmitate, oleate, ricinoleate, linoleate, linolenate, Stearate, rate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 lauryl Sulfate, teracecyl Sulfate, docusate, lauroyl camitines, soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG palmitoyl carnitines, myristoyl camitines, and Salts and 80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 mixtures thereof. lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE 20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-1000 0.178 Particularly preferred ionic Surfactants are lecithin, Succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, lySolecithin, phosphatidylcholine, phosphatidylethanola Tween 40, Tween 60, Sucrose monoStearate, Sucrose mono mine, phosphatidylglycerol, lySophosphatidylcholine, PEG laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol phosphatidylethanolamine, lactylic esters of fatty acids, series, PEG 15-100 octyl phenol series, or a poloxamer. Stearoyl-2-lactylate, Stearoyl lactylate, Succinylated US 2003/0077297 A1 Apr. 24, 2003

monoglycerides, mono- and di-acetylated tartaric acid esters PEG-4 dioleate; PEG-4 distearate; PEG-6 dioleate; PEG-6 of mono- and di-glycerides, citric acid esters of mono- and distearate; PEG-8 dioleate; PEG 3-16 castor oil; PEG 5-10 di-glycerides cholate, taurocholate glycocholate, deoxycho hydrogenated castor oil; PEG 6-20 corn oil; PEG 6-20 late, taurodeoxycholate, glycodeoxycholate, cholylsar almond oil; PEG-6 olive oil; PEG-6 peanut oil; PEG-6 palm cosine, caproate, caprylate, caprate, laurate, oleate, lauryl kernel oil; PEG-6 hydrogenated palm kernel oil; PEG-4 Sulfate, docusate, and Salts and mixtures thereof, with the capric/caprylic triglyceride, mono, di, tri, tetra esters of most preferred ionic Surfactants being lecithin, lactylic vegetable oil and Sorbitol; pentaerythrityl di or tetra Stearate, esters of fatty acids, Stearoyl-2-lactylate, Stearoyl lactylate, isoStearate, oleate, caprylate, or caprate; polyglyceryl 2-4 Succinylated monoglycerides, mono- and di-acetylated tar oleate, Stearate, or isoStearate; polyglyceryl 4-10 penta taric acid esters of mono- and di-glycerides, citric acid esters oleate; polyglyceryl-3 dioleate; polyglyceryl-6 dioleate; of mono- and di-glycerides, taurocholate, caprylate, caprate, polyglyceryl-10 trioleate; polyglyceryl-3 distearate; propy oleate, lauryl Sulfate, docusate, and Salts and mixtures lene glycol mono- or diesters of a C to Co fatty acid; thereof. monoglycerides of C to Co fatty acids; acetylated 0179 Preferred lipophilic Surfactants are alcohols; poly monoglycerides of C to Co fatty acids, diglycerides of C oxyethylene alkylethers, fatty acids, glycerol fatty acid to Co fatty acids; tocopheryl PEG-800 succinate; lactic acid esters, acetylated glycerol fatty acid esters, lower alcohol derivatives of monoglycerides, lactic acid derivatives of fatty acid esters, polyethylene glycol fatty acid esters, poly diglycerides; cholesterol; phytosterol; PEG 5-20 soya sterol; ethylene glycol glycerol fatty acid esters, polypropylene PEG-6 Sorbitan tetra, hexastearate; PEG-6 Sorbitan tetra glycol fatty acid esters, polyoxyethylene glycerides, lactic oleate, Sorbitan monolaurate, Sorbitan monopalmitate, Sor acid derivatives of mono- and di-glycerides, propylene bitan mono, trioleate, Sorbitan mono, tristearate, Sorbitan glycol diglycerides, Sorbitan fatty acid esters, polyoxyeth monoisoStearate, Sorbitan Sesquioleate, Sorbitan Sesquistear ylene Sorbitan fatty acid esters, polyoxyethylene-polyOX ate; PEG 2-5 oleyl ether; POE 2-4 lauryl ether; PEG-2 cetyl ypropylene block copolymers, transesterified vegetable oils, ether; PEG-2 Stearyl ether, Sucrose distearate; Sucrose Sterols, Sterol derivatives, Sugar esters, Sugar ethers, Sucro dipalmitate, ethyl oleate; isopropyl myristate; isopropyl glycerides, polyoxyethylene vegetable oils, and polyoxyeth palmitate, ethyllinoleate, isopropyllinoleate; and poloxam ylene hydrogenated vegetable oils. CS. 0180. As with the hydrophilic surfactants, lipophilic Sur 0185. Among the specifically preferred lipophilic surfac factants can be reaction mixtures of polyols and fatty acids, tants, most preferred are oleic acid; lauric acid; glyceryl glycerides, vegetable oils, hydrogenated vegetable oils, and monocaprate, glyceryl monocaprylate, glyceryl monolau Sterols. rate; glyceryl monooleate; glyceryl dicaprate; glyceryl dica prylate; glyceryl dilaurate; glyceryl dioleate; acetylated 0181 Preferably, the lipophilic Surfactant is selected monoglycerides, propylene glycol oleate; propylene glycol from the group consisting of fatty acids, lower alcohol fatty laurate; polyglyceryl-3 oleate; polyglyceryl-6 dioleate; acid esters, polyethylene glycol glycerol fatty acid esters, PEG-6 corn oil; PEG-20 corn oil; PEG-20 almond oil; polypropylene glycol fatty acid esters, polyoxyethylene Sorbitan monooleate; Sorbitan monolaurate; POE-4 lauryl glycerides, glycerol fatty acid esters, acetylated glycerol ether; POE-3 oleyl ether; ethyl oleate; tocopheryl PEG-800 fatty acid esters, lactic acid derivatives of mono- and di glycerides, Sorbitan fatty acid esters, polyoxyethylene Sor Succinate, and poloxamers. bitan fatty acid esters, polyoxyethylene-polyoxypropylene 0186 B. Triglycerides: block copolymers, polyoxyethylene vegetable oils, polyoxy ethylene hydrogenated vegetable oils, and reaction mixtures 0187 Examples of triglycerides suitable for use in the of polyols and fatty acids, glycerides, vegetable oils, hydro present invention are shown in the following table. In genated vegetable oils, and Sterols. general, these triglycerides are readily available from com mercial Sources. For Several triglycerides, representative 0182 More preferred are lower alcohol fatty acids esters; commercial products and/or commercial Suppliers are listed. polypropylene glycol fatty acid esters, propylene glycol fatty acid esters, glycerol fatty acid esters, acetylated glyc TABLE 1.9 erol fatty acid esters, lactic acid derivatives of mono- and di-glycerides, Sorbitan fatty acid esters, polyoxyethylene Representative Triglycerides vegetable oils, and mixtures thereof, with glycerol fatty acid esters and acetylated glycerol fatty acid esters being most TRIGLYCERIDE COMMERCIAL SOURCE preferred. Among the glycerol fatty acid esters, the esters are Aceituno oil preferably mono- or diglycerides, or mixtures of mono- and Almond oil Super Refined Almond Oil (Croda) Arachis oil diglycerides, where the fatty acid moiety is a C to C fatty Babassu oil acid. Blackcurrant seed oil Borage oil 0183 Also preferred are lipophilic surfactants that are the Buffalo ground oil reaction mixture of polyols and fatty acids, glycerides, Candlenut oil vegetable oils, hydrogenated vegetable oils, and Sterols. Canola oil Lipex 108 (Abitec) Caster oil Preferred polyols are polyethylene glycol, Sorbitol, propy Chinese vegetable tallow oil lene glycol, and pentaerythritol. Cocoa butter Coconut oil 0184 Specifically preferred lipophilic surfactants include Coffee seed oil Pureco 76 (Abitec) myristic acid, oleic acid; lauric acid; Stearic acid; palmitic Corn oil Super Refined Corn Oil (Croda) acid; PEG 1-4 stearate; PEG 2-4 oleate; PEG-4 dilaurate; US 2003/0077297 A1 Apr. 24, 2003 24

TABLE 19-continued TABLE 19-continued Representative Triglycerides Representative Triglycerides

TRIGLYCERIDE COMMERCIAL SOURCE TRIGLYCERIDE COMMERCIAL SOURCE Cottonseed oil Super Refined Cottonseed Glyceryl tricaprylate/caprate Captex 300 (Abitec): Oil (Croda) Captex 355 (Abitec); Miglyol Crambe oil 810 (Huls); Miglyol 812 (Huls) Cuphea species oil Glyceryl tricaprylate/caprate/laurate Captex 350 (Abitec) Evening primrose oil Glyceryl tricaprylate/caprate/linoleate Captex 810 (Abitec): Grapeseed oil Miglyol 818 (Huls) Groundnut oil Glyceryl tricaprylate/caprate/stearate Softisan 378 (Huls); (Larodan) Hemp seed oil Glyceryl tricaprylate/lauratefstearate (Larodan) Illipe butter Glyceryl 12-caprylate-3-linoleate (Larodan) Kapok seed oil Glyceryl 12-caprate-3-stearate (Larodan) Linseed oil Glyceryl 12-laurate-3-myristate (Larodan) Menhaden oil Super Refined Menhaden Glyceryl 12-myristate-3-laurate (Larodan) Oil (Croda) Glyceryl 1,3-palmitate-2-butyrate (Larodan) Mowrah butter Glyceryl 13-stearate-2-caprate (Larodan) Mustard seed oil Glyceryl 1.2-linoleate-3-caprylate (Larodan) Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oil Palm kernel oil 0188 Fractionated triglycerides, modified triglycerides, Peanut oil Super Refined Peanut Oil (Croda) Synthetic triglycerides, and mixtures of triglycerides are also Poppy seed oil Rapeseed oil within the scope of the invention. Rice bran oil Safflower oil Super Refined Safflower 0189 Preferred triglycerides include vegetable oils, fish Oil (Croda) oils, animal fats, hydrogenated vegetable oils, partially Sal fat hydrogenated vegetable oils, medium and long-chain trig Sesame oil Super Refined Sesame Oil (Croda) lycerides, and structured triglycerides. It should be appre Shark liver oil Super Refined Shark Liver ciated that Several commercial Surfactant compositions con Oil (Croda) Shea nut oil tain Small to moderate amounts of triglycerides, typically as Soybean oil Super Refined Soybean a result of incomplete reaction of a triglyceride Starting Oil (Croda) material in, for example, a transesterification reaction. Such Stillingia oil Sunflower oil commercial Surfactant compositions, while nominally Tall oil referred to as “surfactants”, may be suitable to provide all or Tea sead oil part of the triglyceride component for the compositions of Tobacco seed oil the present invention. Examples of commercial Surfactant Tung oil (China wood oil) compositions containing triglycerides include Some mem Ucuhuba Vermonia oil bers of the surfactant families Gelucire (Gattefosse), Wheat germ oil Super Refined Wheat Germ Maisine (Gattefosse), and Imwitor (Hils), such as: Gelucire Oil (Croda) 44/14 (saturated polyglycolized glycerides); Gelucire 50/13 Hydrogenated caster oil Castorwax (Saturated polyglycolized glycerides); Gelucire 53/10 (Satu Hydrogenated coconut oil Pureco 100 (Abitec) rated polyglycolized glycerides); Hydrogenated cottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST (Abitec): 0190. Gelucire 33/01 (semi-synthetic triglycerides of Cs Softisan 154 (Huls) to Cs saturated fatty acids); Gelucire 39/01 (semi-synthetic Hydrogenated soybean oil Sterotex HM NF (Abitec): Dritex S (Abitec) glycerides); other Gelucires, such as 37/06, 43/01, 35/10, Hydrogenated vegetable oil Sterotex NF (Abitec): 37/02, 46/07, 48/09, 50/02, 62/05, etc.; Maisine 35-1 Hydrokote M (Abitec) (linoleic glycerides); and Imwitor 742 (caprylic/capric glyc Hydrogenated cottonseed/castor oil Sterotex K (Abitec) erides). Partially hydrogenated soybean oil Hydrokote AP5 (Abitec) Partially soy and cottonseed oil Apex B (Abitec) 0191 Still other commercial Surfactant compositions yceryl tributyrate (Sigma) having Significant triglyceride content are known to those yceryl tricaproate (Sigma) yceryl tricaprylate (Sigma) skilled in the art. It should be appreciated that Such com yceryl tricaprate Captex 1000 (Abitec) positions, which contain triglycerides as well as Surfactants, yceryl trundecanoate Captex 8227 (Abitec) may be Suitable to provide all or part of the triglyceride yceryl trilaurate (Sigma) component of the compositions of the present invention, as yceryl trimyristate Dynasan 114 (Huls) well as all or part of the Surfactant component, as described yceryl tripalmitate Dynasan 116 (Huls) below. Of course, none of the commonly known triglycer yceryl tristearate Dynasan 118 (Huls) yceryl triarcidate (Sigma) ide-containing commercial Surfactants alone provides the yceryl trimyristoleate (Sigma) unique pharmaceutical compositions and characteristics as igma) recited in the appended claims. yceryl tripalmitoleate (Sigma) yceryl trioleate (Sigma) 0.192 Among the above-listed triglycerides, preferred yceryl trilinoleate (Sigma) triglycerides include: almond oil, babasSu oil; borage oil; yceryl trilinolenate (Sigma) blackcurrant Seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; evening primrose oil; grapeseed oil; US 2003/0077297 A1 Apr. 24, 2003 groundnut oil; mustard Seed oil, olive oil; palm oil; palm 0201 other solubilizers known in the art, such as kernel oil; peanut oil; rapeseed oil; Safflower oil; Sesame oil; dimethyl acetamide, dimethyl isosorbide (Arlasolve Shark liver oil; Soybean oil; Sunflower oil, hydrogenated DMI (ICI)), N-methyl pyrrolidones (Pharmasolve castor oil, hydrogenated coconut oil; hydrogenated palm oil; (ISP)), monooctanoin, diethylene glycol monoethyl hydrogenated Soybean oil, hydrogenated vegetable oil; ether (available from Gattefosse under the trade hydrogenated cottonseed and castor oil; partially hydroge name Transcutol), and water. nated Soybean oil, partially Soy and cottonseed oil; glyceryl tricaproate, glyceryl tricaprylate, glyceryl tricaprate, glyc 0202 Mixtures of solubilizers are also within the scope eryl triundecanoate, glyceryl trilaurate; glyceryl trioleate; of the invention. glyceryl trilinoleate, glyceryl trilinolenate, glyceryl trica 0203 Preferred solubilizers include triacetin, triethylci prylate/caprate, glyceryl tricaprylate/caprate/laurate; glyc trate, ethyl oleate, ethyl caprylate, dimethylacetamide, eryl tricaprylate/caprate/linoleate; and glyceryl tricaprylate/ N-methylpyrrolidone, N-hydroxyethylpyrrollidone, polyvi caprate/Stearate. Other preferred triglycerides are Saturated nylpyrrollidone, hydroxypropyl methylcellulose, hydrox polyglycolized glycerides (Gelucire 44/14, Gelucire 50/13 ypropyl cyclodextrins, ethanol, polyethylene glycol 200 and Gelucire 53/10), linoleic glycerides (Maisine(R) 35-I), 100, glycofurol, transcutol, propylene glycol, and dimethyl and caprylic/capric glycerides (Imwitor(R 742). isosorbide. Particularly preferred solubilizers include Sorbi 0193 Among the preferred triglycerides, more preferred tol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, triglycerides include: coconut oil; corn oil, olive oil, palm and propylene glycol. oil, peanut oil; Safflower oil; Sesame oil, Soybean oil; hydro 0204. In preferred embodiments, the vehicle of the genated castor oil; hydrogenated coconut oil; partially present compositions comprises at least two compounds hydrogenated Soybean oil; glyceryl tricaprate, glyceryl Selected from the group consisting of hydrophilic Surfac trilaurate, glyceryl trioleate; glyceryl trilinoleate; glyceryl tants, lipophilic Surfactants, triglycerides, and Solubilizers. tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate; Among the more preferred embodiments, the vehicle glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/ includes at least two hydrophilic Surfactants and at least one caprate/stearate; Saturated polyglycolized glycerides (Gelu lipophilic Surfactant, or at least one hydrophilic Surfactant, cire 44/14, Gelucire 1450/13 and Gelucire 53/10); linoleic at least one lipophilic Surfactant, and at least one triglycer glycerides (Maisine(E 35-1); and caprylic/capric glycerides ide. (Imwitor(R 742). 0205 The amount of hydrophilic Surfactant, lipophilic 0194 C. Solubilizers: Surfactant, triglyceride, and Solubilizer that can be included 0.195. In one preferred embodiment, the vehicle com in compositions of the present invention is not particularly prises at least one Solubilizer to increase the Solubility of the limited. Of course, when Such compositions are ultimately active agent therein. Examples of Such compounds, referred administered to a patient, the amount of a given excipient is to as “solubilizers', include: limited to a bioacceptable amount, which is readily deter 0.196 Alcohols and polyols, such as ethanol, isopro mined by one of skill in the art. In Some circumstances, it panol, butanol, benzyl alcohol, ethylene glycol, pro may be advantageous to include amounts of the excipient far pylene glycol, butanediols and isomers thereof, glyc in excess of bioacceptable amounts, for example, to maxi erol, pentaerythritol, Sorbitol, mannitol, transcutol, mize the concentration of a therapeutic agent, with exceSS dimethyl isosorbide, polyethylene glycol, polypro Solubilizer removed prior to providing the composition to a pylene glycol, polyvinylalcohol, hydroxypropyl patient using conventional techniques, Such as distillation or methylcellulose and other cellulose derivatives, evaporation. Thus, if present, each can be present in an cyclodextrins, and cyclodextrin derivatives, amount of about 0.5% to about 100% by weight, based on 0.197 Ethers of polyethylene glycols having an the weight of the vehicle. Typically, each is present at about average molecular weight of about 200 to about 5% to about 70% by weight and more typically, about 10% 6000, such as tetrahydrofurfuryl alcohol PEG ether to about 50% by weight. (glycofurol, available commercially from BASF 0206. In particularly preferred embodiments, the amount under the trade name Tetraglycol) or methoxy PEG of hydrophilic Surfactant, lipophilic Surfactant, triglyceride, (Union Carbide); and Solubilizer are Such that upon mixing with an aqueous 0198 Amides, such as 2-pyrrolidone, 2-piperidone, medium, the vehicle forms a clear aqueous dispersion. Any e-caprolactam, N-alkylpyrrolidone, N-hydroxyalky dilution ratio can be Selected, but convenient dilutions are lpyrrolidone, N-alkylpiperidone, N-alkylcaprolac those within the range expected in Vivo, about a 10 to tam, dimethylacetamide, and polyvinylpyrrollidone; 250-fold dilution in purified water, gastric fluid/simulated 0199 Esters, such as ethyl propionate, tributylci gastric fluid, or intestinal fluid/simulated intestinal fluid. The trate, acetyl triethylcitrate, acetyl tributyl citrate, aqueous dispersion is then assessed qualitatively for optical triethylcitrate, ethyl oleate, ethyl caprylate, ethyl clarity. The procedure can be repeated with incremental butyrate, triacetin, propylene glycol monoacetate, variations in the relative amount of lipophilic Surfactant, propylene glycol diacetate, e-caprolactone and iso triglyceride, and/or Solubilizer added, to determine the maxi mers thereof, Ö-Valerolactone and isomers thereof, mum relative amount of that lipophilic Surfactant, triglyc B-butyrolactone and isomers thereof; eride, and/or Solubilizer can be present for a given combi nation. 0200 Oil-soluble vitamin Substances, such as toco pherol, tocopheryl acetate, tocopheryl Succinate, 0207 Alternatively, the optical clarity of the aqueous tocotrienols, isomers thereof and mixtures thereof; dispersion can be measured using Standard quantitative and techniques for turbidity assessment. One convenient proce US 2003/0077297 A1 Apr. 24, 2003 26 dure to measure turbidity is to measure the amount of light and the desired dosage of active agent to be provided. In of a given wavelength transmitted by the Solution, using, for Some cases, the amount of lipophilic Surfactant and/or example, a UV-Visible spectrophotometer. Using this mea triglyceride actually used in a formulation of the present Sure, optical clarity corresponds to high transmittance, Since invention will be less than the maximum that could be used, cloudier Solutions will Scatter more of the incident radiation, and it should be apparent that Such compositions are also resulting in lower transmittance measurements. If this pro within the Scope of the present invention. cedure is used, care should be taken to insure that any Stabilizing agent or other additives that may contribute 0212. In a preferred embodiment, the pharmaceutical turbidity or absorbance to the aqueous dispersion is composition and the dosage form of the invention are excluded from the Suspending vehicle when the aqueous substantially free of added water and are therefore substan dispersion is prepared. It also should be noted whether the tially nonaqueous. By “Substantially aqueous” is meant that Surfactant, triglyceride and/or Solubilizer mixture does not a composition or dosage form, as prepared, contains leSS itself absorb light of the chosen wavelength, as any true than about 20% (v/v) free water, wherein “free” water refers absorbance necessarily reduces the amount of transmitted to any water present that is capable of forming a continuous light and falsely increases the quantitative turbidity value. In aqueous phase or otherwise has the ability to migrate freely the absence of chromophores at the chosen wavelength, (e.g., into the interior wall of a gelatin capsule). More Suitable dispersions, at an aqueous medium to vehicle ratio preferably, a composition or dosage form of the invention of 100:1 by weight, should have an apparent absorbance of contains less than about 10% free water, and, most prefer less than about 0.5, preferably less than about 0.3, and more ably, the composition or dosage form contains less than preferably less than about 0.1. At an aqueous medium to about 5% free water. In turn, as alluded to above, this means vehicle ratio of 10:1 by weight, suitable dispersions should that any water present will not form a continuous aqueous have an apparent absorbance of less than about 0.7, prefer phase and/or does not have the mobility to migrate freely ably less than about 0.3, and more preferably less than about within or out of the composition or dosage form. O.1. 0213 The lack of water provides pharmaceutical com positions and dosage forms with improved Stability and 0208 Optimally, the amounts of hydrophilic surfactant, compatibility, if the presence of a Significant amount of lipophilic Surfactant, triglyceride, and Solubilizer are Such water would present Such problems. For example, numerous that upon mixing with an aqueous medium, the vehicle active agents and excipients are prone to hydrolysis. Exclud forms an aqueous dispersion with a narrow particle size ing Significant amounts of water from the composition distribution. Any dilution amount can be chosen, but con would help slow down or Stop the chemical degradation venient dilutions are those within the range expected in vivo, caused by water. Water-free compositions would allow such about a 10 to 250-fold dilution in purified water, gastric excipients to maintain the desired physical form and pre fluid/simulated gastric fluid, or intestinal fluid/simulated Serve their intended functions. Significant amounts of water intestinal fluid. Measurements of the particle size distribu may not be compatible with certain dosage forms Such as tion of the aqueous dispersion can be performed on com gelatin capsules. Large amounts of water present in the fill mercially available particle Size analyzers, Such as, for may change the water content in the Shells and eventually example, a Nicomp particle size analyzer available from cause Softening, dissolving, leaking, or breaking of the Particle Size Systems, Inc., of Santa Barbara, Calif. It is capsules during Storage. desirable that the average particle size be less than about 1000 nm, preferably less than about 200 nm, more prefer 0214. In a preferred embodiment of the present invention, ably less than about 50 nm, and still more preferably less however, a Small percentage of water is present in the than about 20 nm. It is also preferred that the particle size composition, So that an appropriate equilibrium can be distribution be unimodal. established between the filled material and the hard or soft gelatin capsule shells, to prevent cracking or brittleness of 0209. Other methods of determining optical clarity or the capsules. Compositions containing an appropriate particle size can be used as desired. Such methods are well amount of water would help to maintain the integrity of the known to those skilled in the art. dosage form, making Such encapsulations practical. It also 0210 Although it should be understood that any aqueous appreciated that in a preferred embodiment, certain excipi dispersion having the properties described above is within ents may undergo phase changes, Such as precipitation, the Scope of the present invention, regardless of the Specific Swelling, and gelation, in the presence of Significant relative amounts of lipophilic and hydrophilic Surfactants amounts of water. In Some Such cases, water would thus and triglyceride, it is expected that the amount of lipophilic provide useful Stabilizing or Suspending effects on the Surfactant and/or triglyceride will generally be less than Suspension. Appropriate amounts of water would be thus about 200% by weight of any hydrophilic surfactant present, desirable in these cases. For similar reasons, it is also and more specifically, in the range of about 1% to 200%. preferred that the compositions of the present invention Further, it is expected that the amount of lipophilic Surfac comprise appropriate amount of other hydrophilic compo tant and/or triglyceride will generally be less than about nents, Such as propylene glycol, glycerol, Sorbitol, polyeth 100%, and more specifically in the range of about 5% to ylene oxides, or mixtures thereof. about 100% by weight, or about 10% to about 100% by 0215) IV. The Suspension: weight, of any hydrophilic Surfactant. 0216) The pharmaceutical Suspension is minimally com 0211. Other considerations well known to those skilled in prised of an active agent and a vehicle, Sometimes referred the art will further facilitate the choice of specific propor to herein as a "Suspending vehicle. In Some cases, a tions of each compound. These considerations include, for Significant fraction of the active agent may be Solubilized in example, the degree of bioacceptability of the Surfactants, the vehicle for immediate release and/or absorption, while US 2003/0077297 A1 Apr. 24, 2003 27 the rest of the active agent may be Suspended in the vehicle any of various polymorphs or Solvates), or it may be a for delayed, Sustained, and/or rapid release. By varying the mixture of at least one amorphous phase and at least one fractions of Solubilized and Suspended active agent, the crystalline phase. When the particles include one or more release and/or absorption profile of the active agent can be excipients, additives, or the like, the particulate material can modulated and controlled. It is Surprisingly found that when be amorphous, crystalline, in the form of a Solid Solution the fraction of active agent that is Solubilized varies from with the excipient(s) and/or additive(s), or a mixture of two about 20 to 95 wt %, and the fraction that is suspended or more of these phases. The Solid particles may contain a correspondingly varies from about 5 to 80 wt %, desirable core comprised of the active agent, an excipient, or mixtures release and/or absorption profile characteristics of the active thereof, and may optionally be further coated with at least agent are obtained that can increase the therapeutic efficacy one layer of the active agent, the excipient, or mixtures of the active agent. More preferably, about 30 to 80 wt % of thereof. The solid particles may be core-free, in the form of the active agent present in the Suspension is Solubilized and a powder or a plurality of granules, pellets, and/or beads, or about 20 to 70 wt % of the active agent is suspended in the combinations thereof. vehicle. Most preferably, about 50 to 70 wt % of the active 0221) Any high energy phase in the particulate fraction agent present in the Suspension is Solubilized and about 30 may contain a phase Stabilizing agent. Suitable phase Sta to 50 wt % of the active agent is suspended in the vehicle. bilizing agents are typically: (1) hydrophilic polymers 0217. The invention enables facile modulation of the Selected from the group consisting of (a) polyalkylene pharmacokinetic/pharmacodynamic profile of an active oxides, e.g., polyethylene glycol or ethylene glycol-propy agent because of the high degree of control provided over lene glycol copolymers), (b) polyalkylene oxide-substituted the timing and rate of drug release. If a rapid onset or a large C-C diols and triols, e.g., mono-poly(Oxyethylene)-substi initial loading dose of the active agent is desired, immediate tuted propylene glycol, di-(polyoxyethylene)-substituted release of active agent can be accomplished by Solubilizing propylene glycol, mono-poly(oxyethylene)-substituted the majority of the active agent in the vehicle and/or glycerol, di-(polyoxyethylene)-substituted glycerol, and tri providing rapid dissolution of Suspended particles to obtain (polyoxyethylene)-substituted glycerol, (c) polyalkylene a shorter T (the time from dosing to reach the highest oxide-Substituted Saccharides Such as polyoxyethylated Sor blood concentration of the active agent) and higher C (the bitol, and polyoxyethylated glucose, (d) poly(N-vinyl lac maximum blood concentration of the active agent; the tams) Such as polyvinyl pyrrolidone and poly(N-vinyl capro concentration at T). In this way, a release profile is lactam), (e) acidic polymers and Salts and esters thereof, obtained that involves both rapid onset and rapid apparent Such as Vinyl polymers having pending carboxylic acid, elimination. By “immediate release' is meant that the at Sulfonic acid or phosphonic acid groups, optionally esteri least 50%, preferably at least 75%, and most preferably at fied, ionized by association with a base, or otherwise deriva least 90%, of the solubilized active agent is released within tized (e.g., polystyrene ) and (f) polymers of car 30 minutes at 37 C. as evaluated using standard USP boxyvinyl monomerS Such as acrylic acid, methacrylic acid, dissolution test equipment (Apparatus 1 or Apparatus 2) and/or esters thereof; (2) Surfactants Such as any of those described in USP 24-NF 19, Supplement 4, Section 71 1, described in Section IIIA above; (3) saccharides, including published by the United States Pharmacopeia & National monosaccharides, disaccharides and polysaccharides and Formulary in 2001. derivatives thereof (e.g., dextran Sulfate), with cellulosic polymers (e.g., hydroxypropylmethylcellulose) preferred; 0218. Another preferred release profile is characterized (4) gelatins, and (5) inorganic Salts such as Sodium chloride. as having rapid onset, as above, but also provides for Particulate material in an amorphous State may also include delayed and/or Sustained release of Some fraction of the any of the above phase Stabilizing agents in groups (1) active agent, Such that Some of the drug is not “immediately through (5). released. The Sustained and/or delayed release fraction, which is generally provided by the Suspension fraction of the 0222 Particle size distribution and surface properties can formulation, allows for a longer duration of action, elimi be critical factors affecting the release of the active agent nating or at least minimizing the need for repeated dosing. from the particulate. In general, the Smaller the particle Size, the faster the release of the active agent, due to the larger 0219. If a slower onset or a more Sustained plasma level total Surface area available for dissolution and a higher of the active agent is desired, more of the active agent may Surface-to-volume ratio. In addition, the more readily the be incorporated into the Suspension fraction of the formu Surface of a particle is wetted, the faster the dissolution. To lation than is Solubilized, but a significant Solubilized frac increase the release rate of the active agent from the Sus tion should still be present so that the bioavailability of the pended particles, various Size reduction techniques can be active agent is not compromised. In many cases, the SuS applied. Typically, processes like grinding, milling, microni pension can take advantage of the entire length of the Zation, and nanosizing are well known in the art and can be intestines for complete absorption. utilized to obtain a mean particle Size from Several tens of 0220. The suspended fraction of the active agents is in the micrometers to a tenth of a micrometer. Size reduction can form of a plurality of Solid particles, which may associate to be carried out in the presence of the vehicle, and/or in the form one or more larger dosage units Such as a granule, presence of a Surfactant, a hydrophilic polymer, a lipid, a pellet, bead or tablet, Suspended in the vehicle. The particles gelatin, a Saccharide, or a mixture thereof. may be single phase, or comprised of two or more phases. 0223) To modify the surface properties of the active agent When the solid particles are wholly comprised of the active particles, a Surface coating of an interfacial modifying agent agent, the particulate phase can be amorphous or in a high can be applied, wherein the interfacial modifying agent is as energy State, i.e., a metastable crystalline phase or a stable described above, i.e., Selected from a Surfactant, a hydro crystalline phase (wherein the crystalline State may include philic polymer, a lipid, a gelatin, a Saccharide, or a mixture US 2003/0077297 A1 Apr. 24, 2003 28 thereof. Such agents may also be admixed with the particles capsule is shown as having Suspended particulate material of (by, for example, co-grinding or co-micronizing), applied to very Small particle size (e.g., powder) and the other capsule the particles as a dry powder, and/or Selected to chemically as containing solubilized drug. The embodiment of FIG.2B bind to the particle surface. If faster dissolution is desirable, is similar, except that the Suspended particulate in the first the Surface coating may be one that Speeds wetting and dosage form is in the form of larger granules, pellets or comprises, for example, a hydrophilic Surfactant, a Sugar beads. In FIGS. 2C and 2D, the non-solubilized fraction is Such as lactose, Sucrose, or dextrose, or a hydrophilic a tablet or capsule, respectively. polymer. If controlled release is desirable, e.g., Sustained 0227. If desired, the suspended and solubilized fractions and/or delayed release, a Suitable Sustained and/or delayed of the active agent in a Single dosage form can be Segregated release coating can be applied. Various pharmaceutically using any Suitable Separation means. One Such means acceptable materials can be used for Such coatings, including involves incorporating the Suspended and Solubilized frac cellulose derivatives, polysaccharides, acrylic polymers, tions into discrete regions or compartments of the dosage lipophilic Surfactants, triglycerides, and mixtures thereof. form. For example, as illustrated in FIGS. 3A and 3B, a Some of these materials can erode or dissolve slowly, plug or a Septum can be placed in a two-piece hard gelatin whereas Some do not dissolve in the acidic conditions of the capsule to create two Separate compartments, one containing stomach but will dissolve in the non-acidic conditions of the the vehicle in which the active agent is Solubilized, and the intestines. To further modify the release profile of an active other containing the vehicle in which the active agent is agent from the Solid particles, any of a variety of different Suspended (again, in the form of particles or an aggregate particle preparation techniques may also be employed. thereof) Alternatively, as illustrated in FIGS. 4A, 4B and 0224. That is, particulates comprised of Solid solutions, 4C, a wall or partition can also be inserted into a capsule amorphous mixtures, fused mixtures, eutectic compositions, during the manufacture of the capsule by providing a third or mixtures thereof can be prepared with Similar polymers, gelatin ribbon in between the two shell ribbons to create two lipids, Sugars, and any other pharmaceutically acceptable compartments as described above. A capsule may also be excipients. In addition, Solid particles comprising a water designed So that an interior capsule is wedged into an Soluble complex of an active agent with a complexing agent, exterior capsule, leaving Some Space therebetween, So that Such as cyclodextrin or a derivative thereof, can also be the dosage form contains two Segregated regions. See FIGS. utilized in the present invention. In general, the Solid Solu 5A, 5B and 5C. tion, amorphous mixture, fused mixture, or eutectic compo 0228. Other suitable separation means involves coating Sition should dissolve faster than the crystalline active agent the Suspended active agent particles or Suspended active alone. To further modify the release profile of the active agent"aggregate” (e.g., tablet) with a layer of a material that agent from the active agent particles, size reduction and is impermeable to the vehicle, Such that the vehicle contains Surface coatings can be applied. For example, a eutectic both the Solubilized active agent and the Suspended active mixture formed from an active agent and an excipient using agent coated with a vehicle-impermeable coating. See a melting and cooling process can be ground into Smaller embodiment B of FIG. 1. Still another separation means particles. These particles can then be spray-coated with a involves the use of nested capsules, with a first, interior polymer to modify their Surface and consequently the dis capsule containing particulate active agent (e.g., powder, Solution profile of the active agent. Additional details granules, pellets, a compressed tablet), and a second capsule regarding Suitable particle preparation techniques are containing both the first capsule and an active agent-vehicle described in the following Section. Solution. The interior capsule may or may not be coated with 0225. The solid particulate material (i.e., that fraction of a vehicle-impermeable coating to further ensure Segregation the active agent that does not become Solubilized in the of the active agent fractions. See embodiments B and D of vehicle) may or may not be present in the same dosage form FIG. 1. as the solubilized fraction of active agent. When the par ticulate fraction is present in the same dosage form as the 0229) V. Particle Manufacture: solubilized fraction of the active agent, as illustrated in FIG. 0230. The active agent particles can be manufactured 1, the particles can be in direct contact with the vehicle using any of a wide variety of Suitable techniques, including Solubilizing the active agent, Such that the vehicle contain dry and wet granulation, pelletization, application of one or ing the Suspended active agent particles also contains the more coatings on an inert or active core, and the like. Solubilized fraction of the active agent. The Suspended Commonly utilized coating and pelletization processes active agent may be in the form of particles individually include balling, spheronization, extrusion, fusion, precipita suspended in the vehicle; see embodiment A of FIG. 1, tion, co-precipitation, Spray congealing, Spray drying, pan illustrating the Suspended particles as powder or larger coating, fluidized bed coating, melt extrusion, crystalliza pellets, granules, beads, or the like. Alternatively, the SuS tion, cryopelletization, nanoencapsulation, coacervation, pended active agent may be in the form of a larger dosage etc. Conventional, pharmaceutically acceptable additives unit, Such that the Suspended “particles' are in association can be introduced prior to or during particle manufacture to (e.g., compressed) to form at least one tablet, pellet, granule, facilitate particle preparation, depending on the process, the or the like, and it is this larger dosage unit or units that are active agent, and the nature of the final particulate material. then Suspended in the vehicle. See, e.g., embodiments C and 0231 Coating processes preferably involve spraying a D of FIG. 1. coating Solution onto a Substrate. The coating Solution can 0226 However, the solid particulate material and the be a molten Solution of the encapsulation coat material, free Solubilized fraction of active agent can also be present in of a dispersing medium. The coating Solution can also be Separate dosage form (for concomitant or separate admin prepared by Solubilizing or Suspending the encapsulation istration); see FIGS. 2A through 2D. In FIG. 2A, one coat material in an aqueous medium, an organic Solvent, a US 2003/0077297 A1 Apr. 24, 2003 29

Supercritical fluid, or a mixture thereof. After the coating manipulation of the particles after extrusion. Various types proceSS is complete, the residual dispersing medium can be of extrusion devices can be employed, Such as Screw, Sieve further removed to a desirable level utilizing appropriate and basket, roll, and ram extruders. drying processes, Such as Vacuum evaporation, heating, freeze drying, etc. 0239 Encapsulation by Extrusion: 0232 Pelletization typically involves preparation of a 0240. In this method, the particles components are added molten Solution or a dispersion of the particulate Solubilized to a low moisture melt of a Saccharide, e.g., a low malto or Suspended in an aqueous medium, an organic Solvent, a dextrin (or Sucrose or modified edible Starch), mixed and Supercritical fluid, or a mixture thereof. Such a Solution or extruded into a cold bath. The solidified composition can be dispersion is then extruded through an opening to achieve further ground down. Optionally, centrifugal extrusion can pellets of the desired shape, size, and other properties. AS be utilized for efficiency. above, appropriate drying processes can be adopted to 0241 Melt Extrusion: control the level of the residual dispersing medium, if neceSSary. 0242. The active agent particles can also be melted and extruded with a continuous, Solvent-free extrusion process, 0233 AS is generally known, pellets, granules, and beads with or without inclusion of additives. are formed with the aid of a pelletizer, Spheronizer, or extruder. The pelletizer, Spheronizer, or extruder is able to 0243 Spheronization: continuously form approximately spherical bodies from a 0244) Spheronization, as the term Suggests, is the process mass of finely divided particles, by a rolling or tumbling of converting material into Spheres, the particle shape hav action on a flat or curved Surface with the addition of a ing the lowest ratio of Surface area to Volume. Spheroniza liquid. tion typically begins with damp extruded particles. The 0234 Pelletizers can be classified based on the angle of extruded particles are broken into uniform lengths and their axis as horizontal drum or inclined dish pelletizers. gradually transformed into Spherical shapes. In addition, Rotary fluidized granulators can also be used for pelletiza powdered raw materials, which require addition of either tion. A standard fluidized drier bowl can be replaced with a liquid or material from a mixer, can be processed in an rotating plate as an air distributor. For granulation, a binder air-assisted Spheronizer. liquid is sprayed from via one or two binary nozzles located 0245 Disk Spinning: axially to the rotational movement of the powder bed. This operation results in rounding of the granules to approxi 0246 Spinning disk technology involves formation of mately spherical pellets. Such balling or agitation techniques particles from either a molten or Solubilized composition can be influenced by operating conditions, Such as bridging/ Sprayed onto a rotating disc maintained at a predetermined binding liquid requirements, residence time of the material temperature and rotating at a predetermined speed. When a in the pelletizer, Speed and angle of inclination of the molten composition contacts the Spinning disk, particles pelletizer, amount of material fed to the pelletizer, choice congeal, while with a liquid composition, the liquid rapidly and levels of binder, etc. One skilled in the art can readily evaporates from the Solution resulting in formation of Solid adjust Such factors to produce a Satisfactory product. drug particles. The composition may or may not contain various inert excipients and additives in addition to the 0235. The components of the present formulations can active agent or agents. AS will be appreciated by those of also be Self-binding. Liquid components can be pelletized ordinary skill in the art, the temperature of the disc and its with the aid of Suitable Solidifying, binding, or thickening rotation may be adjusted to produce particles of predeter agents. mined size and shape. 0236. The choice of an appropriate binder for a given application may be readily determined by one of ordinary 0247 Spray Congealing: skill in the art. At a minimum, the binder must be capable of 0248 Spray congealing is process in which a Substance wetting the Surfaces of the particle being pelletized or of interest is allowed to melt, disperse, or dissolve in a hot granulated. Binders must have Sufficient wet strength to melt of other additives, and is then Sprayed into an air allow agglomerates to be handled, and Sufficient dry Strength chamber wherein the temperature is below the melting point to make them Suitable for their intended purposes. Each of the formulation components, to provide Spherical con process, however, makes use of a different System of forces gealed pellets. The air removes the latent heat of fusion. The and may require a different agglomerate Strength. The final temperature of the cooled air used depends on the freezing Selection of the binder should be made on the basis of the point of the product. Due to the absence of Solvent evapo type of equipment that is used. The Size and size distribution ration in most Spray congealing processes, the particles are of pellets, bulk density, Strength, and flow properties also generally nonporous and Strong, and remain intact upon affect the performance of the pellets, and these properties agitation. The characteristics of the final congealed product can be adjusted by one skilled in the art by the inclusion of depend in part on the properties of the additives used. The additives, choice of equipment, and processing conditions. feeding rate and inlet/outlet temperatures are adjusted to ensure congealing of the atomized liquid droplet. The feed 0237 Extrusion: should have adequate Viscosity to ensure homogeneity. The 0238 Extrusion is a well-known method of applying conversion of molten feed into powder is a Single, continu preSSure to a damp or melted composition until it flows ouS Step. Proper atomization and a controlled cooling rate through an orifice or a defined opening. The extrudable are critical to obtain high Surface area, uniform and homo length varies with the physical characteristics of the material geneous congealed pellets. Adjustment of these parameters to be extruded, the method of extrusion, and the process of is readily achieved by one skilled in the art. Spray congeal US 2003/0077297 A1 Apr. 24, 2003 30 ing can, for example, be used to produce free-flowing working agents, and auxiliary materials, nanocapsules as powders from liquids and pellets ranging in size from about small as 80 to 250 nm can be prepared. 0.25 to 2.0 mm. 0257 Precipitation by Anti-Solvent: 0249. The spray congealing method is particularly suit 0258 A Solution of active agent and optionally other able for heating labile Substances (since the ambient tem excipients in a Solvent, preferably a volatile one, is mixed perature is used for drying) and for moisture Sensitive with an anti-Solvent that has significantly lower Solubility Substances (since non-aqueous compositions can be uti for the formulation components than does the Solvent. AS a lized). Spray congealing is similar to spray drying, except result, the active agent precipitates out, together with excipi that no Solvent is utilized. Spray congealing is a uniform and ents if present. The precipitate can be collected and Sub rapid process, and is completed before the product comes in jected to further processes, Such as Size reduction. A pure contact with any equipment Surface. Most additives and precipitate of the active agent can be obtained from a Solvent active agents that are Solid at room temperature and melt if no excipients are present. without decomposition are suitable for use with this method. 0250 Conventional spray dryers operating with cool inlet 0259 Supercritical Fluid Processes: air have been used for Spray congealing. Several methods of 0260 Components of the present invention can be dis atomizing molten materials can be employed, Such as pres persed in a Supercritical fluid and crystallized as needed. Sure, pneumatic, or centrifugal atomization. For perSons Current techniques involving Supercritical fluids include skilled in the Spray congealing art, it is well known that precipitation by rapid expansion of Supercritical Solutions, Several formulation aspects (Such as matrix materials and gas anti-Solvent processes, and precipitation from gas-Satu Viscosity) and processing factors (such as temperature, rated Solutions. atomization, and cooling rate) affect the quality (morphol ogy, particle size distribution, polymorphism, and dissolu 0261 Coacervation: tion characteristics) of spray-congealed pellets. The spray 0262 Coacervation is a transfer of macromolecules with congealed particles can be used in tablets or capsules, or film properties from a Solvated State in a coacervation phase they can be incorporated into a liquid Suspension form. into a phase in which there is a film around each particle. The coacervation method involves dispersing the composi 0251 Solvent Dehydration (Spray Drying): tion in a dispersion of a polymeric colloid, Such as gelatin 0252 For compositions that are oily in nature, the spray alginate, and shock treating the mixture will temperature or drying technique is commonly employed. The oily material pH, etc., to generate a two-phase System. The desired phase is commonly mixed with a polymeric material, Such as is then hardened with a cross-linking agent, Such as glut gelatin, vegetable gum, modified Starch, dextrin, or other araldehyde. appropriate additives. An emulsifier is added, if needed, to 0263 Cryopelletization: The cryopelletization procedure form an oil-in-water emulsion. The emulsion is atomized allows conversion of a molten mass, aqueous Solution, or into a column of heated air in a drying chamber, resulting in Suspension into Solid, bead-like particles. The molten mass rapid evaporation of water. Alternatively, the emulsion is Solutions or Suspensions are dripped by means of an appro atomized directly into a nonaqueous polar Solvent, Such as priately designed device into liquid nitrogen. The production isopropanol, ethanol, glycerol, or polyglycols, to dehydrate of Small dropS and liquid nitrogen cooling permit very rapid the aeroSolized particle. This method is particularly Suitable and uniform freezing of the material processed. The pellets for compositions containing a lipophilic active agent or are further dried in conventional freeze dryers. Cryopelleti additives that result in lipophilic cores. Spray drying/Solvent Zation can also be carried out under aseptic conditions for dehydration can also be applied to hydrophilic active agents Sterile processing. The most critical Step in producing or additives to form an oil-in-water emulsion, which is spray Spherical particles by this proceSS is droplet formation. dried. This results in a homogenous Solid composition. Droplet formation is influenced by formulation related vari Furthermore, water or organic Solvent-based formulations ables, Such as the nature of the active agent and additives, can be spray dried using an inert proceSS gas, Such as Viscosity, total Solid content, Surface tension, etc. Extra care nitrogen, argon, or the like. must be undertaken with the processing of Suspensions to 0253) Crystallization: ensure homogeneity. In addition, equipment design and processing variables also play an important role. One skilled 0254 Components of the present invention can be dis in the art can readily balance the various factors to produce Solved in appropriate Solvents and Subjected to Spherical a Satisfactory product. Enteric matrix pellets can be formed crystallization techniques well known in the art. that include polyacrylic acid (e.g. Carbopol) with a high 0255 Nanoencapsulation: molecular weight polyethylene glycol (such as PEG-20, 000). 0256 Nanoencapsulation involves solubilizing an aque ous Solution of an active agent and other components in a 0264. Other processes suitable for producing solid phar weakly polar vehicle. Micelles are formed with the active in maceutical compositions of the present invention include an organic outer phase. Then, an amphiphilic monomer is extrusion and Spray chilling. These processes are described added to the lipophilic external phase. The mixed micelles in detail in U.S. Pat. Nos. 5,965,161 and 5,539,000 respec thus formed are then polymerized with the aid of a suitable tively, the disclosures of which are incorporated herein by procedure, Such as UV or gamma radiation, heat, or chemi reference. cal agents. The hardened Solidified micelles are made to 0265 For processing of encapsulated compositions, vari undergo phase exchange by replacing an outer lipophilic ous methods can be used. The term “microencapsulation' vehicle by water. By Selecting appropriate monomers, net applies to enclosure or encasement in microcapsules. US 2003/0077297 A1 Apr. 24, 2003

Microencapsulation is a means of applying coatings to Small lets, which are Substantially Smaller in size than the Sub particles of Solids or droplets of liquids and dispersions. The Strate, impact the particles, spread, and Solidify. Multiple terms “coated,”“protected,” or “layered” are commonly layers can be coated, and the completion of Spraying is used interchangeably with the term “encapsulated”. All of followed by a product Stabilization or cooling Step. Some these terms can be used to refer to practically any core critical Success parameters include bed temperature, atomi material that is encased or enclosed in an outer shell. Typical Zation, atomization fluid temperature, droplet size, Spray equipment used to apply coating includes a conventional pan type, Spray rate, rate of coating droplet Solidification on (Pellegrini; Italy), a modified perforated pan (multicoater, particle Surfaces, particle size, shape, etc. Inert materials Thomas Eng., IL) or a Wurster coater in a Glatt powder Such as Sodium chloride, citric acid, and potassium chloride coater/granulator (Glatt Airtechniques). can Serve as Substrates. One skilled in the art can readily adjust Such parameters to achieve a Satisfactory product. 0266 Solvent Based Solution Coating: 0272. The processes described above are suitable for 0267 Solvent-based coating uses coating materials that producing Substrate-based particles or non-Substrate-based are Solubilized and/or dispersed in a Solvent. The Solvent can particles. In the latter case, the particulate material does not be acqueous or non-aqueous. When the Solvent is acqueous include any Seed particle (e.g., a conventional drug or other based, the components can be emulsified with an appropriate additive aggregate Starch or Sugar bead). Instead, the com emulsifier, organic Solvent, or a Supercritical fluid. Solvents positions are processed, and the components are chosen, with a lower melting point than water and higher vapor Such that a Solid composition is formed without need for a preSSures are preferred. Solvent mixtures with other organic substrate bead. The particles formed can be in the form of Solvents or water are often employed to achieve appropriate beadlets, beads, granules, pellets, etc., that have an approxi Viscosity and component Solubilization. Typical Solvents mately homogenous distribution. These particulates can be include ethanol, methanol, isopropanol, acetone, dichlo produced by means of balling in pelletizers or fluid bed romethane, trichloromethane, and ethyl acetate. Appropriate granulators, and compaction or extrusion/Spheronization. In polymers can also be added as needed. Cellulosic deriva addition, these particulates can be produced using Solvent tives and polymethacrylates are particularly Suitable addi free spray congealing processes or dropping (globulization) tives for organic Solvent coating. Dissolution and Solubili methods. Dropping procedures involve conversion of aque Zation of the components is facilitated by rigorous Stirring or ous Solutions or Suspensions to a Solid form. Congealing of heating. Plasticizers may be also be added to Stimulate the liquid droplets in cooling baths can be aided by a dissolution. Colorants and antisticking agents can be chemical reaction (e.g., insoluble Salt or complex forma employed as needed. tion), a Sol/gel transition, or by freezing in a coolant bath of 0268 Substrate surface area, shape, porosity, and stabil liquid nitrogen or halogenated hydrocarbons. ity are important determinants of good coating. Spherical particles are preferred, and these may be produced through 0273 VI. Stabilizing Agents: Spheronization or a spherical crystallization process. Crys 0274 The formulations of the present invention option tals or compact granules from dry compaction or extrusion ally include one or more Stabilizing agents to increase the processes, often available commercially, Serve as good Sub Stability and/or compatibility of the Suspension when for StrateS. mulated into a dosage form. Suitable Stabilizing agents are Suspending agents, flocculating agents, thickening agents, 0269. Encapsulation can be conducted by traditional pan gelling agents, buffering agents, antioxidants, preservatives, coating or fluidized bed techniques. Several process factors antimicrobial agents, and mixtures thereof. Ideally, the agent (air Supply, temperature, spray rate, spray System, powder acts to minimize irreversible aggregation of Suspended par feed, attrition) and formulation factors determine the quality ticles, and to maintain proper flow characteristics to ease of the end product, and one skilled in the art can readily manufacturing processes, e.g., to ensure that the formulation adjust Such parameters as needed. can be readily pumped and filled into desired dosage forms, 0270 Air Suspension in a rotary fluidized bed granulator Such as capsules. In Some instances, however, it may be can be used to deposit the encapsulation coat on to a desirable that the formulation have a high Viscosity, So that Substrate, thus allowing a high rate of coating application no leakage will occur before a capsule or other dosage form with low coating loSS. Furthermore, both aqueous and is permanently Sealed. organic Solvents can be used. The Wurster process, an air Suspension technique, is more Suitable for encapsulations 0275 A preferred stabilizing agent in most cases is a involving very fine powders. Suspending agent that imparts increased Viscosity and retards Sedimentation, to prevent caking. Any pharmaceuti 0271 Solvent-Free Coating: This process entails using cally acceptable excipient with Such attributes, of the many coating materials that can be applied in a molten State. The well known in the art, can be used as Such a Suspending Selection of proper coating materials depends on melting agent. Suitable Suspending agents include cellulose deriva point, melting point range, and the Viscosity in the liquid tives, clays, natural gums, Synthetic gums, or other agents State. A fluidized bed is ideal for molten coatings of Sub known in the art. Specific Suspending agents, by way of strates that range from about 100 micrometers to about 2000 example, include microcrystalline cellulose, Sodium car micrometers in size. Fluidized bed coating using Sprayed boxymethylcellulose, powdered cellulose, ethymethylcellu molten materials involves achieving a proper balance of lose, hydroyxypropyl methylcellulose, methylcellulose, eth process parameters that allow proper encapsulation to occur. ylcellulose, ethylhydroxy ethylcellulose, hydroxypropyl Substrate particles that are Suspended and Separated from cellulose, attapulgite, bentonite, hectorite, montmorillonite, each other by the fluidization air enter a Zone of finely Silica gel, fumed Silicon dioxide, colloidal Silicon dioxide, atomized coating liquid. Coating occurs as the liquid drop acacia, agar, carrageenan, guar gum, locust bean gum, US 2003/0077297 A1 Apr. 24, 2003 32 pectin, Sodium alginate, propylene glycol alginate, tamarind nated vegetable oil, hydrogenated Soybean oil flakes, and gum, Xanthan gum, carbomer, povidone, Sodium Starch other Similar water-indispersible waxy materials having a glycolate, Starches, tragacanth, magnesium aluminum sili melting point greater than about 50 C. By “substantially cate, aluminum Silicate, magnesium Silicate, gelatin, and free” of water-indispersible materials, e.g., “Substantially glycyrrhizin. These Suspending agents can further impart wax-free,” is meant that any Such materials represent leSS different flow properties to the suspension. The flow prop than 5 wt.% of the formulation, preferably less than 3 wt. erties of the Suspension can be Newtonian, plastic, pseudo %, more preferably less than about 1 wt.%. plastic, thixotropic or combinations thereof. Mixtures of Suspending agents may also be used to optimize flow 0280 The stabilizing agent may also be a buffering agent, properties and Viscosity. an antioxidant, or a preservative, and mixtures thereof. 0281 Although optional, Stabilizing agents are preferred 0276 The stabilizing agent may also be a flocculating components of the present formulations, providing a number agent that enables particles to associate in loose aggregates of advantages as described above. In particular, preferred or “flocs.” Although these flocS may settle rapidly, they are agents are used to form thixotropic (shear thinning) formu easily redispersed. Many flocculating agents known in the lations, So that the active agent particles can remain in art can be utilized, including Surfactants, hydrophilic poly Suspension for an extended time period, while at the same mers, clays, and electrolytes. Any other pharmaceutically time providing compositions that are readily processable for acceptable excipient with Such attributes can also be utilized encapsulation procedures or the like. Other preferred Stabi as a flocculating agent. In Some cases, the flocculating agent lizing agents give rise to thermosoftening preparations, may serve a dual purpose, Serving not only as a Stabilizing which, as noted above, are advantageous in that they can be agent but also, for example, as a component of the Solid reversibly liquified at the capsule filling temperature, and particles or as a Suspending agent. Suitable flocculating then Solidified at the Storage temperature, to provide good agents include, but are not limited to, Sodium lauryl Sulfate, manufacturability and stability. Most preferred are formu Sodium docusate, benzalkonium chloride, polySorbate 80, lations containing one or more Stabilizing agents that pro Sorbitan monolaurate, Sodium carboxymethylcellulose, Xan vide the formulations with both thixotropic and thermosoft than gum, tragacanth, methylcellulose, magnesium alumi ening properties. num Silicate, attapulgite, bentonite, potassium dihydrogen phosphate, aluminum chloride, and Sodium chloride. The 0282) VII. Other additives: formulation may include both a flocculating agent and a 0283. Other additives conventionally used in pharmaceu Suspending agent, So that the Sedimentation of flocs can be tical compositions can be included, and these additives are retarded. well known in the art. Such additives include detackifiers, 0277. The stabilizing agent may also be a thickening anti-foaming agents, chelating agents, tonicifiers, flavorants, agent, Selected to increase the Viscosity of the Suspension to colorants, odorants, opacifiers, binders, fillers, plasticizers, a degree Sufficient to reduce and retard Sedimentation of taste-masking agents, lubricants, and mixtures thereof. The Suspended active agent particles. Any pharmaceutically amounts of Such additives can be readily determined by one acceptable excipient with Such attributes can be used in the skilled in the art, according to the particular properties present invention. Typically, compounds that Soften slightly desired. above ambient temperature are desirable for this purpose. 0284. The formulations may also include one or more Preferred thickening agents have a melting point greater enzyme inhibitors, as described in commonly assigned U.S. than about 25 C., and can be reversibly liquified and Pat. No. 6,309,633 to Patel et al.; see also A. Bemskop Solidified. With an appropriate amount of Such a thickening Schnurch (1998), “The use of inhibitory agents to overcome agent, the formulation as a whole can acquire this ther enzymatic barriers to perorally administered therapeutic moSoftening property. peptides and proteins.J. Controlled Release 52:1-16. Suit 0278. The formulations of the invention preferably pro able inhibitors may function as either competitive or non vide for immediate release of that fraction of the active agent competitive inhibitors. Generally, enzyme inhibitors can be that is Solubilized in the vehicle, Such that the active agent divided into the following classes: inhibitors that are not is immediately available for absorption following adminis based on amino acids, Such as p-aminobenzamidine, FK-448 tration to a patient. Therefore, it is preferred that the Stabi (4-(4-isopropyl-piperazinocarbonyl)phenyl 1,2,3,4-tetrahy lized Suspension remain readily water-dispersible at a tem dro-1-naphthoate methaneSulfonate), camoStat meSylate, perature around body temperature, So that a rapid release of and Sodium glycocholate; amino acids and modified amino the Solubilized fraction of the active agent can be achieved. acids, Such as aminoboronic acid derivatives and n-acetyl Accordingly, preferred Stabilizing agents are not only able to cysteine; peptides and modified peptides, Such as bacitracin, Suspend, flocculate, and/or thicken the formulation, but also phosphinic acid dipeptide derivatives, pepstatin, antipain, capable of facilitating release of the active agent. Hydro leupeptin, chymostatin, elastatin, bestatin, phosphoramin philic polymers, hydrophilic Surfactants with a melting point don, puromycin, cytochalasin potatocarboxy peptidase greater than about 25 C., or mixtures thereof are particu inhibitor, and amastatin; polypeptide protease inhibitors, larly useful in this regard. Such as aprotinin (bovine pancreatic trypsin inhibitor), Bow man-Birk inhibitor and soybean trypsin inhibitor, chicken 0279 However, it is also preferred that the formulation egg white trypsin inhibitor, chicken OVoinhibitor, and human be Substantially free of any water-indispersible Suspending/ pancreatic trypsin inhibitor; complexing agents, Such as thickening agent, So that the Overall water dispersibility of EDTA, EGTA, 1,10-phenanthroline and hydroxychinoline; the Suspension is not compromised. Accordingly, the for and mucoadhesive polymers and polymer-inhibitor conju mulation should be Substantially free of materials. Such as gates, Such as polyacrylate derivatives, chitosan, cellulosics, beeswax, paraffin, yellow wax, hydrogenated oils, hydroge chitosan-EDTA, chitosan-EDTA-antipain, polyacrylic acid US 2003/0077297 A1 Apr. 24, 2003 bacitracin, carboxymethyl cellulose-pepStatin, and poly (e.g., included in the vehicle), or it may represent a coating acrylic acid-Bowman-Birk inhibitor. on a dosage form, e.g., on a capsule, tablet, or caplet, or on each of a plurality of granules, beads, or pellets. The bile Salt 0285) The selection and amount of any enzyme inhibitor or acid may take any number of physical forms, e.g., it may will depend on toxicity, Specificity, and potency. be in crystalline, amorphous, nanosized, micronized or 0286 The formulations may also include an absorption milled form. promoter, which can facilitate the absorption of active agent 0291 VIII. Dosage Forms and Administration Routes: released, particularly Suspended active agent. Accordingly, in one alternative embodiment of the invention, part or all of 0292. The pharmaceutical compositions and systems of the Solubilized drug fraction may be replaced by an absorp the present invention are preferably formulated for oral tion promoter. Suitable absorption promoters are described, administration, although other modes of administration are for example, in co-pending U.S. patent application Ser. No. contemplated as well. For oral administration, the Suspen 09/751,968 to Chen et al. for “Pharmaceutical Dosage Sion can be formulated as a liquid or Solid (e.g., powdered) Forms for Oral Administration of Hydrophilic Drugs, Par concentrate, or as an aqueous or organic diluted concentrate. ticularly Low Molecular Weight Heparin,” filed Dec. 29, In the diluted form, the diluent can be water, an aqueous 2000 and assigned to Lipocine, Inc. (Salt Lake City, Utah), Solution, a buffer, an organic Solvent, a beverage, ajuice, or published on Sep. 27, 2001 under Publication No. mixtures thereof. If desired, the diluent can include compo 20010024658. The absorption enhancers described in com nents dissolved or Suspended therein, Such as an active monly assigned U.S. Pat. No. 6,309,633 to Patel et al. may agent, an enzyme inhibitor, Solubilizers, additives, and the also Serve as Suitable absorption promoters in the present like. compositions and Systems. 0293. In a preferred embodiment, the oral dosage form is 0287 Preferred absorption promoters are bile acids and comprised of an encapsulated composition, wherein the bile Salts. AS well known in the art, bile acids are naturally pharmaceutical formulation is typically contained in a cap occurring Surfactants having a nucleus derived from Sule. The capsule can be a hard or Soft gelatin capsule, a cholanic acid and are Substituted with a 3a-hydroxyl group Starch capsule, or a cellulosic capsule. For a two-piece and optionally with other hydroxyl groups as well, typically capsule, the capsule can be further Sealed either by a banding at the C, C, or C. position of the Sterol nucleus. Bile acids or a spray Sealing mechanism after filling with the Suspen include, for example, cholic acid, deoxycholic acid, litho Sion formulation. Such dosage forms (as well as other Solid cholic acid, chenodeoxycholic acid (also referred to as dosage forms, Such as tablets, caplets, granules, pellets, and "chenodiol” or "chenic acid”), and urSodeoxycholic acid. beads) can further be coated with, for example, a seal The aforementioned acids are “unconjugated' bile acids in coating, an enteric coating, an extended release coating, a that the carboxyl group extending from the C7 position of targeted delayed release coating, a film coating, a barrier the Sterol nucleus is in free acid form. Bile acids may also coating, a compressed coating, a fast disintegrating coating, be “conjugated,’ typically by reaction of the aforementioned or an enzyme degradable coating. As a result, the dosage carboxyl group with the free amine moiety of form can be designed for immediate release, controlled (HNCHCOOH) or (HNCHCHSOH) to form a release, extended release, delayed release, targeted release, peptide linkage. Conjugated bile acids thus include, for Synchronized release, or targeted delayed release. Multicom example, taurocholic acid, taurodeoxycholic acid, tauroli partment capsules can also be utilized for multi-stage release thocholic acid, taurochenodeoxycholic acid, taurourSode or pulsatile release of one or more than one active agent. Oxycholic acid, glycocholic acid, glycodeoxycholic acid, Different active agents can be mixed or Separated in different glycolithocholic acid, glycochenodeoxycholic acid, and gly compartments Such that they can be released at different courSodeoxycholic acid. Any of the aforementioned bile Stages or released according to different profiles. Multiple acids can be advantageously used in conjunction with the coatings can be applied for a desired performance. present invention. The bile acids may also be in the form of 0294 The formulations of the invention can also be a Salt, in which case the acidic functionality is ionized and formulated as an osmosis-based dosage form for oral admin asSociated with a cationic counter-ion, e.g., Sodium, potas istration or for implants. The osmosis-based dosage form sium, ammonium, or the like. In addition, the bile acids can be an osmotic capsule or an osmotic tablet filled with the herein may be in the form of a choleic acid, wherein a bile Suspension formulation. Different coatings can further be acid forms a coordination complex with another compound, applied to the capsule or tablet depending on the adminis typically although not necessarily a fatty acid. tration routes and desired release profile of the active agent. 0288 Particularly preferred bile acids for use herein are 0295) These various coatings are known in the art, but for urSodeoxycholic acid and chenodeoxycholic acid, and when clarity, the following brief descriptions are provided: used in the Salt form, the Sodium Salt is particularly pre 0296 Seal coating, or coating with isolation layers: Thin ferred. layers of up to 20 micrometers in thickness can be applied for variety of reasons, including particle porosity reduction, 0289. It will be appreciated by those of skill in the art that to reduce dust, for chemical protection, to mask taste, to bile “acids” and bile “salts herein are interchangeable, in that reduce odor, to minimize gastrointestinal irritation, etc. The the form of the compound will depend on the pH of the isolating effect is proportional to the thickness of the coat Surrounding environment. That is, at lower pH, a bile acid ing. Water-soluble cellulose ethers are preferred for this will be in the form of the free acid, while at higher pH, the application. Hydroxypropyl methyl cellulose and ethyl cel Salt form will predominate. lulose in combination, or Eudragit E100, may be particularly 0290 The bile salt or acid in the present compositions Suitable for taste-masking applications. Such coating mate and dosage forms may be an integral part of the formulation rials can also be applied to form an isolating layer. US 2003/0077297 A1 Apr. 24, 2003 34

0297 Extended Release Coating: 0304 Cellulose Derivatives (also preferred). Examples of suitable cellulose derivatives are ethyl cellulose and 0298 The term “extended release coating” as used herein reaction mixtures of partial acetate esters of cellulose with means a coating designed to effect delivery over an extended phthalic anhydride. The performance can vary based on the period of time. Preferably, the extended release coating is a degree and type of Substitution. Cellulose acetate phthalate pH-independent coating formed of, for example, ethyl cel (CAP) dissolves in pH>6. Aquateric(R) (FMC) is an aqueous lulose, hydroxypropyl cellulose, methylcellulose, based System and is a Spray dried CAP pSuedolatex with hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic particles <1 um. Other components in Aquateric can include esters, or Sodium carboxymethyl cellulose. Various extended pluronics, Tweens, and acetylated monoglycerides. Other release dosage forms can be readily designed by one skilled examples of Suitable cellulose derivatives are cellulose in the art to achieve delivery to both the small and large acetate trimellitate (Eastman); methylcellulose (Pharma intestines, to only the Small intestine, or to only the large coat(R), Methocel(R); hydroxypropyl methyl cellulose phtha intestine, depending upon the choice of coating materials late (HPMCP; the performance can vary based on the degree and/or coating thickness. and type of substitution; HP-50, HP-55, HP-55S, HP-55F 0299 Enteric Coating: grades are Suitable), hydroxypropyl methyl cellulose Succi 0300. The term “enteric coating” as used herein relates to nate (HPMCS; available as Aqoate from Shin Etsu); the a mixture of pharmaceutically acceptable excipients that is performance can vary based on the degree and type of applied to, combined with, mixed with, or otherwise added substitution; suitable grades include AS-LG (LF), which to the carrier or composition. The coating may be applied to dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, a compressed, molded, or extruded tablet, a capsule; and/or and AS-HG (HF), which dissolves at higher pH; these pellets, beads, granules or particles of the carrier or com polymers are offered as granules, or as fine powders for position. The coating may be applied through an aqueous aqueous dispersions); and polyvinyl acetate phthalate dispersion or after dissolving in appropriate Solvent. Addi (PVAP, which dissolves in pH>5, and it is much less tional additives and their levels, and Selection of a primary permeable to water vapor and gastric fluids). Combinations coating material or materials, will depend on the following of the above materials can also be used. properties: resistance to dissolution and disintegration in the 0305 The coating can, and usually does, contain a plas Stomach; impermeability to gastric fluids and drugS/carrierS/ ticizer and possibly other coating excipients Such as colo enzymes while in the Stomach; ability to dissolve or disin rants, talc, and/or magnesium Stearate, which are well tegrate rapidly at the target intestine Site, physical and known in the art. Suitable plasticizers include: triethyl chemical stability during storage; lack of toxicity; ease of citrate (Citroflex(R 2), triacetin (glyceryl triacetate), acetyl application as a coating, and economical practicality. triethylcitrate (Citroflex(R A-2), Carbowax 400 (polyethyl 0301 Delayed release formulations herein enable drug ene glycol 400), diethyl phthalate, tributyl citrate, acetylated release at Some generally predictable location in the lower monoglycerides, glycerol, fatty acid esters, propylene gly intestinal tract more distal to that which would have been col, and dibutyl phthalate. In particular, anionic carboxylic accomplished if there had been no delayed release feature. acrylic polymers usually will contain 10-25% by weight of The preferred method for delay of release is coating. Such a plasticizer, especially dibutyl phthalate, polyethylene gly coatings should be applied at a Sufficient thickness Such that col, triethylcitrate, and triacetin. Conventional coating tech the entire coating does not dissolve in the gastrointestinal niques Such as Spray or pan coating are employed to apply fluids at pH below about 5, but does dissolve at pH about 5 coatings. The coating thickness must be Sufficient to ensure and above. It is expected that any anionic polymer exhibiting that the oral dosage form remains intact until the desired site a pH-dependent Solubility profile can be used as an enteric of topical delivery in the lower intestinal tract is reached. coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. The preferred 0306 Colorants, detackifiers, surfactants, antifoaming polymers for use in the present invention are anionic car agents, lubricants, stabilizers (such as hydroxy propyl cel boxylic polymers. The more preferred polymers and com lulose), acids, or bases may be added to the coatings in patible mixtures thereof, and Some of their properties, addition to plasticizers to Solubilize or disperse the coating include, but are not limited to: material and to improve coating performance. 0302 Shellac, also called purified lac, a refined product 0307. A particularly suitable methacrylic copolymer is obtained from the resinous Secretion of an insect. This Eudragit L, particularly L-30D and L-100-55, manufactured coating dissolves in media of pH>7. by Rohm Pharma, Germany. In Eudragit L-30 D, the ratio of free carboxyl groups to ester groups is approximately 1:1. 0303 Acrylic polymers (preferred). The performance of Further, the copolymer is known to be insoluble in gas acrylic polymers (primarily their Solubility in biological trointestinal fluids having pH below 5.5, generally 1.5-5.5 fluids) can vary based on the degree and type of Substitution. (i.e., the pH generally present in the fluid of the upper Examples of Suitable acrylic polymers include methacrylic gastrointestinal tract), but is readily Soluble or partially acid copolymers and ammonio methacrylate copolymers. soluble at pH above 5.5 (i.e., the pH generally present in the The Eudragit(R) series E, L, S, RL, RS, and NE (Rohm fluid of lower gastrointestinal tract). Pharma) are available Solubilized in organic Solvent, aque ous dispersion, or dry powders. The EudragitE Series RL, 0308 Another methacrylic acid polymer that is suitable NE, and RS are insoluble in the gastrointestinal tract but are for use in coating the composition or Solid carrier, which can permeable and are used primarily for extended release. The be employed in the compositions and methods described Eudragit(R) series E dissolve in the stomach. The Eudragit(R) herein, either alone or in combination with other coatings, is series L., L-30D, and S are insoluble in the stomach and Eudragit S, manufactured by Rohm Pharma, Germany. dissolve in the intestine. Eudragit S differs from Eudragit L-30-D only insofar as the US 2003/0077297 A1 Apr. 24, 2003 ratio of free carboxyl groups to ester groups is approxi Sion, melting, extrusion, drying, chilling, molding, Spraying, mately 1:2. Eudragit S is insoluble at pH below 5.5, but coating, comminution, mixing, homogenization, Sonication, unlike Eudragit L-30-D, is poorly Soluble in gastrointestinal and granulation, to produce a desired dosage form. Upon fluids having pH of 5.5-7.0, such as is present in the small administration or upon dispersion, the further-processed intestine fluids. This copolymer is soluble at pH 7.0 and composition can be reconstituted back to the Suspension above (i.e., the pH generally found in the colon). Eudragit S formulation. Alternatively, the Suspension can be reconsti can be used alone as a coating to provide delivery beginning tuted prior to administration. The compositions of the at the large intestine via a delayed release mechanism. In present invention are not limited to particular Solid dosage addition, Eudragit S, being poorly Soluble in intestinal fluids forms. Thus, compositions of the present invention can be below pH 7, can be used in combination with Eudragit formulated as, for example, pills, capsules, caplets, tablets, L-30-D, which is soluble in intestinal fluids above pH 5.5, granules, beads, pellets, or powders. Granules, beads, and in order to effect a delayed release composition. The more powders can, of course, be further processed to form pills, Eudragit L-30 D used, the more proximal the release and capsules, caplets, or tablets. delivery begins, and the more Eudragit S used, the more 0314. It is to be understood that while the invention has distal the release and delivery begins Both Eudragit L-30-D been described in conjunction with the preferred specific and Eudragit S can be Substituted with other pharmaceuti embodiments thereof, the foregoing description as well as cally acceptable polymers that have Similar pH Solubility the examples that follow are intended to illustrate and not characteristics. limit the Scope of the invention. Other aspects, advantages, 0309 Preferred coating materials include shellac, acrylic and modifications within the scope of the invention will be polymers, cellulosic derivatives, polyvinyl acetate phthalate, apparent to those skilled in the art to which the invention and mixtures thereof. More preferred materials include pertains. Eudragit series E, L, S, RL, RS, NE, L, L300, S, and 100-55, cellulose acetate phthalate (including that commercially 0315 All patents, patent applications, and publications available as AquatericE), cellulose acetate trimellitate, ethyl mentioned herein are hereby incorporated by reference in cellulose, hydroxypropyl methyl cellulose phthalate, their entireties. hydroxypropyl methyl cellulose Succinate, and polyvinyl Experimental acetate phthalate (including that commercially available from Colorcon as Sureteric(R). Most preferred materials 0316 The practice of the present invention will employ, include Eudragit series L., L300, S, and LiO0-55, cellulose unless otherwise indicated, conventional techniques and acetate phthalate, ethyl cellulose, hydroxypropyl methyl equipment used in the fields of pharmaceutical formulation cellulose phthalate, hydroxypropyl methyl cellulose Succi and drug delivery, which are within the skill of the art and nate, and polyvinyl acetate phthalate. described in the pertinent texts and literature. See, for example, Remington. The Science and Practice of Phar 03.10 Extended release and targeted delayed release coat macy, Nineteenth Ed. (Easton, Pa.; Mack Publishing Com ings for dosage forms of the four compositions of the present pany, 1995). In the following examples, efforts have been invention are described more completely in U.S. Pat. Nos. made to ensure accuracy with respect to numbers used (e.g., 5,622,721 and 5,686,105, the disclosures of which are amounts, temperatures, etc.) but Some experimental error incorporated herein by reference. and deviation should be accounted for. Unless otherwise 0311 Fast-Disintegrating Coatings for Immediate indicated, temperature is in degrees Celsius and pressure is Release: An immediate release coating is commonly used to at or near atmospheric pressure at Sea level. All reagents improve product appearance as well as to provide a moisture were obtained commercially unless otherwise indicated. barrier and for taste and odor masking. Rapid breakdown of the film in gastric fluids is necessary, leading to rapid 0317. Also, in these examples, the tradenames used are as disintegration and dissolution. Eudragit RD100 (Rohm) is follows: an example of Such a coating. It is a combination of a 0318 Capryol(R) 90=propylene glycol monocaprylate, water-insoluble cationic methacrylate copolymer with a lipophilic Surfactant (Gattefosse); water-soluble cellulose ether. In powder form, it is readily 03.19 Captex(R 810D=glycerol tricaprylate/caprate/li dispensable into an easily Sprayable Suspension that dries to leave a Smooth film. Such films rapidly disintegrate in noleate, a triglyceride composition (Abitec); aqueous media at a rate that is independent of pH and film O320 Cremopnor hor(E) EL=PEG-35=PEG-35 castor oil,il, a hvidhydro thickness. philic surfactant (BASF); 0312 Although the compositions of the present invention 0321) Cremophor RH40=PEG-40 hydrogenated castor are specifically Suited to oral administration, which is pres oil, a hydrophilic surfactant (BASF); ently preferred, they can also be formulated as injectable 0322 Gelucire(R 44/14=lauroyl macrogol-32 glycer dosage forms for intravenous, intramuscular, Subcutaneous, and intraperitoneal administration. The compositions of the ide, including triglycerides (Gattefosse); present invention can also be formulated for topical, trans 0323 Etocas(R 35=PEG-35 castor oil, a hydrophilic dermal, buccal, ocular, pulmonary, vaginal, rectal, transmu Surfactant (Croda); cosal, or other modes of administration. 0324 Imwitor(R 742=an esterification product of a 0313 The formulations of the present invention can be mixture of approximately 60 parts by weight (ppw) of further processed according to conventional processes caprylic acid and approximately 40 parts by weight known to those skilled in the art. Such processes include, (ppw) of capric acid with glycerol, a lipophilic Surfac without limitation, lyophilization, encapsulation, compres tant (Hils); US 2003/0077297 A1 Apr. 24, 2003 36

0325 Kollidon(R) K17=polyvinyl pyrrolidone, molecu ture of the liquid to about 70° C. and using an appropriate lar weight 7K-11K, a solubilizer (BASF); mixer to facilitate dissolution of the antioxidant. The Solu 0326 Kollidon(R) K30=polyvinyl pyrrolidone, molecu tion of the antioxidant may be cooled to about 40-50 C. or lar weight 44K-54K, a solubilizer (BASF); maintained at a higher temperature, for example 70° C. as a 0327 Labrafile M2125CS=PEG-6 corn oil, a lipo liquid. Isotretinoin was Stirred into the liquid to give a philic Surfactant (Gattefosse); homogeneous dispersion. To prevent the Settling of Solid 0328. Labrasol(R)=PEG-8 caprylic/capric glycerides, a particles of isotretinoin and in order to maintain homoge hydrophilic Surfactant; neity, Lutrol F68 was added. Addition of a chelating agent 0329. Lutrol(R) F68=poloxamer 188, a copolymer of Such as disodium ethylene diamine tetraacetic acid (EDTA) 81% PEG and 19% PPG, a hydrophilic surfactant can also be advantageous in this regard. Mixing was con (BASF); tinued until the Lutrol F68 was uniformly incorporated and 0330 Maisine(R 35-1=glyceryl monolinoleate, a lipo a homogeneous Suspension formed. The Same procedures philic Surfactant (Gattefosse); were used to prepare the formulations of Examples 2-4. 0331 Methocel(R) E3=hydroxypropyl methylcellulose, 0337 Alternatively, Lutrol F68 can be first stirred into the a delayed release coating material (Dow Chemical); oily base of soybean oil and Maisine 35-1 at about 60-70° C. 0332 Miglyol(R) 812=glyceryl tricaprylate/caprate, a until it is uniformly incorporated. Isotretinoin can then be triglyceride composition (Hils); directly Stirred into the mixture to a homogeneous Suspen 0333) Myvacet(R) 9-45=mono-and diacetylated Sion. AS another alternative, the isotretinoin can be first monoglycerides, a lipophilic Surfactant (Eastman); and dispersed in a fraction of the oily base of Soybean oil and 0334) Vitamin TPGS=d-C-tocopheryl PEG-1000 suc Maisine 35-1 prepared as described above, and then stirred cinate, a Solubilizer (Eastman). into the Lutrol F68 containing mixture. However, it should be appreciated that the order and the extent of mixing and EXAMPLES 1-4 heat of individual component of the composition can be 0335 Pharmaceutical suspension formulations contain arranged differently to obtain a homogeneous Suspension of ing isotretinoin were prepared containing the components isotretinoin. indicated below. 0338 If size reduction of isotretinoin particles is desired, various conventional processes Such as grinding, milling, Composition (mg) and/or homogenization can be applied to reduce the active agent particle size. The active agent can be size reduced in Example 1 the absence of soybean oil, Maisine 35-1, and Lutrol F68. Isotretinoin 40 The size of the isotretinoin particles can be directly reduced Soybean Oil 2OO to about 5-30 um by a high Shear homogenizer, Such as Maisine (E) 35-1 1OO Lutrol (R) F68 1OO impeller-type shear mixers from Arde Barinco, Koruma, Example 2 GEI Krieger and Silverson and wet mills from VMA Getzmann GMBH and Willy Bachofen AG Maschinenfab Isotretinoin 40 Labrafil (R) M2125CS 2OO rik). Alternatively, the size of the active agent particles can Cremophor (R) RH40 2OO be reduced to about 50-70 um using a high shear homog Vitamin ETPGS 1OO enizer. In a two-step size reduction, the size of the isotret Example 3 inoin can be further reduced to about 5-30 um Subsequently Isotretinoin 40 using a liquid jut micronizer, for example, Microfluidizer(R) Soybean Oil 1OO by Mirofluidics Corp. Labrafil (R) M2125CS 1OO Cremophor (R) RH40 2OO Lutrol (R) F68 1OO 0339. The isotretinoin in Example 3 can be size reduced Example 4 in the oily base of soybean oil with or without an antioxidant Such as BHA. The isotretinoin can also be co-size reduced Isotretinoin 40 with the remaining components using the processes Miglyol (R) 812 2OO Imwitor (E) 742 2OO described above. The size reduction can be performed at any Vitamin ETPGS 400 conventional temperature at which the desired size reduction PEG 3350 1OO may be achieved. However, it is preferred to carry out the size reduction in the range of 15-50 C., particularly at room temperature. 0336. In Example 1, the formulation was prepared by admixing Soybean oil and Maisine 35-1 and warming the mixture to about 40-50 C. to provide a liquid. Any anti EXAMPLES 5-11 oxidant, for example, butylated hydroxyanisole (BHA) or 0340 Pharmaceutical suspension formulations contain butylated hydroxytoluene (BHT), in an appropriate amount, ing isotretinoin are prepared containing the components can be added to the mixture by further raising the tempera indicated below, using the procedures of Examples 1-4. US 2003/0077297 A1 Apr. 24, 2003 37

Example 13 0343 Absorption of Isotretinoin from the Composition of Composition (mg) the Present Invention: Example 5 0344) Absorption of isotretinoin from formulations of the present invention was compared with that obtained with a Isotretinoin 8O Soybean Oil 2OO conventional Suspension formulation (Accutane(R) in rats. Maisine (E) 35-1 OO The composition of Example 4 (containing at least 20% Lutrol (R) F68 OO Solubilized isotretinoin) and Accutane(E) were given to fasted Sodium Lauryl Sulfate 2O male Sprague-Dawley rats at about 10 mg/kg by intra Example 6 duodenum injection followed by infusing Ringer's Solution Isotretinoin OO in an amount of about 1% of the animal's body weight at a Soybean Oil 2OO rate of 0.1 ml/ml. The blood was withdrawn from the rats by Maisine (E) 35-1 OO heart puncturing at an interval of 15-30 min for at least 90 Lutrol (R) F68 OO Kollidon (E) K30 OO min. The isotretinoin in the blood samples was extracted by Example 7 acetonitrile and injected to HPLC for quantitative analysis. The absorption of isotretinoin in rats from the Suspension of Isotretinoin 40 the invention was found to be significantly better than that Maisine (E) 35-1 400 from the conventional commercial Suspension formulation Gelucire (R) 44f14 2OO Lutrol (R) F68 OO (wherein less than 10% of the isotretinoin is solubilized), as Example 8 illustrated in FIG. 6.

Isotretinoin 40 EXAMPLES 14-26 Maisine (E) 35-1 50 Cremophor (R) RH40 50 0345 Pharmaceutical suspension formulations contain Lutrol (R) F68 OO ing the lipid-regulating agent fenofibrate were prepared Example 9 containing the components indicated below. Isotretinoin 40 Labrafil (R) M2125CS 2OO Cremophor (R) RH40 2OO Lutrol (R) F68 1OO Composition (mg) Example 10 Example 14 Isotretinoin 40 Labrafil (R) M1944CS 150 Fenofibrate 134 Cremophor (R) RH40 1OO Myvacet (R) 9-45 335 Gelucire (R) 53/13 150 Etocas (E) 35 335 Example 11 PEG 3350 1OO Example 15 Isotretinoin 40 Glyceryl Cocoate 1OO Fenofibrate 135 Lauroglycol FCC 2OO Myvacet (R) 9-45 335 Vitamin ETPGS 350 Etocas (E) 35 335 PEG 3350 150 Sodium Lauryl Sulfate 6 Example 16

Fenofibrate 160 Myvacet (R) 9-45 350 Example 12 Etocas (E) 35 350 Sodium Lauryl Sulfate 2O 0341 Preparation of dosage forms containing the formu Water 2O lations of Examples 1-11, containing at least 20% Solubi Example 17 lized active agent: Fenofibrate 135 Cremophor (R) EL 28O 0342. The suspension formulations of Examples 1-11 can Labrasol (R) 18O be processed to provide pharmaceutically acceptable dosage Labrafil (R) M2125CS 28O forms containing a Sufficient amount of isotretinoin So that Glycerol 1O a therapeutically effective level of isotretinoin can be Propylene Glycol 25 achieved in the treated Subject upon administration of the Example 18 dosage form. The compositions can be included in a unit Fenofibrate 135 dosage form to provide 5-100 mg of isotretinoin per unit Cremophor (R) EL 28O dosage form. A preferred dosage form is a capsule encap Labrasol (R) 1OO Labrafil (R) M2125CS 28O Sulating the formulation. The capsule shell can be made of Lutrol (R) F68 50 any conventional capsule material, e.g., gelatin, Starch, or Fumed Silicon Dioxide 3O cellulose. The preferred capsule is a Soft gelatin capsule. The Example 19 Suspension formulation can be filled into the capsule using Fenofibrate 135 conventional filling machines. If a two-piece hard gelatin Cremophor (R) EL 2OO capsule is used, the filled capsule can be further banded or Labrasol (R) 12O Spray Sealed with a Sealing Solution to prevent leakage of the Labrafil (R) M2125CS 2OO formulation from the capsule. US 2003/0077297 A1 Apr. 24, 2003 38

fenofibrate and sodium lauryl sulfate in a volatile solvent, -continued and Subsequently removing the Solvent. The resulting Solid Composition (mg) may be ground into a fine powder for preparing the Suspen Sion. Sodium Lauryl Sulfate 27 Kollidon (E) K17 50 0348. In Example 16, 60 mg offenofibrate was dissolved Example 20 in the mixture of Myvacet 9-45 and Etocas 35 to obtain a Fenofibrate 135 clear solution. To this solution, 100 mg micronized fenofi Cremophor (R) EL 2OO brate intimately mixed with sodium laurylsulfate was added Labrasol (R) 12O Labrafil (R) M2125CS 2OO and mixing was continued until a homogenous dispersion Methocel(R) E3 90 was obtained. Water, as a gelling agent, was then introduced Sodium Carboxymethyl- 50 to the dispersion and mixed evenly to obtain the final cellulose Suspension. Similarly in Example 18, to a homogenous Example 21 dispersion of an intimate mixture of fenofibrate and Sodium Fenofibrate 1OO laurylsulfate in a solution in which 45 mg offenofibrate are Cremophor (R) RH40 150 “predissolved” in a mixture of Cremophor EL, polysorbate Labrafil (R) M2125CS 150 Vitamin ETPGS 150 80, Labrasol, and Labrafil M2125CS, aluminum monostear C-tocopherol 1OO ate (a gelling agent) was added and mixed evenly to obtain Lutrol (R) F68 50 the final Suspension. Example 22

Fenofibrate 90 0349. In Example 19, 90 mg of fenofibrate was sus EtOcas (E) 35 150 pended in an aqueous solution of Kollidon K17. The water Capryol (R) 90 150 was removed by Spray drying and fenofibrate particles Vitamin ETPGS 150 Triethyl Citrate 50 coated with Kollidon K17 were obtained. The coated par Microcrystalline Cellulose 1OO ticles were ground with Sodium lauryl Sulfate and then Example 23 Suspended in a mixture of Cremophor EL, Labrasol, and Fenofibrate 135 Labrafil M2125CS in which 45 mg of fenofibrate was Cremophor (R) EL 240 already Solubilized, to obtain the final Suspension. Labrafil (R) M2125CS 2OO Vitamin ETPGS 240 0350 Similar procedures were used to prepare the C-tocopherol 8O remaining formulations. Propylene Glycol 40 Example 24 EXAMPLES 27-33 Fenofibrate 135 Cremophor (R) EL 338 0351 Pharmaceutical suspension formulations contain Labrafil (R) M2125CS 187 ing fenofibrate are prepared containing the components Labrasol (R) 225 Example 25 indicated below, using the procedures of Examples 14-26. Fenofibrate 135 Cremophor (R) EL 338 Polysorbate 80 187 Composition (mg) Labrasol (R) 225 Example 26 Example 27

Fenofibrate 135 Fenofibrate 135 Cremophor (R) EL 450 Cremophor (R) EL 28O Labrasol (R) 3OO Labrasol (R) 1OO Polysorbate 80 8O Labrafil (R) M2125CS 28O Sodium Lauryl Sulfate 15 0346. In Example 14, micronized fenofibrate was dis Aluminum monostearate 15 persed in the mixture of Myvacet 9-45 and Etocas 35, and Example 28 molten PEG was then added and homogenized to obtain the Fenofibrate 1OO Suspension. Cremophor (R) RH40 150 Labrafil (R) M2125CS 150 0347 In Example 15, the composition was prepared as Vitamin ETPGS 150 follows. 60 mg of fenofibrate was mixed with sodium lauryl C-tocopherol 1OO Sulfate. The resulting powder mixture was added to a Magnesium Aluminum 50 Myvacet 9-45/Etocas 35 mixture containing an already Silicate solubilized 75 mg of fenofibrate, and the dispersion was Example 29 homogenized until a homogeneous Suspension was Fenofibrate 135 obtained. Alternatively, to prepare the Suspended fraction of Cremophor (R) EL 18O Labrafil (R) M2125CS 140 fenofibrate, 60 mg of fenofibrate may be heated to its Vitamin ETPGS 18O melting point or Slightly above and held as a liquid. Sodium Kollidon (E) K30 45 lauryl Sulfate may then be added to form a fused mixture, Mannitol 45 which is then allowed to cool and solidify. As another Propylene Glycol 25 alternative, the mixture may be prepared by dissolving US 2003/0077297 A1 Apr. 24, 2003 39

water-dispersible vehicle, in turn facilitating the dissolution -continued of Suspended particles. Compared with the commercial product, the rate and the extent of dissolution of fenofibrate Composition (mg) from a single capsule of the present invention was found to Example 30 be superior to that observed two Tricor 67 mg capsules combined. Fenofibrate 160 Pravastatin 40 EXAMPLE 36 Cremophor (R) EL 250 Polysorbate 80 170 0356. Absorption of Fenofibrate from the Formulations Labrafil (R) M2125CS 250 Example 31 of the Present Invention in Dogs: 0357 The absorption of fenofibrate in dogs using sus Fenofibrate 1OO Simvastatin 2O pension formulations of the invention was determined. The Cremophor (R) EL 2OO capsules prepared in Example 15 were administered to a Vitamin ETPGS 2OO group of fed Beagle dogs at a dose of 134 mg/dog (one Example 32 capsule per dog for the composition of Example 15 of the Fenofibrate 67 present invention and two capsules for a Solubilized formu Cremophor (R) EL 3OO lation). The plasma concentrations of fenofibric acid were Example 33 determined by HPLC. Concentrations were normalized to a 13.4 mg/kg dose in each dog. FIG. 9 presents the resulting Fenofibrate 2OO data and indicates that the Suspension formulation of the C-tocopherol 500 present invention, with a significant fraction of the active ingredient Solubilized as a loading dose, is able to provide comparable bioavailability to a completely solubilized for EXAMPLE 34 mulation at the same dose Strength but with only one 0352 Preparation of Dosage Forms Containing the Sus capsule. This demonstrates the advantage of the present pension Formulations of Examples 14-33: invention being able to increase the drug loading in a Single unit dosage form and yet provide Sufficient absorption of the 0353. The suspension formulations of Examples 14-33 active ingredient with only one capsule to improve the can be processed to provide pharmaceutically acceptable patient compliance. From the plasma profile, it also dem dosage forms containing a Sufficient amount of fenofibrate onstrates that the Suspension formulation is able to alleviate So that a therapeutically effective level of the lipid-regulat the high peak concentration frequently associated with a ing agent can be achieved in the treated Subject upon completely solubilized formulation. This has the potential administration of the dosage form. The compositions can be benefit of reducing the risk of toxicity resulted from the high included in a unit dosage form to provide 10-200 mg of exposure of certain organs/tissues to the active ingredient by fenofibrate per unit dosage form. A preferred dosage form is a completely Solubilized formulation. a capsule encapsulating the formulation. The capsule shell can be made of any conventional capsule material, e.g., EXAMPLE 37 gelatin, Starch, or cellulose. The preferred capsule is a Soft 0358) A pharmaceutical Suspension formulation contain gelatin capsule. The Suspension formulation can be filled ing progesterone was prepared containing the following into the capsule using conventional filling machines. If a two-piece hard gelatin capsule is used, the filled capsule can components: be further banded or Spray Sealed with a Sealing Solution to prevent leakage of the formulation from the capsule. Composition (mg) EXAMPLE 35 Progesterone 1OO 0354) Dissolution of Fenofibrate from the Formulations Capryol (R) 90 250 of the Present Invention: EtOcas (E) 35 250 PEG 3350 1OO 0355 The fenofibrate formulations of Examples 14 and 15, in which the fraction of solubilized fenofibrate is greater than 30%, were filled into gelatin capsules for a dissolution 0359 Micronized progesterone was dispersed in the mix Study to compare the release profile with that of a commer ture of Capryol(R) 90 and Etocas(R 35, and molten PEG was cial product, the Tricor(R) fenofibrate capsule (Abbott). The then added and homogenized to provide a Suspension. The dissolution study was carried out using a USP type I Suspension was heated slightly So that it was fluid enough to dissolution apparatus at 100 rpm, 37 C., in 1L of dissolution be filled into hard gelatin capsules. After filling and cooling medium containing SGF and 25 mM sodium lauryl Sulfate at room temperature, the fill material became Viscous and or 2% Tween 80. One capsule containing 134 mg fenofibrate incapable of freely flowing ensuring that the formulation of Example 14 or Example 15 or two Tricor 67 mg capsules would not leak out of the capsule even if the capsule were were placed in the basket. At a given time, the dissolution not to be banded or sealed. medium was filtered and assayed by HPLC to determine the release of fenofibrate. The dissolution results shown in EXAMPLES 38-47 FIGS. 7 and 8 demonstrate the Superior release of fenofi 0360 Pharmaceutical suspension formulations contain brate from the novel Suspension formulation in which a ing progesterone and/or estradiol were prepared with the Significant fraction of the drug is Solubilized in the highly components indicated below. US 2003/0077297 A1 Apr. 24, 2003 40

capsule (size 6) is then further encapsulated in a larger two-piece hard gelatin capsule (size 3) containing the other 1 mg of estradiol solubilized in the mixture of Capryol 90 Composition (mg) and Cremophor RH40. Both of the capsules can be sealed or Example 38 banded to prevent leakage of the fill material, using methods well known in the art. Progesterone 1OO C-tocopherol 130 0363. In Example 43, 2 mg of estradiol and 30 mg of Vitamin ETPGS 260 progesterone is mixed with 50 mg of lactose and encapsu Labrafil. M2125CS 230 Propylene Glycol 90 lated in a Small two-piece hard gelatin capsule (size 6), then Cremophor EL 28O further encapsulated in a larger two-piece hard gelatin Example 39 capsule (size 0) that contains the remaining 20 mg of progesterone Solubilized in the mixture of C-tocopherol, Progesterone 75 C-tocopherol 8O Labrafil M2125CS, propylene glycol and Cremophor EL. Vitamin ETPGS 240 Again, both of the capsules can be Sealed or banded to Labrafil (R) M2125CS 2OO prevent the leakage of the fill material using conventional Propylene Glycol 40 methods. Cremophor (R) EL 240 Example 40 0364. The remaining formulations are prepared using Similar procedures. Progesterone 75 Cremophor (R) RH40 6OO EXAMPLE 48 Example 41 0365 Preparation of Dosage Forms Containing the Com Progesterone 75 positions Comprising Suspended Sex Hormone in Examples Miglyol (R) 812 500 37-47: Polysorbate 80 25 Example 42 0366 The suspension formulations of Examples 37-47 Progesterone 75 can be processed to provide pharmaceutically acceptable Maisine (E) 35-1 500 dosage forms containing a therapeutically effective amount Lutrol (E) 68 5 of at least one SeX hormone. The compositions can be Example 43 included in a unit dosage form to provide 0.5-2 mg of Estradiol 2 estradiol and/or 25-150 mg of progesterone per unit dosage Capryl (R) 90 1OO form. However, the dose and the composition in each Cremophor (R) RH40 1OO formulation can be further adjusted or exchanged with the Lactose 50 compositions of other active agents described herein the Example 44 example Section based upon the actual clinical need. A Progesterone 75 preferred dosage form is a capsule encapsulating the for Estradiol 2 mulation. The capsule shell can be made of any conventional PEG 4OO 3OO capsule material, e.g., gelatin, Starch, or cellulose. The Cremophor (R) EL 2OO Example 45 preferred capsule is a Soft gelatin capsule. The Suspension formulation can be filled into the capsule using conventional Progesterone 50 filling machines. If a two-piece hard gelatin capsule is used, Estradiol 2 the filled capsule can be further banded or spray sealed with Vitamin ETPGS 12O Labrafil (R) M2125CS 2OO a Sealing Solution to prevent leakage of the formulation from Cremophor (R) EL 240 the capsule. Propylene Glycol 40 Lactose 50 EXAMPLE 49 Example 46 0367 Dissolution of Progesterone from the Formulations of the Present Invention: Progesterone 75 Estradiol 1. PEG 4OO 3OO 0368. The formulation prepared based on the composi Tween 80 3O tion in Example 37 was filled into a hard gelatin capsule for Example 47 a dissolution Study to compare the release profile with that of a commercial product, Prometrium(R) (Solvay). The dis Progesterone 75 Solution Study was carried out using a USP type I dissolution Estradiol 1. apparatus at 100 rpm, 37 C., in 1L of dissolution medium Vitamin ETPGS 400 containing SGF and 12.5 mM sodium lauryl Sulfate. One capsule containing 100 mg progesterone (in the formulation of Example 37) or one Prometrium(R) 100 mg capsule was 0361. In Example 38, micronized progesterone is dis placed in the basket. At a given time, the dissolution medium persed in a mixture of the remaining components and was filtered and assayed by HPLC to determine the release homogenized to obtain the Suspension. The Suspension may of progesterone. The dissolution results are shown in FIG. be heated slightly, as in Example 37, So that it is fluid enough 10, and demonstrate the Superior release of progesterone to be filled into hard gelatin capsules. from the novel Suspension formulation in which a significant fraction of the drug is solubilized in the highly water 0362. In Example 41, 1 mg of estradiol mixed with 50 mg dispersible vehicle, in turn facilitating dissolution of Sus of lactose and encapsulated in a Small two-piece hard gelatin pended particles. US 2003/0077297 A1 Apr. 24, 2003

EXAMPLE 50 0369 Absorption of Progesterone: -continued 0370. The suspension composition of Example 37 was Composition (mg) tested in human Volunteers. The croSSover Study consisted of Example 56 oral administration of a Suspension (that of Example 37), Rofecoxib 25 and a commercial product, Prometrium(E) (Solvay), under Cremophor (E) EL 3O fasted condition. For comparison, in a separate Study, the Labrafil (R) M2125CS 60 formulation of Example 37 (with progesterone greater than C-tocopherol 210 50% solubilized) was dosed (2 capsules of 25 mg of proges Example 57 terone) in a crossover design with Prometrium(R). The Amprenavir 50 plasma concentrations of progesterone were determined by C-tocopherol 4 OO both RIA and a fluorescence method. The resulting proges Vitamin ETPGS OO terone blood concentrations were normalized against 100 Example 58 mg dose and are summarized in FIGS. 11A and 11B. As can Atovaquone 50 be seen in FIG. 11A, the formulation of Example 37 Peceol OO exhibited a rapid T and higher C compared to the Labrafil (R) M2125CS OO commercial product. However, the solubilized formulation Cremophor (R) RH40 OO plasma levels drop precipitously relative to those of the Example 59 commercial product. After 2 hours, the plasma levels were Clostazol OO below that of the commercial product. FIG. 11B shows that Cremophor (E) EL 2OO the plasma profile can be modulated with the current inven Triethyl Citrate OO tion (Example 37) relative to the commercial product. The Example 60 peak plasma level (C) is lower and Ta occurs earlier Ursodeoxycholic Acid than with the commercial product. However, the extended Propylene Glycol plasma levels remained well above those of the commercial Vitamin ETPGS product and can result in Sustained activity. Such Sustained Example 61 blood concentration may potentially be beneficial to the therapeutic effect of the active ingredient. It also should be Thalidomide Vitamin ETPGS noted that a lower peak plasma concentration of progester Transcutol (R) one could also have the advantage of reducing any side Triacetin effects, Such as drowsiness, associated with high plasma Example 62 concentration of progesterone or its metabolites while not losing the opportunity to Sufficiently Saturate endometrial Terbinafine OO receptors to render desirable efficacy. These data exemplify Olive Oil OO Cremophor (R) RH40 4 OO the wide range of plasma profiles that can be achieved with Maisine (E) 1-35 250 the current invention. Ethanol 50 Example 63 EXAMPLES 51-74 Nelfinavir 2OO 0371 Pharmaceutical suspension formulations contain Tween 80 1OO ing other active agents are prepared containing the compo Captex (R) 810D 400 nents indicated below. Example 64

Pioglitazone 1O Lutrol (E) 68 50 Composition (mg) Triethyl Citrate 50 Propylene Glycol 50 Example 51 Example 65

Modafinil 2OO Zaleplon Labrasol (R) 400 Example 52 Labrafil (R) M2125CS Labrasol (R) Zolpidem 1O Example 66 Capmul (R) MCM 2OO Example 53 Zaleplon 1O Cremophor (R) EL 70 Spironolactone 2OO Labrafil (R) M2125CS 60 PEG 4OO 6OO Example 54 Vitamin ETPGS 60 Propylene Glycol 1O Example 67 Celecoxib 2OO Miglyol (R) 812 240 Example 55 Zolpidem Cremophor (R) EL Zafirlukast 2O Labrafil (R) M2125CS Transcutol (R) 1OO Labrasol (R) Myvacet (R) 9-45 2OO Propylene Glycol US 2003/0077297 A1 Apr. 24, 2003 42

4. The pharmaceutical formulation of claim 2, wherein the -continued additional active agent is at least partially Solubilized in the vehicle. Composition (mg) 5. The pharmaceutical formulation of claim 1, wherein the Example 68 first fraction represents about 5 wt.% to about 80 wt.% of the active agent, and the Second fraction represents about 20 Zolpidem 1O Cremophor (R) EL 12O wt.% to about 95 wt.% of the active agent. Labrafil (R) M2125CS 1OO 6. The pharmaceutical formulation of claim 5, wherein the Vitamin ETPGS 12O first fraction represents about 30 wt.% to about 80 wt.% of C-tocopherol 40 Propylene Glycol 2O the active agent, and the Second fraction represents about 20 Example 69 wt.% to about 70 wt.% of the active agent. 7. The pharmaceutical formulation of claim 6, wherein the Ondansetron 8 Cremophor (R) EL 250 first fraction represents about 50 wt.% to about 70 wt.% of Labrafil (R) M2125CS 130 the active agent, and the Second fraction represents about 30 Water 2O wt.% to about 50 wt.% of the active agent. Example 70 8. The pharmaceutical formulation of claim 1, wherein the Lisinopril 40 Solid particles are comprised of powder, granules, pellets, Vitamin ETPGS 170 beads, or combinations thereof. PEG 4OO 400 9. The pharmaceutical formulation of claim 1, wherein the Water 3O Solid particles are associated with each other to form at least Example 71 one dosage unit comprised of a granule, pellet, bead or tablet Nifedipine 60 Suspended in the vehicle. Cremophor (R) RH40 42O Imwitor (E) 742 150 10. The pharmaceutical formulation of claim 1, wherein Ethanol 3O the Solid particles are contained within at least one capsule Example 72 Suspended in the vehicle. Amiodarone 2OO 11. The pharmaceutical formulation of claim 1, wherein Transcutol (R) 3OO the Solid particles are prepared by a process Selected from Tween (E) 80 250 melt extrusion, nanoencapsulation, lyophilization, Spheroni Ethanol 50 Zation, coacervation, cryopelletization, crystallization, anti Example 73 Solvent precipitation, precipitation from expanded Super Butorphanol 2O critical fluid, Spray drying, Spray coating, Spray congealing, Cremophor (R) EL 250 and combination S thereof. Labrafil (R) M2125CS 130 12. The pharmaceutical formulation of claim 11, wherein Acetic Acid 1O the Solid particles are Subjected to further processing after Example 74 preparation thereof. Rizatriptan 1O 13. The pharmaceutical formulation of claim 12, wherein Vitamin ETPGS 1OO PEG 4OO 1OO the further processing comprises size reduction. Water 5 14. The pharmaceutical formulation of claim 13, wherein the size reduction is carried out by a proceSS Selected from grinding, milling, micronization, nanosizing, and combina We claim: tion thereof. 1. A pharmaceutical formulation, comprising: 15. The pharmaceutical formulation of claim 14, wherein the Solid particles have a mean diameter in the range of (a) an active agent having a first fraction and a second about 0.1 um to about 100 um. fraction, wherein the first fraction is comprised of a 16. The pharmaceutical formulation of claim 13, wherein plurality of Solid particles, and the size reduction is carried out in the presence of a (b) a pharmaceutically acceptable vehicle comprising at Surfactant, a hydrophilic polymer, a lipid, a gelatin, a sac least one compound Selected from the group consisting charide, or a mixture thereof. of a hydrophilic Surfactant, a lipophilic Surfactant, a 17. The pharmaceutical formulation of claim 13, wherein triglyceride and a Solubilizer, the size reduction is carried out in the presence of the wherein the first fraction of the active agent is Suspended vehicle. in the vehicle and the second fraction of the active 18. The pharmaceutical formulation of claim 12, wherein agent is Solubilized in the vehicle, Said first fraction the further processing comprises treatment with an interfa representing about 5 wt.% to about 80 wt.% of the cial modifying agent Selected from the group consisting of active agent and Said Second fraction representing Surfactants, hydrophilic polymers, lipids, gelatins, Saccha about 20 wt.% to about 95 wt.% of the active agent. rides, and mixtures thereof. 2. The pharmaceutical formulation of claim 1, further 19. The pharmaceutical formulation of claim 18, wherein including an additional active agent. the treatment comprises coating the particles with the inter 3. The pharmaceutical formulation of claim 2, wherein the facial modifying agent. additional active agent is (a) Suspended in the vehicle, (b) 20. The pharmaceutical formulation of claim 18, wherein partially Solubilized and partially Suspended in the vehicle, the treatment comprises admixture of the particles with the or (c) fully solubilized in the vehicle. interfacial modifying agent. US 2003/0077297 A1 Apr. 24, 2003

21. The pharmaceutical formulation of claim 18, wherein done, poly(N-vinyl caprolactam), and polymers and copoly the treatment comprises application of a dry powder of the mers of acrylic acid, methacrylic acid and/or esters thereof. interfacial modifying agent to the particles. 34. The pharmaceutical formulation of claim 31, wherein 22. The pharmaceutical formulation of claim 18, wherein the Saccharides are cellulosic polymers. the treatment comprises chemical interaction of the particles 35. The pharmaceutical formulation of claim 34, wherein with the interfacial modifying agent. the Stabilizing agent is hydroxypropyl methylcellulose. 23. The pharmaceutical formulation of claim 20, wherein 36. The pharmaceutical formulation of claim 1, wherein the chemical interaction involves covalent attachment, ionic the vehicle is substantially free of water-indispersible wax binding, hydrogen bonding, complexation, adsorption, or a materials. combination thereof. 37. The pharmaceutical formulation of claim 36, wherein 24. The pharmaceutical formulation of claim 1, wherein the water-indispersible wax materials are Selected from the the Solid particles contain at least one pharmaceutically group consisting of beeswax, paraffin, yellow wax, hydro acceptable excipient. genated oils, hydrogenated vegetable oil, hydrogenated Soy 25. The pharmaceutical formulation of claim 1, further bean oil flakes and mixtures thereof. comprising at least one pharmaceutically acceptable addi 38. The pharmaceutical formulation of claim 1, wherein tive Selected from the group consisting of a Stabilizing agent, the vehicle is substantially free of added water. an antioxidant, a bufferant, an antifoaming agent, a detacki 39. The pharmaceutical formulation of claim 1, wherein fier, a preservative, a chelating agent, a Viscomodulator, a the vehicle contains less than about 20 wt.% water. tonicifier, a flavorant, a colorant, an odorant, an opacifier, a 40. The pharmaceutical formulation of claim 1, wherein binder, a filler, a plasticizer, a taste-masking agent, a lubri the vehicle contains less than about 10 wt.% water. cant, and an enzyme inhibitor. 41. The pharmaceutical formulation of claim 1, wherein 26. The pharmaceutical formulation of claim 25, wherein the vehicle comprises (a) at least one hydrophilic Surfactant, Said at least one pharmaceutically acceptable additive is a (b) at least one lipophilic Surfactant, or (c) at least one Stabilizing agent. hydrophilic Surfactant and at least one lipophilic Surfactant. 27. The pharmaceutical formulation of claim 26, wherein 42. The pharmaceutical formulation of claim 41, wherein the Stabilizing agent is a Suspending agent. the vehicle comprises at least one hydrophilic Surfactant and 28. The pharmaceutical formulation of claim 27, wherein at least one lipophilic Surfactant. the Suspending agent is Selected from the group consisting of 43. The pharmaceutical formulation of claim 1, wherein microcrystalline cellulose, Sodium carboxymethylcellulose, the vehicle comprises a triglyceride, a Solubilizer, or a powdered cellulose, hydroxypropyl cellulose, hydroxypro mixture thereof. pyl methylcellulose, methylcellulose, ethylcellulose, ethyl 44. The pharmaceutical formulation of claim 1, wherein methylcellulose, ethyl hydroxyethylcellulose, attapulgite, Said at least one compound represents about 1 wt.% to about bentonite, hectorite, montmorillonite, Silica gel, fumed sili 99 wt.% of the formulation. con dioxide, colloidal Silicon dioxide, acacia, agar, carrag 45. The pharmaceutical formulation of claim 44, wherein eenan, guar gum, locust bean gum, pectin, Sodium alginate, Said at least one compound represents about 10 wt.% to propylene glycol alginate, tamarind gum, Xanthan gum, about 90 wt.% of the formulation. carbomers, polyvinyl pyrrollidone, Starch, Sodium Starch 46. The pharmaceutical formulation of claim 45, wherein glycolate, tragacanth, magnesium aluminum Silicate, alumi Said at least one compound represents about 20 wt.% to num Silicate, magnesium Silicate, gelatin, and glycyrrhizin. about 80 wt.% of the formulation. 29. The pharmaceutical formulation of claim 1, wherein 47. The pharmaceutical formulation of claim 1, wherein the Solid particles comprise at least one amorphous phase, at the active agent is Selected from the group consisting of least one crystalline phase, or a mixture of at least one analgesic agents, anesthetic agents, anti-anginal agents, anti amorphous phase and at least one crystalline phase. arthritic agents, anti-arrhythmic agents, antiasthmatic agents, antibacterial agents, anti-BPH agents, anticancer 30. The pharmaceutical formulation of claim 29, wherein agents, anticholinergic agents, anticoagulants, anticonvul the Solid particles further include a Stabilizing agent. Sants, antidepressants, antidiabetic agents, antidiarrheals, 31. The pharmaceutical formulation of claim 30, wherein anti-epileptic agents, antifungal agents, antigout agents, Said Stabilizing agent is Selected from the group consisting antihelminthic agents, antihistamines, antihypertensive of Synthetic hydrophilic polymers, Surfactants, Saccharides, agents, antiinflammatory agents, antimalarial agents, anti gelatin, and combinations thereof. migraine agents, antimuscarinic agents, antinauseants, anti 32. The pharmaceutical formulation of claim 31, wherein neoplastic agents, anti-obesity agents, antiosteoporosis the Synthetic hydrophilic polymers are Selected from the agents, antiparkinsonism agents, antiprotozoal agents, anti group consisting of polyalkylene oxides, polyalkylene pruritics, antipsychotic agents, antipyretics, antispasmodics, oxide-Substituted C-C diols and triols, polyalkylene oxide antithyroid agents, antitubercular agents, antiulcer agents, Substituted Saccharides, poly(N-vinyl lactams), and poly anti-urinary incontinence agents, antiviral agents, anxiolyt mers of carboxyvinyl monomers. ics, appetite Suppressants, attention deficit disorder (ADD) 33. The pharmaceutical formulation of claim 32, wherein and attention deficit hyperactivity disorder (ADHD) drugs, the Synthetic hydrophilic polymers are Selected from the calcium channel blockers, cardiac inotropic agents, beta group consisting of polyethylene glycol, mono-poly(Oxyeth blockers, central nervous System Stimulants, cognition ylene)-substituted propylene glycol, di-(polyoxyethylene)- enhancers, corticosteroids, COX-2 inhibitors, deconges Substituted propylene glycol, mono-poly(oxyethylene)-Sub tants, diuretics, gastrointestinal agents, genetic materials, Stituted glycerol, di-(polyoxyethylene)-substituted glycerol, histamine receptor antagonists, hormonolytics, hypnotics, tri-(polyoxyethylene)-Substituted glycerol, polyoxyethy hypoglycemic agents, immunosuppressants, keratolytics, lated Sorbitol, polyoxyethylated glucose, polyvinyl pyrroli leukotriene inhibitors, lipid-regulating agents, macrollides, US 2003/0077297 A1 Apr. 24, 2003 44 mitotic inhibitors, muscle relaxants, narcotic antagonists, 61. The pharmaceutical formulation of claim 59, wherein neuroleptic agents, nicotine, nutritional oils, parasym the first fraction of the active agent further comprises a patholytic agents, Sedatives, SeX hormones, Sympathomi means for controlling release of the active agent from the metic agents, tranquilizers, vasodilators, Vitamins, and com Suspended particles. binations thereof. 62. The pharmaceutical formulation of claim 61, wherein 48. The pharmaceutical formulation of claim 47, wherein the Second fraction of the active agent comprises an imme the active agent is a lipid-regulating agent. diate release composition. 49. The pharmaceutical formulation of claim 48, wherein 63. The pharmaceutical formulation of claim 61, wherein the lipid-regulating agent is Selected from the group con the Second fraction of the active agent exhibits an immediate sisting of bezafibrate, beclobrate, binifibrate, ciplofibrate, release profile. clinofibrate, clofibrate, clofibric acid, etofibrate, eZetimibe, 64. The pharmaceutical formulation of claim 63, wherein etofibrate, fenofibrate, fenofibric acid, gemfibrozil, nicofi the second fraction provides for release of at least 50% of the brate, pirifibrate, probucol, ronifibrate, Simfibrate, and active agent contained therein within 30 minutes at 37 C. as theofibrate. evaluated using Standard USP dissolution test equipment. 50. The pharmaceutical formulation of claim 49, wherein 65. The pharmaceutical formulation of claim 64, wherein the lipid-regulating agent is fenofibrate. the second fraction provides for release of at least 75% of the 51. The pharmaceutical formulation of claim 47, wherein active agent contained therein within 30 minutes at 37 C. as the active agent is a SeX hormone. evaluated using Standard USP dissolution test equipment. 52. The pharmaceutical formulation of claim 51, wherein 66. The pharmaceutical formulation of claim 65, wherein the active agent is Selected from the group consisting of the second fraction provides for release of at least 90% of the progestins, estrogens, and combinations thereof. active agent contained therein within 30 minutes at 37 C. as 53. The pharmaceutical formulation of claim 51, wherein evaluated using Standard USP dissolution test equipment. the active agent comprises (a) a progestin Selected from the 67. The pharmaceutical formulation of claim 1, further group consisting of acetoxypregnenolone, allyleStrenol, including a means for physically Segregating the first and anagestone acetate, chlormadinone acetate, cyproterone, Second fractions So as to prevent contact therebetween. , desogestrel, dihydrogesterone, dime 68. The pharmaceutical formulation of claim 67, wherein thisterone, ethisterone (17O-ethynyltestosterone), ethyno the means for physically Segregating the first and Second diol diacetate, flurogestone acetate, geStadene, hydrox fractions is comprised of a vehicle-impermeable coating on yprogesterOne, hydroxyprogesterone acetate, the Solid particles. hydroxyprogesterone caproate, hydroxymethylprogester 69. The pharmaceutical formulation of claim 67, wherein one, hydroxymethylprogesterone acetate, 3-ketodesogestrel, the Solid particles of the Second fraction are associated with levonorgestrel, lynestrenol, medrogestone, medroxyproges each other to form at least one dosage unit comprised of a terone acetate, megestrol, megestrol acetate, melengestrol granule, pellet, bead or tablet, and the means for physically acetate, norethindrone, norethindrone acetate, norethister Segregating the first and Second fractions is comprised of a one, norethisterone acetate, norethynodrel, norgestimate, vehicle-impermeable coating on Said at least one dosage norgestrel, norgestrienone, normethisterone, and progester unit. one; and (b) an estrogen selected from the group consisting 70. The pharmaceutical formulation of claim 67, wherein of 17 B-estradiol, 17 B-estradiol benzoate, 17 B-estradiol val the formulation is housed within a dosage form and the erate, 17B-estradiol cypionate, 17B-estradiol heptanoate, means for physically Segregating the first and Second frac 17B-estradiol decanoate, 173-estradiol acetate, 17B-estra tions comprises a wall, a plug, a Septum dividing the dosage diol diacetate, ethynylestradiol, ethynylestradiol 3-acetate, form into a first region that contains the first fraction and a ethynyleStradiol 3-benzoate, estriol, estriol Succinate, poly Second region that contains the Second fraction. estrol phosphate, estrone, estrone acetate, estrone Sulfate, 71. The pharmaceutical formulation of claim 70, wherein piperazine estrone Sulfate, quinestrol, and meStranol. the dosage form is a capsule. 54. The pharmaceutical formulation of claim 53, wherein 72. A dosage form comprising the pharmaceutical formu the active agent comprises progesterone and 173-estradiol. lation of claim 1. 55. The pharmaceutical formulation of claim 52, wherein 73. The dosage form of claim 71, comprised of a capsule, the active agent comprises an estrogen. preconcentrate, drop, or drink. 56. The pharmaceutical formulation of claim 55, wherein 74. A pharmaceutical System for administration of an the estrogen is 17 B-estradiol. active agent, comprising: 57. The pharmaceutical formulation of claim 52, wherein the active agent comprises a progestin. (a) an active agent; and 58. The pharmaceutical formulation of claim 57, wherein the progestin is progesterone. (b) a pharmaceutically acceptable vehicle comprising at 59. The pharmaceutical formulation of claim 1, wherein least one compound Selected from the group consisting either the first fraction of the active agent, the Second of a hydrophilic Surfactant, a lipophilic Surfactant, a fraction of the active agent, or both the first and Second triglyceride and a Solubilizer, fractions of the active agent are formulated for immediate wherein the relative amounts of the active agent and the release, pulsatile release, controlled release, extended Vehicle are Such that upon admixture thereof, a first release, delayed release, targeted release, or targeted delayed fraction of the active agent is Suspended in the vehicle, release of the active agent. and a Second fraction of the active agent is Solubilized 60. The pharmaceutical formulation of claim 59, wherein in the vehicle, wherein the Second fraction represents the first fraction of the agent and the Second fraction of the about 20 wt.% to about 95 wt.% of the total active active agent have different release profiles. agent in the formulation. US 2003/0077297 A1 Apr. 24, 2003

75. The pharmaceutical system of claim 74, wherein the 93. The pharmaceutical system of claim 92, wherein the first fraction represents about 10 wt.% to about 80 wt.% of chemical interaction involves covalent attachment, ionic the active agent, and the Second fraction represents about 20 binding, hydrogen bonding, complexation, adsorption, or a wt.% to about 90 wt.% of the active agent. combination thereof. 76. The pharmaceutical system of claim 75, wherein the 94. The pharmaceutical system of claim 74, wherein the first fraction represents about 30 wt.% to about 80 wt.% of Solid particles contain at least one pharmaceutically accept the active agent, and the Second fraction represents about 20 able excipient. wt.% to about 70 wt.% of the active agent. 95. The pharmaceutical system of claim 74, wherein the 77. The pharmaceutical system of claim 76, wherein the vehicle further comprises at least one pharmaceutically first fraction represents about 50 wt.% to about 70 wt.% of acceptable additive Selected from the group consisting of a the active agent, and the Second fraction represents about 30 Stabilizing agent, an antioxidant, a bufferant, an antifoaming wt.% to about 50 wt.% of the active agent. agent, a detackifier, a preservative, a chelating agent, a 78. The pharmaceutical system of claim 77, wherein the Viscomodulator, a tonicifier, a flavorant, a colorant, an Solid particles are comprised of powder, granules, pellets, odorant, an opacifier, a binder, a filler, a plasticizer, a beads, or combinations thereof. taste-masking agent, a lubricant, and an enzyme inhibitor. 79. The pharmaceutical system of claim 74, wherein the 96. The pharmaceutical system of claim 95, wherein said Solid particles are associated with each other to form at least at least one pharmaceutically acceptable additive is a Stabi one dosage unit comprised of a granule, pellet, bead or lizing agent. tablet. 97. The pharmaceutical system of claim 96, wherein the 80. The pharmaceutical system of claim 79, wherein the Stabilizing agent is a Suspending agent. Solid particles are contained within a capsule. 98. The pharmaceutical system of claim 97, wherein the 81. The pharmaceutical system of claim 79, wherein the Suspending agent is Selected from the group consisting of Solid particles are prepared by a proceSS Selected from melt microcrystalline cellulose, Sodium carboxymethylcellulose, extrusion, nanoencapsulation, lyophilization, Spheroniza powdered cellulose, hydroxypropyl cellulose, hydroxypro tion, coacervation, cryopelletization, crystallization, antisol pyl methylcellulose, methylcellulose, ethylcellulose, ethyl vent precipitation, precipitation from expanded Supercritical methylcellulose ethyl hydroxyethylcellulose, attapulgite, fluid, Spray drying, Spray coating, Spray congealing, and bentonite, hectorite, montmorillonite, Silica gel, fumed sili combinations thereof. con dioxide, colloidal Silicon dioxide, acacia, agar, carrag 82. The pharmaceutical system of claim 81, wherein the eenan, guar gum, locust bean gum, pectin, Sodium alginate, Solid particles are Subjected to further processing after propylene glycol alginate, tamarind gum, Xanthan gum, preparation thereof. carbomers, polyvinyl pyrrollidone, Starch, Sodium Starch 83. The pharmaceutical system of claim 82, wherein the glycolate, tragacanth, magnesium aluminum Silicate, alumi further processing comprises Size reduction. num Silicate, magnesium Silicate, gelatin, and glycyrrhizin. 84. The pharmaceutical system of claim 83, wherein the 99. The pharmaceutical system of claim 74, wherein the Size reduction is carried out by a proceSS Selected from Solid particles comprise at least one amorphous phase, at grinding, milling, micronization, nanosizing, and combina least one crystalline phase, or a mixture of at least one tion thereof. amorphous phase and at least one crystalline phase. 85. The pharmaceutical system of claim 84, wherein the 100. The pharmaceutical system of claim 99, wherein the Solid particles have a mean diameter in the range of about Solid particles further include a Stabilizing agent. 0.1 um to about 100 um. 101. The pharmaceutical system of claim 100, wherein 86. The pharmaceutical system of claim 83, wherein the Said Stabilizing agent is Selected from the group consisting Size reduction is carried out in the presence of a Surfactant, of Synthetic hydrophilic polymers, Surfactants, Saccharides, a hydrophilic polymer, a lipid, a gelatin, a Saccharide, or a gelatin, and combinations thereof. mixture thereof. 102. The pharmaceutical system of claim 101, wherein 87. The pharmaceutical system of claim 83, wherein the the Synthetic hydrophilic polymers are Selected from the Size reduction is carried out in the presence of the vehicle. group consisting of polyalkylene oxides, polyalkylene 88. The pharmaceutical system of claim 82, wherein the oxide-Substituted C-C diols and triols, polyalkylene oxide further processing comprises treatment with an interfacial Substituted Saccharides, poly(N-vinyl lactams), and poly modifying agent Selected from the group consisting of mers of carboxyvinyl monomers. Surfactants, hydrophilic polymers, lipids, gelatins, Saccha 103. The pharmaceutical system of claim 102, wherein rides, and mixtures thereof. the Synthetic hydrophilic polymers are Selected from the 89. The pharmaceutical system of claim 88, wherein the group consisting of polyethylene glycol, mono-poly(Oxyeth treatment comprises coating the particles with the interfacial ylene)-substituted propylene glycol, di-(polyoxyethylene)- modifying agent. Substituted propylene glycol, mono-poly(oxyethylene)-Sub 90. The pharmaceutical system of claim 88, wherein the Stituted glycerol, di-(polyoxyethylene)-Substituted glycerol, treatment comprises admixture of the particles with the tri-(polyoxyethylene)-Substituted glycerol, polyoxyethy interfacial modifying agent. lated Sorbitol, polyoxyethylated glucose, polyvinyl pyrroli 91. The pharmaceutical system of claim 88, wherein the done, poly(N-vinyl caprolactam), and polymers and copoly treatment comprises application of a dry powder of the mers of acrylic acid, methacrylic acid and/or esters thereof. interfacial modifying agent to the particles. 104. The pharmaceutical system of claim 103, wherein 92. The pharmaceutical system of claim 88, wherein the the Saccharides are cellulosic polymers. treatment comprises chemical interaction of the particles 105. The pharmaceutical system of claim 104, wherein with the interfacial modifying agent. the Stabilizing agent is hydroxypropyl methylcellulose. US 2003/0077297 A1 Apr. 24, 2003 46

106. The pharmaceutical system of claim 74, wherein the 118. The pharmaceutical system of claim 114, wherein the vehicle is Substantially free of water-indispersible wax mate active agent is a SeX hormone. rials. 119. The pharmaceutical system of claim 118, wherein the 107. The pharmaceutical system of claim 106, wherein active agent is Selected from the group consisting of the water-indispersible wax materials are Selected from the progestins, estrogens, and combinations thereof. group consisting of beeswax, paraffin, yellow wax, hydro 120. The pharmaceutical system of claim 118, wherein the genated oils, hydrogenated vegetable oil, hydrogenated Soy active agent comprises (a) a progestin Selected from the bean oil flakes and mixtures thereof. group consisting of acetoxypregnenolone, allylestrenol, 108. The pharmaceutical system of claim 74, wherein the anagestone acetate, chlormadinone acetate, cyproterone, vehicle is substantially free of added water. cyproterone acetate, desogestrel, dihydrogesterone, dime 109. The pharmaceutical system of claim 108, wherein thisterone, ethisterone (17a-ethynyltestosterone), ethynodiol the vehicle contains less than about 20 wt.% water. diacetate, flurogestone acetate, geStadene, hydroxyprogest 110. The pharmaceutical system of claim 109, wherein the erone, hydroxyprogesterone acetate, hydroxyprogesterone vehicle contains less than about 10 wt.% water. caproate, hydroxymethylprogesterone, hydroxymethyl 111. The pharmaceutical system of claim 110, wherein the progesterone acetate, 3-ketodesogestrel, levonorgestrel, vehicle comprises (a) at least one hydrophilic Surfactant, (b) lynestrenol, medrogestone, medroxyprogesterone acetate, at least one lipophilic Surfactant, or (c) at least one hydro megestrol, megestrol acetate, melengestrol acetate, nore philic Surfactant and at least one lipophilic Surfactant. thindrone, norethindrone acetate, norethisterone, norethis 112. The pharmaceutical system of claim 111, wherein the terone acetate, norethynodrel, norgestimate, norgestrel, vehicle comprises at least one hydrophilic Surfactant and at norgestrienone, normethisterone, and progesterone; and (b) least one lipophilic Surfactant. an estrogen Selected from the group consisting of 173 113. The pharmaceutical system of claim 74, wherein the estradiol, 17 B-estradiol benzoate, 17 B-estradiol valerate, vehicle comprises a triglyceride, a Solubilizer, or a mixture 17B-estradiol cypionate, 17B-estradiol heptanoate, 173-es thereof. tradiol decanoate, 17B-estradiol acetate, 17B-estradiol diac 114. The pharmaceutical system of claim 74, wherein the etate, ethynylestradiol, ethynylestradiol 3-acetate, ethy active agent is Selected from the group consisting of anal nylestradiol 3-benzoate, estriol, estriol Succinate, polyestrol gesic agents, anesthetic agents, anti-anginal agents, antiar phosphate, estrone, estrone acetate, estrone Sulfate, pipera thritic agents, anti-arrhythmic agents, antiasthmatic agents, Zine estrone Sulfate, quineStrol, and meStranol. antibacterial agents, anti-BPH agents, anticancer agents, 121. The pharmaceutical system of claim 120, wherein anticholinergic agents, anticoagulants, anticonvulsants, anti the active agent comprises progesterone and 17 B-estradiol. depressants, antidiabetic agents, antidiarrheals, anti-epilep 122. The pharmaceutical system of claim 119, wherein the tic agents, antifungal agents, antigout agents, antihelminthic active agent comprises an estrogen. agents, antihistamines, antihypertensive agents, antiinflam 123. The pharmaceutical system of claim 122, wherein matory agents, antimalarial agents, antimigraine agents, the estrogen is 17 B-estradiol. antimuscarinic agents, antinauseants, antineoplastic agents, 124. The pharmaceutical system of claim 118, wherein the anti-obesity agents, antiosteoporosis agents, antiparkin active agent comprises a progestin. Sonism agents, antiprotozoal agents, antipruritics, antipsy 125. The pharmaceutical system of claim 124, wherein chotic agents, antipyretics, antispasmodics, antithyroid the progestin is progesterone. agents, antitubercular agents, antiulcer agents, anti-urinary 126. The pharmaceutical system of claim 74, wherein incontinence agents, antiviral agents, anxiolytics, appetite either the first fraction of the active agent, the Second Suppressants, attention deficit disorder (ADD) and attention fraction of the active agent, or both the first and Second deficit hyperactivity disorder (ADHD) drugs, calcium chan fractions of the active agent are formulated for immediate nel blockers, cardiac inotropic agents, beta-blockers, central release, pulsatile release, controlled release, extended nervous System Stimulants, cognition enhancers, corticOS release, delayed release, targeted release, or targeted delayed teroids, COX-2 inhibitors, decongestants, diuretics, gas release of the active agent. trointestinal agents, genetic materials, histamine receptor 127. The pharmaceutical system of claim 126, wherein antagonists, hormonolytics, hypnotics, hypoglycemic the first fraction of the agent and the Second fraction of the agents, immunosuppressants, keratolytics, leukotriene active agent have different release profiles. inhibitors, lipid-regulating agents, macrollides, mitotic 128. The pharmaceutical system of claim 126, wherein inhibitors, muscle relaxants, narcotic antagonists, neurolep the first fraction of the active agent further comprises a tic agents, nicotine, nutritional oils, parasympatholytic means for controlling release of the active agent from the agents, Sedatives, SeX hormones, Sympathomimetic agents, Suspended particles. tranquilizers, vasodilators, Vitamins, and combinations 129. The pharmaceutical system of claim 128, wherein thereof. the Second fraction of the active agent comprises an imme 115. The pharmaceutical system of claim 114, wherein the diate release composition. active agent is a lipid-regulating agent. 130. The pharmaceutical system of claim 128, wherein 116. The pharmaceutical system of claim 115, wherein the the Second fraction of the active agent exhibits an immediate lipid-regulating agent is Selected from the group consisting release profile . of bezafibrate, beclobrate, binifibrate, ciplofibrate, clinofi 131. The pharmaceutical system of claim 130, wherein brate, clofibrate, clofibric acid, etofibrate, eZetimibe, etofi the second fraction provides for release of at least 50% of the brate, fenofibrate, fenofibric acid, gemfibrozil, nicofibrate, active agent contained therein within 30 minutes at 37 C. as pirifibrate, probucol, ronifibrate, Simfibrate, and theofibrate. evaluated using Standard USP dissolution test equipment. 117. The pharmaceutical system of claim 116, wherein the 132. The pharmaceutical system of claim 131, wherein lipid-regulating agent is fenofibrate. the second fraction provides for release of at least 75% of the US 2003/0077297 A1 Apr. 24, 2003 47 active agent contained therein within 30 minutes at 37 C. as 139. The method of claim 136, wherein at least two of the evaluated using Standard USP dissolution test equipment. active agent, the vehicle and the at least one compound are 133. The pharmaceutical system of claim 132, wherein not administered simultaneously. the second fraction provides for release of at least 90% of the 140. The method of claim 139, wherein said at least two active agent contained therein within 30 minutes at 37 C. as of the active agent, the vehicle and the at least one com evaluated using Standard USP dissolution test equipment. pound are housed in different dosage forms. 134. A method of administering an active agent to a 141. In a method for reducing interpatient variability with mammalian patient, the method comprising orally adminis respect to absorption and bioavailability of an orally admin tering to the patient an amount of the formulation of claim istered pharmaceutical formulation containing an active 1 sufficient to deliver a therapeutically effective amount of agent, the improvement comprising administering the active the active agent to the patient. agent in the pharmaceutical formulation of claim 1. 135. The method of claim 134, wherein the mammalian 142. A method for reducing the effect of food on absorp patient is human. tion and bioavailability of an active agent orally adminis 136. A method of administering an active agent to a tered to a patient, comprising administering the active agent mammalian patient, the method comprising orally adminis to the patient in the pharmaceutical formulation of claim 1. tering to the patient a drug delivery System comprised of (a) 143. A method for increasing the onset of a therapeutic an active agent; and (b) a pharmaceutically acceptable effect associated with administration of an active agent to a vehicle comprising at least one compound Selected from the patient, comprising administering the active agent to the group consisting of a hydrophilic Surfactant, a lipophilic patient in the pharmaceutical formulation of claim 1. Surfactant, a triglyceride and a Solubilizer, wherein the 144. A method for both increasing the onset of a thera relative amounts of the active agent and the vehicle are Such peutic effect associated with administration of an active that upon admixture thereof, a first fraction of the active agent to a patient and reducing the time to apparent elimi agent is Suspended in the vehicle, and a Second fraction of nation, comprising administering the active agent to the the active agent is Solubilized in the vehicle, wherein the patient in the pharmaceutical formulation of any one of second fraction represents about 20 wt.% to about 95 wt.% claims 12, 13 or 18. of the total active agent in the formulation. 145. A method for both increasing the onset of a thera 137. The method of claim 136, wherein the active agent, peutic effect associated with administration of an active the vehicle and the at least one compound are administered agent to a patient and providing for an extended duration of Simultaneously. drug release, the therapeutic effect, or both, comprising 138. The method of claim 137, wherein the active agent, administering the active agent to the patient in the pharma the vehicle and the at least one compound are administered ceutical formulation of claim 61. in a Single formulation. k k k k k