WO2006114703A2 - Methode d'administration de (1s,s2)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yle)-1-propanol - Google Patents

Methode d'administration de (1s,s2)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yle)-1-propanol Download PDF

Info

Publication number
WO2006114703A2
WO2006114703A2 PCT/IB2006/001044 IB2006001044W WO2006114703A2 WO 2006114703 A2 WO2006114703 A2 WO 2006114703A2 IB 2006001044 W IB2006001044 W IB 2006001044W WO 2006114703 A2 WO2006114703 A2 WO 2006114703A2
Authority
WO
WIPO (PCT)
Prior art keywords
period
time
phenylpiperidin
hydroxyphenyl
hydroxy
Prior art date
Application number
PCT/IB2006/001044
Other languages
English (en)
Other versions
WO2006114703A3 (fr
Inventor
Jerry John Weaver
Lorraine Yurkewicz
Keith David Wilner
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2006114703A2 publication Critical patent/WO2006114703A2/fr
Publication of WO2006114703A3 publication Critical patent/WO2006114703A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • NMDA N-methyl-D-aspartate
  • NMDA receptor antagonists such as (1S,2S)-1-(4-hydroxyphenyl)-2-(4- hydroxy-4-phenylpiperidin-1-yl)-1-propanol that target NR2B subtype receptors may have therapeutic application in preventing the neurologic deficits and death caused by stroke.
  • the present invention is directed to a method for improving the bioavailability of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1 ⁇ propanol or a pharmaceutically acceptable salt thereof in a human, the method comprising administering over a period of time of at least 24 hours (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof to the human, wherein the period of time over which (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is administered is the sum of a first period of time and a second period of time, wherein the rate of administration over the first period of time is greater than the rate of administration over the second period of time, wherein the bio-ava
  • the administration in accordance with this invention advantageously provides improved bio-availability through administration over a first period of time at a rate that is sufficiently great to provide a desired value of Css.avg (plasma concentration) of (1S,2S)-1- (4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof.
  • the subsequent, lower rate of administration over the second period of time advantageously maintains Css.avg at a desired value while at the same time reducing the possibility of adverse events or side effects.
  • the compound is administered as a composition comprising (1S,2S)-1-(4- hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof, more preferably an aqueous solution. More preferably, the composition is an aqueous solution that is administered intravenously.
  • the first period of time is less than the second period of time. In another embodiment, the first period of time is about 2 hours.
  • the second period of time is at least about 70 hours. In another embodiment, the second period of time ranges from about 22 hours to about 70 hours. In another embodiment, the second period of time ranges from about 70 hours to about 100 hours. In another embodiment, the second period of time is about 70 hours. In another embodiment, administration of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-
  • 4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof provides a Css.avg value of (1S,2S)-1 ⁇ (4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1 ⁇ propanol in the blood of the human of at least about 200 ng/ml, wherein the Css.avg value of at least about 200 ng/ml is maintained for at least the second period of time.
  • the rate of administration over a first period of time of about
  • 2 hours is about 0.5 to about 0.1 mg/kg/hr, preferably about 0.75 mg/kg/hr, and the rate of administration over a second period of time of about 70 hours is about 0.36 to about 0.38 mg/kg/hr, preferably about 0.37 mg/kg/hr. in another embodiment, no greater than about 50 wt% of the total amount of (1S.2S)-
  • 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is administered during a first period of time, which is preferably about
  • the administration occurs within about 8 hours of the onset of traumatic brain injury.
  • Administration of (1 S,2S)-1 -(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 -yl)- 1-propanol or a pharmaceutically acceptable salt thereof according to the invention may occur, for example, gradually and continuously over a first period of time, over a second period of time, or over both a first and a second period of time.
  • administration may be performed, for example, in a pulsatile manner over a first period of time, over a second period of time, or over both a first and a second period of time.
  • Administration may be performed, for example, in a pulsatile manner over a first period of time, and gradually and continuously over a second period of time.
  • Figure 1 shows the Mean Plasma and Cerebrospinal Fluid Concentrations of traxoprodil. DETAILED DESCRIPTION OF THE INVENTION
  • (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof should be understood to include any pharmaceutically acceptable form of (1S,2S)-1-(4-hydroxyphenyl)- 2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or of the salt, respectively.
  • active compound and “traxoprodil” is used herein to denote (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable form is meant any pharmaceutically acceptable derivative or variation, including solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, and prodrugs.
  • compositions of (1S,2S)-1-(4-hydroxyphenyl)-2-(4- hydroxy-4-phenylpiperidin-1-yl)-1-propanol are prepared in a conventional manner by treating a solution or suspension of the free base with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts. Illustrative suitable acids are disclosed in U.S. Pat. No. 5,272,160 and commonly assigned U.S. Pat. No. 5,710,168.
  • (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol include the free base
  • preferred forms of pharmaceutically acceptable salts include (1S,2S)-1-(4- hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol mesylate trihydrate.
  • composition comprising (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof may be, for example, an aqueous solution formed by dissolving in water (1S,2S)-1-(4-hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof in crystalline form.
  • the composition may be an aqueous solution formed by dissolving in water (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1- propanol or a pharmaceutically acceptable salt thereof in amorphous form.
  • the amorphous form may be a lyophile of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1- propanol or a pharmaceutically acceptable salt thereof.
  • amorphous is meant simply that the (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, or a pharmaceutically acceptable salt thereof is in a non-crystalline state.
  • a major portion of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof from which the composition is formed is in amorphous form.
  • the term "a major portion" of means that at least 60 wt% of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is in the amorphous form, rather than the crystalline form.
  • the from which the composition is formed is substantially amorphous.
  • substantially amorphous means that the amount of (1S,2S)-1- (4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof in crystalline form does not exceed about 25 wt%.
  • the (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is "almost completely amorphous,” meaning that the amount of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof in the crystalline form does not exceed about 10 wt%.
  • Amounts of crystalline (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1- yl)-1-propanol or a pharmaceutically acceptable salt thereof may be measured by Powder X-Ray Diffraction ' (PXRD), Scanning Electron Microscope (SEM) analysis, differential scanning calorimetry (DSC), or any other standard quantitative measurement.
  • PXRD Powder X-Ray Diffraction '
  • SEM Scanning Electron Microscope
  • DSC differential scanning calorimetry
  • the amorphous form may be any form in which (1S,2S)-1-(4-hydroxyphenyl)-2-(4- hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is amorphous.
  • amorphous forms include solid amorphous dispersions in a polymer, or an amorphous form stabilized using a matrix material.
  • administration according to the method of the invention provides a steady state area under the concentration of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol in the biood versus time curve after administration in the fed state.
  • a precipitation inhibitor may also be present in the composition to improve the concentration of dissolved (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)- 1-propanol or a pharmaceutically acceptable salt thereof.
  • a "precipitation inhibitor” is meant any material known in the art that is capable of slowing the rate at which (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1- propanol or a pharmaceutically acceptable salt thereof crystallizes or precipitates from an aqueous solution that is supersaturated with (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1 -yl)-1 -propanol or a pharmaceutically acceptable salt thereof.
  • Precipitation inhibitors suitable for use in the present invention should be inert, in the sense that they do not chemically react with (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1- propanol or a pharmaceutically acceptable salt thereof, be pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. 1-8).
  • the precipitation inhibitor can be neutral or ionizable, and should have an aqueous-solubility of at least 0.1 mg/mL over at least a portion of the pH range of 1-8.
  • Precipitation inhibitors may be polymers or non-polymeric.
  • Precipitation-inhibiting polymers suitable for, use with the present invention may be cellulosic or non-celluiosic.
  • the polymers may be neutral or ionizable in aqueous solution. Of these, ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.
  • a preferred class of polymers comprises polymers that are "amphiphilic" in nature, meaning that the polymer has hydrophobic and hydrophilic portions.
  • the hydrophobic portion may comprise groups such as aliphatic or aromatic hydrocarbon groups.
  • the hydrophilic portion may comprise either ionizable or non-ionizable groups that are capable of hydrogen bonding such as hydroxyls, carboxylic acids, esters, amines or amides.
  • One class of polymers suitable for use with the present invention comprises neutral non-cellulosic polymers.
  • Exemplary polymers include: vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, or cyclicamido; polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and polyethylene polyvinyl alcohol copolymers.
  • polymers suitable for use with the present invention comprises ionizable non-cellulosic polymers.
  • exemplary polymers include: carboxylic acid- functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS® manufactured by Degussa, of Maiden, Massachusetts; amine-functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid functionalized starches such as starch glycolate.
  • Non-cellulosic polymers that are amphiphilic are copolymers of a relatively hydrophilic and a relatively hydrophobic monomer. Examples include acrylate and methacrylate copolymers, and polyoxyethylene-polyoxypropylene copolymers. Exemplary commercial grades of such copolymers include the EUDRAGITS, which are copolymers of methacrylates and acrylates, and the PLURONICS supplied by BASF, which are polyoxyethylene- polyoxypropylene copolymers.
  • a preferred class of polymers comprises ionizable and neutral cellulosic polymers with at least one ester- and/or ether-linked substituent in which the polymer has a degree of substitution of at least 0.1 for each substituent.
  • ether-linked substituents are recited prior to "cellulose” as the moiety attached to the ether group; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acid substituents.
  • ester-linked substituents are recited after "cellulose” as the carboxylate; for example, “cellulose phthalate” has one carboxylic acid of each phthalate moiety ester-linked to the polymer and the other carboxylic acid unreacted.
  • a polymer name such as "cellulose acetate phthalate” (CAP) refers to any of the family of cellulosic polymers that have acetate and phthalate groups attached via ester linkages to a significant fraction of the cellulosic polymer's hydroxyl groups.
  • the degree of substitution of each substituent group can range from 0.1 to 2.9 as long as the other criteria of the polymer are met.
  • “Degree of substitution” refers to the average number of the three hydroxyls per saccharide repeat unit on the cellulose chain that have been substituted. For example, if all of the hydroxyls on the cellulose chain have been phthalate substituted, the phthalate degree of substitution is 3.
  • cellulosic polymers that have additional substituents added in relatively small amounts that do not substantially alter the performance of the polymer.
  • Amphiphilic cellulosics comprise polymers in which the parent cellulosic polymer has a degree of substitution of at least one relatively hydrophobic substituent of at least 0.1.
  • Hydrophobic substituents may be essentially any substituent that, if substituted to a high enough level or degree of substitution, can render the cellulosic polymer essentially aqueous insoluble. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate, etc.; and ether- and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.
  • Hydrophilic regions of the polymer can be either those portions that are relatively unsubstituted, since the unsubstituted hydroxyls are themselves relatively hydrophilic, or those regions that are substituted with hydrophilic substituents.
  • Hydrophilic substituents include ether- or ester-linked nonionizable groups such as the hydroxy alky] substituents hydroxyethyl, hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy or methoxyethoxy.
  • hydrophilic substituents are those that are ether- or ester-linked ionizable groups such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.
  • One class of cellulosic polymers comprises neutral polymers, meaning that the polymers are substantially non-ionizable in aqueous solution.
  • Such polymers contain nonionizable substituents, which may be either ether-linked or ester-linked.
  • exemplary ether- linked non-ionizable substituents include: alkyl groups, such as methyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl.
  • Exemplary ester-linked non-ionizable substituents include: alkyl groups, such as acetate, propionate, butyrate, etc.; and aryl groups such as phenylate.
  • alkyl groups such as acetate, propionate, butyrate, etc.
  • aryl groups such as phenylate.
  • the polymer may need to include a sufficient amount of a hydrophilic substituent so that the polymer has at least some water solubility at any physiologically relevant pH of from 1 to 8.
  • Exemplary non-ionizable polymers that may be used as the polymer include: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.
  • a preferred set of neutral cellulosic polymers are those that are amphiphilic.
  • Exemplary polymers include hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate, where cellulosic repeat units that have relatively high numbers of methyl or acetate substituents relative to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions relative to other repeat units on the polymer.
  • a preferred class of cellulosic polymers comprises polymers that are at least partially ionizable at physiologically relevant pH and include at least one ionizable substituent, which may be either ether-linked or ester-linked.
  • exemplary ether-linked ionizable substituents include: carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, the various isomers of alkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalic acid, the various isomers of alkoxynicotinic acid such as ethoxynicotinic acid, and the various isomers of picolinic acid such as ethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; amines, such as aminoe
  • ester linked ionizable substituents include: carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.; tricarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as amino salicylic acid; amines, such as natural or synthetic amino acids, such as alanine or phenylalanine; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate.
  • carboxylic acids such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.
  • tricarboxylic acids such as thiosuccinate
  • substituted phenoxy groups such as amino salicylic acid
  • amines such as natural or
  • aromatic-substituted polymers to also have the requisite aqueous solubility, it is also desirable that sufficient hydrophilic groups such as hydroxypropyl or carboxylic acid functional groups be attached to the polymer to render the polymer aqueous soluble at least at pH values where any ionizable groups are ionized.
  • the aromatic group may itself be ionizable, such as phthalate or trimellitate substituents.
  • Exemplary cellulosic polymers that are at least partially ionized at physiologically relevant pHs include: hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose a
  • Exemplary cellulosic polymers that meet the definition of amphiphilic, having hydrophilic and hydrophobic regions include polymers such as cellulose acetate phthalate and cellulose acetate trimellitate where the cellulosic repeat units that have one or more acetate substituents are hydrophobic relative to those that have no acetate substituents or have one or more ionized phthalate or trimellitate substituents.
  • a particularly desirable subset of cellulosic ionizable polymers are those that possess both a carboxylic acid functional aromatic substituent and an alkylate substituent and thus are amphiphilic.
  • Exemplary polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose prop
  • cellulosic ionizable polymers are those that possess a non-aromatic carboxylate substituent.
  • Exemplary polymers include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, and carboxymethyl ethyl cellulose.
  • especially preferred polymers are hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, and carboxymethyl ethyl cellulose.
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • methyl cellulose acetate phthalate hydroxypropyl methyl cellulose acetate phthalate
  • cellulose acetate terephthalate cellulose acetate trimellitate
  • carboxymethyl ethyl cellulose carboxymethyl ethyl cellulose.
  • the most preferred ionizable cellulosic polymers are hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethyl cellulose.
  • polymers While specific polymers have been discussed as being suitable for use in the compositions of the present invention, blends of such polymers may also be suitable. Thus the term "polymer” is intended to include blends of polymers in addition to a single species of polymer.
  • ionizable cellulosic polymers such as HPMCAS function best over particular pH ranges.
  • HPMCAS aqueous properties are a function of the degree of substitution of each of the substituents: hydroxypropoxy, methoxy, acetate, and succinate, as well as the pH of the use environment.
  • HPMCAS is manufactured by Shin-Etsu, and sold under the trade name AQOAT as three different grades that differ in their levels of substituents and therefore their properties as a function of pH.
  • the H grade of HPMCAS has 22-26 wt% methoxy, 6 10 wt% hydroxypropoxy, 10-14 wt% acetate, and 4-8 wt% succinate groups.
  • the M grade of HPMCAS is preferred.
  • the M grade of HPMCAS has 21-25 wt% methoxy, 5-9 wt% hydroxypropoxy, 7-11 wt% acetate, and 10-14 wt% succinate groups.
  • neutralized acidic polymer any acidic polymer for which a significant fraction of the “acidic moieties” or “acidic substituents” have been “neutralized”; that is, exist in their deprotonated form.
  • acidic polymer is meant any polymer that possesses a significant number of acidic moieties. In general, a significant number of acidic moieties would be greater than or equal to about 0.1 milliequivalents of acidic moieties per gram of polymer.
  • Acidic moieties include any functional groups that are sufficiently acidic that, in contact with or dissolved in water, can at least partially donate a hydrogen cation to water and thus increase the hydrogen-ion concentration.
  • This definition includes any functional group or "substituent,” as it is termed when the functional group is covalently attached to a polymer, that has a pKa of less than about 10.
  • Exemplary classes of functional groups that are included in the above description include carboxylic acids, thiocarboxylic acids, phosphates, phenolic groups, and sulfonates.
  • Such functional groups may make up the primary structure of the polymer such as for polyacrylic acid, but more generally are covalently attached to the backbone of the parent polymer and thus are termed "substituents.”
  • Substituents Such functional groups may make up the primary structure of the polymer such as for polyacrylic acid, but more generally are covalently attached to the backbone of the parent polymer and thus are termed "substituents.”
  • Neutralized acidic polymers are described in more detail in commonly assigned copending US Patent Application Serial No. 10/175,566 entitled “Pharmaceutical Compositions of Drugs and Neutralized Acidic Polymers” filed June 17, 2002, the relevant , disclosure of which is incorporated by reference.
  • the preferred polymers listed above tend to have greater precipitation-inhibiting properties relative to the other polymers of the present invention.
  • those precipitation-inhibiting polymers that have ionizable substituents tend to perform best.
  • In vitro tests of compositions with such polymers tend to have higher MDC and AUC values than compositions with other polymers of the invention.
  • Several methods, such as an in vitro dissolution test or a membrane permeation test may be used to evaluate precipitation inhibitors and the degree of concentration enhancement provided by the precipitation inhibitors.
  • An in vitro dissolution test may be performed by adding a form of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 ⁇ yl)-1-propanol or a pharmaceutically acceptable salt together with the precipitation inhibitor to MFD or PBS or simulated intestinal buffer solution and agitating to promote dissolution.
  • a form of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 ⁇ yl)-1-propanol or a pharmaceutically acceptable salt together with the precipitation inhibitor to MFD or PBS or simulated intestinal buffer solution and agitating to promote dissolution.
  • an acid such as HCI or H 3 PO 4 may be added to PBS or MFD to adjust the pH of the solution to 6.0 or 5.0 and then used in the following dissolution tests.
  • the tested form together with the precipitation inhibitor when tested in an in vitro dissolution test, meets at least one, and preferably both, of the following conditions.
  • the first condition is that the tested form and the precipitation inhibitor provide a higher maximum dissolved drug concentration (MDC) of (1 S,2S)-1 -(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 -yl)-1 -propanol or a pharmaceutically acceptable salt in the in vitro dissolution test relative to a* control composition that consists of the tested form of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1 -yl)-1 -propanol or a pharmaceutically acceptable salt alone, without the precipitation inhibitor.
  • MDC maximum dissolved drug concentration
  • the solubility-improved form and precipitation inhibitor provide a higher aqueous concentration of dissolved (1S,2S)-1-(4-hydroxyphenyl)-2-(4- hydroxy-4-phenylpiperidin-1-yl)-1 -propanol or a pharmaceutically acceptable salt relative to the control composition.
  • the tested form and precipitation inhibitor provide an MDC of (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1 -propanol or a pharmaceutically acceptable salt in aqueous solution that is at least 1.25-fold that of the control composition, more preferably at least 2-fold, and most preferably at least 3-fold.
  • MDC MDC provided by the test composition
  • the MDC provided by the control composition is 1 ⁇ g/ml
  • the test composition provides an MDC that is 5 fold that provided by the control composition.
  • the second condition is that the tested form and precipitation inhibitor provide a higher dissolution area under the concentration versus time curve (AUC) of dissolved (1 S,2S)-1 -(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 -yl)-1 -propanol or a pharmaceutically acceptable salt in the in vitro dissolution test relative to a control composition.
  • the solubility-improved form and precipitation inhibitor provide an AUC for any 90-minute period of from about 0 to about 270 minutes following introduction to the use environment that is at least 1.25-fold that of the control composition.
  • the AUC provided by the composition is at least 2-fold, more preferably at least 3-fold that of the control composition.
  • an in vitro membrane-permeation test may be used to evaluate the precipitation inhibitor.
  • the tested form of (1S,2S)-1-(4- hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1 ⁇ yl)-1-propanol or a pharmaceutically acceptable salt and precipitation inhibitor are placed in, dissolved in, suspended in, or otherwise delivered to the aqueous solution to form a feed solution.
  • a typical in vitro membrane-permeation test to evaluate precipitation inhibitors can be conducted by (1) administering a sufficient quantity of test composition (that is, the tested form and precipitation inhibitor) to a feed solution, such that if all of the drug dissolved, the theoretical concentration of drug would exceed the equilibrium concentration of the drug by a factor of at least 3; (2) in a separate test, adding an equivalent amount of control composition to an equivalent amount of test medium; and (3) determining whether the measured maximum flux of drug provided by the test composition is at least 1.25-fold that provided by the control composition.
  • the tested form and precipitation inhibitor when dosed to an aqueous use environment, provide a maximum flux of drug in the above test that is at least about 1.25-fold the maximum flux provided by the control composition.
  • the maximum flux provided by the test composition is at least about 1.5-fold, more preferably at least about 2- fold, and even more preferably at least about 3-fold that provided by the control composition.
  • the amount of precipitation inhibitor may vary widely.
  • the weight ratio of solubility- improved form to precipitation inhibitor may range from 100 to 0.01. Where the precipitation inhibitor is a polymer, good results are generally achieved where the polymer to drug weight ratio is at least 0.33 (at least 25 wt% polymer), more preferably at least 0.66 (at least 40 wt% polymer), and even more preferably at least 1 (at least 50 wt% polymer).
  • the method of the invention was performed on patients having traumatic brain injury. Administration according to the method of the invention was started within 8 hours of the injury.
  • CT computed tomography
  • CT scan evidence of traumatic brain injury was required with one or more of the following present using the Traumatic Coma Data Bank Classification (1987): Diffuse Injury 2: diffuse injury, cisterns present with shift 0-5 mm and/or lesion densities present, but no high or mixed density lesions > 25 cc. Such an injury may include bone fragments or foreign bodies. Subjects were eligible only if a mass lesion of high or mixed density > 5 cc was present;
  • Diffuse Injury 3 diffuse injury with swelling, cisterns compressed or absent, shift 0-5 mm, no high or mixed density lesion > 25 cc;
  • Diffuse Injury 4 diffuse injury with shift > 5 mm, no high or mixed density lesion > 25 cc;
  • CT classification 5 evacuated lesion, any lesion surgically evacuated
  • CT classification 6 non-evacuated mass lesion, high or mixed density lesion > 25 cc, not surgically evacuated; subarachnoid hemorrhage.
  • the mass lesion could be subdural hematoma, epidural hematoma, or contusion/hemorrhage. /
  • Drug administration was started within 8 hours of injury and the following criteria had to be met: at least one reactive pupil, no known life threatening disease prior to trauma, stable cardiovascular and respiratory function, which, as used herein, is defined as the ability to maintain systolic blood pressure of at least 90 mm Hg and oxygen saturation of 85% with treatment, and body weight between 40 kg ( ⁇ 88 lbs) and 115 kg ( ⁇ 250 lbs) inclusive.
  • Prior to enrollment written informed consent was obtained from the subject's legal representative.
  • Known treatment with another investigational drug therapy within 30 days of injury, anuria, serum creatinine greater than 2 mg/dl or known prior diagnosis of epilepsy or history of convulsions would make the subject ineligible for treatment.
  • Patient demographics are summarized in Table 1.
  • a total of 404 subjects (298 males and 106 females) were randomized and received treatment, 198 with traxoprodil and 206 with placebo.
  • Subject ages ranged from 16 to 66 years, with a mean age of 31.0 and 31.5 years in the traxoprodil and placebo groups respectively.
  • CT classification Major injuries, in addition to the TBI, were assessed for all subjects at screening. The percentage of subjects with injuries to affected body areas was comparable between treatment groups for all body areas except the thorax. The proportion of placebo- treated subjects with injuries to the thorax (132/194) was 17% greater than in the group treated with traxoprodil (98/193).
  • N 185 12 mean 327 1140
  • N 167 12 mean 22300 66300
  • the dosing regimens used resulted in plasma and CSF traxoprodil concentrations that were maintained above the targeted efficacious concentration throughout the duration of the infusion, and the concentration ratios of CSF to plasma at steady state indicated good brain penetration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne, dans un aspect, une méthode pouvant améliorer chez l'être humain la biodisponibilité de (1S,S2)-1-(4-hydroxyphényl)-2-(4-hydroxy-4-phénylpipéridin-1-yle)-1-propanol, ou un sel pharmaceutiquement acceptable dudit composé. La méthode consiste à administrer à un être humain, sur une durée d'au moins 24 heures, (1S,S2)-1-(4-hydroxyphényl)-2-(4-hydroxy-4-phénylpipéridin-1-yle)-1-propanol ou un sel pharmaceutiquement acceptable dudit composé, cette durée représentant la durée totale d'une première durée et d'une seconde durée. Le taux d'administration sur la première durée est supérieur au taux d'administration sur la seconde durée. La biodisponibilité est améliorée par rapport à l'administration d'un taux constant égal au taux d'administration sur la seconde durée.
PCT/IB2006/001044 2005-04-25 2006-04-13 Methode d'administration de (1s,s2)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yle)-1-propanol WO2006114703A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67494705P 2005-04-25 2005-04-25
US60/674,947 2005-04-25

Publications (2)

Publication Number Publication Date
WO2006114703A2 true WO2006114703A2 (fr) 2006-11-02
WO2006114703A3 WO2006114703A3 (fr) 2007-03-22

Family

ID=36688172

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/001044 WO2006114703A2 (fr) 2005-04-25 2006-04-13 Methode d'administration de (1s,s2)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yle)-1-propanol

Country Status (1)

Country Link
WO (1) WO2006114703A2 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1186304A2 (fr) * 2000-09-06 2002-03-13 Pfizer Products Inc. Combinations pharmaceutiques pour le traitement d' attaques et de lésions traumatiques du cerveau

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1186304A2 (fr) * 2000-09-06 2002-03-13 Pfizer Products Inc. Combinations pharmaceutiques pour le traitement d' attaques et de lésions traumatiques du cerveau

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JOHN A MCCAULEY: "NR2B subtype-selective NMDA receptor antagonists: 2001-2004" EXPERT OPINION, [Online] vol. 15, no. 4, 1 April 2005 (2005-04-01), pages 389-407, XP002392768 Retrieved from the Internet: URL:http://www.expertopin.com/doi/abs/10.1 517/13543776.15.4.389> [retrieved on 2006-06-27] *
JOHN. A. KEMP: "NMDA receptor pathways as drug targests" NATURE NEUROSCIENCE SUPPLEMENT, [Online] vol. 5, November 2002 (2002-11), pages 1039-1042, XP002392767 Retrieved from the Internet: URL:http://www.nature.com/neuro/journal/v5 /n11s/pdf/nn936.pdf> [retrieved on 2006-07-27] *
JOHNSON KIM ET AL: "Metabolism, pharmacokinetics, and excretion of a highly selective N-methyl-D-aspartate receptor antagonist, traxoprodil, in human cytochrome P450 2D6 extensive and poor metabolizers." DRUG METABOLISM AND DISPOSITION: THE BIOLOGICAL FATE OF CHEMICALS. JAN 2003, vol. 31, no. 1, January 2003 (2003-01), pages 76-87, XP009069857 ISSN: 0090-9556 Retrieved from the Internet: URL:http://dmd.aspetjournals.org/cgi/repri nt/31/1/76> [retrieved on 2006-06-27] *
LORRAINE YURKEWICZ: JOURNAL OF NEUROTRAUMA, [Online] vol. 22, no. 12, December 2005 (2005-12), pages 1428-1443, XP002392769 Retrieved from the Internet: URL:http://www.liebertonline.com/doi/pdf/1 0.1089/neu.2005.22.1428> [retrieved on 2006-07-27] *

Also Published As

Publication number Publication date
WO2006114703A3 (fr) 2007-03-22

Similar Documents

Publication Publication Date Title
US20200375968A1 (en) Apixaban formulations
KR102225416B1 (ko) 엔잘루타마이드 제제
CN101505733A (zh) 活性剂制剂及其制备和应用方法
CA2719115A1 (fr) Procedes, formes pharmaceutiques, et necessaires pour administrer de la ziprasidone sans nourriture
PL220457B1 (pl) Kapsułka do leczenia dysurii
EP3897834A1 (fr) Compositions de sparsentan amorphe
RU2139053C1 (ru) Способ повышения мочеотделения у человека
CN110063944B (zh) 一种苯磺酸左旋氨氯地平阿托伐他汀钙片及其制备方法
CN102349902A (zh) 一种含有左旋氨氯地平和坎地沙坦酯的全新药物组合物及其制备方法
KR100443891B1 (ko) 당뇨병성합병증의예방·치료제
AU2021291437B2 (en) Acalabrutinib maleate dosage forms
CN112955130A (zh) 包含取代茚满的固体分散体和药物组合物及其制备和使用方法
WO2006114703A2 (fr) Methode d'administration de (1s,s2)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yle)-1-propanol
JP2011507949A (ja) 腎臓病を処置及び予防するための薬学的組成物
JP2005524642A (ja) ハロフジノンおよびその他のキナゾリノン誘導体の安定化医薬組成物
US20090264476A1 (en) CB-1 receptor modulator formulations
JP2011526909A (ja) テルカゲパントカリウムの固形投与製剤
CN103037861A (zh) 黄嘌呤氧化酶抑制剂与血管紧张素ii受体拮抗剂的组合及其用途
JP2023530580A (ja) ナノ微粒子組成物
JP2003518493A (ja) 新規治療方法
TW202245786A (zh) 喹唑啉化合物及藥物組合物的應用
CN113933472A (zh) 测定替米沙坦固体制剂溶出度的溶出介质及其应用
WO2022246200A1 (fr) Méthodes de traitement de maladies ou de troubles rénaux
RU2255728C1 (ru) Средство пролонгированного антикальциевого действия в виде 0,1% раствора для внутривенного введения
JP2008127365A (ja) アレルギー性疾患の予防及び／又は治療剤

Legal Events

Date Code Title Description
DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

NENP Non-entry into the national phase in:

Ref country code: RU

WWW Wipo information: withdrawn in national office

Country of ref document: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06727547

Country of ref document: EP

Kind code of ref document: A2

WWW Wipo information: withdrawn in national office

Ref document number: 6727547

Country of ref document: EP