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 suitable aqueous solubility for a drug (or its salt or other derivative) is not obtainable, it is generally true that a solid composition, for example, a tablet or capsule comprising the drug (or its salt or other derivative), will not provide acceptable oral bioavailability.
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.
Examples of HIV protease inhibiting compounds include N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4(S)-hydroxy-5-(1-(4-(3-py ridylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneamide and related compounds, disclosed in European Patent Application No. EP541168, published May 12, 1993;
N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbony l)-L-asparainyl ]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (i.e., saquinavir) and related compounds, disclosed in U.S. Pat. No. 5,196,438, issued Mar. 23, 1993; PA0 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 Mar. 17, 1993; PA0 1-Naphthoxyacetyl-beta-methylthio-Ala-(2S,3S )-3-amino-2-hydroxy-4-butanoyl1,3-thiazolidine-4-t-butylamide (i.e., 1-Naphthoxyacetyl-Mta-(2S,3S)-AHPBA-Thz-NH-tBu) and related compounds, disclosed in European Patent Application No. EP490667, published Jun. 17, 1992; PA0 [1S-[1R*(R*), 2S*]}-N.sup.1 [3-[[[(1,1-dimethylethyl)amino]carbonyl](2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl) amino]-butanediamide and related compounds, disclosed in PCT Patent Application No. WO92/08701, published May 29, 1992; ##STR1## and related compounds, disclosed in PCT Patent Application No. WO94/05639, published Mar. 17, 1994; and ##STR2## and related compounds, disclosed in PCT Patent Application No. WO93/07128, published Apr. 15, 1993.
It has recently been determined that compounds of the formula I: ##STR3## wherein R.sub.1 is lower alkyl and R.sub.2 and R.sub.3 are phenyl are inhibitors of HIV-1 and HIV-2 protease and 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-1 and HIV-2 protease. ##STR4##
The most preferred compound of formula II is (2S,3S,5S)-5-(N-(N-((N-Methy-N-( (2-isopropyl-4-thiazolyl)methyl)-amino)carbonyl)valinyl) amino)-2-(N-((5-thiazolyl) methoxycarbonyl)amino)- 1,6-diphenyl-3-hydroxyhexane (compound III).
Compound III has an aqueous solubility of approximately 6 micrograms per milliliter at pH &gt;2. Acid addition salts of compound III (for example, bis-hydrochloride, bis-tosylate, bis-methane sulfonate and the like) have aqueous solubilities of &lt;0.1 milligram/milliliter. Therefore, it is not surprising that when compound III or a salt thereof is administered orally to dogs, the bioavailability is less than 2%.
The oral bioavailability of a compound having poor aqueous solubility can sometimes be improved by administering the compound as a polyethylene glycol (PEG) melt (solid dispersion). The bioavailability in dogs of such a composition comprising compound III is &lt;5%.
The oral bioavailability of a compound having poor aqueous solubility can also sometimes be improved by including in a standard solid composition a surfactant (for example, sodium lauryl sulfate) and a pharmaceutically acceptable acid. The bioavailability in dogs of such a composition comprising compound III is &lt;3%.
In order to have a suitable oral dosage form of compound III, the oral bioavailability of compound III should be at least about 25%. Preferably, the oral bioavailability of compound III from the dosage form should be greater than about 40% and, more preferably, greater than about 50%.
It has been found that 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 acid. However, it does not necessarily follow that oral administration of a composition comprising such an organic solution of compound III would provide good bioavailability. Unexpectedly, when a mixture of compound III and one or more pharmaceutically acceptable organic solvents is adsorbed on a pharmaceutically acceptable adsorbent and this composition is administered to dogs, an oral bioavailability as high as about 90% is observed.
USPTO Backgrounds
USPTO Backgrounds