MXPA00011581A - Microemulsion preconcentrates containing a piperidine substance p antagonist - Google Patents
Microemulsion preconcentrates containing a piperidine substance p antagonistInfo
- Publication number
- MXPA00011581A MXPA00011581A MXPA/A/2000/011581A MXPA00011581A MXPA00011581A MX PA00011581 A MXPA00011581 A MX PA00011581A MX PA00011581 A MXPA00011581 A MX PA00011581A MX PA00011581 A MXPA00011581 A MX PA00011581A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- percent
- hydrophilic
- lipophilic
- pharmaceutical composition
- Prior art date
Links
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 19
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000003890 substance P antagonist Substances 0.000 title claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 68
- -1 polyoxyethylene Polymers 0.000 claims description 29
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- 150000003626 triacylglycerols Chemical class 0.000 claims description 22
- 239000004094 surface-active agent Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 239000000194 fatty acid Substances 0.000 claims description 19
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 18
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 17
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 10
- 230000002269 spontaneous Effects 0.000 claims description 10
- 239000008158 vegetable oil Substances 0.000 claims description 10
- 235000005687 corn oil Nutrition 0.000 claims description 8
- 239000002285 corn oil Substances 0.000 claims description 8
- 150000004665 fatty acids Chemical class 0.000 claims description 8
- 239000000969 carrier Substances 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- 239000004359 castor oil Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- NXLUTEDAEFXMQR-BJKOFHAPSA-N N-[(2R,4S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4-chlorophenyl)methyl]piperidin-4-yl]quinoline-4-carboxamide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)N2[C@@H](C[C@H](CC2)NC(=O)C=2C3=CC=CC=C3N=CC=2)CC=2C=CC(Cl)=CC=2)=C1 NXLUTEDAEFXMQR-BJKOFHAPSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- IWHKOTBICJTXOL-LOSJGSFVSA-N FC(C=1C=C(C(=O)N2[C@@H](C[C@H](CC2)NC(=O)C2=NC3=CC=CC=C3C=C2)CC2=CC=C(C=C2)Cl)C=C(C=1)C(F)(F)F)(F)F Chemical compound FC(C=1C=C(C(=O)N2[C@@H](C[C@H](CC2)NC(=O)C2=NC3=CC=CC=C3C=C2)CC2=CC=C(C=C2)Cl)C=C(C=1)C(F)(F)F)(F)F IWHKOTBICJTXOL-LOSJGSFVSA-N 0.000 claims 1
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- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- 206010041250 Social phobia Diseases 0.000 abstract description 6
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- 206010038683 Respiratory disease Diseases 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
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- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical compound OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 7
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 6
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- 239000011630 iodine Substances 0.000 description 6
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
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- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- GHBFNMLVSPCDGN-UHFFFAOYSA-N Monoctanoin Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 4
- 230000003042 antagnostic Effects 0.000 description 4
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- ADNPLDHMAVUMIW-CUZNLEPHSA-N (2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-y Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 3
- GKFPPCXIBHQRQT-UHFFFAOYSA-N 6-(2-carboxy-4,5-dihydroxy-6-methoxyoxan-3-yl)oxy-4,5-dihydroxy-3-methoxyoxane-2-carboxylic acid Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(OC)C(C(O)=O)O1 GKFPPCXIBHQRQT-UHFFFAOYSA-N 0.000 description 3
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 3
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 3
- 210000003169 Central Nervous System Anatomy 0.000 description 3
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- 102100002996 TAC1 Human genes 0.000 description 3
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- 239000005557 antagonist Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
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- 150000003053 piperidines Chemical class 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
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- 239000000126 substance Substances 0.000 description 3
- 150000004670 unsaturated fatty acids Chemical group 0.000 description 3
- DTOSIQBPPRVQHS-PDBXOOCHSA-N (Z,Z,Z)-Octadeca-9,12,15-trienoic acid Natural products CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Polymers OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 2
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-UMZBRFQRSA-N 4-[(3R,5S,7R,12S)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CCC1(C)C1C2C2CCC(C(CCC(O)=O)C)C2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-UMZBRFQRSA-N 0.000 description 2
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- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 2
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Abstract
Microemulsion comprising a piperidine, e.g. 1-acyl-piperidine Substance P Antagonist and its use in the treatment of CNS disorders, e.g. depression and social phobia, and respiratory diseases, e.g. asthma and chronic bronchitis.
Description
NEW PHARMACEUTICAL COMPOSITIONS
The present invention relates to novel pharmaceutical compositions in which the active agent is an antagonist of substance P of piperidine, in particular an N-benzoyl-2-benzyl-4- (azanaphtoyl-amino) piperidine, useful for the treatment and prevention , for example, of disorders of the central nervous system, for example depression and social phobia, or respiratory diseases, for example asthma and chronic bronchitis. Substance P-antagonists of 1-acylpiperidine are a class of compounds described, for example, in European Published Patent Number EP 0532456B1, the content of which publication is incorporated herein by reference. In a similar manner, the N-benzoyl-2-benzyl-4- (azanaphtoyl-amino) piperidines and their activity as substance P antagonists are described in European Published Patent Application Number EP-0707006A, the content of which application is incorporated herein by reference. Substance P piperidine antagonists, such as are disclosed in European Patent Numbers EP-0532456B1 and EP 0707006A, present highly specific difficulties in relation to administration in general, and in galenic compositions in particular, including in particular problems of bioavailability of the drug and variability in the response to the intra- and intra-patient dose, necessitating the development of an unconventional dosage form. In accordance with the present invention, it has now been discovered in a surprising manner that stable pharmaceutical compositions can be obtained with piperidine P-substance antagonists, which have particularly interesting bioavailability characteristics, and a reduced variability in bioavailability parameters. inter- and intra-subjects. It has been found that these novel compositions satisfy or substantially reduce the difficulties previously encountered. It has been demonstrated that the compositions according to the present invention can make possible an effective dosage with a concomitant improvement, as well as a reduced variability of the resorption / bioavailability levels for and between individual patients. Accordingly, the invention can achieve effective therapy with tolerable dosage levels of piperidine substance P antagonists, and may allow for closer standardization and optimization of daily dosage requirements for each individual. As a result, the presentation of undesirable potential side effects decreases, and the overall cost of therapy can be reduced. In one aspect, the present invention provides a spontaneously dispersible pharmaceutical composition, which comprises a piperidine substance P antagonist, hereinafter also referred to as the active agent. These pharmaceutical compositions that can be dispersed in a spontaneous manner are preferably in liquid form, or are produced from at least one liquid component, and preferably are micellar precursors. The term "spontaneously dispersible pharmaceutical composition", as used herein, is defined as a system that can produce colloidal structures, for example solid or preferably liquid particles, for example droplets and / or nanoparticles, and / or micellar compositions, for example aqueous mycelia, for example up to 1,000 nanometers in diameter, when diluted with an aqueous medium, for example in water, for example when diluted in a dilution ratio, for example, of 1:10 of the composition to water, or in gastric juices, for example in simulated conditions after its oral application in a similar dilution ratio, to, for example, 15 to 37 degrees Celsius. Pharmaceutical compositions that can be dispersed in a spontaneous manner are also referred to hereinbelow as compositions of the invention. Colloidal structures can be formed spontaneously, or substantially in a spontaneous manner, when the components of the composition of the invention are brought into contact with an aqueous medium, for example by simple manual agitation for a short period of time, for example for 10 seconds. The compositions of the invention are thermodynamically stable, for example for at least 15 minutes or up to 4 hours, even up to 24 hours. They normally contain dispersed structures of an average diameter of less than about 300 nanometers (3,000 A), for example less than about 200 nanometers (2,000 A), as measured by conventional light scattering techniques, for example using an alvern Zetasizer 3,000. Naturally, there may be particles of an average diameter greater than 200 nanometers present, but these preferably are less than 50 weight percent, for example less than 10 to 20 weight percent of the total. Preferably they comprise droplets or nanoparticles having an average diameter of less than about 150 nanometers (1,500 A), usually less than 100 nanometers (1,000 A), generally greater than 5 nanometers (50 A). Alternatively, pharmaceutical compositions that can be dispersed spontaneously can simultaneously form, upon dilution, a mixture comprising mycelia and nanoparticles. The mycelia can be essentially monophasic and substantially non-opaque, that is, transparent or opalescent when viewed by microscopic optical elements. It was found that the proportion of nanoparticles present may depend on the temperature, but suitable bioavailability characteristics can still be obtained.
In another aspect, the present invention provides a spontaneously dispersible pharmaceutical composition, which comprises a piperidine substance P antagonist as the active agent, and a carrier medium comprising: 1) a hydrophilic component, and ) a surfactant. Preferably, these pharmaceutical compositions which can be dispersed in a spontaneous manner, are for oral administration. Conveniently, the piperidine substance P antagonist is luble in water, for example it has a solubility less than 0.001 percent, for example 0.001 to 0.0001 percent. Conveniently, the active agents are used in free base form. The active agents may show a Substance P antagonistic activity, as indicated in the standard in vitro or in vivo tests, for example, as disclosed in the aforementioned European presentations. The piperidine may be a piperidine derivative which is an analog, or may be poly- (eg, di- or tri-) substituted. The active agents include not only those disclosed in the aforementioned European presentations, but also analogues, for example: a) 1- [2- [3- (3,4-dichlorophenyl) -1- [(3- (1) -isopropoxyphenyl-nyl) acetyl] piperidin-3-yl] ethyl] -4-phenyl-1-azoniabicyclo [2.2.2] octane, b) (2S-cis) -N- [(2-methoxyphenyl) methyl] -2 phenyl) -piperidinamine [CP-99994], c) cis-3- ((3-methyl-5-trimethylsilyl) benzyloxy) -2-phenylpiperidine, d) 4-phenyl-4- ((1- (3, 5 bis (trifluoromethyl) phenyl) -2-hydroxyethoxy) methyl) piperidine [L-733060], e) 2-phenyl-3- (3,5-bis (trifluoromethyl) benzyloxy) piperidine [L-733060], f) ( R) -3- (lH-indol-3-yl) -l- [N- (2-methoxybenzyl) acetyl-ene] -2- [N- (2- (4- (piperidin-1-yl) piperidine -1-yl) acetyl) amino] -propane, g) (R) -3- (lH-indol-3-yl) -1- [N- (2-methoxybenzyl) acetylamino] -2- [N- (2- (4- (piperidin-1-yl) piperazin-1-yl) acetyl) amino] -propane, h) (2-methoxy-5- (5-trifluoromethyl-tetrazol-1-yl) -benzyl) - (2S-phenyl-1-piperidin-3S-yl) -amine [GR -205171], i) (-) - (B) -cis-4- [l- [3,5-bis (trifluoromethyl) benzoyl] -2- (phenylmethyl) -4-piperidin-yl] -N- (2 , 6-dimethylphenyl) -1-piperazineacetamide, including salts thereof. Preferred active agents are substance P antagonists of 1-acylpiperidine, for example as claimed in European Patent Number EP-0532456 B. Preferred compounds of the invention are the compounds of European Patent Number EP-0707006 A, for example N-benzoyl-2-benzyl-4- (azanaphtoyl-amino) piperidines, and more preferably (2R, 4S) -N- (1- (3,5-bis (trifluoromethyl) -benzoyl) -2- (4 -chlorobenzyl) -4-piperidinyl) -quinolin-4-carboxamide, hereinafter referred to as Compound A, as disclosed in European Patent Number EP-707,006. The composition of the invention may also comprise a carrier medium containing additional components. Additional components typical of the compositions of the invention are described in Fiedler, H.P. "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, D-7960 Aulendorf, 4th edition revised and expanded (1996). In accordance with the present invention, the active agent can be present in a weight amount of up to about 20 weight percent of J to composition of the invention, for example about 0.05 weight percent. The active agent preferably. it is present in an amount of 0.5 to 15 weight percent of the composition, for example from about 1 to 10 percent, preferably from 1.5 to 2 percent. The hydrophilic component typically has a solubility in water of at least 1 gram / 100 milliliters or more, for example, when 5 grams / 100 milliliters at 25 degrees Centigrade. Preferably it provides a rapid mixture of an active agent with water. This mixture can be determined by routine experimentation, for example by means of different methods of chromatography, for example Gas Chromatography (GC). Conveniently, the hydrophilic component can also be miscible with an organic solvent, for example ether. Preferably, the hydrophilic component can be an alcohol, for example a water-miscible alcohol, for example absolute ethanol, or glycerol. Other alcohols include glycols, for example any glycol obtainable from an oxide, such as ethylene oxide, for example 1,2-propylene glycol. Other examples are polyols, for example a polyalkylene glycol, for example polyalkylene glycol (of 2 to 3 carbon atoms). A typical example is a polyethylene glycol, for example of a preferred molecular weight of 200 to 1000 Daltons, more preferably 200 to 400 Daltons, especially 400. Alternatively, the hydrophilic component may preferably comprise an N-alkylpyrrolidone, for example N- (C 1-4 alkyl) Ridolidone, for example N-methylpyrrolidone, tri (C 1-4) alkyl citrate, for example triethyl citrate, dimethylisoosorbide, alkanoic acid (from 5 to 13 atoms) of carbon, for example caprylic acid or propylene carbonate, triethyl citrate or propylene glycol is more preferred.
The hydrophilic component can comprise a main or single component, for example an alcohol, for example alcohol of 1 to 4 carbon atoms, for example ethanol, or alternatively a co-component, for example, which can be selected from ethers lower partial or lower alkanoles. Particularly preferred partial ethers are those known and commercially available, for example Transcutol (having the formula C2H5- [O- (CH2) 2] 2-0H), Glycofurol (also known as polyethylene glycol ether of tetrahydrofurfuryl alcohol), or lower alkanols such as as ethanol. Preferred alkanol components include ethanol, 1,2-propylene glycol, or a polyethylene glycol, for example of a molecular weight of 100 to 600 daltons, for example polyethylene glycol 4Q0. When present, the ethanol may comprise 0, for example, from 1 to 60 weight percent of the hydrophilic component; preferably from 20 to about 55 weight percent, and more preferably from about 40 to about 50 weight percent. The hydrophilic component can conveniently contain ethanol as the sole component. The ratio of the hydrophilic component to the hydrophilic co-component is usually from about 0.5: 1 to about 2: 1. The hydrophilic component may comprise from 5 to 50 weight percent of the composition of the invention, for example from 10 to 50 percent; preferably from 15 to 40 percent by weight, more preferably from about 20 to about 30 percent by weight, for example from 15 to 35 percent by weight. Examples of suitable surfactants, for example, preferably surfactants of a high hydrophilic-lipophilic equilibrium value, for example a hydrophilic-lipophilic balance > 10, to be used in this invention are:
(i) The reaction products of a natural or hydrogenated castor oil and ethylene oxide, i.e. natural or hydrogenated polyoxyethylene glycol vegetable oils, for example natural or hydrogenated polyoxyethylene glycolic castor oils. The natural or hydrogenated castor oil can be reacted with ethylene oxide in a molar ratio of about 1:35 to about 1:60, with the optional removal of the polyethylene glycol component from the products. Several of these surfactants are commercially available. Hydrogenated castor oils with polyethylene glycol available under the brand name CREMOPHOR, are especially suitable. Particularly suitable are CREMOPHOR RH 40, which has a saponification number of about 50 to 60, an acid number of less than about 1, a water content (Fischer) of less than about 2 percent, an nD60 of about 1,453 to 1,457, and a hydrophilic-lipophilic balance of about 14 to 16; and CREMOPHOR RH 60, which has a saponification number of about 40 to 50, an acid number less than about 1, an iodine number less than about 1, a water content (Fischer) of about 4.5 to 5.5 percent, a nD25 of about 1453 to 1457, and a hydrophilic-lipophilic balance of about 15 to 17. An especially preferred product of this class is CREMOPHOR RH 40. Also polyethylene glycol castor oils are available as are available under the trade name CREMOPHOR EL , which has a molecular weight (by vapor osmometry) of about 1,630, a saponification number of about 65 to 70, an acid number of about 2, an iodine number of about 28 to 32, and an nD25 of about 1,471, and a hydrophilic-lipophilic equilibrium value of about 12 to 14. The similar or identical suitable products that can also be used, are the d Different tensides available under the trade names NIKKOL (for example NIKKOL HCO-40 and HCO-60), MAPEG (for example MAPEG CO-40h), INCROCAS (for example INCROCAS 40), and TAGAT (for example fatty acid esters of polyoxyethylene glycerol, for example TAGAT RH 40). A preferred polyethoxylated glyceride is TAGAT TO, a polyoxyethylene glycerol trioleate having a hydrophilic-lipophilic equilibrium value of 11.3. These surfactants are further described in Fiedler loe. ci t. , incorporated herein by reference. (ii) Related products belonging to the class of polyoxyethylene alkyl ethers are available under the tradename BRIJ, for example Brij 35 which has a hydrophilic-lipophilic equilibrium value of about16. 9. (iii) Polyoxyethylene sorbitan fatty acid esters (also called polysorbates), for example from 4 to 25 alkylene fractions, for example mono- and tri-lauryl-, palmityl-, stearyl-, and oleyl-esters of the type known and commercially available under the trade name TWEEN
. { Fiedler, loe. ci t. pages 1300-1304, incorporated herein by reference), including the TWEEN products: 20 ^ [polyoxyethylene sorbitan monolaurate (20)], 21 [polyoxyethylene sorbitan monolaurate (4)], 40 [polyoxyethylene sorbitan monopalmitate] (20)], 60 [polyoxyethylene sorbitan monostearate (20)], 65 [polyoxyethylene sorbitan tristearate (20)], 8_0 [polyoxyethylene sorbitan monooleate (20)], 81 [polyoxyethylene sorbitan monooleate (5) )], 85 [polyoxyethylene sorbitan trioleate (20)]. Especially preferred products of this class are TWEEN 40 and TWEEN 80. (v) Polyoxyethylene fatty acid esters, for example esters of polyoxyethylene stearic acid of the type known and commercially available under the tradename MYRJ (Fiedler, loe. 2, pages 834-835, incorporated herein by reference). An especially preferred product of this class is MYRJ 52 having an nD '50 of about 1.1, a melting point of about 40 ° C to 44 ° C, a hydrophilic-lipophilic equilibrium value of about 16.9, an acid value of about 0 to 1, and a saponification number of about 25 to 35. Other related products include saturated polyethoxylated hydroxy fatty acids, which can be produced by the reaction of a saturated fatty hydroxy acid, for example from 18 to 20 carbon atoms, with , for example, ethylene oxide or polyethylene glycol. Suitable examples for the present invention are known and are commercially available, for example in the company BASF, under the trademark Solutol. Especially preferred is Solutol HS15 which is known, for example, from the BASF technical leaflet, MEF 151E (1986), which comprises about 70 percent polyethoxylated 12-hydroxystearate by weight, and about 30 percent by weight of unesterified polyethylene glycol. Solutol HS 15 has a hydrogenation value of 90 to 110, a saponification value of 53 to 63, a maximum acid value of 1, and a maximum water content of 0.5 weight percent.
(v) Polyoxyethylene-polyoxypropylene block copolymers and copolymers, for example of the type known and commercially available under the tradenames PLURONIC, EMKALYX, and POLOXAMER (Fiedler, loc. cit., 2, page 959, incorporated herein by reference) . An especially preferred product of this class is PLURONIC F68, which has a melting point of about 52 ° C, and a molecular weight of about 6,800 to 8,975. A further preferred product of this class is POLOXAMER 188, which has a hydrophilic-lipophilic equilibrium value of about 29. (vi) Propylene glycol mono- and di-fatty acid esters, such as propylene glycol dicaprylate (also known and commercially available under the tradename MIGLYOL 840), propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate, etc. (Fiedler, loc. cit., 2, pages 808-809, incorporated to the present as reference). The propylene glycol monoesters of 8 carbon atoms include Sefsol 218 (Nikko Chemicals) and Capryol 90 (Gattefossé). (vii) Tocopherol esters, for example tocopheryl acetate and tocopheryl acid succinate (hydrophilic-lipophilic balance of about 16). Other classes of ionic surfactants not represented by the categories described above include: (i) docusate salts, for example dioctyl sulfosuccinate or related compounds, for example di- [2-ethylhexyl] succinate (Fiedler, loe. 1, pages 107-108, incorporated herein by reference). (ii) Phospholipids, in particular lecithins
. { Fiedler loe. cit. , 2, pages 943-944, incorporated herein by reference). Suitable lecithins include, in particular, soybean lecithins. The selected surfactant of preference has a hydrophilic-lipophilic balance (HLB) of at least 10, for example Cremophor, for example Cremophor RH 40. A group of surfactants comprises those with a polyoxyethylene fraction. The surfactant may comprise from 5 to 80 weight percent of the composition of the invention; preferably 10 to 70 weight percent, more preferably 20 to 60 weight percent, and still more preferably between about 40 percent and 55 weight percent. The compositions of the invention may further comprise a lipophilic phase or a lipophilic component. These compositions may be capable of producing emulsions as colloidal structures, preferably an aqueous microemulsion such as a mycelium, when mixed with an aqueous medium. In another aspect, the present invention provides a pharmaceutical composition that can be dispersed in a spontaneous manner, preferably in the form of a microemulsion preconcentrate, comprising a piperidine substance P antagonist. In yet another aspect, the present invention provides a pharmaceutical composition that can be dispersed in a spontaneous manner, preferably in the form of a microemulsion preconcentrate, comprising a piperidine substance P antagonist, for example Compound A, and a carrier medium comprising: 1) a hydrophilic phase, 2) a lipophilic phase, and 3) a surfactant. These compositions of the invention may be in the form of "microemulsion preconcentrates" of the type that provide microemulsions of a / ag (oil in water). A "microemulsion preconcentrate" is defined herein as a composition that spontaneously forms a microemulsion in an aqueous medium, for example in water, for example when diluted from 1: 1 to 1:10, for example 1:10, or in gastric juices after oral application. Typically, a "microemulsion" is a colloidal dispersion that is slightly opaque, opalescent, non-opaque, or substantially non-opaque, that is formed spontaneously, or in a substantially spontaneous manner, when its components are brought into contact with an aqueous medium. A microemulsion is thermodynamically stable, and contains dispersed particles of an average diameter less than about 2,000 A. In general, the microemulsions comprise droplets or nanoparticles having an average diameter of less than about 1,500 A; typically less than 100 nanometers, generally greater than 10 nanometers, and stable for periods longer than 24 hours. Naturally, these compositions of the invention, which comprise a hydrophilic phase, a lipophilic phase, and a surfactant, for example, prior to dilution, for example, can preferably be a hydrophilic component, a lipophilic component, and a surfactant in the form of essentially a single-phase system, for example a water-in-oil microemulsion or other micellar composition. The compositions of the invention additionally containing an aqueous phase, preferably water, may be in the form of a microemulsion. The lipophilic component, when present, can be preferably characterized by a low hydrophilic-lipophilic equilibrium value of less than 10, for example up to 8, and may comprise: (i) medium chain fatty acid triglycerides, (ii) mono -, di-, and mixed tri-glycerides, (iii) transesterified ethoxylated vegetable oils, (iv) mixtures of mono- and di-glycerides, or pure or substantially pure mono- or di-glycerides, (v) fatty acid esters of sorbitan, (vi) fatty acid esters of pentaerythritol and the like, and (vii) other suitable components, such as glycerol triacetate and the like. Some of these, for example (iii) a
(vii), they exhibit a type of surfactant behavior, and can also be called co-surfactants. (i) Suitable medium chain fatty acid triglycerides are neutral oils, for example neutral plant oils, in particular fractionated coconut oils, for example those known and commercially available under
• the commercial names Captex, Myritol, Capmul, Captex, Neobee, and Mazol; Miglyol 812 being the most preferred. Miglyol 812 is co-fractionated oil comprising triglycerides of caprylic-capric acid, and having a molecular weight of approximately 520 Daltons. Fatty acid composition = 6 maximum carbon atoms approximately 3 percent, 8 carbon atoms approximately 50 to 65 percent, 10 carbon atoms approximately 30 to 45 percent, 12 carbon atoms maximum 5 percent hundred; acid number = about 0.1, saponification number from about 330 to 345; iodine number = maximum of 1. Miglyol 812 is available from the company Hüls. These triglycerides are described in Fiedler, loe. ci t. , vol., p., incorporated herein by reference. (ii) The mixed mono-, di-, and tri-glycerides preferably comprise mixtures of mono-, di-, and tri-glycerides of fatty acid of 8 to 10 carbon atoms or of 12 to 20 carbon atoms, especially mono-, di-, and tri-glycerides of fatty acid of 16 to 18 mixed carbon atoms. The fatty acid component of the mixed mono-, di-, and tri-glycerides can comprise both saturated and unsaturated fatty acid residues. However, preferably, they are predominantly comprised of unsaturated fatty acid residues; in particular, unsaturated fatty acid residues of 18 carbon atoms. Suitably, the mono-, di-, mixed triglycerides comprise at least 60 percent, preferably at least 75 percent, more preferably at least 85 percent by weight of mono-, di-, and triglycerides of fatty acid unsaturated of 18 carbon atoms (for example linolenic, linoleic, and oleic acid). Suitably, the mono-, di-, and mixed tri-glycerides comprise less than 20 percent, for example about 15 percent or 10 percent by weight or less, of mono-, di-, and tri-glycerides of saturated fatty acid (e.g. palmitic and stearic acid). The mixed mono-, di-, and tri-glycerides are preferably predominantly comprised of mono-, and di-glycerides; for example, the mono- and di-glycerides comprise at least 50 percent, more preferably at least 70 percent, based on the total weight of the lipophilic phase or component. More preferably, the mono- and di-glycerides comprise at least 75 percent (eg, about 80 percent or 85 percent by weight of the lipophilic component). Preferably, the monoglycerides comprise from about 25 to about 50 percent, based on the total weight of the lipophilic component, of the mono-, di-, and mixed tri-glycerides. More preferably, from about 30 to about 40 percent (e.g., 35 to 40 percent) of monoglycerides is present. Preferably, the diglycerides comprise from about 30 to about 60 percent, based on the total weight of the lipophilic component, of the mono-, di-, and mixed tri-glycerides. More preferably, from about 40 to about 55 percent (e.g., 48 to 50 percent) of diglycerides is present. The triglycerides suitably comprise at least 5 percent, but less than about 25 percent, based on total weight of the lipophilic component, of the mixed mono-, di-, and tri-glycerides. More preferably, from about 7.5 to about 15 percent (e.g., about 9 to 12 percent) of triglycerides is present. The mono-, di-, and mixed tri-glycerides can be prepared by mixing the individual mono-, di-, or tri-glycerides in an appropriate relative proportion. However, conveniently, they comprise the transesterification products of vegetable oils, for example almond oil, peanut oil, olive oil, peach oil, palm oil, or preferably corn oil, sunflower oil, or saffron oil, and more preferably corn oil, with glycerol. These transesterification products are generally obtained as described in Patent Numbers GB 2,257,359 or WO 94/09211, the content of which is incorporated herein by reference. Preferably, some of the glycerol is removed first to give a "substantially glycerol free batch" when soft gelatin capsules are to be made. The purified transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di-, and tri-glycerides, hereinafter referred to as "refined oil", and produced according to the description of Patent Numbers GB 2,257,359 or WO 94/09211. (iii) The lipophilic component may alternatively comprise, for example, a pharmaceutically acceptable oil, preferably with an unsaturated component such as vegetable oil or fish oil. The lipophilic component may comprise suitable transesterified ethoxylated vegetable oils, such as those obtained by the reaction of different natural vegetable oils (e.g., corn oil, seed oil, almond oil, peanut oil, olive oil, seed oil). of soybeans, sunflower oil, saffron oil, and palm oil, or mixtures thereof) with polyethylene glycols having an average molecular weight of 200 to 800, in the presence of an appropriate catalyst. These methods are known, and in one example is described in U.S. Patent No. 3,288,824. Transesterified ethoxylated corn oil is particularly preferred. The transesterified ethoxylated vegetable oils are known and commercially available under the tradename LABRAFIL (H. Fiedler, loc. Cit., Volume 2, page 707, incorporated herein by reference). Examples are LABRAFIL M 2125 CS (obtained from corn oil, and having an acid number less than about 2, a saponification number from 155 to 175, a hydrophilic-lipophilic equilibrium value from 3 to 4, and a iodine number 90 to 110), and LABRAFIL M 1944 CS (obtained from seed oil, and having an acid number of approximately 2, a saponification number of 145 to 175, and an iodine number of 60 to 90). LABRAFIL M 2130 CS (which is a transesterification product of a glyceride of 12 to 18 carbon atoms and polyethylene glycol) and having a melting point of about 35 ° C to 40 ° C, a lower acid number of about 2, a saponification number of 185 to 200, and an iodine number less than about 3). The preferred transesterified ethoxylated vegetable oil is LABRAFIL M 2125 CS, which can be obtained, for example, from Gattefossé, Saint-Priest Cedex, France. (iv) The mono-, di-, and mono / diglycerides, for example, the mono-, di-, and tri-glycerides of fatty acids of 8 to 10 carbon atoms include Capmul MCM, Akoline MCM (from the Company Karlshamns), Imwitor 308 and Imiteor 988 (from the Company Contensio), which have a hydrophilic-lipophilic equilibrium value of approximately 3.8 (from the Contensio Company), and especially the esterification products of caprylic or capric acid with glycerol. Preferred products of this class are, for example, those comprising or consisting essentially of mono- and di-glycerides of caprylic / capric acid. Mono- and diglycerides of 8 to 10 carbon atoms having from 6 to 10 mole percent of polyoxyethylene groups, for example Softigen 767 (available from Contensio Chemicals). Monoglycerides, for example mono-oleate, glycerol monopalmitate, and glycerol monostearate, for example as known and commercially available under the tradenames Myvatex, Myvaplex, and Myverol (Fiedler, loc. Cit., 2, page 1044 , incorporated herein by reference), and acetylated monoglycerides, for example mono- and di-acetylated, for example, as they are known under the trade name Myvacet (Fiedler, loc. cit., 2, page 1043, incorporated herein by reference). the present as a reference). The Capmul MCM is more preferred. (v) Sorbitan fatty acid esters, for example of the type known and commercially available under the trade name Span, for example including sorbitan monolaurelester (hydrophilic-lipophilic balance of 8.6), sorbitan monopalmitylester (hydrophilic-lipophilic balance of 6.7) ), sorbitan monostearylester (hydrophilic-lipophilic equilibrium of 4.7), sorbitan tristearyl ester (hydrophilic-lipophilic equilibrium of 2.1), sorbitan mono-oleol ester (hydrophilic-lipophilic equilibrium of 4.3), and sorbitan trioleyl esters (hydrophilic-lipophilic equilibrium of 1.8) (Fiedler, loc. Cit., 2, pages 1430, incorporated herein by reference). (vi) Pentaerythritol fatty acid esters and polyalkylene glycol ethers, for example dioleate, distearate, monolaurate, polyglycol ether, and pentaerythritol monostearate, as well as fatty acid esters of pentaerythritol (Fiedler, loc. cit., 2, pages 1158-1160, incorporated herein by reference). (vii) Other suitable components include glycerol triacetate or (1, 2, 3) -triacetin (Fiedler, loc. cit., 2, page 1580, incorporated herein by reference); and sterols and their derivatives. When present, the lipophilic component may comprise from 5 to 85 weight percent of the composition of the invention, for example from 10 to 85 percent; preferably from 15 to 70 weight percent, more preferably from about 20 to about 50 weight percent. Preferably, the relative proportion of the hydrophilic components, the lipophilic components, and the surfactants, is within the "microemulsion" region, in a standard three-way plot. The present applicants also contemplate compositions of the invention in the form of a preconcentrate in microeulsion, which may be free of refined fish oil and / or ethanol and / or transesterified ethoxylated vegetable oil. The pharmaceutical composition of the invention may further include additives or ingredients, for example antioxidants (such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butyhydroxytoluene (BHT), and tocopherols), antimicrobial agents, enzyme inhibitors, stabilizers, and / or agents Conservatives These additives or ingredients may comprise from about 0.05 to 5 percent, preferably from 0.05 to 1 percent by weight of the total weight of the composition of the invention. The compositions of the invention may also include sweetening or flavoring agents in an amount of up to about 2.5 or 5 weight percent, based on the total weight of the composition of the invention. In another aspect, the invention provides a process for the production of a composition of the invention, which process comprises intimately mixing the active agent and (1) the hydrophilic component, (2) the surfactant, and optionally (3) the component lipophilic When required, the compositions of the invention are preferably compounded in a unit dosage form, for example by filling them into orally administrable capsule shells. The capsule covers can be covered with soft or hard gelatin capsules. When the composition is in a unit dosage form, each unit dosage will suitably contain from 0.1 to 100 milligrams of active agent, for example 0.1 milligrams, 1 milligram, 5 milligrams, 10 milligrams, 15 milligrams, 25 milligrams, or 50 milligrams, of preference between 10 and 100 milligrams of the active agent, more preferably between 10 and 50 milligrams; for example 15, 20, 25, or 50 milligrams, more preferably between 5 and 20 milligrams, and most preferably 5 or 10 milligrams. These unit dosage forms are suitable to be administered from 1 to 5 times a day, depending on the particular purpose of the therapy, the therapy phase, and the like. However, if desired, the compositions may be in the form of a drinking solution, and may include water or any other aqueous system, for example fruit juice, milk, and the like, to provide, for example, colloidal systems, suitable for drink, for example with a dilution of about 1:10 to about 1: 100. The compositions of the invention, for example those of the examples hereinafter, can show good stability characteristics, as indicated by conventional stability tests, for example with a shelf life stability of up to one, two, or three years, and even more. The compositions of this invention, in the form of micellar precursors, produce stable aqueous mycelia, for example for up to a day or more. A group of compositions of the invention can be of high stability, and are capable, when added to water, of providing aqueous microemulsions having an average particle size of < 2,000 Á (200 nanometers), for example < 1,500 Á (150 nanometers). The compositions of the invention exhibit particularly convenient properties when administered orally; for example, in terms of consistency and high level of bioavailability obtained in conventional bioavailability tests. These tests are carried out on animals, for example rats or dogs, or healthy volunteers, using chromatographic methods, for example high performance liquid chromatography, or a specific or nonspecific monoclonal kit to determine the level of the active agent in the blood. For example, the composition of Example 5 administered orally to dogs, can surprisingly give high C max values, as detected by ELISA, using a specific monoclonal antibody. Pharmacokinetic parameters, for example absorption and blood levels, can also become surprisingly more predictable, and problems in administration with erratic absorption can be eliminated or reduced. Additionally, the compositions are effective with tensile materials, for example bile salts, which are present in the gastrointestinal tract. That is, the compositions can be completely dispersed in aqueous systems comprising natural surfactants, and therefore, they can be capable of providing aqueous micellar or microemulsion systems in themselves, which are stable and do not exhibit precipitation of the active agent, or other alteration. of the structure of fine particles. The function of the compositions after oral administration remains substantially independent of, and / or not impaired by, the relative presence or absence of the bile salts at any particular time or for any given individual. It has also been found that the compositions of this invention can reduce the variability in the intra- and intra-patient dose response. The utility of the compositions of the invention can be observed in conventional clinical tests, for example, in known indications in dosages of the active agent that give therapeutically effective blood levels of the active agent. Any greater bioavailability of the compositions of the invention can be observed in standard animal tests and in clinical trials. For example, the utility of the compositions of the invention in the treatment of social phobia can be established, for example, by its administration to subjects having a diagnosis of primary social phobia DSM-III-R, for example diagnosed by the use of the Structured Clinical Interview for DSM-III-R, for example in a 12-week open clinical trial. Treatment begins, for example, using 10 milligrams of an active agent daily, and can be increased according to clinical response and side effects. Patients fill their self-report measurements at the baseline, and for example, at 4, 8, and 12 weeks. These measures include the fear scale of negative evaluation, the social abstinence and alteration scale, the social anxiety thoughts questionnaire, the fear questionnaire, the state-trait anxiety inventory, the Beck depression inventory, the self- Social adjustment scale report, and Sheehan's scale of disability. Individuals who respond, for example, at the end point about global clinical impression, change by defining themselves in a moderate or notoriously improved way. The dose of the active agent in the composition of the invention is of the same order, or up to half, than that used in the known compositions containing the active agent. The compositions of the invention show activity in concentrations of from about 0.1 milligram to about 40 milligrams / day of active agent, preferably from about 0.1 milligram to about 20 milligrams / day, for example, more preferably from about 0.1 to about 1 milligram / day of active agent for respiratory disease states, and from about 5 to about 10 milligrams / day of active agent for central nervous system indications, for a 75 kilogram mammal. The compositions of the invention are particularly useful for the treatment and prevention of the conditions disclosed in European Patent Numbers EP 0532456B1 and EP 0707006A2, the content of which is incorporated herein by reference, including the treatment and prevention of disorders. of the central nervous system, including depression, dysthymia, social phobia, panic disorder, and emesis. The compositions of the invention are also useful for the treatment of respiratory diseases, for example asthma and chronic bronchitis. For these indications, the appropriate dosage will, of course, vary depending on, for example, the particular composition of the invention employed, the host, the mode of administration, and the nature and severity of the conditions being treated. A typical dose for Compound A is 0.1 to 1 milligram / day for asthma and chronic bronchitis, and 5 to 10 milligrams / day of active agent for depression and social phobia for a 75 kilogram mammal, for the form of Example 5 .
Accordingly, in another aspect, the present invention provides a method for the treatment of a subject suffering from a disorder that can be treated with a piperidine substance P antagonist, which comprises administering a therapeutically effective amount of a pharmaceutical composition of the invention to a subject in need of such treatment.
Examples Below is a description by way of example only, of the compositions of this invention. Unless indicated otherwise, the components are shown in percent by weight, based on each composition. The average particle sizes (diameters) are measured at 20 ° C using a Malvern Zetasizer.
All the ingredients of the examples are given in milligrams / capsule.
? ?
Compound A and is dissolved in (1) with stirring at room temperature, and (2) and (3) are added to the obtained solution again with stirring. Portions of 0.5 milliliters of the mixture obtained are filled in size 1 hard gelatin capsules, and sealed, for example, using the Quali-Seal technique, or in soft gelatin capsules. In another embodiment of Examples la and Ib, Compound A is dispersed in a mixture of components 1), 2), and 3), and combined with component 4) -
2 The carrier medium is prepared by mixing the components with one another. Compound A is then dissolved in the carrier medium with stirring.
3 Refined oil = "corn oil transesterified with refined glycerol", substantially free of glycerol, as described in Patent Numbers GB 2,257,359 and WO 94/09211.
No phase separation or precipitation is observed for any of the above compositions 1 to 8, which remain transparent for 4 hours.
Claims (13)
1. A pharmaceutical composition that can be dispersed in a spontaneous manner, which comprises a piperidine substance P antagonist.
2. A pharmaceutical composition that can be dispersed in a spontaneous manner, which comprises a piperidine substance P antagonist, and a carrier medium comprising: 1) a hydrophilic component, and 2) a surfactant.
3. A composition as claimed in claim 1 or 2, for oral administration.
4. A composition as claimed in any of the preceding claims, which comprises a lipophilic component.
5. A pharmaceutical composition comprising (2R, 4S) -N- (1- (3,5-bis (trifluoromethyl) -benzoyl) -2- (4-chlorobenzyl) -4-piperidinyl) -quinolin -carboxamide as the agent active, and a carrier medium comprising: 1) a hydrophilic phase, 2) a lipophilic phase, and 3) a surfactant.
6. A pharmaceutical composition of any of claims 1 to 4, which comprises (2R, 4S) -N- (1- (3,5-bis { Trifluoromethyl) -benzoyl) -2- (4-chlorobenzyl) -4-piperidinyl) -quinolin-4-carboxamide.
7. A composition as claimed in any of the preceding claims, in the form of a microemulsion preconcentrate. A composition as claimed in any of the preceding claims, wherein the hydrophilic component comprises triethyl citrate or propylene glycol, wherein the surfactant comprises a reaction product of a natural or hydrogenated castor oil with ethylene oxide or an ester of polyoxyethylene fatty acid, and wherein the lipophilic component comprises a transesterified ethoxylated vegetable oil, a mono-, di-, and / or tri-glyceride of fatty acid of 8 to 10 carbon atoms, a chain fatty acid triglyceride medium, or a corn oil transesterified with refined glycerol. 9 A pharmaceutical composition that can be dispersed in a spontaneous manner, which comprises from about 0.05 to about 20 weight percent of (2R, 4S) -N- (1- (3,5-bis (trifluoromethyl) -benzoyl) ) -2- (4-chlorobenzyl) -4-piperidinyl) -quinolin-4-carboxamide, from about 5 to about 50 weight percent of a hydrophilic component, from about 5 to about 80 weight percent of a surfactant, and optionally from about 5 to about 85 weight percent of a lipophilic component, all weights being based on the total composition. 10. A composition as claimed in any of the preceding claims, in the form of a microemulsion. 11. A composition according to any of the preceding claims, in a unit dosage form. 12. A composition according to claim 11, in a form encapsulated in soft or hard gelatin. 13. A method for the treatment of a subject suffering from a disorder that can be treated with a piperidine substance P antagonist, which comprises administering a therapeutically effective amount of a pharmaceutical composition as claimed in any of the preceding claims, to a subject that needs such treatment.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB9811200.6 | 1998-05-26 | ||
GB9818105.0 | 1998-08-19 |
Publications (1)
Publication Number | Publication Date |
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MXPA00011581A true MXPA00011581A (en) | 2001-09-07 |
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