AU757970B2

AU757970B2 - Pharmaceutical composition

Info

Publication number: AU757970B2
Application number: AU39414/00A
Authority: AU
Inventors: Laman A. Al-Razzak; Rong Gao; Soumojeet Ghosh; Dilip Kaul; John Lipari
Original assignee: Abbott Laboratories
Current assignee: AbbVie Inc
Priority date: 1996-11-21
Filing date: 2000-06-09
Publication date: 2003-03-13
Anticipated expiration: 2017-11-12
Also published as: AU3941400A

Description

S&F Ref: 458878D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Abbott Laboratories CHAD 0377/AP6D-2 100 Abbott Park Road Abbott Park Illinois 60064-3500 United States of America John Lipari, Laman A Al-Razzak, Soumojeet Ghosh, Rong Gao, Dilip Kaul Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Pharmaceutical Composition 55S5 S. S Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c PHARMACEUTICAL COMPOSITION Technical Field A liquid pharmaceutical composition providing improved oral bioavailability is disclosed for compounds which are inhibitors of HIV protease.

6 In particular, the composition is a solution which comprises the HIV protease inhibitor, a pharmaceutically acceptable organic solvent and optionally, (c) a surfactant. The composition can optionally be encapsulated in either hard gelatin capsules or soft elastic capsules (SEC).

Background of the Invention One measure of the potential usefulness of an oral dosage form of a new pharmaceutical agent is the bioavailability observed after oral administration of the dosage form. Various factors can affect the bioavailability of a drug when administered orally. These factors include aqueous solubility, drug absorption throughout the gastrointestinal tract, dosage strength and first pass effect.

Aqueous solubility is one of the most important of these factors. When a drug has poor aqueous solubility, attempts are often made to identify salts or other derivatives of the drug which have improved aqueous solubility. When a salt or other derivative of the drug is identified which has good aqueous solubility, it is generally accepted that an aqueous solution formulation of this salt or derivative 0 will provide the optimum oral bioavailability. The bioavailability of.the oral solution formulation of a drug is then generally used as the standard or ideal bioavailability against which other oral dosage forms are measured.

For a variety of reasons, such as patient compliance and taste masking, a solid dosage form, such as capsules, is usually preferred over a liquid dosage form. However, oral solid dosage forms of a drug generally provide a lower bioavailability than oral-solutionsof the drug. One goal of the development-of asuitable capsule dosage form is to obtain a bioavailability of the drug that is as close as possible to the ideal bioavailability demonstrated by the oral solution formulation of the drug.

It has recently been determined that HIV protease inhibiting compounds are useful for inhibiting HIV protease in vitro and in vivo, are useful for inhibiting HIV (human immunodeficiency virus) infections and are useful for treating AIDS (acquired immunodeficiency syndrome). HIV protease inhibiting compounds typically are characterized by having poor oral bioavailability and there is a continuing need for the development of improved oral dosage forms for HIV protease inhibitors which have suitable oral bioavailability, stability and side \43 effects profiles.

Examples of HIV protease inhibiting compounds include hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1 pyridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))'pentaneamide indinavir) and related compounds, disclosed in European Patent Application -0 No. EP541168, published May 12, 1993, and U.S. Patent No. 5,413,999, issued May 9, 1995 which are both incorporated herein by reference; N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)- L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide saquinavir) and related compounds, disclosed in U.S. Patent No. 5,196,438, issued March 23, 1993, which is incorporated herein by reference; 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide and related compounds, disclosed in European Patent Application No. EP532466, published March 17, 1993, which is incorporated herein by reference; 1 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanoyl- 1,3-thiazolidine-4-t-butylamide 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA- Thz-NH-tBu), 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2hydroxy-4-butanoyl-l,3-thiazolidine-4-t-butylamide iQoa-Mta-Apns-Thz- NHtBu) and related compounds, disclosed in European Patent Application No.

EP490667, published June 17, 1992 and Chem. Pharm. Bull. AQ 2251 (1992), which are both incorporated herein by reference; [1 ,1 -dimethylethyl)amino]carbo nyl](2methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl-2-[(2quinolinylcarbonyl)amino]-butanediamide SC-521 51) and related compounds, disclosed in PCT Patent Application No. W092/08701, published May 29, 1992 and PCT Patent Application No. W093/23368, published November 25, 1993, both of which are incorporated herein by reference; VX-478) and related compounds, di sclosed in PCT Patent Application No.

W094/05639, published March 17, 1994, which is incorporat~d herein by reference; HO/ N Nr OH DMP-323) or DMP-450) and related compounds, disclosed in PCT Patent Application No. W093/07128, published April 15, 1993, which is incorporated herein by reference; Ph S AG1343, (nelfinavir)), disclosed in PCT Patent Application No. W095/09843, published April 13, 1995 and U.S. Patent No. 5,484,926, issued January 16, 1996, which are both incorporated herein by reference; OH OH BocNH N NHBoc Ph- 0 0 BMS 186,318) disclosed in European Patent Application No. EP580402, published January 26, 1994, which is incorporated herein by reference;

O

H

/N l

OH

H H ,N N N Ph SC-55389a) and related compounds disclosed in PCT Patent Application No. WO 9506061, published March 2, 1995, which is incorporated herein by reference and at 2nd National Conference on Human Retroviruses and Related Infections, (Washington, Jan. 29 Feb. 2, 1995), Session 88; and

N

H

BILA 1096 BS) and related compounds disclosed in European Patent Application No. EP560268, published September 15, 1993, which is incorporated herein by reference; and OH ,CF3 o' 'o U-140690) and related compounds disclosed in PCT Patent Application No. WO 9530670, published November 16, 1995, which is incorporated herein by reference; or a pharmaceutically acceptable salt of any of the above.

Other examples of HIV protease inhibiting compounds include compounds of the formula I: wherein R1 is lower alkyl and R2 and R 3 are phenyl and related compounds or a pharmaceutically acceptable salt thereof, disclosed in PCT Patent Application No. W094/14436, published July 7, 1994 and U.S. Patent No. 5,541,206, issued July 30, 1996, both of which are incorporated herein by reference. The compounds of formula I are useful to inhibit HIV infections and, thus, are useful for the treatment of AIDS.

In particular, the compound of formula II, has been found to be especially effective as an inhibitor of HIV protease.

I I I *1* 0 CH Gil 8 The most preferred compound of formula II is Methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N- ((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (ritonavir; compound III) or a pharmaceutically acceptable salt thereof.

Other examples of HIV protease inhibiting compounds also include compounds of the formula IV: N R 7 CH 3 OH R 2

O

IV

wherein R 1 is benzyl, R 2 is benzyl or loweralkyl, R 3 is loweralkyl and R 5 is -1 NH

N)NH

or O and related compounds or a pharmaceutically acceptable salt thereof, disclosed in U.S. Patent Application No. 08/572,226, ,5 filed December 13, 1996 and U.S. Patent Application No. 08/753,201, filed S. November 21, 1996 and International Patent Application No. W097/21685, published June 19, 1997, all of which are incorporated herein by reference.

A preferred compound is the compound of formula IV wherein R 1 and R 2 are benzyl, R 3 is isopropyl and R 5 is 0 -N NH A most preferred compound of the formula IV is (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydro-pyrimid-2-onyl)- 3-methyl butanoyl] amino-1,6-diphenylhexane (compound V) or a pharmaceutically acceptable salt thereof. The preparation of compound V is disclosed in U.S. Patent Application No. 08/572,226, filed December 13, 1996 5and U.S. Patent Application No. 08/753,201, filed November 21, 1996 and International Patent Application No. W097/21685, published June 19, 1997.

I 1I Compound III has an aqueous solubility of approximately 6 micrograms per milliliter at pH This is considered to be extremely poor aqueous solubility and, therefore, compound IIlin the free base form would be expected to provide very low oral bioavailability. In fact, the free base form of compound III, administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.

Acid addition salts of compound III (for example, bis-hydrochloride, bistosylate, bis-methane sulfonate and the like) have aqueous solubilities of <0.1 \O milligrams/milliliter. This is only a slight improvement over the solubility of the free base. This low aqueous solubility would not make practical the administration of therapeutic amounts of an acid addition salt of compound III as an aqueous solution. Furthermore, in view of this low aqueous solubility, it is not surprising that the bis-tosylate of compound III, administered as an unformulated solid in a capsule dosage form, is characterized by a bioavailability of less than 2% following a 5 mg/kg oral dose in dogs.

In order to have a suitable oral dosage form of compound III, the oral bioavailability of compound III should be at least 20%. Preferably, the oral bioavailability of compound III from the dosage form should be greater than "0 about 40% and, more preferably, greater than about While some drugs would be expected to have good solubility in organic solvents, it would not necessarily follow that oral administration of such a S. solution would give good bioavailability for the drug. It has been found that .o compound III has good solubility in pharmaceutically acceptable organic .solvents and that the solubility in such solvents is enhanced in the presence of a pharmaceutically acceptable long chain fatty acid. Administration of the solution as an encapsulated dosage form (soft elastic capsules or hard gelatin capsules) provides an oral bioavailability of as high as about 60% or more.

Disclosure of the Invention In accordance with the present invention, there is a pharmaceutical composition which is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds (preferably, a compound of the formula II or IV or saquinavir or nelfinavir or indinavir or VX-478, more preferably, a compound of the formula III or V orsaquinavir or nelfinavir or indinavir or VX-478, or a combination of a compound of the formula II or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir or VX-478), or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or 0 indinavir or nelfinavir or VX-478)), a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, optionally, a pharmaceutically acceptable surfactant.

In the above solution composition, preferred HIV protease inhibitors as individual compounds are the compound of the formula III or V or saquinavir or nelfinavir or indinavir or VX-478. In the above composition, preferred -0 combinations of HIV protease inhibitors are the compound of formula III and the compound of formula V, the compound of formula III and saquinavir, the compound of formula III and indinavir, the compound of formula III and nelfinavir, the compound of formula III and VX-478, nelfinavir and the compound of formula V, nelfinavir and saquinavir, nelfinavir and indinavir, 25 nelfinavir and VX-478.

Also in accordance with the present invention, there is a pharmaceutical composition which is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease S. inhibiting compounds (preferably, a compound of the formula II or IV or saquinavir or nelfinavir or indinavir or VX-478, more preferably, a compound of the formula III or V or saquinavir or nelfinavir or indinavir or *VX-478, or a combination of a compound of the formula II or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir or VX-478), or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or indinavir or nelfinavir or VX-478)), a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and optionally, a pharmaceutically acceptance surfactant, wherein the solution is encapsulated in a soft elastic gelatine capsule (SEC) or a hard gelatin capsule.

In the above encapsulated solution composition, preferred HIV protease inhibitors as individual compounds are the compound of the formula III or V or saquinavir or nelfinavir or indinavir or VX-478.

In the above composition, preferred combinations of HIV protease inhibitors are the compound of formula III and the compound of formula V, the compound of formula III and saquinavir, the compound of formula III and indinavir, the compound of formula III and nelfinavir, the compound of formula III and VX-478, nelfinavir and the compound of formula V, nelfinavir and saquinavir, nelfinavir and indinavir, nelfinavir and VX-478.

According to another embodiment of this invention there is provided a pharmaceutical composition for oral administration which is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable .organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and a pharmaceutically acceptable surfactant.

According to a further embodiment of this invention there is provided use of an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable 25 alcohol, and, optionally, a pharmaceutically acceptable surfactant for the preparation of a pharmaceutical composition for oral administration which is a solution.

*According to yet a further embodiment of this invention there is provided use of an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and a pharmaceutically acceptable surfactant for the preparation of a pharmaceutical composition for oral administration which is a solution.

The solution composition of the invention can also comprise an antioxidant (for example, absorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E PEG 1000 succinate and the like) for chemical stability.

The compositions of this invention (solution or encapsulated solution) provide improved oral bioavailability for HIV protease inhibitors. In particular, the compositions of this invention (solution or encapsulated solution) provide improved oral bioavailability for compound III when compared to nonformulated compound III (base) or non-formulated compound III (acid addition salt).

The term "pharmaceutically acceptable long chain fatty acid" as used herein refers to saturated, us mono-unsaturated or di-unsaturated C 1 2 to C18 carboxylic acids which are liquids at room temperature.

Preferred long chain fatty acids are mono-unsaturated C 16 -C2 0 carboxylic acids which are liquids at Z oom temperature. A most preferred long chain fatty acid is oleic acid.

FF[I:\DAYLIBIIBC]08626b.doc:JFM The term "pharmaceutically acceptable alcohol" as used herein refers to alcohols which are liquids at about room temperature, approximately 200C, for example, ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol (Transcutol® Gattefosse, Westwood, NJ 07675),benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400 and the like. A preferred pharmaceutically acceptable alcohol is ethanol or propylene glycol or a mixture thereof.

The term "pharmaceutically acceptable surfactant" as used herein refers to a pharmaceutically acceptable non-ionic surfactant for example, 0 polyoxyethylene castor oil derivatives (for example, polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (Cremophor®EL, BASF Corp.) or polyoxyethyleneglycerol oxystearate (Cremophor®RH (polyethyleneglycol 40 hydrogenated castor oil)) or Cremophor®RH (polyethyleneglycol 60 hydrogenated castor oil), BASF Corp. and the like) or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropylene glycol, such as Poloxamer®124, Poloxamer®188, Poloxamer®237, Poloxamer®388, Poloxamer®407 and the like, (BASF Wyandotte Corp.) or a mono fatty acid ester of polyoxyethylene sorbitan (for example, polyoxyethylene (20) sorbitan monooleate (Tween® polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene :"oi sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20) and the like) and the like) or a sorbitan fatty acid ester (including sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan 5- stearate and the like). A preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil (Cremophor@EL, BASF Corp.), polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene (20) sorbitan monooleate (Tween® 80) or a sorbitan fatty acid ester, for example sorbitan oleate. A most preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil 30 (Cremophor@EL, BASF Corp.).

A preferred composition of the invention is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease .inhibiting compounds (preferably, a compound of the formula II or IV or -11saquinavir or nelfinavir or indinavir or, more preferably, a compound of the formula III or V or saquinavir or nelfinavir or indinavir, or, most preferably, a compound of the formula III or or a combination of a compound of the formula II or nelfinavir-and-another HIV protease inhibitor (preferably, the compound of the formula IV or saquinavir or indinavir or nelfinavir, or, more preferably, a combination of a compound of the formula III or nelfinavir and another HIV protease inhibitor (preferably, the compound of the formula V or saquinavir or indinavir or nelfinavir), or, most preferably, a combination of a compound of formula III and a compound of formula V) in the amount of from o about 1% to about 50% (preferably, from about 1% to about 40%; more preferably, from about 10 to about 40%; most preferably, from about 15% to about 40%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution and (2) a pharmaceutically acceptable alcohol in the amount of from about 0% to about (preferably, from about 6% to about 12%) by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% (preferably, from about 2% to about 20% and most preferably, from about 5% to about 15%) by weight of the total solution. In a preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

Preferably, the pharmaceutically acceptable organic solvent comprises from about 50% to about 99% by weight of the total solution. More preferably, 0 the pharmaceutically acceptable organic solvent or mixture of pharmaceutically acceptable organic solvents comprises from about 50% to about 75% by weight of the total solution.

-12- Preferred pharmaceutically acceptable solvents comprise a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and ethanol or propylene glycol in the-amount of from about 1% to about 15% by-weight-of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 1% to about 15% by weight of the total solution. More preferred pharmaceutically acceptable solvents comprise a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about by weight of the total solution and ethanol in the amount of from about to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 5% to about 15% by weight of the total solution. Even more preferred pharmaceutically acceptable solvents comprise oleic acid in the amount of from about 40% to about by weight of the total solution and ethanol in the amount of from about 100/% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about'l 10% to about 15% by weight of the total solution.

In one embodiment of the invention, a more preferred composition of the invention is a solution comprising S:•i ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% (preferably, from about 30% to about more preferably, from about 40% to about 60%) by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and -13- I a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

57 An even more preferred composition of the invention is a solution comprising ritonavir in the amount of from about 1% to about 30% (preferably, from about 5% to about 25%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid \0 in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 60%) by weight of the total solution and ethanol in the amount of from about 0% to about 12% (preferably, from about to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about by weight of the total solution or a mixture thereof in,the amount of from about 0% to about 15% (preferably, from about 10% to about 15%) by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

A most preferred composition of the-invention is a solution comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 62% to about 64%by weight of the total solution and ethanol in the amount of from about 10% to about 12%, preferably, about 12%, by weight of the total solution and polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution. In a most preferred embodiment of the invention, the solution is -14encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of about 0.05% by weight of the total solution.

Another most preferred composition of the invention is a solutoin comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 65% by weight of the total solution and ethanol in the amount of about 10% by weight of the total w\ solution and polyoxyl 35 castor oil in the amount of about 5% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most preferred composition of the invention is a solution comprising o ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and 5 polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most preferred composition of the invention is a solution comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 70% by weight of the total solution and a mixture of ethanol in the amount of about 5% by weight of the total solution and propylene glycol in the amount of about 5% by'weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

In another embodiment of the invention, a more preferred composition of the invention is a solution comprising (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% (preferably, from about 2% to about 20% and preferably, from about to about 15%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

-16- A more preferred composition of the invention is a solution comprising (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably ,from about 5% to about 35%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about vO to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and ethanol in the amount of from about 0% to about 12% (preferably, from about 10% to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about 10%) by weight of the total solution or a mixture thereof in the amount of from about 0% to about (preferably from about 5% to about 15%, most preferably, about 10%) by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

A most preferred composition of the invention is a solution comprising (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the 5 f amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total o 0 solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated -17hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

In yet another embodiment of the invention, a more preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of from about 1% to about (preferably, from about 5% to about 25%) by weight of the total solution and another HIV protease inhibitor in the amount of from about 1 to about (preferably, from about 5% to about 40%) by weight of the total solution, \0 a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% (preferably, from about 6% to about 12%) by weight of the total solution and a pharmaceutica'illy acceptable surfactant in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution. In a more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

An even more preferred composition of the invention is a solution a mixture of ritonavir in the amount of from about 1% to about (preferably, from about 5% to about 25%) by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about (preferably, from about 5% to about 40%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 10% to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the -18total solution or (ii) a mixture of oleic acid in the amount of from about to about 98% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and ethanol in the amount of from about 0% to about 12% (preferably,.from about 10% to about 12%) by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% (preferably, from about 5% to about by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% (preferably, from about 10% to about 15%) by weight of the total solution and \O polyoxyl 35 castor oil in the amount of from about 0% to about (preferably, from about 5% to about 10%) by weight of the total solution. In an even more preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule.

A most preferred composition of the invention is a solution comprising LS" a mixture of ritonavir in the amount of from about 1% to about (preferably, from about 5% to about 25%) by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% (preferably, from about 40% to about 65%) by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and Os polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight 0 of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of from about 1% to about S(preferably, from about 5% to about 25%) by weight of the total solution and (2S, 6 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1-tetrahydropyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% (preferably, from about 40% to about 65%) by weight of the total solution and propylene glycol in the amount of from about 5% to about 10% (preferably, from about 6% to about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total I\ solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

A most highly preferred composition of the invention is a solution comprising S(a) a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 45% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated oe hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution Scomprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, \0 a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 5% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total 9 solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated -21hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution Scomprising a mixture of ritonavir in the amount of about 10% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 20% by weight of the total solution, \O a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of Sthe total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total p3V solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule -22and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.03% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 6.0% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention comprises a solution of a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy- 5-[2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6diphenylhexane in the amount of about 25% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule -23and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 8% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the vO amount of about 24% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01 to about 0.08% by weight 0of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 8.25% by weight of the total 25 solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino- 1,6-diphenylhexane in the amount of about 22% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of S. oleic acid in the amount of about 52.25% by weight of the total solution and 0 propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule -24and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

S Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the \O amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 47.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and 1\ polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by-weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) \O [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated S hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).

Another most highly preferred composition of the invention is a solution comprising 2 a mixture of ritonavir in the amount of about 10% by weight of the total solution and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1-tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6-diphenylhexane in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of 30 oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution S. and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. In a most preferred embodiment of the invention, the solution is -26encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01% to about 0.08% by weight of the total solution (preferably, from about 0.01 to about 0.05% by weight of SS the total solution).

In the compositions of the invention, preferred HIV protease inhibitors are selected from ritonavir, (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6diphenylhexane, indinavir, saquinavir, nelfinavir and VX-478.

In the compositions of the invention, preferred combinations of HIV protease inhibitors include ritonavir and (2S, 3S, 5S)-2-(2,6dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2-onyl)-3methyl butanoyl] amino-1 ,6-diphenylhexane, ritonavir and indinavir, ritonavir and saquinavir, ritonavir and netfinavir, ritonavir and VX-478, saquinavir and nelfinavir, indinavir and nelfinavir, nelfinavir and (2S, 3S. 5S)-2-(2,6dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-( 1 -tetrahydro-pyrimid-2-onyl)-3methyl butanoyl] amino-1 ,6-diphenylhexane and nelfinavir and VX-478.

In the compositions of the invention which comprise a mixture of ritonavir and (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1- 2zO tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) amino-3hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1,6diphenylhexane ranges from about 1:16 to about 5:1 (preferably, from about 1:8 to about 3:1).

29 The compounds of formula I, 11 and IV contain two or more asymmetric carbon atoms and thus can exist as pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. The present invention is intended to include within its scope all of the isomeric forms. The terms and configuration as used herein are as 0006 30 defined by IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

-27- The preferred isomer of the compound of formula II is (2S,3S,5S)-5-(N- (N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3hydroxyhexane (compound III). Thepreferred isomer of the compound of formula IV is (2S, 3S, 5S)-2-(2,6-dimethylphenoxyacetyl) [2S-(1 -tetrahydro-pyrimid-2-onyl)-3-methyl butanoyl] amino-1 ,6-diphenylhexane (compound V).

The term "lower alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.

The HIV protease inhibiting compounds can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogencontaining groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oilsoluble or dispersible products are thereby obtained.

Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali -28metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.

The composition and preparation of the soft elastic gelatin capsule itself is well known in the art. The composition of a soft elastic gelatin capsule typically comprises from about 30% to about 50% by weight of gelatin NF, from about 10% to about 40% by weight of a plasticizer or a blend of plasticizers and from about 25% to about 40% by weight of water. Plasticizers useful in the preparation of soft elastic gelatin capsules are glycerin, sorbitol or sorbitol derivatives (for example, sorbitol-special and the like) or propylene glycol and the like; or combinations thereof.

The soft elastic gelatin capsule material can also comprise additives such as preservatives, opacifiers, pigments, dyes or flavors and the like.

Various methods can be used for manufacturing and filling the soft elastic gelatin capsules, for example, a seamless capsule method, a rotary method \s (developed by Scherer) or a method using a Liner machine or an Accogel machine and the like. Also various manufacturing machines can be used for manufacturing the capsules.

Typically, the soft elastic gelatin capsule is prepared by preparing the gel mass, encapsulating the fill material (forming, filling and sealing the PO capsule) and softgel drying.

During gel mass preparation, the ingredients comprising the gel mass (typically, gelatin, water and plasticizer) are mixed to form a uniform fluff. After blending, the fluff gel mass is melted, preferably, under vacuum, and the melted gel mass is transferred to heated receivers. Colorants or other additives can be 2 added to the melted gel mass, which is then blended until uniform.

In one method a rotary die encapsulation apparatus is then used to encapsulate the liquid capsule fill. In general, in this method two gel ribbons are gooo 4. fed between two rotating dies. The dies contain paired pockets which form the C shape of the softgel and provide the sealing mechanism. At the moment the two die half pockets line up, the fill material is injected through an encapsulation wedge in between the gel ribbons. The softgel is formed and sealed as a result of pressure between the dies and heat applied by the encapsulation wedge.

Finally, the filled softgels are dried. In one method the filled softgels are first placed in a rotary drier in a low humidity, forced air environment. A final step in the drying process involves discharging the filled softgels from the rotary drier and placing them in a monolayer on shallow dryingtrays, over which is circulated low humidity air of less than 50% relative humidity. The drying process is stopped by transferring the softgels into deep holding trays.

Preferred soft elastic gelatin capsules are manufactured by R.P. Scherer Corp.

Hard gelatin capsules can be purchased from Capsugel, Greenwood, SC \0 and other suppliers. Capsules are filled manually or by capsule filling machine.

The target filling volume/weight depends on the potency of the filling solution in combination with the desired dosage strength.

In general, the compositions of this invention can be prepared in the following manner. The pharmaceutically acceptable long chain fatty acid and \Sr the pharmaceutically acceptable alcohol are mixed at room temperature, along with the antioxidant. The HIV protease inhibitor, or mixture of HIV protease inhibitors, is added and stirred until dissolved. The pharmaceutically acceptable surfactant is added with mixing. The appropriate volume of the resulting mixture needed to provide the desired dose of the HIV protease 0 inhibiting compound(s) is filled into hard gelatin capsules or soft elastic gelatin capsules.

.o The following examples will serve to further illustrate the invention.

Example 1 (non-formulated capsule) An amount of compound III (free base) equivalent to a 5 mg/kg dose was 2 placed in hard gelatin capsules (gray, size These capsules were administered to fasted dogs with 10 ml of water.

Example 2 (Capsule) An amount of compound III (free base) equivalent to a 5 mg/kg dose was placed in hard gelatin capsules (gray, size These capsules were administered to non-fasted dogs with ten milliliter of water.

Example 3 (Caosule) An amount of the bis-tosylate salt of compound III equivalent to a mg/kg dose of compound III (base equivalent) was filled into hard gelatin capsules (gray, size These capsules were administered to fed dogs with ten milliliter of water.

Example 4 (capsule) Component ritonavir (free base) Ethanol (USP, 200 proof) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF By Weight 69.99 0.01 r Example 5 (capsulel Component %l ritonavir (free base) Ethanol (USP, 200 proof) Tween® 80 (NF) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF Examole 6 (caosule) By Weight 64.99 0.01 By Weight 64.99 0.01 Component ritonavir (free base) Ethanol (USP, 200 proof) Tween® 20 (NF) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF -31- Example 7 (capsule or SEC) Component By Weight ritonavir (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF 64.99 Butylated hydroxy toluene (BHT), NF 0.01 The mixing tank was purged with nitrogen. Oleic acid (649.9 g) and ethanol (100g) were mixed in the tank. This solution was warmed to about 33 0

C

(28-37°C) and maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (200 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (50 g) was added to the tank and mixed.

Heating was discontinued and the solution allowed to cool to amibient temperature (20-30°C). The resulting solution was filled into soft elastic capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g of solution/SEC to provide a dosage of 200 mg of ritonavir/SEC.

Example 8 (capsule) 0 0 0.00 o o oo o 00.00 '0.0 .00.0 Component ritonavir (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Sorbitan monooleate Oleic acid, 6321, NF S5" Butylated hydroxy toluene (BHT), NF By Weight 64.99 0.01 Example 9 (capsule or SEC) Component By Weight ritonavir (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF 59.99 Butylated hydroxy toluene (BHT), NF 0.01 -32- The mixing tank was purged with nitrogen. Oleic acid (599.9 g) and ethanol (100g) were mixed in the tank. This solution was warmed to about 33°C (28-37- 0 C) and-maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (200 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g)was added to the tank and mixed.

Heating was discontinued and the solution allowed to cool to amibient temperature (20-300C). The resulting solution was filled into soft elastic capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g of solution/SEC to provide a dosage of 200 mg of ritonavir/SEC.

Example 10 (SEC) Component By Weight ritonavir (free base) Ethanol (USP, 200 proof) 12 polyoxyl 35 castor oil (Cremophor® EL) 6 Oleic acid, 6321, NF 61.95 Butylated hydroxy toluene (BHT), NF 0.05 The mixing tank was purged with nitrogen. Ethanol (118 g) was weighed out and blanketed with nitrogen. Ethanol (2 g) and butylated hydroxytoluene (0.5 g) were charged into a second mixing tank and mixed until uniform under a blanket of nitrogen. The main mixing tank was set for a temperature of 28°C (range 23-33oC). Oleic acid (614.5 g) was charged into the main mixing tank and mixing began. Ritonavir (200 g) was charged into the main mixing tank while mixing and mixed until uniform. The ethanol and and ethanol/butylated 2 hydroxytoluene mixture were charged into the main mixing tank and mixed until clear. The polyoxyl 35 castor oil (60 g) was charged into the main mixing tank.

Oleic acid (5 g) was charged into the main mixing tank and mixed until clear.

The resulting solution was discharged through a 70 mesh or finer filter for storage at 2-8 0 C under nitrogen prior to encapsulation. The resulting solution was filled into soft elastic capsules (1000 mg of solution/SEC) to provide a -33dosage of 200 mg of ritonavir/SEC or (500 mg of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC.

Examole 11 (SEC) Component compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF By Weight 49.99 0.01 Kt The mixing tank was purged with nitrogen. Oleic acid (499.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The Compound V (300 g) was slbwly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g)was added to the tank and mixed. The resulting solution was filled into soft elastic capsules (0.333 g of solution/SEC) to provide a dosage of 100 mg of compound V/SEC or 0.667 g of solution/SEC to provide a dosage of 200 mg of compound V/SEC.

Example 12 (capsule) Component By Weiaht .e.

ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF 9 27 43.99 0.01 -34- Example 1 Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF 3 (capsule) Bv Weight 42.49 0.01 Example 14 (capsule) \0 Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF By Weight 17.5 17.5 44.99 0.01 Example 15 (capsule) o o o* Component ritonavir (free base) :0 compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF By Weight 14 28 37.99 0.01 Example 1 Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF 6 (capsule) By Weight 9 27 48.99 0.01 Example 1 Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF 7 (capsule) By Weight 47.49 0.01 Example 18 (SEC) Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF 44.99 0.01 The mixing tank was purged with nitrogen. Oleic acid (449.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir g) was slowly charged into the tank and mixed until the solution was clear.

The Compound V (300 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g) was added to the tank and -36mixed. The resulting solution was stored at 2-8 0 C before being filled into soft elastic capsules.

ExamDle 19A (SEC) Component .3 ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF QO Butylated hydroxy toluene (BHT), NF By Weight 49.99 0.01 The mixing tank was purged with nitrogen. Oleic acid (499.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (150 g) was slowly charged into the tank and mixed until the solution was clear.

\S Compound V (150 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The resulting solution was filled into soft elastic capsules (1.0 g of solution/SEC) to provide a dosage of 150 mg each of ritonavir and compound

V/SEC.

?Example 19B (SEC) Component By Weight ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF 54.99 Butylated hydroxy toluene (BHT), NF 0.01 -37- Example 20 (SEC) Component By Weight ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF 59.99 Butylated hydroxy toluene (BHT), NF 0.01 Example 21 (SEC) Component ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF By Weight 52.47 0.03 0 0*0* Example 22 (SEC) Component By Weight ritonavir (free base) compound V (free base) Propylene glycol (USP) 6 Oleic acid, 6321, NF 53.97 polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF 0.03 -38- Example 23 (SECj Comonnt B Wegh ritonavir (free base) I11 compound V (free base) 22 Propylene glycol (USP) Oleic acid, 6321, NE 49.47 polyoxyl 35 castor oil (CremophorOD EL) Butylated hydroxy toluene (BHT), NF 0.03 Example 24 (SECQ ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NE polyoxyl 35 castor oil (Cremophor& EL) Butylated hydroxy toluene (BHT), NF 9 27 46.47 0.03 C C C Example 25 (SEC Comnent

BM

ritonavir (free base) compound V (free base) 32.5 Propylene glycol (USP) Oleic acid. 6321, NE 34 polyoxyl 35 castor oil (Cremophor@ EL) Butylated hydroxy toluene (BHT), NE 0.03 S C -39- Example 26 (SEC) Component ritonavir (free base) compound V (free base) S Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF By Weight 4.4 53.07 0.03 Example 27 (SEC) Component ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF 47.47 0.03 *S b oooo ooo

S

role r+

S

9*@ r.oe

S

S 4 Example 28 (SEC) Component By Weight ritonavir (free base) compound V (free base) Propylene glycol (USP) 6 Oleic acid, 6321, NF 48.97 polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF 0.03

S.

S

*SS.

4**S 5.5.

4 5* *e 0 Example 29 (SEC) Comoonent dtonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor EL) Butylated hydroxy toluene (BHT), NF By Weight 52.47 0.03 The mixing tank was purged with nitrogen. Oleic acid (524.7 g) and propylene glycol (75g) were mixed in the tank. The butylated hydroxytoluene (0.3 g) was charged into the tank and mixed until the solution was clear. The ritonavir (100 g) was slowly charged into the tank and mixed until the solution was clear. Heat was applied as necessary. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. Compound V (200 g) was slowly charged into the tank and mixed until the solution was clear. Heat was applied as necessary. The resulting solution was stored at 2-8 0 C before being filled into soft elastic capsules.

Example 30 (SEC) *r Component ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) 25" Butylated hydroxy toluene (BHT), NF By Weight 33 43.97 0.03 -41-

I

Example 31 (SEC) Component ritonavir (free base) compound V (free base) S" Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF Bv Weiaht 24 52.47 0.03 The mixing tank was purged with nitrogen. Oleic acid (524.7 g) and butylated hydroxytoluene (0.3 g) were charged into the tank and mixed.

Propylene glycol (75.0 g) was charged into the tank. The ritonavir (60 g) was slowly charged into the tank and mixed until the solution was clear. Heat may be applied as necessary. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. Compound V (240 g) was slowly charged into the tank and mixed until the solution was clear. Heat may be applied as necessary. The resulting solution was filled into soft elastic capsules (1.0 g of solution/SEC) to provide a dosage of 60 mg of ritonavir and 240 mg of compound V/SEC.

Example 32 (SEC) Component ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NF polyoxyl 35 castor oil (Cremophor® EL) Butylated hydroxy toluene (BHT), NF B Weight 52.47 0.03 2Z- -42- Examp~le 33 (SEC) Componnt y Wight ritonavir (free base) 8 compound V (free base) -24 Propylene glycol (USP) Oleic acid, 6321, NF 50.47 polyoxyl 35 castor oil (Cremophor@ EL) Butylated hydroxy toluene (BHT), NF 0.03 Examnple 34 (SEC) \0 Component ritonavir (free base) compound V (free base) Propylene glycol (USP) Oleic acid, 6321, NIF S polyoxyl 35 castor oil (Cremophor®

EL)

Butylated hydroxy toluene (BHT), NF 8.25 22 52.22 0.03 20 Examale 35 (SEC) ionavir (free base) Propylene glycol (USP) Ethanol (USP, 200 proof) Oleic acid, 6321, NF 69.99 Butylated hydroxy toluene NE 0.01 Example 36 (SEC Compnen1 yWih ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NE 49.99 Butylated hydroxy toluene (BHT), NF 0.01 630 -43- The mixing tank was purged with nitrogen. Oleic acid (499.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed-until the solution was clear. The ritonavir (100 g) was slowly charged into the tank and mixed until the solution was clear.

The Compound V (200 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The resulting solution was stored at 2-8 0 C before being filled into soft elastic capsules.

Example 37 (SEC)

I

S Component ritonavir (free base) compound V (free base) Ethanol (USP, 200 proof) polyoxyl 35 castor oil (Cremophor® EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF Example 38 (SEC) Component ritonavir (free base) aO compound V (free base) Propylene glycol (USP) polyoxyl 35 castor oil (Cremophor@ EL) Oleic acid, 6321, NF Butylated hydroxy toluene (BHT), NF Bv Weight 13 17 49.99 0.01 By Weight 13 17 52.47 0.03 -44- Example 39 (SEC) Component By Weiaht.

ritonavir (free base) compound V.(free-base) SPropylene glycol (USP) polyoxyl 35 castor oil (Cremophor@ EL) Oleic acid, 6321, NF 52.47 Butylated hydroxy toluene (BHT), NF 0.03 Example (2S.3S.5S)-5-(N-(N-((N-Methyl-N-((2-isoropvl-4-thiazolyl)methylami no)carbonylvalinylaminao)-2-(N-((5-thiazoyl)methoxvcarbonyl)amino)-1 .6diDhenyl-3-hydroxhexane (ritonavir: compound III) Compound Ill can be prepared according to the procedures disclosed in U.S. Patent No. 5,541,206, issued July 30, 1996 and U.S. Patent No. 5,491,253, issued February 13, 1996, U.S. Patent No. 5,567,823, issued October 22, 1996, U.S. Patent Application No. 08/673,445, filed June 28, 1996, U.S. Patent Application No. 08/673,445, filed June 28, 1996 and U.S. Patent Application No.

08/862,951, filed May 30, 1997, all of which are incorporated herein by :i reference.

S. Example41 S(2S. 3S. 5S)-2-(2.6-DimethylhenoxyacetvlI amino-3-hydroxv-5-12S-(1 tetrahydro-pyrimid-2-onyl)-3-methyl butanovyll amino-i .6-diphenylhexane (compound V Compound V can be prepared according to the methods disclosed in U.S. Patent Application No. 08/753, filed November 21, 1996 and International Patent Application No. W097/21685, published June 19, 1997, and which are incorporated herein by reference.

Protocol For Oral Bloavailabllitv Studies Dogs (beagle dogs, mixed sexes, weighing 7-14 kg) were fasted overnight prior to dosing, but were permitted water ad libitum. Each dog received a 100 gg/kg subcutaneous dose of histamine approximately minutes prior to dosing. Each dog received a single solid dosage form corresponding to a 5 mg/kg dose of the drug. The dose was followed by approximately 10 milliliters of water. Blood samples were obtained from each animal prior to dosing and 0.25, 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours after drug administration. The plasma was separated from the red cells by \O centrifugation and frozen (-30 0 C) until analysis. Concentrations of parent drug were determined by reverse phase HPLC with low wavelength UV detection following liquid-liquid extraction of the plasma samples. The parent drug area under the curve was calculated by the trapezoidal method over the time course of the study. The absolute bioavailability of each test composition was calculated by comparing the area under the curve after oral dosing to that obtained from a single intravenous dose. Each capsule or capsule composition was evaluated in a group containing at least six dogs; the values reported are averages for each group of dogs. The average bioavailability data for the compositions of the Examples is shown in Table I.

-46- TABLE 1 Mean Example No Bioavailabilitv Example 1 0.0 Example 2 0.0 Example 3 Example 4 39 Example 5 38.8 Example 6 39.6 C Example 7 55.7 Example 8 40.3 Example 9 61.9 This data indicates that solution compositions provided significantly better bioavailability than non-formulated compound III. Additionally, the solution composition, encapsulated in hard gelatin capsule or soft elastic capsule, demonstrated greatly improved bioavailability.

Compounds I, II, III, IV and V are inhibitors of HIV protease. They are useful for inhibiting an HIV infection and treating AIDS in humans. Total daily dose of compound I, II or III administered to a human in single or divided doses 20 may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily but more usually 0.1 to 50 mg/kg body weight daily. Total daily dose of compound IV or V administered to a human in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 20 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, rate of excretion, drugs administered in combination and the severity of the particular disease undergoing therapy.

-47- The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds, methods and compositions.

Variations and changes which are obvious to one skilled in the art are intended to be within the-scope and nature of the invention which are defined-in-the appended claims.

6@06eD p 0 -48-

Claims

1. A pharmaceutical composition for oral administration which is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, optionally, a pharmaceutically acceptable surfactant.

2. The composition of claim 1, comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% by weight of the total solution.

3. The composition of claim 1, wherein the solution is encapsulated in a hard gelatin capsule or a soft elastic gelatin capsule.

4. The composition of claim 1 wherein the solvent comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol or propylene glycol in the amount of from about 1% to about 15% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 1% to about by weight of the total solution.

5. The composition of claim 1, wherein the solvent comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 5% to about 15% by weight of the total solution.

6. The composition of claim 1, wherein the solvent comprises oleic acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 10% to about 15% by weight of the total solution.

7. The composition of claim 1, wherein the HIV protease inhibiting compound is selected from the group consisting of: (2S,3S,5S)-5-(N-(N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N- ((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane (ritonavir); (RAUIBC]08626a.doc:gcc (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1 ,6-diphenylhexane; N-(2(R)-hydroxy- 1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(l1-(4-(3-pyridylmethyl)-2(S)-N butylcarboxamido)-piperazinyl))-pentaneamide (indinavir); N-tert-butyl-decahyd ro-2-(2(R)-hyd roxy-4-phenyl-3(S)-)) N-(2-q u inolylcarbonyl)-L-asparag inyl) amino) butyl)-(4aS,8aS)-isoquinoline-3(S)-carboxamide (saquinavir); 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-VaI-(L)-Phe-morpholin-4- ylamide; 1 -naphthoxyacetyl-beta-methylth io-Aa-(2S,3S)-3-amino-2-hyd roxy-4-butanolyl-1 ,3-thiazolid ine-4-t- butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hyd roxy-4-butanoyl-1 ,3-thiazolidine-4-t- butylamide; (1 S-(1 I -dimethylethyl)aminolcarbonyl)(2-methylpropyi)amino)-2-hydroxy-1 (phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; OH NH 2 HO/N) OH 0 NH K N 15O2P 00o HOT OH 0 HC QH. N')LN H OH"H *H 2 N NH 2 H 0 000 HO OH Ih H H OH H OH H Boc H 0 H OH H P o I INN NNyN OH C)y H H OHCF 0 PhN/ 0 ON> N HH OH I,~ H 'and 0 0 or a pharmaceutically acceptable salt of any of the above.

8. The composition of claim 1, wherein the FIN protease inhibiting compound is ritonavir, (2S,3S,5S)-2-(2,6-d imethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(l1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1 ,6-diphenylhexane, indinavir, saquinavir, nelfinavir or VX-478. [R:\LIBCIO8626adC:9CC

9. The composition of claim 1, wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and another HIV protease inhibiting compound. The composition of claim 1, wherein the combination of HIV protease inhibiting compounds is: ritonavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; ritonavir and indinavir; ritonavir and saquinavir; ritonavir and nelfinavir; ritonavir and VX-478; saquinavir and nelfinavir; indinavir and nelfinavir; nelfinavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5- (2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; or nelfinavir and VX-

478. 11. The composition of claim 1, wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane. 12. The composition of claim 1, comprising ritonavir in the amount of from about 1% to about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and 20 a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% by weight of the total solution. 13. The composition of claim 12, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). 14. The composition of claim 12, comprising 25 ritonavir in the amount of from about 5% to about 25% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 5% to about 10% by weight of the total solution. The composition of claim 14, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). 16. The composition of claim 1, comprising ritonavir in the amount of from about 1% to about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 15% to about 99% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 15% to about 99% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about [R:LIBC]08626a.doc:gcc 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. 17. The composition of claim 16, comprising ritonavir in the amount of from about 5% to about 25% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. 18. The composition of claim 16, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). 19. The composition of claim 16, comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 62% to about 64% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution and 20 polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution. 20. The composition of claim 16, comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 65% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 5% by weight of the total solution. 21. The composition of claim 16, comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 22. The composition of claim 1, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about [R:.LIBC]08626a.doc:gcc to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% by weight of the total solution. 23. The composition of claim 22, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 2% to about 20% by weight of the total solution. 24. The composition of claim 22, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, 20 a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 20% to about 99% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. The composition of claim 24 comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10%to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. 26. The composition of claim 22, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenyl hexane in the amount of about 30% by weight of the total solution, [R:LIBC]08626a.doc:gcc 54 a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 27. The composition of claim 1, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 98% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 20% by weight of the total solution. 28. The composition of claim 27 comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 120% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 5% to about 10% by weight of the total solution. 29. The composition of claim 27 comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution, 0 a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 10% to about 98% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. The composition of claim 29, comprising (R:LIBC]08626a.doc:gcc a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. 31. The composition of claim 29, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 32. The composition of claim 31, comprising :i a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- S methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, 25 a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 33. The composition of claim 27, comprising a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 45% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 34. The composition of claim 27, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, [R:\LIBC]08626a.doc:gcc a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 35. The composition of claim 27, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 5% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 36. The composition of claim 27, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio (wlw) of ritonavir to (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:16 to about 5:1. 37. The composition of claim 36, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:8 to about 3:1. S38. The composition of claim 1, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution 25 and another HIV protease inhibiting compound in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and propylene glycol in the amount of from about 5% to about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 39. The composition of claim 38, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 40. The composition of claim 38, comprising [R:LIBC]08626a.doc:gcc a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and propylene glycol in the amount of from about 5% to about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 41. The composition of claim 40, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 42. The composition of claim 41, comprising a mixture of ritonavir in the amount of about 6.0% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the S'amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 43. The composition of claim 41, comprising a solution of a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 25% by weight of the total solution 30 and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution. 44. The composition of claim 41, comprising a mixture of ritonavir in the amount of about 8% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, (R:AlBC]08626a.doc:gcc V 58 a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 45. The composition of claim 41, comprising a mixture of ritonavir in the amount of about 8.25% by weight of the total solution and (2S,3S,5S)- 2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 22% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.25% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 46. The composition of claim 41, comprising a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 47.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and S 20 polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 47. The composition of claim 41, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- S (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 48. The composition of claim 41, comprising 30 a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 49. The composition of claim 41, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S,3S,5S)-2-(2,6-dimethyiphenoxyacetyl)amino-3- [R:LIBC08626a.doc:gcc hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:16 to about 5:1. The composition of claim 47, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S,3S,5S)-2-(2,6-dimethyiphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:8 to about 3:1. 51. A pharmaceutical composition for oral administration which is a solution, said composition being as defined in claim 1 and substantially as hereinbefore described with reference to any one of the examples. 52. A pharmaceutical composition for oral administration which is a solution comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a 15 pharmaceutically acceptable alcohol, and, a pharmaceutically acceptable surfactant. 53. The composition of claim 52, comprising an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the 2. amount of from about 0% to about 15% by weight of the total solution and 25 a pharmaceutically acceptable surfactant in the amount of from about 2% to about 40% by weight of the total solution. :54. The composition of claim 52 or 53, wherein the solution is encapsulated in a hard gelatin capsule or a soft elastic gelatin capsule. The composition of claim 52 wherein the solvent comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol or propylene glycol in the amount of from about 1% to about 15% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 1% to about by weight of the total solution. 56. The composition of claim 52, wherein the solvent comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 5% to about 15% by weight of the total solution. I:\DAYLIBLIBC]08626b.doc:JFM 57. The composition of claim 52, wherein the solvent comprises oleic acid in the amount of from about 40% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture of ethanol and propylene glycol in the amount of from about 10% to about 15% by weight of the total solution. 58. The composition of claim 52, wherein the HIV protease inhibiting compound is selected from the group consisting of: iazolyl)methoxycarbonyl)amino)-1 ,6-diphenyl-3-hyd roxyhexane (ritonavir); (2S,3S,5S)-2-(2,6-d imethylphenoxyacetyl)amino-3-hyd roxy-5-(2S-( 1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1 ,6-diphenylhexane; N-(2(R)-hydroxy-1 (S)-indanyl)-2(R)-phenylmethyl-4(S)-hyd roxy-5-(l1-(4-(3-pyridylmethyl)-2(S)-N'-(t- butylcarboxamido)-piperazinyl))-pentaneamide (indinavir); N-tert-butyl-decahydro-2-(2(R)-hydroxy-4-phenyl-3(S)-))N-(2-quinolylcarbonyl)-L-asparaginyl)amino) 15 butyl)-(4aS,8aS)-isoquinoline-3(S)-carboxamide (saquinavir); 5(S)-Boc-amino-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4- ylamide; 1 -naphthoxyacetyl-beta-methylthio-Ala-(2S,3S)-3-amino-2-hydroxy-4-butanolyl-1 ,3-thiazolidine-4-t- butylamide; 5-isoquinolinoxyacetyl-beta-methylthio-Ala-(2S ,3S)-3-amino-2-hydroxy-4-butanoy-1,3-thiazolid ine-4-t- butylamide; (1 S-(1 1 1 -dimethylethyl)amino]carbonyl)(2-methylpropyl)amino)-2-hydroxy-1 (phenylmethyl)propyl)-2-((2-quinolinylcarbonyl)amino)-butanediamide; *OH H 2 HO"'AK OH *0 NH N, K 00 HO OH HH, OH N' H 2 N NH 2 H0 0 HO OH 0Ih PA:DAYLlB\LIBC08626bdoc:JFM 61 N Val- C F 3 Sand; and or a pharmaceutically acceptable salt of any of the above. 59. The composition of claim 52, wherein the HIV protease inhibiting compound is ritonavir, (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane, indinavir, saquinavir, nelfinavir or VX-478. The composition of claim 52, wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and another HIV protease inhibiting compound. 61. The composition of claim 52, wherein the combination of HIV protease inhibiting compounds is: ritonavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1- 10 tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; ritonavir and indinavir; Sritonavir and saquinavir; ritonavir and nelfinavir; ritonavir and VX-478; saquinavir and nelfinavir; indinavir and nelfinavir; nelfinavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5- (2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane; or nelfinavir and VX- 478. 62. The composition of claim 52, wherein the HIV protease inhibiting compound is ritonavir or a combination of ritonavir and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1- tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane. S. :63. The composition of claim 52, comprising ritonavir in the amount of from about 1% to about 30% by weight of the total solution, *i 20 a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable S long chain fatty acid in the amount of from about 40% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about S 40% to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 2% to about 20% by weight of the total solution. 64. The composition of claim 63, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). The composition of claim 63, comprising ritonavir in the amount of from about 5% to about 25% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and [I:DUAYLIB\LIBC08626b.doc:JFM a pharmaceutically acceptable surfactant in the amount of from about 2% to about 10% by weight of the total solution. 66. The composition of claim 65, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). 67. The composition of claim 52, comprising ritonavir in the amount of from about 1% to about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 15% to about 99% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 15% to about 99% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. 68. The composition of claim 67, comprising 15 ritonavir in the amount of from about 5% to about 25% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. :69. The composition of claim 67, wherein the solution is encapsulated in a soft elastic gelatin capsule (SEC). 25 70. The composition of claim 67, comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the "amount of from about 62% to about 64% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 6% by weight of the total solution. 71. The composition of claim 67, comprising ritonavir in the amount of about 20% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 65% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 5% by weight of the total solution. 72. The composition of claim 67, comprising ritonavir in the amount of about 20% by weight of the total solution, [I:DAYLIB\LIBC]08626b.doc:JFM a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 73. The composition of claim 52, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and :o a pharmaceutically acceptable surfactant in the amount of from about 2% to about 40% by weight 15 of the total solution. 74. The composition of claim 73, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 12% by weight of the total solution and 25 a pharmaceutically acceptable surfactant in the amount of from about 2% to about 20% by weight of the total solution. 75. The composition of claim 73, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 20% to about 99% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. 76. The composition of claim 75 comprising I:\DAYLIBLIBC]08626b.doc:JFM (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 35% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10%to about 12% by weight of the total solution or propylene glycol in the amount of from about to about 10% by weight of the total solution or a mixture thereof in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. 77. The composition of claim 73, comprising (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenyl hexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the 1i amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 78. The composition of claim 52, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution 20 and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about S.o 25 20% to about 98% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 2% to about 20% by weight S* of the total solution. S79. The composition of claim 78 comprising S 30 a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about to about 70% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 6% to about 120% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 5% to about 10% by weight of the total solution. 0 80. The composition of claim 78 comprising :\DAYLIBLIBC]08626b.doc:JFM a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibitor in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 10% to about 98% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 10% to about 98% by weight of the total solution and ethanol in the amount of from about 0% to about 12% by weight of the total solution or propylene glycol in the amount of from about 0% to about 10% by weight of the total solution or a mixture thereof in the amount of from about 0% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 0% to about 20% by weight of the total solution. 81. The composition of claim 80, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and another HIV protease inhibitor in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises oleic acid in the amount of from about 30% to about 70% by weight of the total solution or (ii) a mixture of oleic acid in the amount of from about 30% to about 70% by weight of the total solution and ethanol in the amount of from about 10% to about 12% by weight of the total solution or propylene glycol in the amount of from about 5% to about 10% by weight of the total solution or a mixture thereof in the amount of from about S 20 10% to about 15% by weight of the total solution and polyoxyl 35 castor oil in the amount of from about 5% to about 10% by weight of the total solution. 82. The composition of claim 80, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and ethanol in the amount Sof about 10% by weight of the total solution and S 30 polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 83. The composition of claim 82, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- niethylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. b 40 84. The composition of claim 78, comprising [:\DAYBLIB.IBC108626b.doc:JFM a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 45% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. The composition of claim 78, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 86. The composition of claim 78, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 5% by weight of the total solution, 20 a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 60% by weight of the total solution and ethanol in the amount of about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 87. The composition of claim 78, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- S 25 dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio (wlw) of ritonavir to (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:16 to about 5:1. S88. The composition of claim 87, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio (wlw) of ritonavir to (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:8 to about 3:1. 89. The composition of claim 52, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and another HIV protease inhibiting compound in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and propylene glycol in the U S4 amount of from about 5% to about 10% by weight of the total solution and (I:DAYLIB\LIBC]08626b.doc:JFM polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. The composition of claim 89, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 91. The composition of claim 89, comprising a mixture of ritonavir in the amount of from about 1% to about 30% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 10% to about 88% by weight of the total solution and propylene glycol in the amount of from about 5% to about 10% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 20 92. The composition of claim 81, comprising a mixture of ritonavir in the amount of from about 5% to about 25% by weight of the total solution and (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of from about 5% to about 40% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of from about 40% to about 65% by weight of the total solution and propylene glycol in the amount of from about 6% to about 8% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 93. The composition of claim 92, comprising a mixture of ritonavir in the amount of about 6.0% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 94. The composition of claim 92, comprising a solution of a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- [I:\DAYLIB\LIBC08626b.doc:JFM methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 25% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution. The composition of claim 92, comprising a mixture of ritonavir in the amount of about 8% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 24% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 50.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 1s 96. The composition of claim 92, comprising a mixture of ritonavir in the amount of about 8.25% by weight of the total solution and (2S,3S,5S)- 2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1 -tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 22% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.25% by weight of the total solution and propylene glycol in the amount of about 7.5% by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 97. The composition of claim 92, comprising a mixture of ritonavir in the amount of about 5% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 30% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 47.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and 30 polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 98. The composition of claim 92, comprising a mixture of ritonavir in the amount of about 15% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 15% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 99. The composition of claim 92, comprising [I:\DAYLIBLIBC]08626b.doc:JFM a mixture of ritonavir in the amount of about 13% by weight of the total solution and (2S,3S,5S)-2- (2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3- methylbutanoyl)amino-1,6-diphenylhexane in the amount of about 17% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a mixture of oleic acid in the amount of about 52.5% by weight of the total solution and propylene glycol in the amount of about by weight of the total solution and polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution. 100. The composition of claim 92, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S,3S,5S)-2-(2,6-dimethyiphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:16 to about 5:1. 101. The composition of claim 98, comprising a mixture of ritonavir and (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl)-3-methylbutanoyl)amino- 1,6-diphenylhexane, the ratio of ritonavir to (2S,3S,5S)-2-(2,6-dimethyiphenoxyacetyl)amino-3- hydroxy-5-(2S-(1-tetrahydropyrimid-2-onyl-3-methylbutanoyl)amino-1,6-diphenylhexane being from about 1:8 to about 3:1. 102. A method of inhibiting an HIV infection in a human requiring such inhibition comprising orally administering to said human an effective amount of a composition of any one of 20 claims 1 to 101. 103. A method of treating AIDS in a human requiring such treatment comprising orally administering to said human an effective amount of a composition of any one of claims 1 to 101. 104. A composition of any one of claims 1 to 101 when used to inhibit an HIV infection in a human requiring such inhibition by orally administering to said human an effective amount of said composition. 105. A composition of any one of claims 1 to 101 when used to treat AIDS in a human requiring such treatment by orally administering to said human an effective amount of said composition. 106. Use of: an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, optionally, a pharmaceutically acceptable surfactant for the preparation of a pharmaceutical composition for oral administration which is a solution. 107. Use of: an HIV protease inhibiting compound or a combination of HIV protease inhibiting [I:DAYLIBIBC108626b.doc:JFM a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid or a mixture of a pharmaceutically acceptable long chain fatty acid and a pharmaceutically acceptable alcohol, and, a pharmaceutically acceptable surfactant for the preparation of a pharmaceutical composition for oral administration which is a solution. 108. Use according to claim 106 of: an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds in the amount of from about 1% to about 50% by weight of the total solution, a pharmaceutically acceptable organic solvent which comprises a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution or (ii) a mixture of a pharmaceutically acceptable long chain fatty acid in the amount of from about 20% to about 99% by weight of the total solution and a pharmaceutically acceptable alcohol in the amount of from about 0% to about 15% by weight of the total solution and a pharmaceutically acceptable surfactant in the amount of from about 0% to about 40% by weight of the total solution •for the preparation of a pharmaceutical composition for oral administration which is a solution. 109. Use according to any one of claims 106 to 108 wherein the solution is encapsulated in a S:i• hard gelatin capsule or a soft elastic gelatin capsule. 110. Use according to any one of claims 106 to 109 wherein the HIV protease inhibiting S 20 compound is ritonavir or a combination of ritonavir and another HIV protease inhibiting compound. Dated 13 December, 2002 ABBOTT LABORATORIES 999* 9 9 Patent Attorneys for the ApplicantlNominated Person SPRUSON FERGUSON [I:\DAYLIB\IBC08626b.doc:JFM