ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY

Abstract

A pharmaceutical preparation comprising ⊖A2-73 substantially free of A2-73. This invention further includes a method treating Alzeheimer's disease in a subject in need of such treatment by the method of administering a therapeutically effective amount of ⊖A2-73 substantially free of A2-73.

This invention yet further includes a method of classifying cells as to sigma receptor type by the method of exposing said cells to a detectable amount of ⊖A2-73 substantially free of A2-73 and determining the level of sigma receptor binding.

Claims

1. A method of classifying a cell as to sigma receptor type, comprising the steps of: (i) exposing the cell to a composition comprising enantiomer (−) A2-73; (ii) measuring the specific binding of the composition to the cell using a competitive binding assay and a competing constitutively binding ligand; and (iii) classifying the cell as a sigma receptor type 1 cell if the level of specific binding of the composition is 30% or more greater than the non-specific binding of the competing constitutively binding ligand.

2. The method of claim 1, wherein the composition is substantially free of ⊕A2-73.

3. The method of claim 1, wherein the composition comprises less than about 2% (w/w) of (+) Anavex2-73.

4. The method of claim 1, wherein the composition comprises less than about 1% (w/w) of (+) Anavex2-73.

5. The method of claim 1, wherein the composition comprises less than about 0.5% (w/w) of (+) Anavex2-73.

6. The method of claim 1, wherein the composition comprises less than about 0.1% (w/w) of (+) Anavex2-73.

7. The method of claim 1, wherein the composition comprises from about 0.5 mg to about 100 mg of (−) Anavex2-73.

8. The method of claim 1, wherein the composition comprises from about 1 mg to about 20 mg of (−) Anavex2-73.

9. A method of distinguishing sigma receptor type 1 profile in cell populations, comprising the steps of: (i) collecting a first cell population and a second cell population; (ii) exposing the first cell population to an amount of a composition comprising enantiomer (−) A2-73 for a period of time, and obtaining a first level of cell binding with (−) A2-73 by measuring the specific binding of the composition to the first cell population using a competitive binding assay and a competing constitutively binding ligand; (iii) exposing the second cell population to the same amount of the same composition comprising enantiomer (−) A2-73 for the same period of time, and obtaining a second level of cell binding with (−) A2-73 by measuring the specific binding of the composition to the first cell population using a competitive binding assay and a competing constitutively binding ligand; (iv) comparing the first level of cell binding with the second level of cell binding; (v) determining the first cell population possessing more sigma receptor type 1 than the second cell population if the first level of cell binding is higher than the second level of cell binding; wherein the first cell population and the second cell population are obtained from different organs of the same subject or the same organ of different subjects.

10. The method of claim 9, wherein the composition is substantially free of (+) A2-73.

11. The method of claim 9, wherein the composition comprises less than about 2% (w/w) of (+) Anavex2-73.

12. The method of claim 9, wherein the composition comprises less than about 1% (w/w) of (+) Anavex2-73.

13. The method of claim 9, wherein the composition comprises less than about 0.5% (w/w) of (+) Anavex2-73.

14. The method of claim 9, wherein the composition comprises from about 0.5 mg to about 100 mg of (−) Anavex2-73.

15. The method of claim 9, wherein the dose composition comprises from about 1 mg to about 20 mg of (−) Anavex2-73.

16. The method of claim 9, wherein the subject is a human subject.

17. A method of determining a therapeutic effect of a sigma 1 therapy in a subject, comprises the steps of: (i) collecting a first cell population from the subject at a first time point; (ii) exposing the first cell population to a composition of enantiomer (−) A2-73; (iii) determining a first level of cell binding at the first time point by measuring the specific binding of the composition to the first cell population using a competitive binding assay and a competing constitutively binding ligand; (iv) repeating step (ii) in a fixed cadent for a period of time, and obtain a post-treated cell population; (v) exposing the post-treated cell population to the same amount of the same composition as exposed to the first cell population; (vi) determining a post-treated cell binding from the post-treated cell population by measuring the specific binding of (−) A2-73 to the post-treated cell population using the competitive binding assay and the competing constitutively binding ligand; and (v) comparing the post-treated cell binding with the first level of cell binding; determining there is a positive therapeutic effect of sigma 1 therapy, if the post-treated cell binding is higher than the first level of cell binding; or determining there is a negative therapeutic effect of sigma 1 therapy, if the post-treated cell binding is lower than the first level of cell binding.

18. The method of claim 17, wherein the subject is a subject having or suspect of having a neurological disorder.

19. The method of claim 17, wherein the composition of enantiomer (−) A2-73 is substantially free of (+) A2-73.

20. The method of claim 17, wherein the composition of enantiomer (−) A2-73 comprises from about 0.5 mg to about 100 mg of (−) Anavex2-73.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0031] This invention will be better understood with reference to the following definitions:

[0032] A. ANAVEX2-73, or A2-73 shall mean tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride. This is listed in some of the test data as AE 37. A2-73 is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range.

[0033] B. ANAVEX19-144 or A19-144 shall mean 1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride. A19-144 is a compound which is believed to bind to muscarinic acetylcholine and sigma-1 receptors with affinities in the low micromolar range.

[0034] C. ANAVEX1-41 or A1-41 shall mean tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanamine hydrochloride. This is listed in some of the test data as AE 14. A1-41 is reported in Villard et al., “Antiamnesic and Neuroprotective Effects of the Aminotetrahydrofuran Derivative ANAVEX1-41 Against Amyloid b25-35-Induced Toxicity in Mice,” Neuropsychopharmacology, 1-15 (2008).

[0035] D. The term “enantiomer” or “enantiomeric” refers to a molecule that is nonsuperimposeable on its minor image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its minor image rotates the plane of polarized light in the opposite direction.

[0036] E. “Substantially free” as to defining enantiomers form absent ⊖ form or ⊖ form absent form shall mean less than about 2% (w/w) of the excluded form and preferably less than about 1% and more preferably less than about 0.5%, and in some cases less than about 0.1%.

[0037] F. “Classifying” cells as to the σ 1 or 2 receptor populations shall mean determining the presence and or density of either a 1 or 2 receptors on cell surfaces in a given cell population. Classifying takes advantage of the differential populations of sigma receptors used as biomarkers. Biomarkers are useful as a means to define cell population propensities such as the likelihood of proliferation as to breast cancers. Testing methodology is more fully set forth in the following:

[0038] Hashimoto et al., “Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals,” Curr Pharm Des. 2006; 12(30):3857-76;

[0039] Mach R H et al., “Sigma 2 receptors as potential biomarkers of proliferation in breast cancer,” Cancer Res 1997; 57: 156-61;

[0040] Al-Nabulsi, I et al., “Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells,” Br J Cancer 1999; 81: 925-33; and,

[0041] Wheeler K T et al., “Sigma-2 receptors as a biomarker of proliferation in solid tumours,” Br J Cancer 2000; 82: 1223-32.

[0042] A2-73⊖ is a selective noncompetitive agonist for σ1 receptors and a significantly stronger agonist than A2-73.

[0043] The pharmacologically active compositions of this invention can be processed in accordance with conventional methods of Galenic pharmacy to produce medicinal agents for administration to subjects, e.g., mammals including humans.

[0044] Studies were conducted to on the effects of several compounds in various in vitro receptor binding and isolated organ assays.

[0045] 1. Materials and Methods

[0046] 1.1. In Vitro Pharmacology: Binding Assays

[0047] 1.1.1. General Procedures

TABLE-US-00001 Reference Assay Origin Compound Bibliography σ.sub.1 (h) Jurkat cells haloperidol Ganapathy et al. (1999) σ.sub.2 rat cerebral haloperidol Bowen et cortex al. (1993)

[0048] 1.1.2. Experimental Conditions

TABLE-US-00002 Non Incu- Method of Assay Ligand Conc. Specific bation Detection σ.sub.1 (h) [.sup.3H](+) 8 nM haloperidol 120 Scintillation penta- (10 μM) min./ counting zocine 22° C. σ.sub.2 [.sup.3H]DTG 5 nM haloperidol 120 Scintillation (+ 300 nM (10 μM) min./ counting (+)penta- 22° C. zocine)

[0049] As a general statement, in vitro results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds. 50% is the most common cut-off value for further investigation (determination of IC.sub.50 or EC.sub.50 values from concentration-response curves).

[0050] Results showing an inhibition (or stimulation) between 20% and 50% are indicative of weak to moderate effects (in some assays, they may be confirmed by further testing as they are within a range where more inter-experimental variability can occur).

[0051] Results showing an inhibition (or stimulation) lower than 20% are not considered significant and mostly attributable to variability of the signal around the control level.

[0052] Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level. High negative values (>50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to non-specific effects of the test compounds in the assays.

[0053] 1.1.3. Analysis and Expression of Results

[0054] The specific ligand binding to the receptors is defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabelled ligand.

[0055] The results are expressed as a percent of control specific binding and as a percent inhibition of control specific binding obtained in the presence of the test compounds. Individual and mean values are presented in the results section.

[0056] The IC.sub.50 values (concentration causing a half-maximal inhibition of control specific binding) and Hill coefficients (n.sub.H) were determined by non-linear regression analysis of the competition curves using Hill equation curve fitting. The inhibition constants (K.sub.i) were calculated from the Cheng Prusoff equation (K.sub.i=IC.sub.50/(1+(L/K.sub.D)), where L=concentration of radioligand in the assay, and K.sub.D=affinity of the radioligand for the receptor).

[0057] 1.2. In Vitro Pharmacology: Isolated Organ Bioassay

[0058] 1.2.1. General Procedures

TABLE-US-00003 Reference Reference Biblio- Assay Tissue agonist Response antagonist graphy M.sub.1 rabbit vas McN-A- inhibition pirenzepine Eltze deferens 343 of twitch (1988) (field- contraction stimulated)

[0059] 1.2.2. Experimental Conditions

[0060] Prostatic segments of rabbit vas deferens were suspended in 20-ml organ baths containing an oxygenated (95% O.sub.2 and 5% CO.sub.2) and pre-warmed (30° C.) physiological salt solution of the following composition (in mM): NaCl 118.0, KCl 4.7, MgSO.sub.4 0.6, CaCl.sub.2) 2.5, KH.sub.2PO.sub.4 1.2, NaHCO.sub.325 and glucose 11.0 (pH 7.4).

[0061] Yohimbine (1 μM) and naloxone (1 μM) were also present throughout the experiments to block the α.sub.2-adrenergic and opioid receptors, respectively.

[0062] The tissues were connected to force transducers for isometric tension recordings. They were stretched to a resting tension of 1 g then allowed to equilibrate for 60 min during which time they were washed repeatedly and the tension readjusted. Thereafter, they were stimulated electrically with square wave pulses (submaximal intensity, 1 msec duration, 0.1 Hz) delivered by a constant current stimulator.

[0063] The experiments were carried out using a semi-automated isolated organ system possessing eight organ baths, with multichannel data acquisition.

[0064] 1.2.3. Experimental Protocols

[0065] Test for Agonist Activity

[0066] The tissues were exposed to a submaximal concentration of the reference agonist McN-A-343 (1 μM) to verify responsiveness and to obtain a control response. Following washings and recovery of the initial twitch contractions, the tissues were exposed to the test compounds or the same agonist which were left in contact with the tissues until a stable response was obtained or for a maximum of 15 min.

[0067] If an agonist-like response (inhibition of twitch contractions) was obtained, the reference antagonist pirenzepine (0.1 μM) was tested against the test compounds to confirm the involvement of the M.sub.1 receptors in this response.

[0068] Test for Antagonist Activity

[0069] The tissues were exposed to a submaximal concentration of the reference agonist McN-A-343 (1 μM) to obtain a control response.

[0070] After stabilization of the McN-A-343-induced response, the tissues were exposed to the test compounds or the reference antagonist pirenzepine which were left in contact with the tissues until a stable response was obtained or for a maximum of 15 min. If it occurred, a recovery of the twitch contraction amplitude by the test compounds indicated an antagonist activity at the M.sub.1 receptors.

[0071] 1.2.4. Analysis and Expression of Results

[0072] The parameter measured was the maximum change in the amplitude of the electrically-evoked contractions induced by the compounds.

[0073] The results are expressed as a percent of the control response to McN-A-343 (mean values).

[0074] Compounds

[0075] 1.3. Test Compounds

[0076] From: EURO GENET Lab A.E.

TABLE-US-00004 CEREP Compound Reference Submitted Stock Intermediate I.D. I.D. Number F.W. Solution Dilution 9327-1 (+) A1-41 318.00 1.E−02M 1.E−04M DMSO H2O 1.E−02M Direct DMSO addition * 9327-2 (−) A1-41 318.00 1.E−02M 1.E−04M DMSO H2O 1.E−02M Direct DMSO addition * 9327-3 (+) A2-73 318.00 1.E−02M 1.E−04M DMSO H2O 9327-4 (−) A2-73 318.00 1.E−02M 1.E−04M DMSO H2O 5.E−02M Direct DMSO* addition * 9327-6 AdPhAE/C6 compound 376.00 1.E−02M 1.E−04M 6 DMSO H2O 9327-7 Al142Me/C8 compound 332.00 1.E−02M 1.E−04M 8 DMSO H2O 9327-8 Ad2PhPZMe/ compound 437.00 1.E−02M 1.E−04M C3 3 DMSO H2O 9327-9 AdPh3/VC7 compound 374.00 1.E−02M 1.E−04M VC7 DMSO H2O F.W.: Formula Weight * : for the isolated organ bioassay

[0077] Results

[0078] 1.4. In Vitro Pharmacology: Binding Assays

[0079] The mean values for the effects of the test compounds are summarized in table 1-1.

[0080] The individual data obtained with the test compounds are reported in table 1-2.

[0081] The IC.sub.50 and K.sub.I values for each reference compound are indicated in table 1-3. Each is within accepted limits of the historic average±0.5 log units.

[0082] 1.5. Reference Compounds

[0083] In each experiment, the respective reference compound was tested concurrently with the test compounds in order to assess the assay suitability. It was tested at several concentrations and the data were compared with historical values. The assay was rendered valid if the suitability criteria were met, in accordance with the corresponding Standard Operating Procedure.

TABLE-US-00005 TABLE 1-1 Summary Results Assay Client Test % Inhibition of Cerep Compound Concentration Control Compound I.D. I.D. (M) Specific Binding σ.sub.1 (h) 9327-1 (+) A1-41 1.0E−06 66 9327-2 (−) A1-41 1.0E−06 65 9327-3 (+) A2-73 1.0E−06 19 9327-4 (−) A2-73 1.0E−06 50 9327-6 AdPhAE/C6 1.0E−06 97 9327-7 Al142Me/C8 1.0E−06 63 9327-8 Ad2PhPZMe/C3 1.0E−06 81 9327-8 Ad2PhPZMe/C3 1.0E−05 95 9327-9 AdPh3/VC7 1.0E−06 95 9327-9 AdPh3/VC7 1.0E−05 102 σ.sub.2 9327-1 (+) A1-14 1.0E−06 42 9327-2 (−) A1-14 1.0E−06 59 9327-3 (+) A2-73 1.0E−06 14 9327-4 (−) A2-73 1.0E−06 −13 9327-6 AdPhAE/C6 1.0E−06 78 9327-7 Al142Me/C8 1.0E−06 17 9327-8 Ad2PhPZMe/C3 1.0E−06 −9 9327-8 Ad2PhPZMe/C3 1.0E−05 57 9327-9 AdPh3/VC7 1.0E−06 84 9327-9 AdPh3/VC7 1.0E−05 106

TABLE-US-00006 TABLE 1-2 Individual Data Assay Client Test % of Control Cerep Compound Compound Concentration Specific Binding I.D. I.D. (M) 1.sup.st 2.sup.nd Mean σ.sub.1 (h) 9327-1 (+) A1-41 1.0E−06 35.0 32.9 34.0 9327-2 (−) A1-41 1.0E−06 35.7 33.3 34.5 9327-3 (+) A2-73 1.0E−06 81.5 81.1 81.3 9327-4 (−) A2-73 1.0E−06 50.7 50.0 50.4 9327-6 AdPhAE/C6 1.0E−06 4.3 1.9 3.1 9327-7 Al142Me/C8 1.0E−06 46.2 28.1 37.1 9327-8 Ad2PhPZMe/C3 1.0E−06 22.1 15.1 18.6 9327-8 Ad2PhPZMe/C3 1.0E−05 5.0 5.7 5.4 9327-9 AdPh3/VC7 1.0E−06 7.5 2.6 5.0 9327-9 AdPh3/VC7 1.0E−05 −4.4 0.8 −1.8 σ .sub.2 9327-1 (+) A1-41 1.0E−06 60.0 56.8 58.4 9327-2 (−) A1-41 1.0E−06 41.0 40.3 40.7 9327-3 (+) A2-73 1.0E−06 88.9 83.2 86.1 9327-4 (−) A2-73 1.0E−06 126.1 100.6 113.4 9327-6 AdPhAE/C6 1.0E−06 19.6 24.6 22.1 9327-7 Al142Me/C8 1.0E−06 84.0 81.0 82.5 9327-8 Ad2PhPZMe/C3 1.0E−06 103.7 113.9 108.8 9327-8 Ad2PhPZMe/C3 1.0E−05 45.2 40.5 42.9 9327-9 AdPh3/VC7 1.0E−06 1.6 30.2 15.9 9327-9 AdPh3/VC7 1.0E−05 −11.1 −0.2 −5.7

TABLE-US-00007 TABLE 1-3 Reference Compound Data Assay IC.sub.50 K.sub.i Reference Compound (M) (M) n.sub.H σ.sub.1 (h) haloperidol 1.3E−08 1.1E−08 0.8 σ .sub.2 haloperidol 1.5E−07 1.3E−07 1.1 haloperidol 1.0E−07 8.6E−08 0.6

[0084] 1.6. In Vitro Pharmacology: Isolated Organ Bioassay

[0085] The effects of (+) A1-41, (−) A1-41 and (−) A2-73 investigated for agonist and antagonist activities at the muscarinic M.sub.1 receptors in the rabbit vas deferens are presented in table 2-1 where those of the reference compounds are also reported.

[0086] In the field-stimulated rabbit vas deferens, the M.sub.1 receptor agonist McN-A-343 induced a concentration-dependent decrease in the twitch contraction amplitude which was reversed by the antagonist pirenzepine in a concentration-dependent manner.

[0087] In the untreated tissues, (+) A1-41, (−) A1-41 and (−) A2-73 did not decrease the twitch contraction amplitude but caused a slight to moderate increase.

[0088] In the tissues previously depressed with McN-A-343, (+) A1-41, (−) A1-41 and (−) A2-73 produced a concentration-dependent and almost complete recovery of the twitch contraction amplitude.

[0089] These results indicate that (+) A1-41, (−) A1-41 and (−) A2-73 behave as antagonists at the M.sub.1 receptors.

TABLE-US-00008 TABLE 2-1 Effects of (+) AE 14, (−) AE 14 and (−) AE 37 investigated for agonist and antagonist activities at the muscarinic M.sub.1 receptors in the rabbit vas deferens Test for agonist activity Control response to Responses to increasing McN-A-343 concentrations + pirenzepine Compounds (1.0E−06M) of the compounds (1.0E−07M) 1.0E−06M 1.0E−05M 5.0E−05M (+) AE 14 100 −16 −31 not tested (−) AE 14 100 −5 −8 not tested (−) AE 37 100 −20 −33 not tested 1.0E−07M 3.0E−07M 1.0E−06M McN-A-343 100 29 67 99 −5 Test for antagonist activity Control Responses to McN-A-343 response to (1.0E−06M) in the presence McN-A-343 of increasing concentrations Compounds (1.0E−06M) of the compounds 1.0E−06M 1.0E−05M 5.0E-05M (+) AE 14 100 13 1 (−) AE 14 100 20 9 (−) AE 37 100 16 −1 1.0E−08M 3.0E−08M 1.0E−07M pirenzepine 100 72 43 4

[0090] The results are expressed as a percent of the control response to McN-A-343 (decrease in twitch contraction amplitude) (mean values; n=2)

Example 1

Neuroprotection Against Beta Amyloid

[0091] A 67 year old male diagnosed with early stage Alzheimer's dementia is treated with 10 mg of ⊖Anevex2-73 substantially free of Anavex2-73, once per week for three years. His mental function is tested quarterly and does not decrease over the period. On autopsy, his brain is found to contain senile plaques but very low content in amyloid peptide oligomers.

Example 2

Neuroprotection Against Oxidative Stress

[0092] A 29 year old female balloonist, anticipating anoxic stress, is orally administered 10 mgs of oral ⊖Anevex2-73 substantially free of Anavex2-73 daily for 5 days preceding a balloon ascent. The balloonist ascends to 6,000 meters without oxygen assist and suffers no anoxic damage.

Example 3

Neuroprotection Against Neurotoxicity

[0093] A 37 year old male hazardous materials engineer, anticipating neurotoxic stress is orally administered 1 mg of ⊖ Anevex2-73 substantially free of Anavex2-73, daily for 5 days preceding exposure to tetanus toxin. The engineer is exposed 0.1 ng/kg of said neurotoxin and suffers no damage.

Example 4

Neuroprotection in Stroke Patient

[0094] A 57 year old male enters the emergency room and is diagnosed with an 30 ischemic event involving the middle cerebral artery, with symptomatology onset being less than 1 hr. Immediately, the patient is administered an i.v. supplemented with 1 mg of ⊖Anevex2-73 substantially free of Anavex2-73 while blood supply to the restricted area is restored. Daily testing of cognitive and motor systems show no deficits in physical or mental capacities. In addition, CT/MRI imaging shows no signs of lesioning in the affected region, immediately following recovery and that this was maintained and confirmed by follow-up imaging and behavior testing.

Example 5

Neuroprotection Against Amyloid

[0095] An 80 year old female patient is diagnosed with AD and treated with 10 mg of ⊖Anevex2-73 substantially free of Anavex2-73 daily for 3 yrs. The patient's cognitive score stabilizes and then increases slowly and regularly over the following months.

[0096] Dosing Information/Dosage Forms:

[0097] For ⊖Anevex2-73 substantially free of Anavex2-73 dosages of about 0.01-100 mg/daily, preferably 0.5-10 mg/daily, more preferably 0.5-2 mg/daily are noted. Dosing once every two days (3 times a week) is noted. AD is a chronic disease, so staring treatment promptly with diagnosis is preferred.

[0098] Particular attention is drawn to the method of this invention comprising ⊖ Anevex2-73 substantially free of Anavex2-73 administration. In some instances therapeutic treatment includes administration of at least one cooperating acetylcholinesterase inhibitor (donepezil, galantamine, rivastigmine, or memantine), wherein at least one of said therapeutically effective amounts of either or the dose of cooperating acetylcholinesterase inhibitor is sub-therapeutic (sub-MAD) as compared to the active dose when used alone. Either the ⊖Anevex2-73 substantially free of Anavex2-73 or the cooperating acetylcholinesterase inhibitor is used. In this regard, reference is made to U.S. Ser. No. 13/940,352 to Vamvakides et al entitled “ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION AND METHOD FOR NEUROPROTECTION” the teachings of which are incorporated herein by reference.

[0099] The compositions of this invention individually or in combination are employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral or inhalation) or topical application which do not deleteriously react with the active compositions. Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil, fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compositions. They can also be combined where desired with other active agents, e.g., vitamins.

[0100] In some embodiments of the present invention, dosage forms include instructions for the use of such compositions.

[0101] For parenteral application, particularly suitable are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. Ampules, vials, and injector cartridges are convenient unit dosages.

[0102] “Unit dosage form” shall mean single drug administration entity. By way of example, a single tablet, capsule, dragee, or trochee, suppository, or syringe.

[0103] Also for parenteral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules. A syrup, elixir, or the like can be used wherein a sweetened vehicle is employed. Sublingual and buccal forms are also noted.

[0104] Sustained or directed release compositions can be formulated, e.g., liposomes or those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compositions and use the lyophilizates obtained, for example, for the preparation of products for injection.