HK1059575B - Nmda receptor agonist pharmaceutical compositions - Google Patents

Description

Pharmaceutical compositions of N-methyl-D-aspartate receptor antagonists

Background

The present invention provides antagonists of the N-methyl-D-aspartate (NMDA) receptor, stable pharmaceutical compositions of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, methods of preparing such pharmaceutical compositions and uses of such pharmaceutical compositions, can be used for treating apoplexy, spinal cord injury, brain trauma, multi-infarct dementia, and CNS degenerative diseases, such as Alzheimer's disease, senile dementia of the Alzheimer's type, Huntington's disease, Parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychosis, drug addiction, migraine, hypoglycemia, anxiety, urinary incontinence and localized bleeding caused by CNS surgery, open heart surgery or any other treatment process that impairs cardiovascular function.

(1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol (hereinafter "the compound") is a neuroprotective agent useful in the treatment of stroke, spinal cord injury, brain trauma, multi-infarct dementia, CNS degenerative diseases such as Alzheimer 'S disease, senile dementia of the Alzheimer' S type, Huntington 'S disease, Parkinson' S disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychosis, drug addiction, migraine, hypoglycemia, anxiety, urinary incontinence and regional hemorrhage following CNS surgery, open heart surgery or any other therapeutic procedure that impairs the function of the cardiovascular system. The compounds exhibit NMDA receptor antagonist activity. NMDA is an excitatory (excitatory) amino acid involved in excitatory neurotransmission in the central nervous system. NMDA antagonists are compounds that act with the NMDA receptor binding site to block the receptor.

Neurotransmission antagonists acting on NMDA receptors are useful as therapeutic agents for the treatment of neurological diseases. Us patent 4,902,695) to a series of competitive NMDA antagonists useful for the treatment of neurological disorders including epilepsy, stroke, anxiety, cerebral hemorrhage, muscle spasm, and neurodegenerative disorders such as alzheimer's disease and huntington's disease. Us patent 4,968,878) to another series of competitive NMDA receptor antagonists useful for treating similar neurological and neurodegenerative diseases. Us patent 5,192,751) discloses a method of treating urinary incontinence in a mammal comprising administering an effective dose of a competitive NMDA antagonist.

Commonly assigned U.S. patent 5,272,160 and commonly assigned U.S. patent 5,710,168, which are incorporated herein by reference, disclose compounds and methods of using the compounds to treat certain diseases or conditions susceptible to treatment by blocking the NMDA receptor site, including stroke, spinal cord injury, brain trauma, multi-infarct dementia, CNS degenerative diseases, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychosis, drug addiction, migraine, hypoglycemia, anxiety, urinary incontinence, and localized bleeding.

Commonly assigned U.S. patent 6,008,233, incorporated herein by reference, discloses the mesylate trihydrate of this compound and its use to treat the above-mentioned diseases or conditions.

The preferred mode of administration of the compound is intravenous infusion over several hours. This mode of administration is intended to maintain the desired blood level during the treatment period. Typically, the compounds are initially used in a hospital emergency room, followed by treatment in an ICU or other intensive care unit for an appropriate period of time.

The dosage forms and dosages of the compounds should be designed for convenient and effective administration, and should be particularly suitable for use in emergency situations. Degradation of the compound in the formulation should be minimized.

Summary of The Invention

The present invention provides aqueous formulations of relatively stable compounds prepared by reducing or removing trace amounts of metal ions from solution. The stability is further improved by using a pharmaceutically acceptable buffer. Reducing the oxygen content in the formulation may additionally increase stability.

One aspect of the present invention is a pharmaceutical composition comprising a pharmaceutically effective dose of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof and water, wherein the composition comprises less than about 2ppm free copper ions and less than about 2ppm free iron ions.

Another aspect of the invention is a pharmaceutical composition comprising (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, water and a pharmaceutically acceptable chelating agent, preferably ethylenediaminetetraacetic acid, citric acid, succinic acid or tartaric acid or a pharmaceutically acceptable salt thereof, in a concentration effective to chelate trace amounts of metal ions in the composition.

Another aspect of the present invention is a pharmaceutical composition comprising an aqueous solution of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, wherein the percentage of the degradation product 4-hydroxybenzaldehyde after 12 weeks storage of the above composition at 50 ℃ is only about 0.15%, preferably only about 0.07%, most preferably only about 0.04%.

Another aspect of the present invention is a pharmaceutical composition comprising an aqueous solution of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, wherein the percentage of the degradation product 4-hydroxy-4 phenylpiperidine in the above composition after 12 weeks at 50 ℃ is only about 0.2%, preferably only about 0.1%, most preferably only about 0.05%.

Another aspect of the present invention is directed to a method of treating stroke, spinal cord injury, brain trauma, multi-infarct dementia, CNS degenerative diseases, such as alzheimer's disease, senile dementia of the alzheimer's type, huntington's disease, parkinson's disease, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychosis, drug addiction, migraine, hypoglycemia, anxiety, urinary incontinence, and localized bleeding resulting from CNS surgery, open heart surgery or any process that impairs cardiovascular function in a mammal in need thereof, comprising administering to the mammal an effective amount of a pharmaceutical composition of claims 1-14.

In a preferred embodiment of the composition of the present invention, the composition is substantially free of free copper ions and free iron ions.

In another preferred embodiment of the composition of the present invention, the composition comprises less than about 2ppm, more preferably substantially no free trace metal ions.

Another preferred embodiment of the compositions of the present invention provides that the compositions comprise a pharmaceutically acceptable buffer at a concentration effective to maintain the pH of the composition between about 3.8 and about 5.0, more preferably between about 4.0 and about 4.5. In a more preferred embodiment, the buffer anion is selected from acetate, citrate, tartrate, formate and lactate, most preferably lactate.

Another preferred embodiment of the composition of the present invention provides a composition that is substantially free of oxygen.

In a preferred embodiment of the method of treatment of the present invention, the mammal is a human.

The term "chelating agent" as used herein refers to a compound that chelates with trace metal ions to form a complex or interacts with trace metal ions to minimize the destabilization of the compound in aqueous solution by these metal ions. Typical chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts, trans-1, 2-diaminocyclohexanetetraacetic acid (DCTA) and its salts, bis- (2-aminoethyl) ethylene glycol-NNN 'N' -tetraacetic acid (EGTA) and its salts, diethylenetriaminepentaacetic acid (DTPA) and its salts, tris- (2-aminoethyl) ammonia (tris (aminoethyl) amine), NNN 'N' -tetrakis- (2-aminoethyl) ethylenediamine (pentaethylenehexamine), nitrilotriacetic acid (NTA) and its salts, 2, 3-dimercapto-1-propanesulfonic acid (DMPS) and its salts, meso-2, 3-mercaptosuccinic acid (DMSA) and its salts, hydroxy acids such as citric acid, tartaric acid, lactic acid, succinic acid, and the like and their salts, certain amino acids such as glycine, succinic acid, and its salts, Histidine and glutamic acid and salts thereof.

The term "degradant 1" as used herein refers to the degradation product of a compound, 4-hydroxybenzaldehyde.

The term "degradation product 2" as used herein refers to the degradation product of a compound, 4-hydroxy-4-phenylpiperidine.

As used herein, the terms "free copper ions", "free iron ions" and "free trace metal ions" refer to copper ions, iron ions or trace metal ions, respectively, which when present in an aqueous composition containing a compound in some form or state, cause, accelerate or catalyze the degradation of the compound.

"Headspace (Headspace)" refers to the difference in volume between the volume of a sealed container (e.g., a vial) and the volume of liquid contained in the container. The headspace can be quantified as a percentage of the total volume of the sealed container.

The expression "method for removing trace metal ions" as used herein refers to any method that can be used to remove trace metal ions from an aqueous solution. For example, these methods include the use of metal chelating resins or other chelating agents familiar to those of ordinary skill in the art.

The term "non-reactive gas" as used herein refers to any gas that does not react or chemically interact with the pharmaceutical composition or any of its components. This gas is preferably nitrogen, but may also be argon, helium or any other non-reactive gas familiar to those of ordinary skill in the art.

The expressions "1 percent degradant" and "2 percent degradant" refer to the percentage of the applicable degradation products in the pharmaceutical composition of the present compounds, as a weight ratio (w/w). The percentage was calculated by HPLC analysis of peak area according to the following formula:

percent of degradation product [ (A)_SAMPXD_SAMP)/(R_AVGXC_LAB)]×100

Wherein:

A_SAMParea of impurity peak

D_SAMPThe dilution factor is calculated as follows:

D_SAMP＝C_LAB/C_SAMP

wherein:

C_LABlabeled concentration of compound in the tested preparation (free base concentration)

C_SAMPFree base concentration (base) of test sample compoundDilution mark concentration for sample preparation,)

R_AVGThe average standard reaction coefficient ("R"), obtained from analysis of the standard solution, was calculated as follows:

R＝A_STD/(C_STDXPF)

wherein:

A_STDpeak area of compound in standard solution

C_STDConcentration of compound in standard solution

PF ═ intensity (strength) coefficient of the compound in the standard solution, obtained by dividing the molecular weight of the free base compound by the molecular weight of the actual compound in the standard solution.

Dilution factor D_SAMPBecause dilution is performed as necessary to bring the sample to be tested within the effective concentration range of the HPLC method.

The expression "pharmaceutically acceptable" as used herein refers to those carriers, diluents, excipients, buffers and/or salts which are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the term "substantially free" with respect to trace amounts of metal ions in a pharmaceutical composition containing a compound means less than an amount that has a substantial effect on the degradation of the compound in the composition. Although described above, the amount is less than about 2ppm for any trace metal ion that may be used. The term "substantially free" as used herein with respect to oxygen present in or exposed to a pharmaceutical composition containing a compound means less than an amount of oxygen that has a substantial effect on the degradation of the compound in the composition. For example, the composition is packaged in a sealed container or vial with a headspace wherein the headspace is 25% or less of the volume of the container or vial and the term "substantially free" means that the proportion of oxygen in the headspace is less than 10%.

The term "trace metal ions" as used herein refers to any metal ions which, when present in an aqueous solution of a pharmaceutical composition comprising the compound, cause, initiate, accelerate or catalyze the degradation of the compound, particularly transition metal ions, especially iron and copper ions.

Detailed Description

The active ingredient in the pharmaceutical composition of the present invention is (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, which may be present as a free base or in the form of a pharmaceutically acceptable salt, preferably the mesylate salt. The preparation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is described in us 5,272,160 and us 6,008,233. The preparation of the mesylate trihydrate is described in us patent 6,008,233.

In a representative example, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol is administered as an intravenous infusion in an emergency department or hospital emergency room to a patient suffering from stroke or brain injury. Treatment continues in the ICU or other intensive care unit. The amount of the compound administered will depend, in part, on the weight of the patient.

Concentrates of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol, which can be diluted according to the needs of the patient, provide flexibility in the required dosage. The concentrate is either diluted to the appropriate concentration for administration to the patient when necessary.

The pharmaceutical compositions of the present invention may be formulated in the form of a concentrate which is diluted with a suitable IV diluent prior to administration. The formulation may also be formulated for use, i.e. at an administration concentration that does not require further dilution. Preferably, the concentration of the concentrated composition is 10mg of the free base of the active compound, (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol per mL of solution (i.e. 10 mgA/mL). The preferred form of use has a concentration of 1.25 mgA/mL.

The composition is administered at full concentration (full strength) or diluted as required. The preferred dosage concentration for administration to a patient is from 0.1mgA/mL to 10 mgA/mL. The dosage concentration is more preferably 0.5 mgA/mL-2.0 mgA/mL. More preferably, the concentration of the administered dose is 1.25 mgA/mL. The preferred IV diluent for the composition is standard saline solution (0.9% NaCl).

Two chemical degradation products of aqueous (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol solution are the compounds 4-hydroxybenzaldehyde (hereinafter "degradant 1") and 4-hydroxy-4-phenylpiperidine (hereinafter "degradant 2"). Such a reduction, while not critical to the practice of the present invention and not intended to be limiting in any way, is believed to be the result of the oxidation of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol.

Trace metal ion contamination has been found to be a key factor in compound degradation. These effects are exemplified by the solution experiments of compounds spiked with iron or copper ions. Table 1 shows the effect of iron and copper ions in unbuffered water injection (WFI) solutions on the formation of degradation products.

TABLE 1.Fe²⁺And Cu⁺Effects of incorporation on compound degradation.

Data represent the percentage of degradent 1 (w/w).

Days at 70 ℃	Only WFI	Fe2+(20ppm)	Cu+(20ppm)
				Day 0	0.002％	0.024％	0.085％
3 days	0.007％	0.061％	0.107％
				7 days	0.009％	0.110％	0.128％

WFI is water for injection. Chelex^*The treatment solution contained 1.25mgA/ml of the compound, to which 20ppm of iron or copper was added, followed by autoclaving at 121 ℃ for 8 minutes.

An effective method to improve the stability of compounds is to remove traces of metal ions from aqueous formulations. One method of removing metal ions is to use reagents specifically designed for this purpose. Typical metal ion removers include chelating resins, such as Chelex^*(Chelex^*Under the trademark Bio-Rad Laboratories, Inc, Hercules, Calif.). However, other pharmaceutically acceptable chelating resins or agents that perform the same function are acceptable as long as they do not have a deleterious effect on the compound or other formulation components.

The treatment to remove trace metal ions may be carried out on the individual formulation components prior to final formulation or on the formulation itself. For example, the water used in the formulation may be treated to remove trace metals. Alternatively, the concentration buffer is treated prior to dilution with water and formulation with the active ingredient. Alternatively, an aqueous solution comprising all formulation components except the active pharmaceutical ingredient may be treated to remove metal ions. Alternatively, the whole formulation containing all the components, including the active component, is processed.

Another method of removing trace metal ions is to incorporate into the formulation certain compounds which form chelates with trace metal ions, thereby minimizing their degradation effects. Examples of such chelating agents include disodium ethylenediaminetetraacetic acid (EDTA) and citrate and tartrate buffers. The preferred concentrations of disodium EDTA, citrate buffer and tartrate buffer are each 10 mM. Citrate and tartrate are believed to act as chelating agents for trace metal ions. Additionally, succinate is believed to act as a chelating agent. Other chelating agents will be apparent to those of ordinary skill in the art from the perspective of this disclosure.

Aqueous solutions of the compounds are susceptible to pH changes. It is believed that the compounds exhibit optimal chemical stability at pH4.0-4.5. When the compound is formulated with water only, the pH of the formulation rises above 5. This pH shift provides favorable reaction conditions for oxidative degradation, thereby accelerating the degradation of the aqueous formulation. Increasing the PH also decreases the solubility of the compound, thereby increasing the likelihood of precipitation in solution.

Using a suitable buffer, the pH change will be minimized. One of ordinary skill in the art will recognize that any pharmaceutically acceptable buffer that can maintain the pH of the formulation within a certain range can be used. The pH of these buffers is preferably in the range of about 3.8 to about 5.0, most preferably between 4.0 and 4.5. Suitable buffers include, but are not limited to, acetate, benzoate, citrate, formate, lactate and tartrate buffers, preferably lactate.

Table 2 illustrates the use of various buffers to stabilize the pH of a formulation containing 10mgA/ml of the compound.

TABLE 2 pH at 70 ℃

Buffer solution	Initially (after TS)	2 days	4 days	7 days	21 days
						10mM acetate salt	4.16	N/T	4.14	4.14	4.17
10mM benzoate salt	4.21	N/T	4.16	4.20	N/A
						10mM citrate	4.16	4.16	N/T	4.17	4.11
10mM formate salt	4.17	4.18	N/T	4.16	4.13
						3mM lactate	4.24	4.21	N/T	4.20	4.14
10mM tartrate salt	4.15	4.17	N/T	4.17	4.07

N/T not recorded

N/A is not provided

TS-terminal Sterilization

To further increase the stability of the active compound, it is preferred to reduce the oxygen content of the formulation. This can be achieved by introducing nitrogen, argon or other non-reactive gas into the formulation solution, and filling the headspace with these inert gases when the composition of the invention is contained in a vial or similar container containing the headspace. When the compositions of the present invention are charged, they contain headspace, preferably the headspace oxygen content is less than about 12%, most preferably less than about 8%. Other methods of deoxygenation may be used, including the use of vacuum to remove air and oxygen. Other deoxygenation methods will be apparent to one of ordinary skill in the art.

Preferred forms of the present composition include a concentration of the compound of 10mgA/mL, near the maximum solubility of the compound (about 12mgA/mL at 5 ℃). A preferred composition solution is 10mM lactate buffer. However, one of ordinary skill in the art will recognize that other anion buffer solutions may be used, including but not limited to buffer solutions of acetate, citrate, tartrate, and formate anions.

The preferred storage container for the composition is a 40cc, Friedel (Flint) type I molded glass vial with a rubber stopper and aluminum shell. Additional alternative forms include other vial or container types, pre-filled syringes or pre-filled IV bags. Other packaging forms will be apparent to those of ordinary skill in the art.

The vials are preferably sterilized by a terminal autoclaving method. Preferably, sterilization is carried out at 121 ℃ for 8 minutes. Sterilization causes a slight change in pH. In the lactate buffer formulation, the pH shifted slightly downward. To obtain the midpoint of the preferred pH range, the initial pH is preferably 4.5. Terminal sterilization lowers the pH to about 4.2.

Examples of the experiments

The present invention is illustrated by the following examples, which are not intended to limit the invention to the details thereof.

The percentages of degradant 1 and degradant 2 were determined by reverse phase HPLC analysis on a Kromasil C4 column (5 μm, 25cm length. times.4.6 mm ID, EKA Chemicals, Bohus Sweden). The column temperature was 30 ℃. + -. 5 ℃. Mobile phase A: water/acetonitrile/trifluoroacetic acid, 90/10/0.1 (v/v/v). Mobile phase B: water/acetonitrile/trifluoroacetic acid, 40/60/0.1 (v/v/v). Gradient profile: and (4) linearity. And (3) detection: UV215 nm. Flow rate: 1.5 mL/min. Injection volume: 10 μ L.

Example 1

Effect of treatment with chelate resin

0.3, 0.6 and 0.9% sodium chloride solution with 5% w/w Chelex^*Resin treatment and slow stirring for 1 hour. The solution pH was adjusted to 4.6 while stirring with Chelex resin. The mixture was filtered. As control samples, 0.3, 0.6 and 0.9% sodium chloride solutions were prepared without treatment with Chelex resin. The treated and untreated solutions were mixed with (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol at a concentration of 1.25mgA/ml and contained in a sealed 5cc Friedel' S model I vial containing 4.0ml of the filling liquid and 2.0ml of air headspace and stored at 70 ℃ for 7 days. The results of this experiment are shown in table 3.

TABLE 3 data show the percentage of degradent 1 (w/w)

％NaCl	Untreated	Treatment of
			0.3	0.034％	0.004％
0.6	0.038％	0.003％
			0.9	0.033％	0.003％

Example 2

Effect of formulation with chelating agent.

Each of the following solutions was prepared at a concentration of 10mM at pH 4.2.

1. Unbuffered standard saline solution (0.9% NaCl);

2.10mM citrate buffered standard saline (0.9% NaCl);

3.10mM tartrate-buffered standard salt solution (0.9% NaCl); and

4.10mM EDTA disodium salt standard solution (0.9% NaCl);

each solution was mixed with (1S, 2S) -1- (4-hydroxyphenyl) -2 (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol to a concentration of 1.25mgA/ml, and the pH was adjusted to 4.2. Each formulation was autoclaved at 121 ℃ for 8 minutes and stored at 70 ℃. The experimental results are shown in table 4 below.

TABLE 4 data represent the percentage of degradent 1 (w/w)

	0.9％NaCl	10mM tartrate salt	10mM citrate	10mMEDTA
					Day 0	N/A	0.002％	0.000％	0.000％
3 days	N/A	0.003％	0.001％	0.000％
					7 days	0.033％	0.006％	0.001％	0.002％

N/A ═ no data provided

Example 3

4-hydroxybenzaldehyde (degradation product 1)

NMR analysis was performed at ambient temperature using a Bruker Avance DRX 500MHz NMR spectrometer using a Bruker 5mm gradient broadband inversion probe (Bruker Instruments, Inc, Billerica, MA). The samples were dissolved in 99.9% deuterated Dimethylsulfoxide (DMSO).

13C-NMR		1H-NMR
				Carbon (PPM)	Number of hydrogen bonded	Proton (PPM) delta	Number of proton peak split
115.84	1	6.92	Double peak
				128.43	0
132.10	1	7.74	Double peak
				163.32	0
190.95	1	9.77	Single peak

Example 4

4-hydroxy-4-phenylpiperidine (degradation product 2).

NMR analysis was performed at ambient temperature using a Bruker Avance DRX 500MHz NMR spectrometer using a Bruker 5mm gradient broadband inversion probe. The samples were dissolved in 99.9% deuterated Dimethylsulfoxide (DMSO).

13C-NMR		1H-NMR
				Carbon (PPM)	Number of hydrogen bonded	Proton (PPM) delta	Number of proton peak split
39.05	2	1.491.77	Double peak and three peak
				42.03	2	1.702.92	Double peak and three peak
70.41	0
				124.70	1	7.46	Double peak
125.97	1	7.18	Three peaks
				127.76	1	7.30	Three peaks
150.76	0

Example 5

Lactate buffer solution for (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol was prepared

Components	Rank of	Function of	Weight (mg/vial)	Concentration (mg/ml)
					(1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol mesylate trihydrate	Medicine	Active ingredient	586.01	14.577 (equal to 10mgA/ml)
Lactic acid	USP	Buffer solution	41.12	1.023
					Sodium hydroxide	NF	pH regulator	Ca 13.87	Ca 0.345
Hydrochloric acid	NF	pH regulator	0	0
					Water for injection	USP	Solvent	39711.76	987.855

USP ═ united states pharmacopeia

NF ═ national regulation

The initial formulation pH was set at pH4.5 to allow a slight downward shift in pH upon terminal sterilization. Terminal sterilization lowers the pH to about 4.2. The solution is adjusted to the desired pH with sodium hydroxide and hydrochloric acid, if necessary.

Example 6

Accelerated stability study

10mgA/ml (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol was prepared in 10mM lactate buffer. The pH of the individual 3 portions was adjusted so that the initial pH after terminal sterilization was 3.9, 4.2 or 4.6. The preparations were contained in vials containing different concentrations of oxygen or air. Final Sterilization was autoclaved at 121 ℃ for 8 minutes. Samples were stored in 40ml friett type I vials with a 40ml fill volume and 10ml headspace and stored at 30 ℃, 40 ℃ and 50 ℃ for 12 weeks.

The results of the experiments are shown in tables 5 and 6 below.

TABLE 5 data show the percentage of degradent 1 (w/w)

Head space, pH	Initial	After T.S	30℃	40℃	50℃
						4％O2，pH4.2	0.002％	0.004％	0.003％	0.005％	0.009％
6％O2，pH4.2	0.002％	0.004％	0.004％	0.005％	0.011％
						10％O2，pH4.2	0.004％	0.003％	0.004％	0.006％	0.015％
Air, pH4.6	0.003％	0.003％	0.008％	0.015％	0.033％
						Air, pH4.2	0.003％	0.004％	0.004％	0.006％	0.032％
Air, pH3.9	0.003％	0.003％	0.009％	0.019％	0.040％

TABLE 6 data shows the percentage of degradant 2 (w/w)

Head space, pH	Initial	After T.S	30℃	40℃	50℃
						4％O2，pH4.2	0.003％	0.006％	0.008％	0.010％	0.017％
6％O2，pH4.2	0.003％	0.006％	0.008％	0.010％	0.019％
						10％O2，pH4.2	0.002％	0.006％	0.009％	0.013％	0.024％
Air, pH4.6	0.002％	0.005％	0.012％	0.018％	0.043％
						Air, pH4.2	0.001％	0.005％	0.008％	0.012％	0.042％
Air, pH3.9	0.001％	0.003％	0.013％	0.023％	0.051％

Claims (15)

1. A pharmaceutical composition comprising a pharmaceutically effective amount of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof, water and a pharmaceutically acceptable chelating agent in a concentration effective to chelate trace metal ions in the composition, wherein the composition comprises less than 2ppm free copper ions and less than 2ppm free iron ions.

2. The pharmaceutical composition of claim 1, wherein the composition is substantially free of free copper ions and free iron ions.

3. The composition of claim 1, wherein the composition comprises less than 2ppm of any free trace metal ions.

4. The pharmaceutical composition of claim 3, wherein the composition is substantially free of any free trace metal ions.

5. The pharmaceutical composition of claim 1, wherein the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid, citric acid, succinic acid, and tartaric acid, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition of any one of claims 1-5, further comprising a pharmaceutically acceptable buffer in a concentration effective to maintain the pH of the composition between 3.8 and 5.0.

7. The pharmaceutical composition of claim 6, wherein the buffer is used at a concentration effective to maintain the pH of the composition between 4.0 and 4.5.

8. The pharmaceutical composition of claim 6, wherein the anion of the buffer is selected from the group consisting of acetate, citrate, tartrate, formate, and lactate.

9. The pharmaceutical composition of claim 8, wherein the anion of the buffer is lactate.

10. The pharmaceutical composition of claim 1, wherein the composition is substantially free of oxygen.

11. A pharmaceutical composition comprising an aqueous solution of (1S, 2S) -1- (4 hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable chelating agent at a concentration effective to chelate trace amounts of metal ions in the composition, wherein the percentage of degradation product 4-hydroxybenzaldehyde after storage of the composition for 12 weeks at 50 ℃ is only 0.15%.

12. The pharmaceutical composition of claim 11, wherein the percentage of degradation products is only 0.07%.

13. The pharmaceutical composition of claim 12, wherein the percentage of degradation products is only 0.04%.

14. Use of the pharmaceutical composition of claim 1 in the manufacture of a medicament for treating stroke, spinal cord injury, brain trauma, multi-infarct dementia, CNS degenerative diseases, epilepsy, amyotrophic lateral sclerosis, pain, AIDS dementia, psychosis, drug addiction, migraine, hypoglycemia, anxiety, urinary incontinence, and localized bleeding resulting from CNS surgery, open heart surgery, or any process that impairs cardiovascular function in a mammal.

15. The use of claim 14, wherein said CNS degenerative disease is alzheimer's disease, senile dementia of the alzheimer's type, huntington's disease, parkinson's disease.