Oral pharmaceutical formulation which improves the bioavailability of pharmaceuticals which are substantially water and oil insoluble is disclosed. In addition to the pharmaceutical, the formulation includes an emulsifier, an oil and an solubilizer. Alternatively, the formulation includes an aqueous solution of solubilizer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a means for orally delivering the necessary concentration of an active form of a pharmaceutical which is substantially insoluble in both water and oil to the systemic circulation of an animal or human being to elicit a desired therapeutic response. Pharmaceuticals, which would otherwise be good candidates for use in treatments, are frequently dropped or rejected due to their substantial insolubility in both water and oil. This insolubility problem typically results in low, if any, bioavailability of the pharmaceutical.

As a class, HIV protease inhibitors tend to have low oral bioavailability and short plasma half-lives. Thus it is difficult to maintain adequate therapeutic blood levels of the drug for a prolonged time period. Surprisingly, by solubilizing the water and oil insoluble pharmaceutical with a solubilizer in the dosage formulation of the present invention, the pharmaceutical's bioavailability substantially increases. For example, the compound N.sup.1-[3-[N.sup.2-[[(1,1-dimethylethyl)amino]carbonyl]-N.sup.2-(2-methy- lpropyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-2(S)-[N.sup.3-(2-qu- inolinylcarbonyl)amino]butanediamide which has the formula -- see Original Patent --is an effective HIV protease inhibitor (see U.S. patent application Ser. No. 08/152,934, filed Nov. 15, 1993, incorporated herein by reference in its entirety). Because of its low solubility in both water (about 0.01 mg/mL) and oil (less than 1 mg/mL), its bioavailability was also very low when measured in animals. By utilizing a solubilizer in the dosage formulation, the bioavailability increased about 25 30 fold thereby making the compound a potentially effective pharmaceutical for the treatment of HIV infections.

The present invention can also be used with other pharmaceuticals which are not only substantially insoluble in both water and oil, but which are substantially insoluble in water or oil or soluble in water or oil. Such pharmaceuticals include, but are not limited to, Ro 31 8959 (Roberts, N. A. et al. Science 1990, 248, 358 361 and Drugs of the Future 1991, 16(3), 210 212); cyclosporin; FK506 (immunomodulator); [1S-[1R*(R*),2S*]]-2-(acetylamino)-N-[3-[[[(1,1-dimethylethyl)amino]carbo- nyl](3-methyl-butyl)amino]-2-hydroxy-1-(4-fluorophenylmethyl)propyl]-3,3-d- imethyl-butaneamide; [1S-[1R*(2S*,3R*),2S*]]-N1-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-met- hylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2,3-dimethyl-butanediami- de; [1S-[1R*(R*),2S*]]-N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methyl- butyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-methyl-3-(2-phenylethylsu- lfonyl)-propanamide and its diastereomer; [1S-[1R*(S*),2S*]]-3-(4-methoxybenzyl-oxycarbonyl)-N-[3-[[[(1,1-dimethyle- thyl)amine]carbonyl](3-methylbutyl)amino]-2-hydroxy-1-(phenylmethyl)propyl- ]-2-methyl-propanamide; [1S-[1R*(R*),2S*]]-N-[3-[[[(1,1-dimethylethyl)amino]carbonyl](3-methylbut- yl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-pr- opanamide and its diastereomer; [2R-hydroxy-3-[N-(4-hydroxyphenylsulfonyl)-N-(2-methyipropyl)amino]-1S-(p- henylmethyl)propyl-carbamic acid 3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; [2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenyl- methyl)propyl-carbamic acid 3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(ph- enylmethyl)propyl]-2,6-dimethylbenzamide; N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(ph- enylmethyl)propyl]-2-methyibenzamide; N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(ph- enylmethyl)propyl]-2,6-dimethylbenzamide; [1S-[1R*(S*),2S*]]-[3-[[2-hydroxy-3-[(3-methylbutyl)(phenylsufonyl)amino]- -1-(phenylmethyl)propyl]amino]-2-methyl-3-oxopropyl]-carbamic acid (4-methoxyphenyl)methyl ester; N.sup.1-[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N.sup.4-met- hyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide- ; [1S-[1R*(S*),2S*]]-N.sup.4-[2-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)- amino]-1-(phenylmethyl)propyl]-2,2,3-trimethyl-butanediamide; [1S-[1R*(R*),2S*]]-N-[2-hydroxy-3-[(3-methylbutyl)](4-aminophenylsulfonyl- )amino]-1-(phenylmethyl)propyl]-2-methyl-3-(methylsulfonyl)-propanamide; and 8-chlorodibenz[b,f][1,4]oxazapine-10-(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-l-oxopropyl]hydrazide.

The present invention is particularly beneficial for pharmaceuticals with a dose to solubility ratio in excess of about 1000 and even more beneficial for pharmaceuticals with a dose to solubility ratio in excess of about 10,000. For example, dose to solubility ratio of the compound N.sup.1-[3-[N.sup.2-[[(1,1-dimethylethyl)amino]carbonyl]-N.sup.2-(2-methy- ipropyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-2(S)-[N.sup.3-(2-qu- inolinyl carbonyl)amino]butanediamide was determined to be in excess of about 75,000.

The present invention is an oral pharmaceutical composition comprising a) a pharmaceutical which is substantially water and oil insoluble; b) an edible emulsifier; c) an edible oil; and d) an edible solubilizer. The pharmaceutical may be at a concentration within the range of about 0.1 to about 17% (w/w); preferably, at a concentration within the range of about 2 to about 10% (w/w); and more preferably, at a concentration within the range of about 5 to about 10% (w/w). The emulsifier may be at a concentration within the range of about 10 to about 55% (w/w); preferably, at a concentration within the range of about 10 to about 45% (w/w); and more preferably, at a concentration within the range of about 30 to about 45% (w/w). The oil may be at a concentration within the range of about 10 to about 50% (w/w); preferably, at a concentration within the range of about 10 to about 45% (w/w); and more preferably, at a concentration within the range of about 25 to about 45% (w/w). The solubilizer may be at a concentration within the range of about 2 to about 50% (w/w); preferably, at a concentration within the range of about 5 to about 40% (w/w); and more preferably, at a concentration within the range of about 10 to about 35% (w/w).

Alternatively, the present invention is an oral pharmaceutical composition comprising a) a pharmaceutical which is substantially water and oil insoluble; b) an edible solubilizer; and c) water. The pharmaceutical may be at a concentration within the range of about 0.1 to about 17% (w/w), and preferably, at a concentration within the range of about 2 to about 10% (w/w). The solubilizer may be at a concentration in the water within the range of about 40 to about 90% (w/w); preferably, at a concentration within the range of about 50 to about 80% (w/w); and more preferably, at a concentration within the range of about 60 to about 80% (w/w). The solubilizer concentration will frequently depend on the solubility properties of the pharmaceutical and the total volume of the dose.

An "edible emulsifier" is an emulsifier which may be consumed by an animal or human being without substantial side effects or substantial toxic reaction. Emulsifiers which are suitable for use in this invention include polyoxyethylene glycerol esters of fatty acids, such as Tagat TO, Tagat L, Tagat I, Tagat I2 and Tagat O (commercially available from Goldschmidt Chemical Co., Essen, Germany); ethylene glycol esters, such as glycol stearate and distearate; propylene glycol esters, such as propylene glycol myristate; glyceryl esters of fatty acids, such as glyceryl stearates and monostearates; sorbitan esters, such as spans and tweens; polyglyceryl esters, such as polyglyceryl 4-oleate; fatty alcohol ethoxylates, such as Brij type emulsifiers; ethoxylated propoxylated block copolymers, such as poloxamers; polyethylene glycol esters of fatty acids, such as Labrafil 2125 CS, Labrafil M 1944 CS and Labrasol; cremophores, such as cremophore E and Cremophore RH 40P; glycerol monocaprylate/caprate, such as Campmul CM 10; and the like. Tagat TO is preferred.

An "edible oil" is an oil which may be consumed by an animal or human being without substantial side effects or substantial toxic reaction. Most edible oils are suitable for use in this invention, including Neobee oil (commercially available from Stephan Co., Ill.), Myglyol derivatives (fractionated coconut oil), soy oil, almond oil, olive oil, peanut oil, other fatty acid esters of glycerols having about 14 to about 18 carbon atoms, medium chain triglycerides having about 8 to about 10 carbon atoms, and the like. Neobee oil is preferred.

An "edible solubilizer" is a material which can dissolve a pharmaceutical that is substantially insoluble in water and oil and may be consumed by an animal or human being without substantial side effects or substantial toxic reaction. Solubilizers which are suitable for use in this invention include ethanol, tert-butanol, sweet peppermint flavor, orange oil flavor, cherry flavor, raspberry flavor, lemon oil flavor, oleic acid, linoleic acid, propylene glycol, butyric acid, propionic acid, lauryl alcohol, limonene, myristyl alcohol, polyethylene glycol and the like. Ethanol is preferred.

"Substantially water insoluble" means that the measurable solubility in water (pH 7) is preferably less than one part per hundred, more preferably less than one part per thousand and most preferably less than one part per ten thousand.

"Substantially oil insoluble" means that the measurable solubility in oil is preferably less than one part per hundred, more preferably less than one part per thousand and most preferably less than one part per ten thousand.

Typically the formulation of the present invention is prepared by forming an "emulsifiable concentrate" comprising the pharmaceutical, solubilizer, emulsifier and oil in the final concentration ranges disclosed above. The emulsifiable concentrate is preferably prepared by first dissolving the pharmaceutical in the solubilizer. The pharmaceutical is preferably fully dissolved in the solubilizer, which may require vigorous mixing, stirring or heating. This solution is combined with the emulsifier to form a uniform solution. This mixture is then combined with the oil to form the emulsifiable concentrate.

The emulsifiable concentrate may be used directly, for example, as an elixir or in soft gelatin capsules, or may be combined with an aqueous solution prior to distribution or use. Because a preferred emulsifiable concentrate spontaneously forms emulsions in aqueous solutions, it may be combined with the aqueous solution just prior to use which can minimize the effect of any long term emulsion instability. It may be necessary in some formulations to combine the emulsifiable concentrate with the aqueous solution just prior to use to avoid gelling of the mixture. For example, the composition of Tagat TO, Neobee Oil, ethanol and an aqueous solution has been observed to form a gel above five degrees Celsius. The aqueous solution may be water (such as buffered water), beverages (such as soft drinks, milk and the like), juices (such as orange juice, grape juice, apple juice, and the like) and the like. Preferably, the aqueous solution has a pH within the range of about 3 to about 8.5 and more preferably, within the range of about 5 to about 7.5. The preferred ratio of emulsifiable concentrate to aqueous solution, i.e., oil:water ratio, is within the range of about 1:5 to about 1:1000 and more preferably, within the range of about 1:50 to about 1:200.

The particle size of the emulsion particles may be critical to the effectiveness of the present invention. The smaller the emulsion particles, the larger the total surface area and the greater the likelihood of absorption into the systemic circulation. The particle size distribution can be readily determined from dynamic light scattering techniques well known in the art. Preferably the mean emulsion particle size is within the range from about 20 nm to about 25 nm in diameter and more preferably, about 22 nm in diameter.

With regards to the compound N.sup.1-[3-[N.sup.2-[[(1,1-dimethylethyl)amino]carbonyl]-N.sup.2-(2-methy- lpropyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-2(S)-[N.sup.3-(2-qu- inolinylcarbonyl)amino]butanediamide, a preferred formulation under the present invention is about 5% (w/w) pharmaceutical, about 35% (w/w) Tagat TO, about 25% (w/w) Neobee Oil and about 35% (w/w) ethanol.

While the pharmaceutical of the present invention may be administered as the sole active pharmaceutical agents, the pharmaceutical may also be used in combination with other pharmaceuticals which are effective for the same treatment. These additional pharmaceuticals may be added to the formulation of present invention and may be water soluble, oil soluble, or substantially water or oil insoluble. For example, N.sup.1-[3-[N.sup.2-[[(1,1-dimethylethyl)amino]carbonyl]-N.sup.2-(2-methy- lpropyl)amino]-2(R)-hydroxy-1(S)-(phenylmethyl)propyl]-2(S)-[N.sup.3-(2-qu- inolinylcarbonyl)amino]butanediamide may be administered as the sole active pharmaceutical agent, it may also be used in combination with other antiviral agents which are effective against retroviruses such as HIV. Such compounds include, but are not limited to, other HIV protease inhibitors, various nucleoside analogs, nonnucleoside reverse transcriptase inhibitors, tat antagonists and glycosidase inhibitors (U.S. patent application Ser. No. 08/253,638, filed Jun. 3, 1994, which is incorporated by reference herein in its entirety). Such other antiviral agents may also be added to the formulation of the present invention.

Examples of HIV protease inhibitors include, but not limited to, Ro 31 8959 (Roberts, N. A. et al. Science 1990, 248, 358 361 and Drugs of the Future 1991, 16(3), 210 212), KNI-272, (Kagayama, S., et al. Antimicrobial Agents and Chemotherapy 1993, 810 817), the cyclic urea series (Lam, P., et al., "De Novo Design and Discovery of Potent, Nonpeptidal HIV-1 Protease Inhibitors," paper 96 at the 205th American Chemical Society National Meeting, Medicinal Chemistry Division, Denver, Colo., Mar. 28 Apr. 2, 1993), L-735,524 (Dorsey, B. D., et al., "L-735,524: The Rational Design of a Potent and Orally Bioavailable HIV Protease Inhibitor," paper 6 at the 206th American Chemical Society National Meeting, Medicinal Chemistry Division, Chicago, Ill., Aug. 22 27, 1993) and analogs thereof.

Examples of competitive nucleoside analogs include, but are not limited to, azidothymidine (AZT), dideoxyinosine (DDI), DDC, 3TC, D4T and PMEA. Examples of non-nucleoside, non-competitive reverse transcriptase inhibitors include, but are not limited to, the pyridone class (Wei, J. S., et al. J. Med. Chem. 1993, 36, 249 255; Hoffman, J. M., et al. J. Med. Chem. 1992, 35, 3784 3791; Saari et al. J. Med. Chem. 1992, 35 3792 3802; Drugs of the Future 1992, 17(4), 283 285, and analogs thereof); the bis-(heteroaryl)piperazines class (Romero, D. L., et al. J. Med. Chem. 1993, 36, 1505 1508; Romero, D. L., et al. Proc. Natl. Acad. Sci. USA 1991, 34, 746 751 and 3187 3198; and analogs thereof) and the tricyclic pyridobenzo- and depyridodiazepinones (Hargrave, K. D., J. Med. Chem. 1991, 34, 2231 2241; Merluzzi, M. J. Science 1990, 250, 1411 1413; and analogs thereof) and 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide and its analogs (Williams, T. M. et al., J. Med. Chem. 1993, 36, 1291 1294). Examples of tat antagonists include, but are not limited to, Ro 5 3335 and Ro 24 7429 (Hsu, M. C. et al., Proc. Natl. Acad. Sci. USA 1993, 909, 6395 6399; Tam, S. et al.,"TAT INHIBITORS: A NEW CLASS OF ANTI-HIV AGENTS," paper 372, at the 204th American Chemical Society National Meeting, Organic Chemistry Division, Washington, D.C., Aug. 23 28, 1992) and analogs thereof. Examples of glycosidase inhibitors include, but are not limited to, castanospermine, castanospermine 6-butryl ester, N-butyl-1-deoxynojirimycin, N-butyl-1-deoxynojirimycin per-butryl ester and analogs and prodrugs thereof.

Other pharmacologically active or inactive compounds, excipients or additives may be added to the formulation to enhance the efficacy of the pharmaceutical, to reduce the side effects and/or toxic effects of the pharmaceutical, to prolong the duration of the active form of the pharmaceutical in the systemic circulation and the like. Additional ingredients may also be added to the formulation which enhance the stability of the pharmaceutical or formulation, such as anti-oxidants (BHA, BHT, vitamin E, ascorbyl palmitate and the like). Still other ingredients may be added to the formulation, such as colorings, flavorings (sweet peppermint flavor, orange oil flavor, cherry flavor, raspberry flavor, lemon oil flavor and the like), sweeteners (aspartame, saccharin, glucose, sucrose, dextrose and the like) and the like to enhance the receptivity and compliance by patients or other users of the formulations.
 

Claim 1 of 13 Claims

1. A pharmaceutical composition in the form of an emulsion, said composition comprising an emulsified mixture of (I) an emulsifiable concentrate, comprising: (a) an antiviral compound that is substantially water and oil insoluble, (b) an edible emulsifier, (c) an edible oil, and (d) an edible solubilizer, and (II) an aqueous solution, wherein said emulsifiable concentrate comprising (a) (d) and said aqueous solution are present in a ratio of emulsifiable concentrate: water from about 1:10 to about 1:1000, to provide said pharmaceutical composition as an emulsion, prior to use.

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