Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-03-20
2004-05-04
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S231200, C514S307000, C514S365000, C514S458000
Reexamination Certificate
active
06730679
ABSTRACT:
The present invention relates to novel pharmaceutical formulations containing HIV protease inhibitors, specifically including 3S-[3R*(1R*, 2S*)]-[3-[[(4-aminophenyl)sulphonyl](2-methylpropyl)-amino]-2-hydroxy-1-phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester (alternatively known as VX 478 or 141W94), and a tocopherol, and their use in medical therapy.
The present invention is within the field of pharmaceutical science, in particular in the area of drug delivery, specifically the delivery of HIV protease inhibitors.
Inhibitors of HIV protease have potent activity against Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS) and related conditions such as AIDS-related Complex (ARC). Examples of protease-inhibiting compounds include those disclosed in WO94/05639, WO95/24385, WO94/13629, WO92/16501, WO95/16688, WO/US94/13085, WO/US94/12562, US93/59038, EP541168, WO94/14436, WO95/09843, WO95/32185, WO94/15906, WO94/15608, WO94/04492, WO92/08701, WO95/32185, and U.S. Pat. No., 5,256,783, in particular (S)-N-((.alpha.S)-((1R)-2-((3S, 4aS,8aS)-3-(tert-Butylcarbomoyl)octahydro-2-(1H)-isoquinolyl)-1-hydroxyethyl)phenethyl)-2-quinaldaminosuccinamide monomethanesulfonate (saquinavir), N-(2(R)-Hydroxy-1(S)indanyl)-2(R)-(phenylmethyl)-4(S)-hydroxy-5-[1-[4-(3-pyridylmethyl)-2(S)-(N-tert-butylcarbamoyl)piperazinyl]]pentaneamide (indinavir), 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester (ritonavir), (N-(1,1-dimethyl)decahydro-2-[2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxamide monomethanesulfonate (nelfinavir), and related compounds.
In particular 3S-[3R*(1R*, 2S*)]-[3-[[(4-aminophenyl)sulphonyl](2-methylpropyl)-amino]-2-hydroxy-1-phenylmethyl)propyl]carbamic acid, tetrahydro-3-furanyl ester; [3-(S)-N-(3-tetrahydrofuranyloxycarbonyl)amino-1-(N,N-isobutyl-4-aminobenzenesulfonyl)amino-2-(S)-hydroxy-4-phenylbutane; 4-amino-N-(2(R)-hydroxy-4-phenyl-3-(S)-(tetrahydrofuran-3-(S)-yloxycarbonylamino)butyl)-N-isobutylbenzenesulfonamide (alternatively known as VX 478 or 141W94) as shown as the structure of compound of formula (I) below
The compound of formula (I), disclosed in WO94/05639 and incorporated herein by reference, has been found to be especially effective as an inhibitor of HIV-1 and HIV-2. Particularly preferred is the compound of formula (I).
It may be that an HIV protease inhibitor has a high degree of potency against HIV but it is, of course, essential that when administered to a patient that the HIV protease inhibitor reaches the site of action at an amount and for a duration sufficient for a therapeutic effect to occur, but yet not to reach such levels that excessive and unavoidable toxic effects are present. Therefore in common with other drugs the bioavailability of the HIV protease inhibitor is determined so as to deduce the amount of drug needed to be administered to the patient in order to satisfy the above criteria.
A definition of “bioavailability” can be found in Pharmaceutical Sciences, Remington, 17th Ed., page 1424, quoted below.
“Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form”.
There are many factors which affect the bioavailability of a drug. A drug must first go into solution prior to absorption and, therefore, a key factor is the dissolution rate of a drug. Typical of the class of drugs HIV protease inhibitors have poor physical characteristics of low solubility and wettability and accordingly their dissolution rate is low. Therefore, simple tablet or capsule formulations of such drugs will have a low bioavailability and need to be administered in much higher quantities in order to achieve a therapeutic effect.
Current formulations of HIV protease inhibitors for oral administration are in powder or tablet form. However, HIV protease inhibitors in these oral formulations are generally poorly soluble and, therefore, poorly bioavailable for the above reasons. For example, the aqueous solubility of the compound of formula (I) is only 0.095 mg/mL at room temperature and does not significantly vary with pH (FIG.
1
). In addition, the compound of formula (I) is poorly wetted. Therefore, formulating the compound using standard formulary techniques is difficult and leads in any event to a formulation with low bioavailability.
Therefore, improvements in the bioavailability of HIV protease inhibitors is an important goal in this field offering many advantages, such as, lower quantities of drug administered to achieve the same therapeutic effect and fewer dosages required at less frequent intervals thereby improving patient compliance.
To avoid a dissolution rate limiting formulation and improve bioavailability we formulated the compound of formula (I) as a solution suitable for oral administration. We found that 10 mg/mL of the compound of formula (I) in Polyethylene Glycol 400 (PEG400) solution had an oral bioavailability of 25-30% (Table 1). However, at higher concentrations of the compound of formula (I) in PEG400 (250 mg compound of formula (I)/gram solution), the bioavailability dropped to half the value achieved with the 10 mg/mL solution and the maximal concentration (Cmax) achieved was also drastically reduced (Table 1).
Surprisingly, we have found that when the compound of formula (I) is administered as a solution comprising d-Alpha Tocopheryl Polyethylene Glycol
1000 Succinate (Vitamin E-TPGS) the bioavailability of the compound of formula (I) is greatly improved.
Vitamin E-TPGS is a water soluble form of vitamin E and has been recognised as an excipient to promote emulsification of lipophilic substances, acting as a non-ionic surfactant, and in improving the bioavailability of certain drugs.
In The Lancet, 1991. 338, 212-214 Sokol R. J. et al teaches that coadministration of Vitamin E-TPGS with cyclosporin improves the bioavailability of cyclosporin.
In WO95/31217 (Dumex Ltd) it is taught that tocopherols can be used as a solvents and/or emulsifiers of drugs substantially insoluble in water, in particular for the preparation of topical formulations. Use of Vitamin E-TPGS is specifically mentioned at pages 7-8 and 12 as an emulsifier for use in formulations containing high levels of &agr;-tocopherol as the lipid layer. Examples of formulations for topical administration disclosed containing Vitamin E-TPGS, such as Examples 1 to 5, typically comprises a lipid layer (an &agr;-tocopherol), the drug and Vitamin E-TPGS, in quantities of less than 25% w/w of the formulation, as an emulsifier. There is no reference to formulation of HIV protease inhibitors.
In WO96/36316 (Abbott Laboratories), which published after the priority date but before the filing date of this application, it is taught that Vitamin E-TPGS can be used for the enhanced delivery of lipophilic compounds as a self-emulsifying preconcentrate formulation comprising a) a lipophilic drug (a cyclosporin is specifically exemplified), b) vitamin E-TPGS and c) a lipophilic phase. Typical examples of formulations disclosed, such as Examples 2 and 4, contain less than 14% w/w Vitamin E-TPGS as an emulsifier, a lipid layer and the drug. There is no reference to formulation of HIV protease inhibitors.
We have now found that the bioavailability of an HIV protease inhibitor can be significantly enhanced by formulation as a liquid formulation comprising a water soluble tocopherol derivative, in particular Vitamin E-TPGS.
We surprisingly found that formulations comprising (a) an HIV protease inhibitor and (b) a water soluble tocopherol derivative in a ratio of from about 1:0.5 to about 1:10 w/w have advantageous properties in terms of bioavailability.
The present invention thus provides, in a first aspect, a pharmaceutical fo
Roy Arup K.
Tillman Lloyd Gary
Birch Stewart Kolasch & Birch
SmithKline Beecham Corporation
Travers Russell
Wiener Marc S.
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