WO2006114703A2

WO2006114703A2 - Method of administration of (1s,s2) -1- (4 -hydroxyphenyl) -2- (4-hydr0xy-4-phenylpiperidin-1-yl) -1- propano (traxoprodil)

Info

Publication number: WO2006114703A2
Application number: PCT/IB2006/001044
Authority: WO
Inventors: Jerry John Weaver; Lorraine Yurkewicz; Keith David Wilner
Original assignee: Pfizer Products Inc
Current assignee: Pfizer Products Inc
Priority date: 2005-04-25
Filing date: 2006-04-13
Publication date: 2006-11-02
Anticipated expiration: 2007-10-25
Also published as: WO2006114703A3

Abstract

The present invention in one aspect is directed to a method for improving the bio-availability of (IS, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-l-yl) -1-propanol traxoprodil or a pharmaceutically acceptable salt thereof in a human, the method comprising administering over a period of time of at least 24 hours (IS, 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 (IS, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-l-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-availability is improved relative to administration at a constant rate that is equal to the rate of administration over the second period of time.

Description

METHOD OF ADMINISTRATION OF (1S,2SH-(4-HYDROXYPHENYU-2-(4-HYDROXY-4-

PHENYLPIPERIDIN-1 -YLM -PROPANOL

BACKGROUND OF THE INVENTION

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol exhibits activity as an NMDA receptor antagonist. NMDA is an excitatory amino acid involved in excitatory neurotransmission in the central nervous system. NMDA antagonists are compounds that block the NMDA receptor by interacting with the receptor's binding site. Pathologic overactivation of the N-methyl-D-aspartate (NMDA) class of receptors has been implicated in the neurodegeneration that occurs following stroke. There are multiple subtypes of NMDA receptors, of which the NR2B subtype appears to play a prominent role in these pathologic processes. The distribution of the NR2B subunit in specific forebrain regions (eg, hippocampus) imparts a regional selectivity to (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol in brain areas that are especially vulnerable to injury from ischemia. Thus, 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.

Commonly assigned U.S. Pat. No. 5,272,160 and commonly assigned U.S. Pat. No. 5,710,168 (the disclosures of which are hereby incorporated by reference) disclose (1S,2S)-1- (4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol and methods of using (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol for treatment of diseases or conditions that are susceptible to treatment by blocking NMDA receptor sites, including stroke, spinal cord trauma, traumatic brain injury, multiinfarct dementia, CNS degenerative diseases, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychotic conditions, drug addictions, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence and ischemic events.

Commonly assigned U.S. Pat. No. 6,008,233 (the disclosure of which is hereby incorporated by reference) discloses the methanesulfonate trihydrate of (1S,2S)-1-(4- hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1~yl)-1-propanol and uses thereof for treatment of the aforesaid diseases and conditions. In view of the relevance of (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol to the treatment of neurodegenerative conditions such as stroke, it is desirable to provide a new method of administration of (1S,2S)-1-(4- Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof to a human that advantageously improves bio-availability in the human. SUMMARY OF THE INVENTION

Accordingly, 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-availability is improved relative to administration at a constant rate that is equal to the rate of administration over the second period of time.

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. Preferably, 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.

In one embodiment, 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.

In another embodiment, 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. In a further embodiment, 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

2 hours. More preferably, no greater than about 20 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 the first period of time of about 2 hours. Even more preferably, no greater than 10 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 the first period of time of about 2 hours.

In another embodiment, 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. Alternatively, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the Mean Plasma and Cerebrospinal Fluid Concentrations of traxoprodil. DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "(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. Each of the terms "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. By "pharmaceutically acceptable form" is meant any pharmaceutically acceptable derivative or variation, including solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, and prodrugs. Pharmaceutically acceptable salts 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. Preferred forms of (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.

The 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. As another example, 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. By "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. In one embodiment, 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. As used herein, 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. In another embodiment, the from which the composition is formed is substantially amorphous. As used herein, "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%. More preferably, 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.

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. Examples of amorphous forms include solid amorphous dispersions in a polymer, or an amorphous form stabilized using a matrix material. In another aspect, 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.

By 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.

Another class of 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.

It should be noted that in the polymer nomenclature used herein, 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. Analogously, 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.

It should also be noted that 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. Generally, 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. Also included within each polymer family type are 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. Particularly preferred 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. However, when aryl groups are included, 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 aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy, etc.; phosphates, such as phosphate ethoxy; and sulfonates, such as sulphonate ethoxy. Exemplary 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. For 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. In some cases, 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 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 acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, 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 propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

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 propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

Another particularly desirable subset of 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.

While, as listed above, a wide range of polymers may be used, the inventors have found that relatively hydrophobic polymers have shown the best performance as demonstrated by high MDC and AUC values. In particular, cellulosic polymers that are aqueous insoluble in their nonionized state but are aqueous soluble in their ionized state perform particularly well. A particular subclass of such polymers are the so-called "enteric" polymers, which include, for example, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), and carboxymethyl ethyl cellulose (CMEC). In addition, non-enteric grades of such polymers, as well as closely related cellulosic polymers, are expected to perform well due to the similarities in physical properties.

Thus, 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. 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.

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. In particular, it has been found that ionizable cellulosic polymers such as HPMCAS function best over particular pH ranges. For example, 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. For example, 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. Thus, it has been found in in vitro tests, that the H grade of HPMCAS is preferred for inhibition of crystallization in a pH 6.5 use environment. The H grade of HPMCAS has 22-26 wt% methoxy, 6 10 wt% hydroxypropoxy, 10-14 wt% acetate, and 4-8 wt% succinate groups. At lower pH values, say 5 to 6, 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.

Another preferred class of polymers consists of neutralized acidic polymers. By "neutralized acidic polymer" is meant 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. By "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." 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.

In addition, the preferred polymers listed above, that is amphiphilic cellulosic polymers, tend to have greater precipitation-inhibiting properties relative to the other polymers of the present invention. Generally 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. To evaluate the utility of precipitation inhibitors at other pH values, it may be desirable to use other similar dissolution media that have pH values adjusted to other values. For example, an acid such as HCI or H₃PO₄ 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. That is, once the tested form and the precipitation inhibitor are introduced into a use environment, 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. Preferably, 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. For example, if the MDC provided by the test composition is 5 μg/ml, and the MDC provided by the control composition is 1 μg/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. More specifically, in the use environment, 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. Preferably, the AUC provided by the composition is at least 2-fold, more preferably at least 3-fold that of the control composition. Alternatively, an in vitro membrane-permeation test may be used to evaluate the precipitation inhibitor. In this test, described above, 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. Preferably, 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).

In the examples below, 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.

EXAMPLES

In addition to specific entry criteria (see below), patients were stratified by baseline severity based on the Motor Score component of the Glasgow Coma Scale (GCS; 2-3 versus 4-5). Within each stratum, patients were randomized in a 1 :1 ratio to receive either traxoprodil or matching placebo. Trauma centers were selected for participation based on their treatment practices, which had to be consistent with the American Association of Neurological Surgeons for the Management of Severe Head Injury (AANS Guidelines).

A central reader reviewed each computed tomography (CT) scan in a blinded fashion to ensure subject eligibility as well as the rater scores during the course of the trial to ensure quality and standardization of ratings across sites.

Males or non-pregnant females between 16-70 years of age (or as permitted by local law) treated by the method of the invention had sustained a severe head trauma requiring intracranial pressure monitoring, a GCS score of 4-8 inclusive, with the Motor Score component between 2 and 5 inclusive.

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. Subjects requiring ketamine, high dose systemic corticosteroids (e.g. methylprednisolone >15 mg/kg or equivalent), or hypothermia in the last 24 hours were also excluded. Once enrolled, subjects were treated and closely monitored throughout the first two weeks or until day of discharge whichever came first. Laboratory results, clinical safety data and adverse events were collected during the acute phase through day 14 or day of discharge, whichever came first. For determination of traxoprodil plasma levels, pharmacokinetic samples were collected pre-dose and at time points up to 120 hours from the start of infusion. One blood sample was collected from each subject prior to dosing to assess the cytochrome P450 CYP2D6 metabolic status: extensive metabolizer (EM) or poor metabolizer (PM). For those subjects having ventriculostomy monitors, a one ml cerebrospinal (CSF) sample was collected as close as possible to the same time points as the blood sample collections.

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.

Table 1 Patient Demographics

Traxoprodil Placebo

TOTAL (N) 198 206

Males 146 152

Females 52 54

Baseline Motor Score

Low (2,3) 65 63

High (4,5) 133 143

Age (years)

Mean 31.0 31.5

Range 16-66 16-66

All of the subjects had a primary diagnosis of severe head injury. The results from CT scans taken at screening showed that the treatment groups were comparable with respect to subarachnoid hemorrhage grade, presence or absence of cisterns, lesion mass size and

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).

There were no apparent imbalances between the two treatment groups with respect to demographics, prior medical history, severity of injury (baseline motor score), or time to drug infusion. Of 429 subjects screened, 25 did not meet the entry criteria. Of 404 subjects enrolled,

198 and 206 subjects were randomized to traxoprodil or placebo, respectively.

Administration was provided by the method of the invention disclosed hereinabove.

The resulting Css.avg values are shown in Table 2. The resulting AUC values are shown in

Table 3. Table 2

Css (hα/ml) EM PM

N 185 12 mean 327 1140

%CV 57 37

Geometric mean 286 1040

Table 3

AUC(0-72) nα.hr/ml EM PM

N 167 12 mean 22300 66300

%CV 51 24

Geometric mean 19900 64400

Pharmacokinetic data (Figure 1) show that the dosing regimen used resulted in plasma traxoprodil concentrations that were generally reached by 2 hours and were maintained above the targeted efficacious concentration of 200 ng/ml throughout the duration of the infusion. The concentration ratios of CSF to plasma at steady state (0.9 and 0.60 for extensive metabolizers (EMs) and poor metabolizers (PMs), respectively) indicated good brain penetration.

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.

The terms and expressions which have been employed in the foregoing specification are not intended to limit the scope of the invention or of excluding equivalents thereof. The scope of the invention is defined by the claims appended hereinbelow.

Claims

WE CLAIM:

1. A method for improving the bio-availability 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 bioavailability is improved relative to administration at a constant rate that is equal to the rate of administration over the second period of time.

2. The method of claim 1 , wherein the first period of time is less than the second period of time.

3. The method of claim 1 , wherein the first period of time is about 2 hours.

4. The method of claim 1 , wherein the second period of time is at least about 70 hours.

5. The method of claim 1 , wherein 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.

6. The method of claim 1 , wherein the first period of time is about 2 hours and the second period of time is about 70 hours, wherein the rate of administration over the first period of time of about 2 hours is about 0.5 to about 0.1 mg/kg/hr and the rate of administration over the second period of time of about 70 hours is about 0.36 to about 0.38 mg/kg/hr.

7. The method of claim 1 , wherein 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 of about 2 hours.

8. The method of claim 7, wherein no greater than about 20 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 of about 2 hours.

9. The method of claim 1 , wherein (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is administered within about 8 hours of onset of traumatic brain injury.

10. The method of claim 1 , wherein (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4- phenylpiperidin-1-yl)-1-propanol or a pharmaceutically acceptable salt thereof is administered within about 4 hours of onset of traumatic brain injury.