KR20070018003A - Microemulsion formulations comprising particular substance p antagonists - Google Patents

Abstract

The present invention relates to a substance P antagonist useful for the treatment and prevention of respiratory diseases including asthma and chronic obstructive pulmonary disease, intestinal diseases including irritable bowel syndrome (IBS), incontinence and cough, in particular 5-aryl-4. A dispersible pharmaceutical composition that is (R) -arylcarbonylamino-pent-2-enoic acid amide.

Substance P antagonist, 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide, spontaneously dispersible pharmaceutical composition, microemulsion, respiratory disease, carrier medium, lipophilic component, surfactant, hydrophilic component

Description

Microemulsion formulations containing certain substance P antagonists {MICROEMULSION FORMULATIONS COMPRISING PARTICULAR SUBSTANCE P ANTAGONISTS}

The present invention is directed to agents that are useful for the treatment and prevention of respiratory diseases, including asthma and chronic obstructive pulmonary disease, intestinal diseases including irritable bowel syndrome (IBS), urinary incontinence and cough, especially 5-aryl-4 A novel pharmaceutical composition is (R) -arylcarbonylamino-pent-2-enoic acid amide.

5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist is a class of compounds described in international patent application WO 98/07694, the contents of which are incorporated herein by reference. to be.

5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonists, such as those described in WO 98/07694, in particular, have a range of variability in drug bioavailability and inter- and intra-patient dose response. Including the problem, there is a need for the development of non-conventional dosage forms as it presents very specific difficulties with general administration and in particular with galenic compositions.

According to the invention, 5-aryl-4 (R) -arylcarbonyl amino-pent-2-enoic acid amide material P with surprisingly interesting bioavailability properties and reduced variability in inter- and intra-patient bioavailability parameters It has been found that stable pharmaceutical compositions containing antagonists can be obtained. These new compositions have been found to cope with or substantially reduce the difficulties previously encountered. It has been shown that the compositions of the present invention can be administered effectively with increasing bioavailability, as well as with reduced variability in absorption / bioavailability levels for each patient and between each patient. Thus, the present invention can achieve effective treatment using acceptable dosage levels of such 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist, Closer standardization and optimization of the daily dosage requirements for. Thus, the occurrence of potential undesirable side effects is reduced and the overall cost of treatment can be reduced.

In a first aspect the present invention provides a spontaneously dispersible pharmaceutical composition comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist. In the following, spontaneously dispersible pharmaceutical compositions are also referred to as "compositions of the present invention". This is preferably a microemulsion preconcentrate.

The terminology used herein has the following meanings:

As used herein, "active agent" means a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as described in WO 98/07694.

As used herein, “poorly water soluble” is one having a solubility in water of less than 1%, eg, 0.01% weight / volume at 20 ° C., ie Remington: The Science and Practice of Pharmacy, 19 ^th Edition, Ed.AR Gennaro, Mack Publishing Company, US, 1995, vol. 1, p. 195), means "a little or very difficult drug to melt."

As used herein in the context of a composition, “bioavailability” means that the composition provides at least 1.5 times the highest concentration of the composition in the environment of use, as compared to a control drug comprising an equivalent amount of undispersed drug. .

As used herein, a “voluntarily dispersible pharmaceutical composition” contains an active agent as defined herein and is capable of producing a colloidal structure when diluted with an aqueous medium, eg, water, or gastric juice. Means. The colloidal structure may be a solid or, preferably, liquid particles comprising droplets and nanoparticles. Spontaneously dispersible pharmaceutical compositions are preferably microemulsion preconcentrates.

As used herein, "microemulsion preconcentrate" refers to, for example, 1:10 to 1: 300, preferably 1: 1 to 1:70, in particular 1: in an aqueous medium such as water. A composition that spontaneously forms a microemulsion in gastric juice upon dilution 1 to 1:10 or after oral application.

As used herein, a "microemulsion" is a weakly opaque, milky, non-opaque, or substantially non-opaque colloid that spontaneously or substantially spontaneously forms when its components are brought into contact with an aqueous medium. Means a sex dispersion. Microemulsions are thermodynamically stable and generally contain dispersed droplets of average diameter less than about 200 nm (2000 mm 3). In general, microemulsions include droplets or liquid nanoparticles having an average diameter of less than about 150 nm (1500 Hz), typically less than 100 nm and generally greater than 10 nm, which are stable over a period of up to 24 hours Do.

Microemulsions are more due to spontaneous formation, thermodynamic stability, transparent and refined appearance, increased drug loading, enhanced permeation through biological membranes, increased bioavailability, and inter- and intra-subject variability in less pharmacodynamics compared to crude emulsions. Provides great ease of manufacture. Further features of microemulsions are described in British Patent GB 2,222,770; Rosof, Progress in Surface and Membrane Science , 12, 405 et al., Acadedmic Press (1975); Friberg, Dispersion Science and Technology , 6 (3), see below 317 (1985); And Muller et al. Pharm . Ind . , 50 (3), 370 cf. (1988).

Throughout this specification and in the claims below, the word "comprises" or "including" and "including" will be referred to unless the context requires otherwise. It is to be understood that the term includes an integer or a step or a group of integers or steps, but does not exclude any other integer or step or a group of integers or steps.

In a second aspect, the present invention provides a carrier comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as an active agent, and a lipophilic component, a surfactant, and optionally a hydrophilic component. It provides a spontaneously dispersible pharmaceutical composition comprising a.

Preferably, spontaneously dispersible pharmaceutical compositions are suitable for oral administration.

5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide Substance P antagonist is poorly soluble as defined herein. It has a water solubility of 0.001% or less, for example, 0.001% to 0.0001%.

The active agent is preferably used in free base form.

In a third aspect, the present invention provides a microemulsion preconcentrate comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist.

In a fourth aspect, the present invention comprises a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist and a carrier medium comprising a lipophilic component, a surfactant and optionally a hydrophilic component. Microemulsion preconcentrates are provided.

The microemulsion preconcentrate is preferably diluted with water to form an o / w (oil-in-water) microemulsion.

Preferably, the relative proportions of lipophilic component (s), hydrophilic component (s) and surfactant (s) are in the “microemulsion” portion on a standard three way plot graph. These phase diagrams can be generated in a conventional manner as described, for example, in GB 2,222,770 or WO 96/13273.

In a fifth aspect, the present invention provides a microemulsion comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist.

The microemulsion is preferably an o / w (oil-in-water) microemulsion.

In a sixth aspect, the present invention provides a microemulsion comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist, lipophilic component, surfactant, water, and optionally hydrophilic component. To provide.

The colloidal structure of the microemulsion is spontaneous or substantially spontaneous if the components of the composition of the present invention are brought into contact with the aqueous medium, for example by brief shaking by hand, for a short time, for example 10 seconds. Form. The compositions of the present invention are thermodynamically stable, for example, for at least 15 minutes, or up to 4 hours, further up to 24 hours. In general, they are measured by a distributed structure, i.e. using a standard light scattering technique, for example, using a MALVERN ZETASIZER 3000 ™ particle characterizing machine, which is approximately 200 nm (2,000 kPa). ), Eg, less than about 150 nm (1,500 mm 3), typically less than 100 nm (1,000 mm 3), and generally contain droplets or liquid nanoparticles of average diameter greater than 10 nm (100 mm 3).

Solid drug particles of average diameter greater than 200 nm may be present. The proportion of particles present can be temperature-dependent.

The active agent is a neurokinin antagonist (NK antagonist), and therefore prevents disease symptoms caused by the activation of NK1 receptor by substance P and the activation of NK2 receptor by neurokinin A [= NKA], among others. Can be. Substance P-antagonist effects can be demonstrated, for example, as follows: in vitro, for example, in radioactivity receptor assay according to H. Bittiger, Ciba Foundation Symposium 91 [1982] 196-199. In the receptor assay, the binding of ³ H-substance P to the bovine retina is suppressed with an IC ₅₀ value from about 0.2 nM.

More particularly, the active agent is a 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist. Compounds of this class are described in WO 98/07694.

Preferred active agents described in WO 98/07694 include the following:

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid N -[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid N -[(S) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid N -Cyclohexyl-amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -2-methyl-pent- 2-enoic acid N-cyclohexyl-amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -2-methyl-pent- 2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -2-methyl-pent- 2-enoic acid N-[(S) -epsilon-caprolactam-3-yl] -amide;

(4R)-(N'-Methyl-N'-benzoyl-amino) -5- (1-methyl-indol-3-yl) -2-methyl-pent-2-enoic acid N-[(R) -epsilon- Caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naphth-2-yl) -pent-2-enoic acid N-[( R) -epsilon-caprolactam-3-yl] -amide;

(4R)-(N'-Methyl-N'-benzoyl) -amino-5- (naphth-2-yl) -pent-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amides;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naphth-2-yl) -2-methyl-pent-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,4,5-trimethoxy-benzoyl) -amino] -5- (naphth-2-yl) -2-methyl-pent-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naphth-2-yl) -2-methyl-pent-2-enoic acid N-[(S) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (naphth-2-yl) -2-methyl-pent-2-enoic acid N-cyclohexyl-amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (1-methyl-indol-3-yl) -pent-2-enoic acid N -[(S) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid N-[(R) -Epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid N-[(S) -Epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid N-cyclohexyl-amide ;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N-cyclohexyl -amides;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-difluorobenzyl) -but-2-enoic acid N- Cyclohexyl-amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-chlorophenyl) -2-methyl-pent-2-enoic acid N- Cyclohexylamide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-chlorophenyl) -2-methyl-pent-2-enoic acid N- [(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -2-methyl-but-2-enoic acid [( S) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Ethyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-chlorophenyl) -pent-2-enoic acid N-[(S) -Epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -5- (4-chlorophenyl) -3-methyl-pent-2-enoic acid N- Cyclohexyl-amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -3-methyl-but-2-enoic acid [( R) -epsilon-caprolactam-3-yl] -amide;

(4R)-[N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-chlorobenzyl) -but-2-enoic acid N-[(R) -Epsilon-caprolactam-3-yl] -amide;

(4R) -4- [N'-Methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N- [(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3-fluoro-4-chlorobenzyl) -But-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-difluorobenzyl)- But-2-enic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4-dibromobenzyl)- But-2-enic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (3,4,5-trifluorobenzyl ) -But-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) -amino] -4- (4-fluorobenzyl) -but-2 -Enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide;

(4R)-and (4S) -4- [N '-(3,5-bistrifluoromethyl-benzoyl) -N'-methyl-amino] -5,5-diphenyl-pent-2-enoic acid N -[(S) -epsilon-caprolactam-3-yl] -amide;

(4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N-[( R) -epsilon-caprolactam-3-yl] -amide;

(4R) -4- [N'-methyl-N '-(3,5-bistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N-[( S) -epsilon-caprolactam-3-yl] -amide; And

(4S) -4- [N'-methyl-N '-(3,5-bistrifluoromethylbenzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N-[( S) -epsilon-caprolactam-3-yl] -amide.

Particularly preferred active agents are (4R) -4- [N'-methyl-N '-(3,5-bistrifluoromethyl-benzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2 N-[(R) -epsilon-caprolactam-3-yl] -amide, ie a compound of formula (I):

This compound is referred to as Compound A below.

Preferred, particularly preferred active agents in free or pharmaceutically acceptable salt form can be prepared as described in international patent application WO 98/07694. As mentioned herein, they may be in their hydrate form and / or include other solvents, for example solvents that may be used for crystallization of the compound in solid form.

According to the present invention, the active agent may be present in an amount of, for example, from about 0.05% to about 20% by weight of the composition of the present invention. The active agent is preferably present in an amount of 0.5 to 15% by weight of the composition, more preferably in an amount of 1.5 to 5% by weight of the composition.

Because the active agent is poorly water soluble, it is contained in a carrier medium.

In some embodiments of the compositions of the present invention, the carrier medium comprises a lipophilic component and a surfactant. In another embodiment, the carrier medium comprises a lipophilic component, a hydrophilic component and a surfactant.

The lipophilic component includes one or more lipophilic substances. Hydrophilic components include one or more hydrophilic materials. In addition, the carrier medium may contain one or more surfactants.

Compositions of the present invention include antioxidants, antimicrobials, enzyme inhibitors, stabilizers, preservatives, fragrances, sweeteners, and Fiedler, H.P. And various additives, including additional ingredients as described in "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, D-7960 Aulendorf, revised and enlarged 4th edition (1996).

The composition of the present invention comprises a lipophilic component or phase. The active agent may be contained in this component of the carrier medium.

The lipophilic component (if present) is preferably characterized by a low HLB value of less than 10, for example 8 or less. Suitable lipophilic ingredients include:

1) Glyceryl mono - C ₆ - C ₁₄ - fatty acid esters

They are obtained by esterifying glycerol with vegetable oil, followed by molecular distillation. Monoglycerides suitable for use in the compositions of the present invention include both symmetrical (ie, β-monoglycerides) and asymmetric monoglycerides (α-monoglycerides). They also include both uniform glycerides (here the fatty acid component is mainly composed of a single fatty acid) and mixed glycerides (ie the fatty acid component here is composed of various fatty acids). Fatty acid components may include both saturated and unsaturated fatty acids having, for example, a chain length of C ₈ -C ₁₄ . Particularly suitable are, for example, caprylic or lauric monoglycerides which are commercially available from Sasol, for example under the trade names Imwitor ™ 308 or Imbitor 312, respectively. For example, Imbitor 308 contains at least 80% monoglycerides and shows additional characteristic data as follows: free glycerol up to 6%, acid value up to 3, saponification up to 245-265, iodine up to 1, moisture Content up to 1%. In general, this includes 1% free glycerol, 90% monoglycerides, 7% diglycerides (H. Fiedler, loc . Cit . , Volume 1, page 798). A further example is Capmul MCM C8 provided by Abitec Corporation.

2) C ₆ - C ₁₈ fatty acid mono-and di-glyceride mixture of

They are both symmetrical (ie β-monoglycerides and α, α ¹ -diglycerides) and asymmetric mono- and di-glycerides (ie α-monoglycerides and α, β-diglycerides) and Acetylated derivatives thereof. They are also both homogenous glycerides (here the fatty acid component is mainly composed of a single fatty acid) and mixed glycerides (ie the fatty acid component here is composed of various fatty acids) and their derivatives with lactic or citric acid It includes. Fatty acid components may include, for example, both saturated and unsaturated fatty acids having a chain length of C ₈ -C ₁₀ . Particularly suitable are, for example, mixed caprylic and capric acid mono- and di-glycerides commercially available from Sasol, for example under the trade names Imbitor 742 or Imbitor 928, respectively. For example, Imbitor 742 contains at least 45% monoglycerides and shows additional characteristic data as follows: free glycerol up to 2%, acid value up to 2, saponification up to 250-280, iodine up to 1, moisture Up to 2% (H. Fiedler, loc . Cit . , Volume 1, page 798). Other suitable mixtures are commercially available and known, for example under the trade name Capmul ™ MCM, available from Abitec Corporation, for example caprylic / capric acid in glycerol. Mono / diglycerides. Capmul MCM shows the following additional characteristic data: acid value up to 2.5, alpha-mono (as oleate) at least 80%, free glycerol up to 2.5%, iodine up to 1, chain length distribution: caproic acid (C6) up to 3 %, Caprylic acid (C8) minimum 75%, capric acid (C10) minimum 10%, lauric acid (C12) maximum 1.5%, water (by Karl Fisher) maximum 0.5% (manufacturer information) . Suitable examples of mono- / di-glycerides further derivatized with lactic or citric acid are those sold under the name Imvitor 375, 377 or 380 by Sasol. In addition, fatty acid components may include both saturated and unsaturated fatty acids having, for example, a chain length of C ₁₆ -C ₁₈ . Suitable examples are Tegin ™ O (glyceryl oleate), which shows additional characteristic data as follows: Monoglyceride content 55-65%, peroxide up to 10, moisture content up to 1%, acid value up to 2 , Iodine 70-76, saponification 158-175, free glycerol up to 2% (manufacturer's information).

3) Glyceryl di - C ₆ - C ₁₈ fatty acid ester

These include symmetrical (ie α, α ¹ -diglycerides) and asymmetric diglycerides (ie α, β-diglycerides) and their acetylated derivatives. They also contain both homogenous glycerides (here the fatty acid component is mainly composed of a single fatty acid) and mixed glycerides (ie the fatty acid component here is composed of various fatty acids) and their derivatives with lactic or citric acid. Include. Fatty acid components may include both saturated and unsaturated fatty acids having a chain length of C ₆ -C ₁₈ , for example C ₆ -C ₁₆ , for example C ₈ -C ₁₀ , for example C ₈ . have. Especially suitable are caprylic diglycerides which are commercially available, for example, from Taiyo Kagaku Co., Ltd., for example under the trade name Sunfat ™ GDC-S. . Sunpat GDC-S has an acid value of about 0.3, a diglyceride content of about 78.8%, and a monoester content of about 8.9.

4) Medium chain fatty acid triglycerides

These include triglycerides of saturated fatty acids having 6 to 12, for example 8 to 10 carbon atoms. Suitable medium chain fatty acid triglycerides are known and are trade names Acomed ™, Myritol ™, Captex ™, Neobee ™ M 5F, Miglyol ™ 810 Commercially available as Migolol 812, Migolol 818, Mazol ™, Sesol ™ 860, Cefsol 870; Miglyol 812 is most preferred. Miglyol 812 is a fractionated coconut oil that includes capryl-capric triglyceride and has a molecular weight of about 520 Daltons. Fatty acid composition = C ₆ up to about 3%, C ₈ about 50 to 65%, C ₁₀ about 30 to 45%, C ₁₂ up to 5%; Acid number of about 0.1; Saponification of about 330 to 345; Iodine up to 1. Migliol 812 is available from Condea. Neobi M 5F is fractionated capryl-capric acid triglyceride available from palm oil; The acid value is up to 0.2, the saponification value is about 335 to 360, the iodine value is up to 0.5, the water content is up to 0.15%, D. ²⁰ is 0.930-0.960 and n _D ²⁰ is 1.448-1.451 (manufacturer information). NeoBi M 5F is available from Stepan Europe. A further example is migliol 829 which further contains an ester with succinic acid.

5) Glyceryl mono - C ₁₆ - C ₁₈ - fatty acid esters

They are obtained by esterifying glycerol with vegetable oil followed by molecular distillation. Monoglycerides suitable for use in the compositions of the present invention include both symmetrical (ie β-monoglycerides) and asymmetric monoglycerides (ie α-monoglycerides). They also include both uniform glycerides (here the fatty acid constituents are predominantly composed of a single fatty acid) and mixed glycerides (ie the fatty acid components here are composed of various fatty acids). Fatty acid components may include, for example, both saturated and unsaturated fatty acids having a chain length of C ₁₆ -C ₁₈ . Suitable examples include GMOrphic by Eastman, Rylo MG20 distilled monoglycerides by Danisco Ingredients, or monomers by Henkel ( Monomuls) 9O-O18. For example, GMO Lepic-80 (glyceryl monooleate) shows additional characteristic data as follows: at least 94% monoglyceride content, at least 75% C18: 1 content, at most 2.5 peroxide, C18: 2 + C18: 3 up to 15%, C16: 0 + C18: 0 + C20: 0 up to 10%, moisture up to 2%, acid value up to 3, iodine up to 65-75, saponification up to 155-165, free glycerin up to 1% , Hydroxyl number 300-330 (manufacturer information).

6) Mixed Mono-, Di-, Tri- glycerides

These include mixed mono-, di-, tri-glycerides commercially available from Gattefosse under the trade name Meisine ™. These are the transesterification products of corn oil and glycerol. This product consists mainly of linoleic acid and oleic acid mono-, di- and tri-glycerides together with trace amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself is about 56% linoleic acid, 30% oleic acid, about 10% palmitic acid and about 3% stearic acid components). Physical properties are as follows: up to 10% free glycerol, about 40% monoglycerides, about 40% diglycerides, about 10% triglycerides, about 1% free oleic acid content. Additional physical properties are as follows: acid value up to 2, iodine value 85-105, saponification value 150-175, inorganic acid content = 0. The fatty acid content for Meisin is typically as follows: about 11% palmitic acid, About 2.5% stearic acid, about 29% oleic acid, about 56% linoleic acid, and other about 1.5% (H. Fiedler, loc . Cit . , Volume 2, page 958; manufacturer information).

Mixed mono-, di-, tri-glycerides are preferably C ₈ to C ₁₀ or C _12-20 fatty acid mono-, di- and tri-mixture of glycerides, especially mixed C _{16 -18} fatty acid mono- , Di- and triglycerides. The fatty acid component of the mixed mono-, di-, tri-glycerides may comprise both saturated and unsaturated fatty acid residues. However, they preferably consist mainly of unsaturated fatty acid residues, in particular C ₁₈ unsaturated fatty acid residues. Suitably, the mixed mono-, di-, tri-glycerides contain at least 60% by weight, preferably at least 75% by weight, more preferably at least 85% by weight of C ₁₈ unsaturated fatty acids (eg linolenic acid, Linoleic acid and oleic acid) mono-, di- and tri-glycerides. Suitably, the mixed mono-, di-, tri-glycerides are less than 20% by weight, for example about 15% or 10% by weight or less of saturated fatty acids (eg palmitic acid and stearic acid). Acid) mono-, di- and tri-glycerides. Mixed mono-, di-, tri-glycerides preferably consist mainly of mono- and di-glycerides; For example, mono- and di-glycerides comprise at least 50%, more preferably at least 70%, based on the total weight of the lipophilic phase or component. More preferably, the mono- and diglycerides comprise at least 75% by weight (eg about 80% or 85% by weight) of the lipophilic component. Preferably, the monoglycerides make up about 25 to about 50% of the mixed mono-, di-, tri-glycerides based on the total weight of the lipophilic component. More preferably, about 30 to about 40% (eg 35 to 40%) monoglycerides are present. Preferably, the diglycerides comprise from about 30 to about 60% of the mixed mono-, di-, tri-glycerides based on the total weight of the lipophilic component. More preferably, about 40 to about 55% (eg 48 to 50%) diglycerides are present. Triglycerides suitably comprise at least 5% and less than about 25% of the mixed mono-, di-, tri-glycerides based on the total weight of the lipophilic component. More preferably, about 7.5 to about 15% (eg, about 9 to 12%) triglycerides are present. Mixed mono-, di-, tri-glycerides can be prepared by mixing the individual mono-, di- or tri-glycerides in appropriate relative proportions. However, conveniently they are vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil, or preferably corn oil, sunflower oil or safflower oil. And most preferably a transesterification product of corn oil and glycerol. Such transesterification products are generally obtained as described in GB 2 257 359 or WO 94/09211. Preferably, when preparing soft gelatin capsules, some of the glycerol is first removed to provide a "batch substantially free of glycerol." The purified transesterification products of corn oil and glycerol are hereinafter referred to as "refined oils" and are particularly suitable mono-, di-produced according to the process described in British Patent GB 2,257,359 or International Patent Publication WO 94/09211. And tri-glycerides.

7) Activated Monoglycerides ( C18 )

These include Myvacet 9-45.

8) Propylene Glycol Monofatty Acid Ester

Fatty acid components may include, for example, both saturated and unsaturated fatty acids having a chain length of C ₈ -C ₁₂ . Particularly suitable are for example from Nikko Chemicals Co., Ltd. or Gattefosse, for example the tradename Sefsol ™ 218, Capryol ™ 90 or Propylene glycol mono esters of caprylic and lauric acid, which are commercially available as Lauroglycol ™ 90, or as Capmul PG-8 from Abitec Corporation. For example, lauroglycol 90 has additional characteristic data of up to 8 acid values, 200-220 saponification, up to 5 iodine, up to 5% free propylene glycol content, and at least 90% moisture content of monoester content. Represent; Cefsol 218 shows additional characteristic data of acid values up to 5 and hydroxy values 220-280 (H. Fiedler, loc . Cit . , Volume 2, page 906, manufacturer information).

9) Propylene Glycol Mono- and Di-fatty Acid Ester

These include Laroglycol FCC and Capryol PGMC.

10) Propylene Glycol Diester

Propylene Glycol Dicaprylate (from Sasol to trade name Miglyol ™ 840 (H. Fiedler, loc . Cit . , Volume 2, page 1008), or from Abitec Corporation) Propylene glycol di-fatty acid esters.

11) Propylene Glycol Monoacetate and Propylene Glycol Diacetate

12) the transesterification Ethoxylated Vegetable Oils

These include various natural vegetable oils (e.g., corn oil, kernel oil, almond oil, peanut oil, olive oil, soybean oil, sunflower oil, safflower oil and palm oil, or mixtures thereof) in the presence of a suitable catalyst. Transesterified ethoxylated vegetable oils such as those obtained by reaction with polyethylene glycols having an average molecular weight of from 800 to 800. These methods are described in US Pat. No. 3,288,824. Particular preference is given to transesterified ethoxylated corn oil.

Transesterified ethoxylated vegetable oils are known and are commercially available under the trade name Labrafil ™ (H. Fiedler, loc . Cit . , Vol. 2, page 880). Examples are Labrafil M 2125 CS (obtained from corn oil, having an acid value of less than about 2, a saponification of 155 to 175, an HLB of 3 to 4, and an iodine value of 90 to 110), and Labrafil M 1944 CS (obtained from Kernel oil, having an acid value of about 2, a saponification value of 145 to 175, and an iodine value of 60 to 90). La bra and Phil M 2130 CS (C _{12 -18} glycerides and a transesterification product of a polyethylene glycol having a melting point of about 35 to 40 ℃, an acid value of less than about 2, 185 to 200 and the degree of saponification is less than the iodine of about 3 Have a). Preferred transesterified ethoxylated vegetable oils are, for example, Labrafil M 2125 CS which can be obtained from Gattefosse, Saint-Priest Cedex, France.

13) sorbitan fatty acid ester

Such esters include, for example, include a sorbitan C _{12 -18} fatty acid esters, or sorbitan tree C _{12 -18} fatty acid esters are, for example, under the trade name Span (Span ™) from the uni-kwema (Uniqema) commercially available Can be. Particularly preferred products of this class are, for example, Span ™ 20 (sorbitan monolaurate) or Span 80 (sorbitan monooleate) (Fiedler, loc . Cit. , 2, p. 1430; Handbook) of Pharmaceutical Excipients, loc . cit ., page 473).

14) Fatty Acids and Payments Alcoholic Esterified compounds

These are esterified compounds of fatty acids having 8 to 20 carbon atoms and primary alcohols having 2 to 3 carbon atoms, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, ethyl myri States and the like, esterified compounds of linoleic acid and ethanol are particularly preferred, and isopropyl myristate and isopropyl palmitate are also preferred.

15) Glycerol triacetate or (1,2,3) -triacetin

This is obtained by esterifying glycerin with acetic anhydride. Glycerol triacetate is, for example, Uniacema International from Priacetin ™ 1580, or from Eastman to Eastman ™, or Quortaulds Chemicals Ltd.) is commercially available. Glycerol triacetate shows additional characteristic data as follows: molecular weight 218.03, D. ^20.3 1.159-1.163, n _D ²⁰ 1.430-1.434, water content up to 0.2%, viscosity (25 °) 17.4 mPa s, acid value up to 0.1, Saponification is about 766-774, at least 97% triacetin content (Fiedler, loc . Cit . , Vol. 2, page 1580; Handbook of Pharmaceutical Excipients, loc . Cit ., Page 534, manufacturer information).

16) Acetyl Triethyl Citrate

This is obtained by esterification of stric acid with ethanol followed by acetylation with acetic anhydride, respectively. Acetyl triethyl citrate is commercially available, for example, from Morflex Inc. under the trade name Citroflex ™ A-2.

17) Tributyl Citrate or Acetyl Tributyl Citrate

18) Polyglycerol Fatty Acid Ester

They have, for example, 2 to 10, for example 6 glycerol units. Fatty acid components may include, for example, both saturated and unsaturated fatty acids having a chain length of C ₈ -C ₁₈ . Particularly suitable is Plurol Oleique CC497, available from Gattefosse having, for example, a saponifier of 133-155 and a saponifier of 196-244. Further suitable polyglycerol fatty acid esters are known and can be used, for example, diglycerol monooleate (DGMO) and hexaglin-5- commercially available from Nikko Chemicals Co., Ltd. O is included.

19) PEG -fatty alcohol ether

This includes Brij 30 ™ polyoxyethylene (4) lauryl ether.

20) fatty alcohols and fatty acids

Fatty acids can be obtained by hydrolyzing various animal and vegetable fats or oils, such as olive oil, and then separating the liquid acid. Fatty acid / alcohol components may include, for example, both saturated and mono- or di-unsaturated fatty acids / alcohols having a chain length of C ₆ -C ₂₀ . Particularly suitable are, for example, oleic acid, oleyl alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecanol, or decanol. Oleyl alcohol is commercially available, for example, under the tradename HD-Etananol ™ from Henkel KGaA. Oleyl alcohol shows additional characteristic data as follows: acid value up to 0.1, hydroxy value about 210, iodine about 95, saponification up to 1, D. ²⁰ about 0.849, n _D ²⁰ 1.462, molecular weight 268, viscosity ( 20 °) approximately 35 mPa s (manufacturer information). Oleic acid shows additional characteristic data as follows: molecular weight 282.47, D. ²⁰ 0.895, n _D ²⁰ 1.45823, acid value 195-202, iodine 85-95, viscosity (25 °) 26 mPa s (H. Fiedler, loc .. cit, volume 2, page 1112;. "Handbook of Pharmaceutical Excipients", 2nd Edition, Editors A. Wade and PJ Weller (1994) ,, Joint publication of Amercian Pharmaceutical Assoc, Washington, USA and The Pharmaceuticals Press, London, England, page 325).

21) Tocopherol and its derivatives (eg acetate)

These include Coviox T-70, Copherol 1250, Coperol F-1300, Covitol 1360 and Cobitol 1100.

22) pharmaceutically acceptable oils

Instead, the lipophilic component comprises a pharmaceutically acceptable oil, preferably having an unsaturated component, such as vegetable oil, for example.

23) alkylene Polyol ethers or esters

These include C _{3 -5-alkylene} triols, in particular glycerol, ethers or esters. Suitable C _{3 -5} alkylene triol ethers or esters include mixed component including the ethers or esters, i.e., other ether or ester ingredients, for example, C _{3 -5} alkylene triol esters with other mono-, di Or transesterification products with poly-ols. A glycol fatty acid esters, particularly suitable alkylene polyol ethers or esters are mixed C _{3 -5} alkylene triol / poly - (C _{2 -4-alkylene)} glycol fatty acid esters, especially mixed glycerol / polyethylene-or polypropylene. Particularly suitable alkylene polyol ethers or esters include glycerides, e.g., triglycerides, with poly- (C _{2 -4-alkylene)} glycol, e.g., poly-ethylene glycols and, optionally, be obtained by the transesterification of glycerol Products that can be included. Such transesterification products are generally obtained by the polyalcoholation of glycerides such as triglycerides (ie, in the presence of poly- (C _2-4 alkylene) glycols such as polyethylene glycol and optionally glycerol The transesterification reaction from the glycerides to the poly-alkylene glycol / glycerol component takes place, i.e. via poly-alkylene glycol degradation / glycerol decomposition). In general, this reaction is carried out by reacting the components mentioned (glycerides, polyalkylene glycols and optionally glycerol) with continuous stirring at elevated temperatures under an inert atmosphere.

Preferred glycerides are fatty acid triglycerides, including natural and hydrogenated oils, in particular vegetable oils, for example (C _{10 -22} fatty acids) triglycerides. Suitable vegetable oils include, for example, include an olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and Mac Ayurvedic, and in particular the ester residue-rich natural or hydrogenated _(-18 C ₁₂ fatty acid) oil. Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of about 500 to about 4,000, for example about 1,000 to about 2,000.

Suitable alkylene polyol ethers or esters include C _{3 -5} alkylene triol esters, e.g., different relative amounts of mono-, di- and tri-ester, and a poly (C _2-4 alkylene) glycol mono- and D-glass with a small amount of ester C _{3 -5} alkylene triol and free poly - (C _{2 -5} alkylene) comprises a mixture of glycol. As mentioned above, the preferred alkylene triol moiety is glyceryl; Preferred polyalkylene glycol moieties include polyethylene glycol, in particular having a molecular weight of about 500 to about 4,000; Preferred fatty acid sites may be C _{10 -22} fatty acid ester residues, in particular saturated C _10-22 fatty acid ester residues.

Particularly suitable alkylene polyol ethers or esters include transesterified products of natural or hydrogenated vegetable oils and polyethylene glycols and, optionally, glycerol; Or glyceryl mono-, di- and tri-C _{10 -22} fatty acid esters and polyethylene glycol mono- and di-C _{10 -22} fatty esters (optionally with, for example, trace free glycerol and free polyethylene glycol) Or compositions comprising them.

Preferred vegetable oils, polyethylene glycol or polyethylene glycol moieties and fatty acid moieties according to the above definitions are as described above.

Particularly suitable alkylene polyol ethers or esters as described above for use in the present invention include, for example, those commercially available under the trade name Gelucire ™ from Gattefosse, in particular the following products do:

a) gelucsir 33/01 having a melting point of about 33-37 ° C. and a saponifier of about 230-255;

b) gelusir 39/01 having a melting point of about 37.5-41.5 ° C. and a saponifier of about 225-245; And

c) Zelusir 43/01 having a melting point of about 42-46 ° C. and a saponifier of about 220-240.

The products (a) to (c) all have an acid value of at most 3. The composition of the present invention may comprise a mixture of such ethers or esters.

24) Hydrocarbon

These include, for example, squalene available from, for example, Nikko Chemicals Co., Ltd.

25) Ethylene Glycol Ester

These include, for example, Montyle ™ (ethylene glycol monostearate) available from Gattefosse.

26) Pentaerythritol Fatty Acid Esters and Polyalkylene Glycol Ethers

These include, for example, pentaerythrite-dioleate, -distearate, -monolaurate, -polyglycol ether, and -monostearate, and pentaeryrite-fatty acid esters (Fiedler, loc . cit ., 2, p. 1158-1160, incorporated herein by reference).

Some of these, for example (1-3, 5-6, 8-9, 12-13, 19), exhibit surfactant-yang behavior and may also be called co-surfactants.

The lipophilic component (if present) is preferably 5 to 85% by weight of the composition of the invention, for example 10 to 85%; Preferably from 15 to 60%, more preferably from about 20 to about 40% by weight.

For embodiments in which the carrier medium comprises a hydrophilic component in addition to the lipophilic component and the surfactant, the relative proportions of the lipophilic component (s), hydrophilic component (s) and surfactant (s) are "micro" on a standard three-way plot graph. In the "emulsion" section.

The composition of the present invention may comprise a hydrophilic component or phase.

Suitable hydrophilic components include the following materials:

1) Polyethylene Glycol Glyceryl C ₆ - C ₁₀ Fatty Acid Ester

Fatty acid esters may include mono and / or di and / or tri fatty acid esters. This optionally includes both saturated and unsaturated fatty acids having a chain length of, for example, C ₈ -C ₁₀ . Polyethylene glycols can have, for example, 5 to 10 [CH ₂ -CH ₂ -O] units, for example 7 units. Particularly suitable fatty acid esters are, for example, from Henkel KGaA, for example the tradename Cetiol ™ HE [here, the cetiol HE has a D. (20 °) of 1.05, an acid value of less than 5, saponification of about 95 Has a hydroxyl number of about 180, and an iodine number of less than 5 (H. Fiedler, loc . Cit . , Vol. 1, page 337)] or Lipestrol E-810. Polyethylene glycol (7) is glyceryl monocoate.

2) N -alkylpyrrolidone

Particularly suitable is N-methyl-2-pyrrolidone, which is commercially available, for example, from the International Specialty Products (ISP), for example under the tradename Pharmasolve ™. N-methylpyrrolidone shows additional characteristic data as follows: molecular weight 99.1, D. ²⁵ 1.027-1.028, purity (as area% by GC) (including methyl isomers) at least 99.85% (H. Fiedler, loc. cit., vol. 2 , page 1004, manufacturer information).

3) benzyl alcohol

It is commercially available from Merck or may be obtained by distilling benzyl chloride with potassium carbonate or sodium carbonate. Benzyl alcohol shows additional characteristic data as follows: molecular weight 108.14, D. 1.043-1.049, n _D 1.538-1.541 (H. Fiedler, loc . Cit . , Vol. 1, page 238; Handbook of Pharmaceutical Excipients, loc . cit., page 35).

4) triethyl Citrate

This is obtained by esterifying citric acid with ethanol. Triethyl citrate is commercially available, for example, from Morflex Inc. under the trade name Citroflex ™, or in pharmaceutical grade under the trade name TEC-PG / N. Can be. Especially suitable are triethyl having a molecular weight of 276.3, specific gravity of 1.135-1.139, refractive index of 1.439-1.441, viscosity of 35.2 mPa s (25 °), analytical test of 99.0-100.5% (based on anhydride), 0.25% maximum moisture Citrate (Fiedler, HP, loc . Cit . , Vol. 1, page 371; "Handbook of Pharmaceutical Excipients", loc . Cit ., Page 540).

Other suitable hydrophilic compounds include transcutol (C ₂ H _5- [O- (CH ₂ ) ₂ ] ₂ -OH), glycofurol (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), 1, 2-propylene glycol, dimethylisosorbide (Arlasolve), polyethylene glycol, triethylene glycol, ethyl acetate and ethyl lactate.

The hydrophilic component is 5 to 60% by weight of the composition of the present invention, for example 10 to 50%; Preferably from 10 to 40% by weight, more preferably from about 10 to about 30% by weight.

The hydrophilic component may comprise a mixture of two or more hydrophilic components.

The composition of the present invention may comprise a lower alkanol such as ethanol as the hydrophilic component. Although the use of ethanol in the composition is not essential, it has been found to be of particular advantage when the composition is intended to be prepared in soft gelatin encapsulated form. This is because the storage properties are improved, especially since the risk of precipitation of the active ingredient after the encapsulation process is reduced. Thus, shelf life stability can be extended by using ethanol or some other such co-component as an additional component of the composition. Ethanol is 0 to 60% by weight of the composition; Preferably from 5 to about 30 weight percent, more preferably from about 5 to 20 weight percent.

The composition of the present invention preferably contains one or more surfactants to provide thermodynamic stability by reducing interfacial tension. The surfactant may be a complex mixture containing by-products or unreacted starting products involved during its preparation, for example surfactants prepared by polyethoxylation may contain another by-product, for example polyethylene glycol. Can be. The surfactant or each thereof preferably has a hydrophilic-lipophilic equilibrium (HLB) value of 8 to 17, in particular 10 to 17. The HLB value is preferably an average HLB value.

Suitable surfactants include the following materials:

1) Reaction product of natural or hydrogenated castor oil with ethylene oxide

Natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60, optionally removing the polyethylene-oxide component from the product. These various surfactants are commercially available. Particularly suitable surfactants include a saponification of about 50 to 60, a cremo having an acid value of less than about 1, a moisture content of less than about 2% (Fisher), n _D ²⁰ of about 1.453-1.457, and an HLB of about 14-16 A saponification of Cremophor RH 40, and a saponification of about 40-50, an acid value of less than about 1, an iodine of less than about 1, a water content (Fisher) of about 4.5-55.%, N _D ²⁰ of about 1.453-1.457 And polyethylene-hydrogenated castor oil available as Cremophor ™, including Cremophor RH 60 having an HLB of about 15 to 17.

A particularly preferred product of this class is Cremophor RH 40. Other useful products of this class include the trade names Nikkol ™ (eg, Nicole HCO-40 and Nicole HCO-60), Mapeg ™ (eg, Mapeg CO-40h), Inc. Incrocas ™ (eg, Incrocas 40), Tagat ™ (eg, polyoxyethylene-glycerol-fatty acid esters such as Tagat RH 40) and thizols ( Simulsol) OL-50 (approximately 55-65 saponification, up to 2 acid values, 25-35 iodine, available from Seppic, having up to 8% water content of about 2% and HLB of about 13 PEG-40 castor oil). These surfactants are also described in the literature (Fiedler loc. Cit.).

Another suitable surfactant of this class includes a molecular weight of about 1630 (by steam osmosis), a saponification of about 65 to 70, an acid value of about 2, an iodine value of about 28 to 32, and an n _D ²⁵ of about 1.471. Polyethyleneglycol castor oils such as those that can be used for cremophor EL having are included.

2) Polyoxyethylene - Sorbitan -Fatty Acid Ester

These are known and are mono- and tri-lauryl, including the following products of the type commercially available from Uniqema under the tradename Tween ™ (Fiedler loc . Cit . P. 1615 ff). , Palmityl, stearyl and oleyl esters:

Tween 20 [polyoxyethylene (20) sorbitan monolaurate],

Tween 21 [polyoxyethylene (4) sorbitan monolaurate],

Tween 40 [polyoxyethylene (20) sorbitan monopalmitate],

Tween 60 [polyoxyethylene (20) sorbitan monostearate],

Tween 65 [polyoxyethylene (20) sorbitan tristearate],

Tween 80 [polyoxyethylene (20) sorbitan monooleate],

Tween 81 [polyoxyethylene (5) sorbitan monooleate], and

Tween 85 [polyoxyethylene (20) sorbitan trioleate].

Particularly preferred products of this class are Tween 20 and Tween 80.

3) polyoxyethylene fatty acid ester

These are known and include polyoxyethylene stearic acid esters of the type commercially available from Uniqema under the trade name Myrj ™ (Fiedler loc . Cit . , 2, p. 1042). Particularly preferred products of this class are Meiz 52 having a D ²⁵ of about 1.1, a melting point of about 40 to 44 ° C., an HLB value of about 16.9, an acid value of about 0 to 1 and a saponification value of about 25 to 35.

4) Polyoxyethylene-polyoxypropylene Copolymers and Blocks Copolymer or poloxamer

These are known and include types commercially available under the tradenames Pluronic ™ and Emalix ™ (Fiedler loc . Cit . , 2, p. 1042). Particularly preferred products of this class are Pluronic F68 (poloxamer 188) provided from BASF having a melting point of about 52 ° C. and a molecular weight of about 6800 to 8975. A further preferred product of this class is Synperonic ™ PE L44 (Poloxamer 124) from Uniqema.

5) saturated A C ₁₀ to C ₂₂ polyoxyethylene mono esters

These are, for example, C ₁₈ substituted, for example hydroxy fatty acids such as 12 hydroxy stearic acid PEG esters such as BASF (eg, BASF (600-900, for example 660 Dalton molecular weight) Solutol ™ HS 15 available from Ludwigshafen, Germany). According to BASF Technical Leaflet, MEF 151E comprises about 70% by weight of polyethoxylated 12-hydroxystearate and about 30% by weight of unesterified polyethylene glycol component. Solutol HS 15 has a hydrogenation of 90 to 110, a saponification of 53 to 63, an acid value of at most 1, and a maximum moisture content of 0.5% by weight.

6) polyoxyethylene Alkyl ether

These are known and commercially available under the trade name Brij ™ from Uniqema, and are polyoxyethylene glycol ethers of C ₁₂ to C ₁₈ alcohols, for example polyoxyl 2-, 10- or 20-cetyl ether or polyoxyl 23-lyluri ether, or polyoxyl 20-oleyl ether, or polyoxyl 2-, 10-, 20- or 100-stearyl ether. Particularly preferred products of this class are, for example, Breeze 35 (polyoxyl 23 lauryl ether) or Breeze 98 (polyoxyl 20 oleyl ether) (Fiedler, loc . Cit ., 1, pp. 259; Handbook of Pharmaceuticals Excipients, loc . Cit . , Page 367). Similarly, suitable products are polyoxyethylene-polyoxypropylene-alkyl ethers, for example polyoxyethylene-polyoxypropylene-ethers of C ₁₂ to C ₁₈ alcohols, for example known and for example Polyoxyethylene-20-polyoxypropylene-4-cetylether commercially available from Nikko Chemicals Co., Ltd. under the trade name Nikkol PBC ™ 34 (Fiedler, loc . cit., vol. 2, pp. 1239). Also suitable are polyoxypropylene fatty acid ethers, such as Acconon ™ E.

7) Sodium Alkyl Sulfates and sulfonates , and sodium alkyl aryl sulfonates

These are also known as sodium dodecyl sulfate and include, for example, sodium lauryl sulfate commercially available from Henkel KGaA under the trade name Texapon K12 ™.

8) water-soluble tocopheryl polyethylene glycol succinic acid phenyl ester (TPGS)

These include, for example, those available from Eastman Fine Chemicals, Kingsport, Texas, USA and having a polymerization water of about 1000.

9) Polyglycerol Fatty Acid Ester

These include, for example, those having 10 to 20, for example 10 glycerol units. Fatty acid components may include both saturated and unsaturated fatty acids having, for example, a chain length of C ₈ -C ₁₈ . Particularly suitable are known, for example, and are known, for example, from the Nikko Chemicals Co., Ltd. tradenames Decaglyn ™ 1-L or decaglin 1-M or decaglin, respectively. Decaglyceryl monolaurate or decaglyceryl monomyristate, commercially available as 1-O (Fiedler loc . Cit . , Vol. 2, pp. 1228).

10) alkylene Polyol ether or ester

These include C _{3 -5-alkylene} triols, in particular glycerol, ethers or esters. Suitable C _{3 -5} alkylene triol ethers or esters include mixed component including the ethers or esters, i.e., other ether or ester ingredients, for example, C _{3 -5} alkylene triol esters with other mono-, di- Or transesterification products of poly-ols. A glycol fatty acid esters, particularly suitable alkylene polyol ethers or esters are mixed C _{3 -5} alkylene triol / poly - (C _{2 -4-alkylene)} glycol fatty acid esters, especially mixed glycerol / polyethylene-or polypropylene.

Particularly suitable alkylene polyol ethers or esters include glycerides, e.g., triglycerides, with poly- (C _{2 -4-alkylene)} glycol, e.g., poly-ethylene glycols and, optionally, by the transesterification reaction of glycerol Products obtainable are included.

Such transesterification products are generally poly (C _{2 -4-alkylene)} glycol, e.g., poly-ethylene glycols and, optionally, glycerides, in the presence of glycerol, for example, the triglyceride is by alcoholysis (Ie, transesterification from glycerides to the poly-alkylene glycol / glycerol component takes place, ie via poly-alkylene glycol degradation / glycerol decomposition). In general, this reaction is carried out by reacting the components mentioned (glycerides, polyalkylene glycols and optionally glycerol) with continuous stirring at elevated temperatures under an inert atmosphere.

Preferred glycerides are fatty acid triglycerides, including natural and hydrogenated oils, in particular vegetable oils, for example (C _{10 -22} fatty acids) triglycerides. Suitable vegetable oils include, for example, include an olive oil, almond oil, peanut oil, coconut oil, palm oil, soybean oil and Mac Ayurvedic, and in particular the ester residue-rich natural or hydrogenated _(-18 C ₁₂ fatty acid) oil.

Preferred polyalkylene glycol materials are polyethylene glycols, in particular polyethylene glycols having a molecular weight of about 500 to about 4,000, for example about 1,000 to about 2,000.

Suitable alkylene polyol ethers or esters include C _{3 -5} alkylene triol esters, e.g., different relative amounts of mono-, di- and tri-ester, and a poly (C _2-4 alkylene) glycol mono- and D-glass with a small amount of ester C _{3 -5} alkylene triol and free poly - (C _{2 -5} alkylene) comprises a mixture of glycol. As mentioned above, the preferred alkylene triol moiety is glyceryl; Preferred polyalkylene glycol moieties include polyethylene glycol, in particular having a molecular weight of about 500 to about 4,000; Preferred fatty acid sites may be C _{10 -22} fatty acid ester residues, in particular saturated C _10-22 fatty acid ester residues.

Particularly suitable alkylene polyol ethers or esters include transesterified products of natural or hydrogenated vegetable oils and polyethylene glycols and, optionally, glycerol; Or glyceryl mono-, di- and tri-C _{10 -22} fatty acid esters and polyethylene glycol mono- and di-C _{10 -22} fatty esters (optionally with, for example, trace free glycerol and free polyethylene glycol) Or compositions comprising them.

Preferred vegetable oils, polyethylene glycol or polyethylene glycol moieties and fatty acid moieties according to the above definitions are as described above.

Particularly suitable alkylene polyol ethers or esters as described above for use in the present invention include, for example, those commercially available under the trade name Gelucire ™ from Gattefosse, in particular the following products do:

a) gelusir 44/14 having a melting point of about 42.5-47.5 ° C. and a saponifier of about 79-93; And

b) Zelushir 50/13 having a melting point of about 46-51 ° C. and a saponifier of about 67-81.

The products (a) to (b) all have an acid value of at most 2.

Alkylene polyol ethers or esters having an iodine number of at most 2 are generally preferred. The composition of the present invention may comprise a mixture of such ethers or esters.

The gelusir product is an inert semisolid waxy material with amphiphilic properties. These are confirmed by their melting point and their HLB values. Most gelusir grades are saturated polyglycol degraded glycerides that can be obtained by polyglycolysis of natural hydrogenated vegetable oils with polyethylene glycol. These consist of a mixture of mono- and di- and tri-glycerides and mono- and di-fatty acid esters of polyethylene glycol. Particularly suitable is gelusir 44/14 having a nominal melting point of 44 ° C. and an HLB of 14. This is obtained by reacting hydrogenated palm kernel oil and / or hydrogenated palm oil with polyethylene glycol 1500. It consists of approximately 20% mono-, di- and triglycerides, 72% polyethylene glycol 1500 mono- and di-fatty acid esters, and 8% free polyethylene glycol 1500. The fatty acid distribution for Zelusir 44/14 is as follows: 4-10 C ₈ , 3-9 C ₁₀ , 40-50 C ₁₂ , 14-24 C ₁₄ , 4-14 C ₁₆ , 5-15 C ₁₈ . Gelucir 44/14 shows additional characteristic data as follows: up to 2 acid values, up to 2 iodine numbers, saponification of 79-93. 36-56 hydroxyl number. Up to 6 peroxides, up to 80 alkaline impurities, up to 0.50 water content, up to 3 free glycerol content, monoglyceride content of 3.0-8.0 (H. Fiedler, loc . Cit . , Vol. 1, page 676 Manufacturer information).

11) Polyethylene Glycol Glyceryl Fatty Acid Ester

Fatty acid esters may include mono and / or di and / or tri fatty acid esters. Fatty acid components may include, for example, both saturated and unsaturated fatty acids having a chain length of C ₁₂ -C ₁₈ . Polyethylene glycols may have, for example, 10 to 40 [CH ₂ —CH ₂ —O] units, for example 15 or 30 units. Especially suitable are polyethylene glycol (15) glyceryl monostearate, which is commercially available, for example, under the trade name TGMS ™ -15 from Nikko Chemicals Co., Ltd. Other suitable glyceryl fatty acid esters are described, for example, from Goldschmidt, for example under the trade name Tagat ™ O (H. Fiedler, loc . Cit . , Vol. 2, p. 1502-1503 Commercially available polyethylene glycol (30) glyceryl monooleate, and tacat O2 (polyethylene glycol (20) glycerol monooleate), and takat L (polyethylene glycol (30) glyceryl monolaurate) And Takat L2 (polyethylene glycol (20) glycerol monolaurate), all of which are provided from Goldschmidt (H. Fiedler, loc . Cit . , Vol. 2, p. 1502-1503). . Further suitable polyethylene glycol glyceryl fatty acid esters are Takat TO.

12) sterols and derivatives thereof

These include products comprising cholesterol and derivatives thereof, in particular phytosterols such as cytosterol, campestrol or stigmasterol, and ethylene oxide adducts thereof such as soy sterols and derivatives thereof such as polyethylene glycol sterols Such as polyethylene glycol phytosterol or polyethylene glycol soy sterol. Polyethylene glycols can have, for example, 10 to 40 [CH ₂ -CH ₂ -O] units, for example 25 or 30 units. Particularly suitable are polyethylene glycol (30) phytosterols which are commercially available, for example, from Nikko Chemicals Co., Ltd. under the trade name Nikkol BPS ™ -30. . Further suitable are polyethylene glycol (25) soy sterols commercially available, for example from Henkel, for example Generol ™ 122 E 25 (H. Fiedler, loc . Cit . , vol. 1, p. 680).

13) the transesterification, polyoxy ethylated Capryl - Capric Acid Glyceride

These include, for example, those commercially available under the trade name Labrasol ™ from Gattefosse. Labrazole has an acid number of up to 1, a saponification value of 90-110, and an iodine number of up to 1 (H. Fiedler, loc. Cit . , Vol. 2, page 880).

14) sugar fatty acid ester

These include C _{12 -18} fatty acid ester of a sugar, e.g., sucrose monolaurate, e.g., e.g., Mitsubishi-Kasei hood commercially available from the Corporation (Mitsubishi-Kasei Food Corp., Tokyo, Japan) Ryoto L-1695 ™, which may be present.

15) PEG Sterol Ether

These include, for example, those having from 5 to 35 [CH ₂ -CH ₂ -O] units, for example from 20 to 30 units, for example, solu commercially available from Amerchol. Solulan ™ C24 is included.

16) Dioctyl Sodium Sulfosuccinate

This is, for example, the trade name Aerosol OT ™ (Fiedler, loc . Cit . , 1, p. 118), or di- [2-ethylhexyl] -quartz from American Cyanamid Co. Nate (Fiedler, loc . Cit . , Volume 1, p. 487).

17) phospholipids

These include in particular lecithin (Fiedler, loc . Cit . , Volume 2, p. 910, 1184). Suitable lecithins include especially soy lecithins.

18) salts of fatty acids, fatty acid sulfates and sulfonates

These are known and are commercially available, for example, from Fluka and include, for example, salts of C ₆ -C ₁₈ fatty acids, -fatty acid sulfates and sulfonates.

19) Salts of Acylated Amino Acids

These include salts of C ₆ -C ₁₈ acylated amino acids, for example sodium lauroyl sarcosinate commercially available from Fluka.

20) medium or long chain Alkyl, e.g., C ₆ - C _18, an ammonium salt

These are C ₆ -C ₁₈ acylated amino acids such as E. Cetyl trimethyl ammonium bromide commercially available from E. Merck AG.

The surfactant may comprise 5 to 90 weight percent, preferably 15 to 85 weight percent, more preferably 20 to 60 weight percent, even more preferably about 35 to about 55 weight percent of the composition of the present invention.

Certain embodiments of the compositions of the invention additives, for example, antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavors, sweeteners, and articles such as those described in (Fiedler, HP, loc. Cit .) Contains other ingredients.

Preferred antioxidants include ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) and tocopherol. Particular preference is given to the antioxidant α-tocopherol (vitamin E).

These additives or components may comprise about 0.05 to 5 weight percent of the total weight of the composition. Antioxidants, antimicrobials, enzyme inhibitors, stabilizers, or preservatives generally provide up to about 0.05 to 1 weight percent based on the total weight of the composition. Sweeteners or fragrances generally provide up to about 2.5 or 5 weight percent based on the total weight of the composition.

The aforementioned additives may also include components that solidify the liquid microemulsion preconcentrate (MEPC). These include solid polyethylene glycols (PEGs) and Gelucire (TM) products, such as gelucsir 44/14 or gelucsir 50/13, which also act as additional surfactants.

In a seventh aspect, the present invention relates to an active agent, comprising the preparation of an active agent and a carrier medium comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) a hydrophilic component, Provided are methods for preparing spontaneously dispersible pharmaceutical compositions containing 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist as a medicament.

The carrier medium may be prepared separately before the active agent is made in intimate mixture with the carrier medium. Alternatively, two or more of the components of the carrier medium may be mixed together with the active agent.

Spontaneously dispersible pharmaceutical compositions are preferably microemulsion preconcentrates as defined herein.

Spontaneously dispersible pharmaceutical compositions are preferably 1: 1 to 1: 300, for example 1: 1 to 1:70, in particular 1:10 to 1:70, and more particularly, for example 1:10. When diluted in an aqueous medium, such as water, or in the gastric juice of a patient after oral application at a dilution of, spontaneously or substantially spontaneously forms an o / w (oil-in-water) emulsion, for example a microemulsion.

In an eighth aspect, the present invention provides a pharmaceutical composition that is spontaneously dispersible by making an intimate mixture of (i) an active agent and (1) a lipophilic component, (2) a surfactant, and optionally (3) a hydrophilic component. And (ii) diluting the spontaneously dispersible pharmaceutical composition in an aqueous medium to form a microemulsion, as the active agent 5-aryl-4 (R) -arylcarbonylamino-pent-2- Provided are a process for preparing a microemulsion containing an enacid amide substance P antagonist.

As mentioned above, the active agent may be present in, for example, from about 0.05% to about 20% by weight of the composition of the present invention. The active agent is preferably present in an amount of 0.5 to 15% by weight of the composition, more preferably in an amount of 1.5 to 5% by weight of the composition.

The lipophilic component may be comprised between 5 and 85 weight percent of the composition of the present invention, for example, 10 to 85 weight percent; Preferably from 15 to 60% by weight, more preferably from about 20 to about 40% by weight.

The hydrophilic component (if present) may comprise 5 to 60 weight percent, for example 10 to 50 weight percent, of the composition of the invention; Preferably from 10 to 40% by weight, more preferably from about 10 to about 30% by weight. It may comprise a mixture of two or more hydrophilic components. The ratio of the predominant hydrophilic component to hydrophilic component is generally from about 0.5: 1 to about 2: 1.

The surfactant is 5 to 90% by weight, preferably 15 to 85% by weight of the composition of the present invention; More preferably from 20 to about 60 weight percent, even more preferably from about 35 to about 55 weight percent.

The relative proportions of active agent (s), lipophilic component (s), surfactant (s), and hydrophilic component (s) (if present) are in the “microemulsion” portion on a standard three-way plot graph. Thus, the composition may have a high stability to provide a microemulsion, for example with an average particle size of <200 nm when added to an aqueous medium.

If the composition of the invention is a microemulsion preconcentrate, it may be combined with water or an aqueous solvent medium to obtain an emulsion, for example a microemulsion. Emulsions or microemulsions can be administered, for example orally, in the form of ingestible solutions, for example orally.

If the composition of the present invention is a microemulsion preconcentrate, a unit dose of the microemulsion preconcentrate is used to fill the capsule shell, which is preferably orally administrable. The capsule shell may be, for example, a soft or hard capsule shell made of gelatin. Each unit dosage is suitably 0.1 to 100 mg of active agent, for example 0.1 mg, 10 mg, 15 mg, 25 mg or 50 mg, preferably 10 to 100 mg of active agent, more preferably May contain 10 to 50 mg, for example 15, 20, 25 or 50 mg, more preferably 5 to 20 mg, most preferably 5 or 10 mg of active agent. Such unit dosage forms are suitable for administration 1 to 5 times daily, depending on the particular therapeutic purpose, the nature of the treatment, and the like. However, if desired, the composition may be in the form of a drinking solution and diluted to, for example, from about 1:10 to about 1: 100, including water or other aqueous systems such as fruit juice, milk, and the like. Thus, for example, a colloidal system suitable for drinking can be provided.

The compositions of the present invention, for example the compositions described in the examples below, have excellent stability characteristics, for example, having shelf life stability up to 1, 2 or 3 years and longer, as indicated by extended stability experiments. Can be represented. One group of compositions of the invention, when added to water, has an average particle size of <200 nm (2,000 kPa), for example <150 nm (1,500 kPa), for example <100 nm (1,000 kPa). It may be one having a high stability capable of providing an aqueous microemulsion having.

The composition of the present invention exhibits particularly advantageous properties when administered orally, for example in terms of consistency and high levels of bioavailability obtained in standard bioavailability experiments.

Pharmacodynamic parameters, for example drug component absorption, as measured in blood levels, are also surprisingly more predictable and can eliminate or reduce problems with administration with irregular absorption. In addition, the pharmaceutical compositions are effective with biosurfactants or tenside substances, such as bile salts, present in the gastrointestinal tract. That is, the pharmaceutical composition of the present invention is sufficiently dispersible in an aqueous system comprising such natural tensides, and thus can provide an emulsion or microemulsion system and / or particulate system that is stable at that location. The action of the pharmaceutical composition upon oral administration is maintained at any particular time, or for any given individual, substantially independently and / or intact of the relative presence or absence of bile salts. Compositions of the invention can also reduce variability in inter- and intra-patient dose responses.

The utility of the compositions of the present invention can be observed, for example, in standard clinical trials in known indications of active agents at dosages that provide therapeutically effective active agent blood levels. Increased bioavailability of the compositions of the invention can be observed in standard animal tests and clinical trials.

The dose of active agent in the compositions of the present invention is about the same or up to half as used in known compositions containing the active agent. The composition of the present invention comprises about 0.1 mg to about 40 mg / day of active agent, preferably about 0.1 mg to about 20 mg / day, for example, most preferably about 0.1 to about 1 mg for respiratory disease Activity at a concentration of / day.

The compositions of the present invention are useful for the treatment of respiratory diseases such as asthma and chronic bronchitis. For these indications, the appropriate dosage will of course vary depending, for example, on the particular composition, host, mode of administration, and the nature and severity of the disease to be treated, for example.

Typical doses of active agent are 0.1 to 1 mg / day for asthma and chronic bronchitis.

Thus, in a ninth aspect, the present invention comprises administering a therapeutically effective amount of a pharmaceutical composition of the invention to a subject in need thereof, wherein 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide Provided are methods for treating a subject suffering from a disease treatable with a substance P antagonist.

The invention is illustrated by the following examples.

In the following examples, the pharmaceutically active agent is compound A, i.e. (4R) -4- [N'-methyl-N'- (3,5-bistrifluoro-methyl-benzoyl) amino] -4- (3 , 4-dichlorobenzyl) -but-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide.

Example  One

Filled Capsule  (Or oral solution)

The formulation contains:

Compound A 20 mg

Cremophor RH 40 215 mg

C8 / C10 mono- / di-glycerides 130 mg

Triethylcitrate 85 mg

Ethanol 50 mg

Example  2

Filled Capsule  (Or oral solution)

The formulation contains:

Compound A 10 mg

Cremophor RH 40 219 mg

Corn oil glycerides 174 mg

Propylene Glycol 27 mg

Ethanol 75 mg

Tocopherol 0.5 mg

Example  3

Oral solution

The formulation contains:

Compound A 10 mg / ml

Cremophor RH 40 439 mg

Corn oil glycerides 343 mg

Propylene Glycol 88 mg

Ethanol 99 mg

Tocopherol 1.0 mg

The compositions of all three examples are prepared by mixing the carrier components and dissolving the active ingredient in the carrier with stirring. The mixture of the formulations of Examples 1 and 2 is filled into hard gelatin capsules and sealed using the Quali-Seal ™ sealing technique.

Similarly, further examples are made as follows:

Excipient Mg / 1 g

Cremophore RH 40 423

Corn oil glycerides 253.8

PEG400 169.2

Ethanol 94

Compound a 60

Cremophore RH 40 423

Corn oil glycerides 253.8

Triethyl Citrate 169.2

Ethanol 94

Compound a 60

Cremophor RH 40 418.5

C8 / C10 mono- / diglycerides 251.1

PEG400 167.4

Ethanol 93

Compound a 70

Cremophor RH 40 400.5

C8 / C10 mono- / diglycerides 240.3

Propylene Glycol 160.2

Ethanol 89

Compound a 110

Cremophor RH 40 480

C8 / C10 mono- / diglycerides 288

Triethyl citrate 192

Compound a 40

PEG-20 glyceryl oleate 380

C8 / C10 mono- / diglycerides 285

Triethyl citrate 190

Ethanol 95

Compound a 50

Cremophor RH 40 432

Propylene Glycol Monocaprylate 345.6

Span 80 86.4

Triethyl citrate 96

Compound a 40

Cremophore RH 40 405

C8 / C10 mono- / diglycerides 180

Propylene Glycol Monocaprylate 180

Ethanol 135

Compound a 100

Cremophore RH 40 405

C8 / C10 mono- / diglycerides 180

Propylene Glycol Monocaprylate 90

Triethyl Citrate 90

Ethanol 135

Compound a 100

Cremophor EL 480

Capriol 288

Triethyl citrate 192

Compound a 40

No phase separation or precipitation is observed for any of the compositions and is clear for at least 4 hours.

2. Bioavailability

The bioavailability analysis of Example 1 in a dog test showed that a single oral dose of 20 mg Compound A administered as a standard capsule formulation using Formulated DS (Formulation A) was higher than that administered as a microemulsion (Formulation B). A significantly lower plasma level (A-50%) of A was given. For a description of the data, see Table 1 below and FIG. 1 attached.

shape t _max [h] medium n C _max [mg / ml] C _max / dose [(ng / ml) / (mg / kg)] AUC (0-48 h) [(ng / ml) .h] AUC (0-48 h) / dose [(ng / ml) .h / (mg / kilo)] f _ref (%) A 1.5 721 ± 545 385 ± 285 2622 ± 1584 1397 ± 811 46 ± 27 B One 2109 ± 1136 1151 ± 666 6779 ± 4066 3683 ± 2335 100 ± 0  Form A: powder in capsule, Form B: microemulsion

3. Embodiment

In general, the most preferred embodiment for the microemulsion of the present invention is a soft gelatin capsule. This is due to the fact that many microemulsion excipients, such as propylene glycol, are incompatible with hard gelatin capsules and cause them to break. Soft gelatin capsules contain large amounts of softeners and are therefore more compatible.

Claims (16)

A spontaneously dispersible pharmaceutical composition comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist. Spontaneously dispersible pharmaceutical composition comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist and a carrier medium comprising a lipophilic component, a surfactant and optionally a hydrophilic component . The 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist according to claim 1 or 2 is (4R) -4- [N'-methyl-N '-( 3,5-Bistrifluoro-methyl-benzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide Phosphorus pharmaceutical composition. (4R) -4- [N'-methyl-N '-(3,5-bistrifluoro-methyl-benzoyl) amino] -4- (3,4-dichlorobenzyl) -but-2- as active agent A pharmaceutical composition comprising N-[(R) -epsilon-caprolactam-3-yl] -amide and a carrier medium comprising a lipophilic component, a surfactant and, optionally, a hydrophilic component, and in a form suitable for oral administration. The composition of claim 2 or 4, wherein the lipophilic component comprises C ₈ -C ₁₀ fatty acid monoglycerides and diglycerides or purified glycerol- transesterified corn oil. The composition of any one of claims 2, 4 and 5, wherein the hydrophilic component comprises propylene glycol. 7. The composition of any one of claims 2, 4, 5 and 6, wherein the surfactant comprises polyethylene glycol-hydrogenated castor oil. From about 0.05 to about 20 weight percent of (4R) -4- [N'-methyl-N '-(3,5-bistrifluoro-methyl-benzoyl) amino] -4- (3,4-dichlorobenzyl) -But-2-enoic acid N-[(R) -epsilon-caprolactam-3-yl] -amide, about 5 to about 85 weight percent lipophilic component, about 5 to about 90 weight percent surfactant and optionally, A spontaneously dispersible pharmaceutical composition comprising from about 5 to about 60 weight percent hydrophilic component, wherein all weights are based on the total composition. The composition of claim 1, which is in the form of a microemulsion preconcentrate. The composition of claim 1, which is in the form of a microemulsion. The composition of any one of claims 1 to 10 in unit dosage form. The composition of claim 11 in the form of soft or hard gelatin encapsulated. A 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1. A method of treating a subject suffering from a disease treatable with an amide substance P antagonist. 5-aryl-4 (R)-as an active agent, comprising making a close mixture of the active agent and a carrier medium comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) a hydrophilic component. Arylcarbonylamino-pent-2-enoic acid amide substance P A process for preparing a spontaneously dispersible pharmaceutical composition containing an antagonist. (i) an intimate mixture of the active agent and a carrier comprising (1) a lipophilic component, (2) a surfactant, and optionally (3) a hydrophilic component to form a spontaneously dispersible pharmaceutical composition; (ii) 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P as an active agent comprising diluting a spontaneously dispersible pharmaceutical composition in an aqueous medium to form a microemulsion Process for the preparation of microemulsions containing antagonists. Spontaneously dispersible pharmaceutical composition comprising 5-aryl-4 (R) -arylcarbonylamino-pent-2-enoic acid amide substance P antagonist substantially as described herein with reference to any one of the embodiments. .

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