HU228026B1 - Compositions comprising an hiv protease inhibitor and a water soluble vitamin e compound - Google Patents

Description

The invention also relates to a process for the preparation of the above pharmaceutical compositions.

The pharmaceutical compositions of the present invention show good solubility and advantageous bioavailability.

I

S »TODAY & IADL i« S » ^lake version

NYOMDAPÉ1.IMNV

-protease inhibitor and you have watered your mouths,

The present invention relates to novel pharmaceutical compositions which are 3S- [3R '(1R', 2S) p [3-U (4-aminophenyl) sulfonyl] -3- (2-methyl-propyl) - which is η oj - 2-super-droxy-1-phenylphenylmethyl) - propyl 11 - aromatic acid - (tetrahydro-5-furanyl) ester (also known as VX 478 or 141W94), contain a tocopherol and a non-aqueous solvent for hldrophil mixed with tocopherol

More particularly, the present invention provides a pharmaceutical composition for oral administration comprising (a) a HIV-protease inhibitor, <b> a water-soluble tocofend derivative, and (e) a non-aqueous hydrophilic solvent miscible with this water-soluble cofofetol derivative, wherein (a). (ratio of bj-bez to about 1: 0.5 to 1:10 w / w).

The present invention is within the field of pharmaceutical science, particularly in the field of fish oil release, more particularly the release of HIV protease inhibitors.

HIV protease inhibitors may be effective against the human immune deficiency virus (HIV), which is the causative agent of acquired immunodeficiency syndrome (AIDS) and related conditions such as AlDS-associated complex (ARC). Examples of prolase inhibiting compounds include those disclosed in WO94 / 95639, WO'95 / 2438-5, WO94 / 13399, WO92 / 100501, WO9S / 1000888, WO / HS94 / 13085,

WO / US94 / 12562, US95 / 59930, BP54US,

WO95 / 09843, WO95 / 32185, WO94 / IS906,

WO94 / 04492, WO92 / 037601, WO95 / 32183 and U.S. Patent No. 5,256,7S3; of these, especially noteworthy are the {.S) ~ N - ((al .f &gt;) - ((1R) -2 - {(3S, 4aS, 8aS) -3- (tert-butylcarbamoyl) -is). .alphaedro ~ 2 - ((1H) -isoquinoyl) -1-hydroxy-ethyl) -phenethyl) -2-quinaldaminosuccinamide monomephane mononephonate (saquinavir), NWO94 / 14436, W 094/15698,

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4 * 4 «» «4 *» »» * * '·> _Λ ~ (2 (R) ~ hydr ο χ i' -1 (S) ind a «i 1) - 2 (R) - (fe ni I - Me 1 (1) - 4 (S) - H 2 x - 5 - [1- (4- (3-pyridyl) -ethyl) - 2 (S) - (N-tefc-butylcarboxylic acid) -pperperazyl ]} - pentanamide (Indisavir)., 1,1'-hydroxy-2-methyl-5 - [(2-methyl-ethyl) -1- (2- (1-methylethyl) -4-thiazolyl] -6,6 -áío.xo ~ 8th ₅ 11 -bis phenylmethyl) -2,4,7,12-tetr.aaz.airidekan acid-13, S-tlazolii methyl ester (ritonavir), the FN ( l, l- dimeti 1) - dek ahi dro - 2 - [2 - h i dr ox i - 3 - [(3 - hydr ο xi - 2 - me 111 - be η · ζ ο ί 1) ~ am í no ] -4-phenylthio) benzyl] -3-isoquinolinecarboxamide mono-neylan sulfone (nefliaavir), and the like.

Particularly preferred is 38- [3R '(1R ^x , 2 S ^x )] - {3 - [[(4-aminophenyl) sulfonyl] -1- (2-methylpropyl) amino} -2-hydroxy- 1-Phenylmethyl-propyl] -carbamic acid tetrahydro-3-furanyl Compound: p- (S) -N- (3-tetrahydrofuran-1-oxycarbonyl) -amino-1- (N, N-isobutyl-4-aminobenzenesulfone (1) - amino - 2 - (S) - hyalodine - 4 - fe η i - 1 - bntane; a 4 - am i η ο - N ~ (2 (R) - h 1 dr ο x 1 - 4 - fe η i 1 - 3 - (S) - {te tr ah 1 dro fu n - 3 ~ (S ) - 1 - ο xi - k or n - 1 - amino - butyl I - N - isobutylbenzenesulfonamide (which is also known as VX 478 or 141W94), the structure of which is illustrated by formula (I).

The compound of formula (I) is described in WO 94/05639, the disclosure of which is hereby incorporated by reference and has been found to be an effective inhibitor of HIV-1 and HIV-2. Among the compounds listed above, the compound of formula (I) is particularly beneficial.

However, it is not enough for an HIV inhibitor to be highly effective against HIV, and, of course, there is a need for the HIV protease inhibitor to reach the site of treatment and to expose it sufficiently after administration to the patient being treated. however, it should not be so severe as to cause unnecessary toxic side effects. Thus, as with other drugs, the bioavailability of the HIV protease inhibitor is determined by determining the amount of drug required for administration to the patient, taking into account the above criteria.

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The term bioavailability is defined in the literature as follows (Pbarmaceutical Sciences, Remington 17th Edition, 1424):

Bioavailability is an absolute term that denotes the time (velocity) and total volume (extent) that enter the bloodstream after administration of a drug dosage form. "

There are many factors that influence the bioavailability of drugs. A drug is required to dissolve first prior to absorption, so the extent of dissolution is a decisive factor for drugs. In general, drugs belonging to the class of HIV inhibitors have poor physical properties, low solubility and wettability, and hence low solubility and low solubility. As a result, the bioavailability of simple tablets or capsules made from these active substances is not clear. in order to ensure a therapeutic effect, they should be administered in larger amounts than necessary.

HIV protease inhibitors for oral administration are currently in the form of powders or tablets. However, in these oral formulations, HIV protease inhibitors are generally poorly soluble, and therefore, for these reasons, the bioavailability of these inhibitors is low. Thus, for example, the water solubility of the compound of formula (I) at room temperature is only 0.15 mg / ml, which does not change significantly with the pH (see Figures 1). In addition, the compound of formula (I) is slightly wetted, it is not easy to convert it into a formulation using standard technology, and in any case, it results in a formulation which has poor bioavailability.

Therefore, improving the bioavailability of HIV protease inhibitors in this area is an important task, which may have many benefits, such as administering smaller amounts of the active ingredient sufficient to provide the same therapeutic effect, at lower doses and less frequently, thereby improving patient compliance.

«« ♦ ***

In order to eliminate inadequate solubility of the formulations and to improve bioavailability, the compound of formula (I) was formulated as a solution for oral administration. It was found. that the compound of formula (1) is dissolved in polyethylene glycol 4-O (FEG400) at a concentration of 10 mg / ml to achieve a bioavailability of 25-30% (see Table 1). However, formulations of the compound of formula (1) with a higher concentration of PEG40O (250 rag of compound (1) / g solution) reduce the bioavailability by half compared to the results obtained with the 10 mg / ml solution and the maximal concentration reached (€ max. ) is also drastically reduced (see Table 1).

Surprisingly, it has been found that if the compound of formula (1) is d-terminated by a tree 1 o coefficients 1 - ρ ο 1 i (et ί 1 e ng 11 k ο 1) I O 0 0 (E- vitamin-1TP GS) solution, the bioavailability of the compound of formula (I) is greatly improved.

Vitamin B-TPGS ("VítE-TPGS" in the tables) is a water-soluble form of Vitamin E, which is known to enhance lipophilicity, act as a nonionic surfactant, and improve the bioavailability of certain active ingredients.

It is described in Lanud [Sokol R.J. et al., 338, 212-214 (1991) 1, with the addition of vitamin E-TP6S to ciclosporin &lt; 1 &gt; improves the bioavailability of ciclosporin.

WO 95/31217 (Domex Ltd.) discloses that tocopherols can be used as solvents and / or emulsifiers of substantially water-insoluble active ingredients, in particular for the preparation of formulations for topical use. AE-Vitamin-TPGS is specifically mentioned on pages 8 and 12 of the above description as a mammalian gel that can be used as a high concentration lipid phase for the preparation of compositions containing α-tocopherol. For topical administration of Vitamin B-TPGS Examples 1-5 are examples of formulations containing a tipid phase (an α-tocopherol), the active ingredient and Evitamirs-TPSS in an amount of less than 25% by weight of the composition as an ethnulsifier. However, preparations containing H.IV-inhifehor are not mentioned here.

International Publication No. WO96 / 03003I (Abbott Laboratories) (published prior to the filing date of this application, but after the priority date) discloses that Vitamin E-TPGS may be used to enhance the release of lipophilic compounds in the form of a self-emulsifying concentrated formulation. comprising a) a lipophilic active ingredient (specifically ciclosporin), b) vitamin E-TPGS, and c) a lipophilic phase. These formulations are illustrated in Examples 2 and 4, wherein these formulations contain less than 14% by weight of emulsifier E-vitmin-TPGS, a lipid phase, and the active ingredient. However, there is no mention of HIV protease inhibitors.

It has been found that the bioavailability of HIV protease inhibitors can be significantly improved by the use of liquid formulations containing a water-soluble tocopherol derivative, in particular Εν 1 tamin-TPG S-1.

Surprisingly, it has been found that compositions containing (a) a VX 47S and (fe) a water-soluble tocopherol derivative. containing from about 1: 0.5 to 1:10% by weight, exhibiting favorable bioavailability.

Thus, a first aspect of the invention is a pharmaceutical composition for oral administration comprising (a) VX 478, (fe) a water-soluble tocopherol derivative, and (e) a non-aqueous hydrophilic solvent miscible with this water-soluble tocopherol derivative, wherein (a): (b) a weight ratio of about 1: 0.5 to 1:10.

In addition, it has been found that formulations containing a) VX 478 and b) at least 20% by weight of a water soluble locolerol derivative as vitamin E-TPGS have a beneficial bioavailability even when the HIV protease. inhibitor is present in high concentrations.

It has been found that formulations containing VX 478 ~ and a water soluble tocopherol derivative do not require the presence of a lipophilic phase, thus reducing the cost of preparation and simplifying the preparation. The lack of A. lipophilic phase, and the ability to dissolve VX 478 in much higher concentrations without adversely affecting bioavailability, results in smaller, easier, more manageable, less expensive, and more readily available formulations. .

Another embodiment of the present invention is pharmaceutical compositions for oral administration comprising (a) VX 478, (b) at least 20% water-soluble tocopherol derivative, and (c) a non-aqueous hydrophilic solvent miscible with this water-soluble tocopherol derivative, wherein: a) :( h) has a weight ratio of about 1: 0.5 to 1:10 and (a), (h) and (e) are in the form of a pourable liquid.

Water ο 1 d h a t 6 t o k o f e r e 1 close the ze k η í preferably E - v i t am 1 n - T P G S is present.

Preferably, the compositions of the present invention comprise from about 10% to about 60% by weight of a water soluble tocopherol derivative, preferably E-vinyl TPGS, more preferably from about 20 to about 50% by weight, such as about 30 to about 50% by weight, e.g. Vitamin TPGS is used in tars.

In the compositions of the invention, the weight ratio of VX 478 to the water soluble tocopherol derivative is preferably from about 1: 0.5 to 1: 3, such as from about 1: 0.67 to 1: 2.6, more preferably from about 1: 0.67 to 1: 2.6. : 1.3 - 1: 3,

Water soluble phosphorol derivatives, especially Evitamin-TPGS, form a waxy solid at room temperature. Although the HIV protease inhibitory compounds may be administered to patients in a water soluble tocopherol derivative only, it is preferred that additional pharmaceutical excipients be added to the formulation to improve the physical properties of the composition, such as addition of a non-aqueous hydrophilic solvent miscible with water soluble tocopherol derivatives to form a liquid which facilitates industrial scale production, for example in the form of soft gelatin capsules.

It has been found that a non-aqueous hydrophilic solvent miscible with a water soluble tocopherol derivative enhances the solubility of the HIV protease inhibitor, allowing further reduction of the volume of the composition containing the effective dose. Among the pharmaceutically acceptable solvents are poly (ethylene glycol) and propylene glycol. addition of poly (vinylpyrrolidones), Polyethylene glycol) and propylene glycol to a composition comprising the HIV protease inhibitor and Vitamin E-TPGS provides a pourable liquid which can be filled into soft gelatine capsules. forms.

When the compounds of formula (I) are formulated into a pharmaceutical composition in the presence of E-Vitamin N-TPGS, PEG 4 O 5 and propylene glycol, the bioavailability of the compound of Formula (I) is more favorable than the delayed use of E-Vitamin-TPGS alone. shoot  11 shooting ο z,

Preferably, the non-aqueous hydrophilic solvent is polyphenylene glycol, propylene glycol or poly (vinylpyrrolidone). More preferably, a non-aqueous hydrophilic solvent is a mixture of polyethylene glycol, such as a mixture of poly (ethylene glycol) 40 and propylene glycol. The non-aqueous hydrophilic solvent is present in the composition of the invention in an amount of from about 15 to about 95% by weight, preferably from about 25 to about 60% by weight.

Another preferred embodiment of the present invention is a pharmaceutical composition as described above which is essentially wood) 3S-p & '(1R *, 2S') j - (3 - {[(4 - am i η o - fe η i 1}). - sulfonitrile (2-methylpropyl) -amino] -2-hydroxy-1-phenylmethyl-propyl] -carbamic acid dihydrohydrofuranyl ester, (b) Vitamin E-TPGS , (c) polyethylene glycol) and (i) propylene glycol, and (a), (h), (c) and (d) are in the form of a pourable liquid,

The compositions of the present invention are preferably capsules, yet. more preferably in the form of soft gelatin capsules,

The present invention also encompasses HIV protease inhibitor compounds, in particular pharmaceutically acceptable salts, esters or salts of these esters, or any other compound capable of direct or indirect administration of a therapeutically effective amount of a therapeutically effective amount to a brown patient. it is effective to dispense or remove the remainder of the metaholyte.

Compounds of formula (I) are disclosed in WO 94/05639, the disclosure of which is incorporated herein by reference.

Water soluble tocopherol derivatives can be prepared by appropriate esterification operations. These procedures are well known to those skilled in the art. For example, Vitamin E-TPGS can be prepared by esterifying 1.0 Ö of polybutylene glycol with a acidic group of crystalline d-alpha-phosphoric acid in the method described in U.S. Patent Nos. 2,680,649 and 5,234,695. according to.

As used herein, the term "solvent" refers to a solvent or co-solvent that is pharmaceutically or medically compatible, capable of dissolving and forming a solution of the HIV protease inhibitor compound, without substantially damaging the capsule shell.

Preferred solvents are polyethylene glycols containing from 300 to 1000 ethylene glycol monomer units (CH-1CHaO), and polyltyl glycol glycols having an average molecular weight of 300 to 1000 ethylene glycol monomer units.

In addition, other suitable compounds which may be used as suitable solvents or co-solvents include, but are not limited to,

Propylene glycol, alcohol, glycerol and sorbitol. In addition, it can be used as a co-solvent with about 10% water.

As used herein, the term lipophilic phase refers to one or more hydrophobic components, such as glycerol fatty acid esters, propylene glycol fatty acid esters, and vegetable oils.

When the compositions of the present invention are formulated as capsules, the capsule shell may preferably be made of gelatin and may contain plasticizers such as aniomorphe, glycerol or sorbitol, water, preservatives, dyes, and opacifying agents. Gelatin capsules that rapidly dissolve in the gastrointestinal tract and their preparation are described in Remington's Practiee of Pharmaey, Martin et al., Twelfth Edition, 4-07-49. page, Chapter Mind: Elastic Capsules, which is incorporated herein by reference. Reference is also made to U.S. Patent Nos. 2,899,361 and 2,928,128, which describe soft gelatine capsules and their preparation; these two patents are also incorporated herein by reference. Further reference is to The Pharmaceutical and Theory and Practice, The Pharmaey, Lackman, Lieerman, and Kanig, 359-389. pages, publisher; tea and Febiger, Philadelphia, Pennsylvania (1970)], which discuss the technology for making a soft gelatin capsule, refer to these pages 359-389 and are incorporated herein by reference.

The capsules according to the invention may be of any shape, preferably capsules of elongated, ellipsoidal, oval or cylindrical shape with a spherical end, preferably in the form of 50 mg of a compound of the formula I per capsule. may. Preferably, the capsules contain 25 mg, 50 mg, 150 mg or 200 mg of the compound of formula (I). Preferably, each capsule contains the compound of formula (I) in the form of a solution at a concentration of from 1 to 1000 mg / ml, most preferably from 25 to 500 mg / ml. As used herein, the concentration of the compound of formula (I) is given in mg / ml of the solution. Soft gelatin capsules are available from various manufacturers to accommodate the volumes and concentrations given in the examples. Preferably, size 12 capsules, which are oblong, or number 2, which form an oval, white, opaque gelatin capsule (manufactured by Scherer, R.F., North America).

The preferred composition of the present invention comprises from about 1 to about 50% by weight of a HIV protease inhibitor compound (preferably a compound of formula (1)) and from about 5 to about 5% by weight of about 15-95% by weight of vinylamine-TPGS-L. It contains from 10% polyethylene glycol and 0.1% to 10% propylene glycol based on the total weight of the solution. Preferably, the composition may also contain from about 0% to about 1% water,

As used herein, the term &quot; pharmaceutically effective amount &quot; for a compound of formula (1) refers to one or more capsules of the type described above, each capsule preferably containing 25 mg, 50 mg, ISO mg or 300 mg of compound of formula (1). For the treatment of patients, an initial dose of about 100 to about 3,000 mg of compound of formula (I) is administered, followed by administration of about 100 to about 50 mg of compound of formula (I). Doses of 100 to 5000 mg of Formula I may be administered to maintain the effect, depending on the patient being treated. * * ** * * * ♦ *

X V ♦ XX «» «« from flat. A suitable dosage regimen may be, for example, administration of 1200 mg twice daily of a compound of formula (I).

The compositions of the present invention may be prepared in a variety of forms, including liquid forms suitable for direct oral administration, such as syrups, suspensions, or solutions. The compositions of the invention may also contain other pharmaceutically acceptable carriers and excipients commonly used in formulations of this type. For example, syrups may contain sugar syrup, sorbitol or hydrogenated glucose syrup or artificial sweeteners such as aspartame, sodium saccharin, acesalfam K and so on. The suspensions may contain methylcellulose, microcrystalline cellulose, carmellose sodium or dispersible cellulose. The solutions may contain liquid glucose, levulose or xylitol.

The compositions of the invention may be prepared by methods and techniques generally known in the pharmaceutical industry.

The preparation of the compositions of the present invention may be accomplished by conventional operations such as thoroughly mixing the components in one or more cans or dissolving or suspending the components using known pharmaceutical technology. A HIV protease Inhibitor compound can be dissolved in a liquid emulsifier solvent mixture which is preheated to about 65 ° C to facilitate dissolution. After complete solubilization of Compound A, propylene glycol is added to the solution; the final solution, which is a pourable liquid liquid poured between 2S-35, preferably into soft gelatin capsules. This formulation is dissolved in water to provide a clear solution with improved bioavailability. we get.

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The amount of the compound of formula (I) required in the compositions of the present invention will depend on various factors, including the condition, age of the patient being treated; the dosage used for treatment is ultimately determined by the attending physician. However, in general, the effective dose is 5 to 100 'mg / kg body weight per day, preferably 8 to 10 mg / kg body weight, and more preferably the effective dose is 8 to 50 mg / kg body weight. The required dose may be administered in one, two, three, four or more acioses, in unit dosage form, for example, 25 to 500 mg of heat in the blood.

Készítmény The compositions of the invention are useful in the treatment or prevention of human retroviral infections, including HIV infection, and clinical conditions resulting from any of these infections such as AIDS, ARC, generalized lymph node disease (FGL) and HIV seropositive and AlDS-positive. conditions.

The compositions of the present invention may also be used in combination with other therapeutic agents for the therapeutic treatment of HIV infections, including reverse transcriptase inhibitors such as zidovudine, zalcitabine, larnivudine, didanosine, stavudine, S-chimeras. S-'-dioxoxy-G'-fluorouridine and ali R 2, $ 5) -5-fluoro-1- (2- (hydroxy-1-methyl) -1,3-ο x 11 11 an-5 -1Π-cytosine; non-nucleoside reverse transcriptase inhibitors include, for example, uevirapine, ΉΒ0 and a-APA; may include HIV protease inhibitors such as saquinavir, tndinavir, and ritonavir; other anti-HIV agents such as soluble CD4, immune modulators such as interleukin II, erythropoietin, lucarezole, interferons such as interferon alpha.

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In combination therapy, the components may be administered simultaneously, in separate or combined formulations, or at different times, such that they are exemplary sequentially to provide a combination effect.

Figure 1 illustrates the solubility of compounds of formula (I) at blinding pH 1.

The following examples illustrate the present invention without limiting it.

c o m m e n t i n g T h e a n d i n g

Preparation 1 Compound of formula (Vi) ViolininBETTPGS Poly (ethylene glycol) 400 U'F Propylene glycol USP (United States Pharmacopoeia).

150.0

400.0

200.5

9.5

Production Method 2 kg η ρΕ ~ TPGS -1 (Producer: E astman C hemiea 1 € p.) At a temperature of 5 k ² C, we heat treat until the substance is dissolved. Liquid salt amine ECTPGS is added with 2.005 kg of po {r (ethylene glycol) 400-ax (PEG400) (low aldehyde, <10 ppm, manufactured by Union Carbide or Dow Chemical Co.) heated to 50 ° C and the mixture is stirred until a homogeneous solution is obtained. formed. The solution thus obtained is heated to 65 ° C. Included in VAT are H-TPGS and PEG400

*. »« «♦ *» »♦ ♦» * ·, *::. Dissolve 1.5 kg of the compound of formula (1) in a liquid solution of 0.395 kg of propylene glycol at room temperature and add: the mixture is stirred until a homogeneous solution is formed. The solution was then cooled to 28-35 ° C and then degassed. Preferably, the mixture is filled into capsules at 28 to 35 ° C, containing 150 mg of a compound free of volatile matter; Size 12 oblong, white, opaque soft gelatin capsules and capsule filling machine are used. The capsule shell is dried to a constant water content of 3% and to a Newton hardness of 7, and the capsules are transferred to a suitable container.

Pharmacokinetics of Compounds of Formula I in Dogs (Hunter Dachshund)

Following intravenous and oral administration, the pharmacokinetic behavior of the compounds of formula (1) is monitored in rats of the Hsd / Sprague Dawley S0 species, administered at 10, 24.1 and 50 mg / kg (dissolved in EBG4000). Pharmacokinetic studies were performed with D-alpha tocopheryl - PEGF0? O - succinate (TPGS) and a mixture of vitamin E-TPGS, PEG400 and propylene glycol, using Hsd-type rats and dogs (hound dachshund).

Pharmacokinetic studies in rats

The compound of formula (I) is administered via a spoon to groups of Hsd-type rats of 4 to 4 animals, injected at doses of 10 and 50 0 mg / kg, or 10, 24.1 and 50 mg / kg of active ingredient dissolved in PEG4000 by gavage. for animals. Four additional animals receive one capsule at an average dose of .11 mg / kg, wherein the capsules contain the compound of formula (1) with PEG4CO and vitamin E;

-TEGS, as a solution. The check in

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Blood samples are taken at different times after 2 minutes to 7 hours after X. The most important pharmacokinetic parameters of the compounds of formula I are summarized in Table 1.

Pharmacokinetic Studies in Dogs The most important parameters for in vitro studies of dachshund dog pharmacokinetics are summarized in Table 2.

Table 1 Pharmacokinetic Studies of Compounds of Formula I Using Different Pharmaceutical Preparations in Rats

mganl (I) compound in PEG4ÖCK

Take 250 mg'g (1). PBG4CXkbétt ^ dw

50mg ^: kg j ív 107211 po _ | 7,923,4

p.a.

218% il) v ^ yûkt 633% VkB7PGSand 14.9% cggébpuBer ktKftponeosekbeo dava llmgkg po

25% (l) of the compound is 5% duty and 14.25%.

232% (I) was solubilized in 27.2% PB34OQ <8% VM2TCS in 4.8% yield rogkg p.o.

mg / kg: no.

S? -V? S

4,221.6 i 42.4% j 2,621.3 j 0.423.2

9, up, δ: 2.6207 29% j 71.5243 18228.6 25% 1 2,823,8 11.6 ^ | 2, otl2 263%

27.5% ^ · 5>

In the table, the roles of average value deviation.

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A. measured at the earliest date. value, the concentration is not extrapolated to the initial time.

F values for i.v. Normalized to 10 mg / kg data. (Converted).

χ *

Cmax · maximum detectable concentration »of the individual detection values.

tmax is the time at which the maximum concentration was measured from each of the detection data.

AUC: area under the concentration-time curve determined for each animal.

F: bioavailability is AUC p.o./AUC i.v. values.

The percentages are in%% ha.n ..

Table 2

Pharmacokinetic study of compound (Ϊ) in dachshund dogs; in the form of separate preparations containing ISO mg (Ϊ) per capsule

Kesoteéay Cmax Ttnax AUC Duas crowd% <Pmoles> (Hours) pmohíra) (Mg'kg) 2, S 33® is 33% VkE ~ TPG8 II Well, 8 l, ö he ± 9 29.3 ± 5.3 15.3 14.9% other powder component 23.2% (I) v ^ Yukta 272% PE64Ö0 Vá.E ~ 44.8% TPGS n öd2j DiFi 3W, 4 15.3 2 (A9% (Ib) 32% PEG4O0 1.33144 üóiO.4 3o, 5il.1,2 153 30.0% VAE-lK5S 2% propÍ5éfgfeíl ................ _______ _____

The table shows the mean value deviation

Ft,; pr «x * *« * * * * - «.» «* · *> *

Crnax. · Maximum detectable concentration, calculated from the individual detection values.

tmax is the time at which the maximum concentration was measured from each of the detection data.

AUC: area under the concentration-time curve determined individually for each animal.

The percentages. larvae are given in%.

After administering Table 3, who performed experiments

formalized to a dose of 300 mg. (Converted).

Claims (8)

A pharmaceutical composition for oral administration comprising (a) 3S- (3 R * (1 R. \ 2 S *) j · 13 - {((4 - which η o - fe η i 1) - su 1 f ο η i 1} - (2-Methos 1 -pr ο pi 1) -amino] -2-hydro xi - 1 - phen 1 - m ethyl) - p rop i 1 j - k or amine in the acid - (tetra hydro) A 3-furanyl ester, (b) a water soluble tocopherol derivative, and (e) a non-aqueous hydrophilic solvent miscible with the water soluble tocopherol derivative, wherein the weight ratio of (a) to (b) is about 1: 0 , 5 to 1:10, and (a), (h) and <e) are in the form of a pourable liquid. 2. A pharmaceutical composition for oral administration which (a) 1-50% by weight of the total composition of H 3 S- ^: [3 R '(1 R *, 2 S) 1- [3 ~ [«4- which η o -phenyl 1] ~ 1 f ο ni 1] - í 2. - met ί i - pro pi!) - am 1 η o] - 2 - h 1 dr ο xi -1 - f e ní-methyl) - pr ο pi 1] - carbamic acid - (bet r ah idro - 3 - fu r η ί 1) - y volume, (b) 10 to 60% by weight of the water soluble tocopherol derivative and (e) 25 to 60% by weight of the total composition comprising a non-aqueous hydrophilic solvent miscible with the water soluble tocopherol derivative and in the form of (a), (b) and (e) as a pourable liquid. Pharmaceutical composition according to claim 1, comprising at least 20% of a water soluble tocopherol derivative. The pharmaceutical composition according to claim 1 or 2, wherein the components (a) and (b) are present in an amount of about 1 to about 10 mg. 1: 0.5 to 1: 1.3 by weight. 5th Acts 1-3. Pharmaceutical composition according to any one of claims 1 to 3, which comprises vitamin E TPGS as a water soluble tocopherol derivative. - Chapters 1-4, 196. A pharmaceutical composition according to any one of claims 1 to 6, wherein the non-aqueous hydrophilic solvent is poly (ethylene glycol). containing propylene glycol or polyvinylpyrrolane. A pharmaceutical composition for oral administration, which is essentially (a) 3S- [3R '' (R, 2S *)] - (3-η 4 -aminophenyl) -phenyl-3- (2-methylphenyl) -? amino] -2-hydroxy-1-phenylmethyl) -propyl] -carbamic acid (tetrabidro-3-foranyl) ester. (b) containing vitamin E TFGS, (c) polyethylene glycol _: -i, and (d) propylene glycol, and (a), (b), (e), and (d) still in the form of a pourable liquid, 8. A composition according to any one of claims 1 to 6, which is in the form of a capsule. 9. A composition according to any one of claims 1 to 6 in the form of a solution. 10. Procedure 1-9. For the preparation of a pharmaceutical composition for oral administration according to any one of claims 1 to 3, characterized in that 3S-pR '(1R. ^x . 2S ^x )] - {3 - [[(4-aminophenyl) -phenyl] - (2-methyl-1- propyl 1) - am η η oj - 2 - hydrocarbonyl - 1 - methyl 1) - propyl 1} - carbamic acid - (tetrahydro-3-furanyl) ester water-soluble rockerol derivative and