Hydroxynorketamine for the use in the treatment of depression

Abstract

The present invention relates to hydroxynorketamine for the use in the treatment of depression. In particular, the present invention concerns hydroxynorketamine for use in the treatment of depression, wherein hydroxynorketamine is administered in form of at least one prodrug, and wherein the at least one prodrug is orally administered in a modified-release dosage form. The prodrug is selected from (S)-Ketamine, (R)-Ketamine, (R,S)-Ketamine, (S)-Norketamine, (R)-Norketamine, (R,S)-Norketamine, (S)-Hydroxyketamine, (R)-Hydroxyketamine, (R,S)-Hydroxyketamine.

Claims

1. A modified-release dosage form for use in a method for the treatment of depression, to be orally administered, wherein the treatment of depression is a long-term treatment, and wherein the modified-release dosage form is a prolonged-release dosage form, wherein the prolonged-release dosage form is in the form of a diffusion-controlled release system comprising a multitude of particles which are pellets containing a core comprising at least one prodrug of hydroxynorketamine and a release control layer coated upon the core, wherein the at least one prodrug is (R,S)-ketamine hydrochloride and wherein the oral administration of the prolonged-release dosage form comprising (R,S)-ketamine hydrochloride results in plasma concentration profiles exhibiting a ratio of AUC.sub.K/HNK between 1:7 and 1:20.

2. The modified-release dosage form for use in a method for the treatment of depression according to claim 1, wherein the long-term treatment lasts for at least one month.

3. The modified-release dosage form for use in a method for the treatment of depression according to claim 1, wherein the dosage form is a single-unit or a multiple-unit dosage form.

4. The modified-release dosage form for use in a method for the treatment of depression according to claim 1, wherein the dosage form is a tablet or a capsule.

5. A method of treating depression, said method comprising orally administering a modified-release dosage form to a patient in need thereof, wherein the treatment of depression is a long-term treatment, and wherein the modified-release dosage form is a prolonged-release dosage form, wherein the prolonged-release dosage form is in the form of a diffusion-controlled release system comprising a multitude of particles which are pellets containing a core comprising at least one prodrug of hydroxynorketamine and a release control layer coated upon the core, wherein the at least one prodrug is (R,S)-ketamine hydrochloride and wherein the oral administration of the prolonged-release dosage form comprising (R,S)-ketamine hydrochloride results in plasma concentration profiles exhibiting a ratio of AUC.sub.K/HNK between 1:7 and 1:20.

6. The method of claim 5, wherein the long-term treatment lasts for at least one month.

7. The method of claim 5, wherein the dosage form is a single-unit or a multiple-unit dosage form.

8. The method of claim 5, wherein the dosage form is a tablet or a capsule.

9. The method of claim 5, wherein the long-term treatment lasts for at least two months.

10. The method of claim 5, wherein the long-term treatment lasts for at least three months.

11. The method of claim 5, wherein the dosage form is a tablet.

Description

EXAMPLES

Example 1: Preparation of Matrix Controlled Release Tablets Containing 20 mg Ketamine Hydrochloride

(1) TABLE-US-00001 Ketamine HCl 20.00 mg Kollidon ® SR 78.50 mg Aerosil 200 1.00 mg Magnesium stearate 0.50 mg Total tablet 100.00 mg

(2) Ketamine HCl, Kollidon® SR and Aerosil 200 are sieved through a 630 μm sieve and mixed for 15 minutes.

(3) Magnesium stearate is added to the mixture and further mixed for 2 minutes. Tablets with the composition outlined in the table above are pressed on a rotary machine with oblong punches 9*4 mm.

Example 2: Preparation of Capsules Containing 20 mg Ketamine Hydrochloride

(4) Step 1:

(5) A spraying solution is prepared from the following ingredients:

(6) TABLE-US-00002 Hypromellose  22.5 g Ketamine hydrochloride 150.0 g Ethanol 96% q.s. Water, purified q.s.

(7) A spraying suspension is prepared by successively dissolving hypromellose and ketamine hydrochloride in a mixture of purified water and ethanol [1:2.75 m/m].

(8) 60.0 g sugar spheres (saccharose, particle size range (90%) 200 to 400 μm) are filled into a fluid-bed processor with a bottom-spray nozzle and pre-heated. The spraying suspension is then sprayed onto the sugar spheres in the fluid-bed processor, thus preparing a plurality of sugar spheres having a layer of ketamine coated thereupon. The coated sugar spheres are then sieved to remove agglomerates (vibration sieve or equivalent).

(9) Step 2:

(10) A coating suspension is prepared from the following ingredients:

(11) TABLE-US-00003 Ethylcellulose 54.0 g Hydroxypropyl cellulose  5.4 g Propylene glycol 10.8 g Talc  5.4 g Ethanol 96% q.s Water, purified q.s

(12) Hydroxypropyl cellulose is dissolved in water. Ethylcellulose and ethanol are then added to the solution. Finally, propylene glycol and talc are added and the suspension is continuously stirred.

(13) The coated sugar spheres from Step 1 are filled into a fluid-bed processor and preheated. The coated suspension prepared as indicated above is sprayed onto the coated sugar spheres. The pellets obtained thereby as then sieved to remove the agglomerates.

(14) Step 3:

(15) 41 mg of coated pellets from step 2 are filled into capsule.

Example 3: Example of a Prolonged-Release Tablet Containing 10, 20, 40 and 80 mg Ketamine Hydrochloride

(16) The following tables show the compositions of prolonged-release tablet containing 10, 20, 40 and 80 mg ketamine hydrochloride. The coated pellets were similarly prepared to example 2.

Example 3.1 Prolonged-Release Tablet Containing 10 mg Ketamine Hydrochloride

(17) TABLE-US-00004 Component Function Amount/Unit Quality Standard.sup.# Active Pellets Ketamine hydrochloride Drug substance 10.00 mg Ph. Eur. Sugar spheres (250-355 μm) Carrier 4.00 mg Ph. Eur. Hypromellose Binder 1.50 mg Ph. Eur. Ethanol 96% Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate I 15.50 mg Retard Coating Ethylcellulose Retarding polymer 6.50 mg Ph. Eur. Hydroxypropylcellulose Pore builder 1.45 mg Ph. Eur. Propylene glycol Plasticizer 1.95 mg Ph. Eur. Talc Glidant 0.65 mg Ph. Eur. Ethanol (96%) Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate II 26.05 mg Final Blending Carmellose sodium Filler 28.00 mg Ph. Eur. Cellulose, microcrystalline Filler 15.21 mg Ph. Eur. Magnesium stearate Lubricant 0.04 mg Ph. Eur. Silica, colloidal anhydrous Glidant 0.70 mg Ph. Eur. Core tablet 70.00 mg Tablet coating Opadry ® II White, consisting of: Dye 3.00 mg In-house Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc Water, purified Solvent q.s Ph. Eur. Final weight of tablet 73.00 mg

Example 3.2 Prolonged-Release Tablet Containing 20 mg Ketamine Hydrochloride

(18) TABLE-US-00005 Component Function Amount/Unit Quality Standard.sup.# Active Pellets Ketamine hydrochloride Drug substance 20.00 mg Ph. Eur. Sugar spheres (250-355 μm) Carrier 8.00 mg Ph. Eur. Hypromellose Binder 3.00 mg Ph. Eur. Ethanol 96% Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate I 31.00 mg Retard Coating Ethylcellulose Retarding polymer 13.00 mg Ph. Eur. Hydroxypropylcellulose Pore builder 2.90 mg Ph. Eur. Propylene glycol Plasticizer 3.90 mg Ph. Eur. Talc Glidant 1.30 mg Ph. Eur. Ethanol (96%) Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate II 52.10 mg Final Blending Carmellose sodium Filler 56.00 mg Ph. Eur. Cellulose, microcrystalline Filler 30.42 mg Ph. Eur. Magnesium stearate Lubricant 0.08 mg Ph. Eur. Silica, colloidal anhydrous Glidant 1.40 mg Ph. Eur. Core tablet 140.00 mg Tablet coating Opadry ® II White, consisting of: Dye 5.40 mg In-house Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc Opadry ® II Yellow, consisting Dye 0.60 mg In-house of: Polyvinyl alcohol, Iron oxide yellow, Macrogol, Talc Water, purified* Solvent 24.00 mg Ph. Eur. Final weight of tablet 146.00 mg

Example 3.3 Prolonged-Release Tablet Containing 40 mg Ketamine Hydrochloride

(19) TABLE-US-00006 Component Function Amount/Unit Quality Standard.sup.# Active Pellets Ketamine hydrochloride Drug substance 40.00 mg Ph. Eur. Sugar spheres (250-355 μm) Carrier 16.00 mg Ph. Eur. Hypromellose Binder 6.00 mg Ph. Eur. Ethanol 96% Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate I 62.00 mg Retard Coating Ethylcellulose Retarding polymer 26.00 mg Ph. Eur. Hydroxypropylcellulose Pore builder 5.80 mg Ph. Eur. Propylene glycol Plasticizer 7.80 mg Ph. Eur. Talc Glidant 2.60 mg Ph. Eur. Ethanol (96%) Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate II 104.20 mg Final Blending Carmellose sodium Filler 112.00 mg Ph. Eur. Cellulose, microcrystalline Filler 60.84 mg Ph. Eur. Magnesium stearate Lubricant 0.16 mg Ph. Eur. Silica, colloidal anhydrous Glidant 2.80 mg Ph. Eur. Core tablet 280.00 mg Tablet coating Opadry ® II White, consisting of: Dye 11.40 mg In-house Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc Opadry ® II Red, consisting of: Dye 0.60 mg In-house Polyvinyl alcohol, Iron oxide, Macrogol, Talc Water, purified Solvent 48.00 mg Ph. Eur. Final weight of tablet 292.00 mg

Example 3.4 Prolonged-Release Tablet Containing 80 mg Ketamine Hydrochloride

(20) TABLE-US-00007 Component Function Amount/Unit Quality Standard.sup.# Active Pellets Ketamine hydrochloride Drug substance 80.00 mg Ph. Eur. Sugar spheres (250-355 μm) Carrier 32.00 mg Ph. Eur. Hypromellose Binder 12.00 mg Ph. Eur. Ethanol 96% Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate I 124.00 mg Retard Coating Ethylcellulose Retarding polymer 52.00 mg Ph. Eur. Hydroxypropylcellulose Pore builder 11.60 mg Ph. Eur. Propylene glycol Plasticizer 15.60 mg Ph. Eur. Talc Glidant 5.20 mg Ph. Eur. Ethanol (96%) Solvent q.s Ph. Eur. Water, purified Solvent q.s Ph. Eur. Intermediate II 208.40 mg Final Blending Carmellose sodium Filler 112.00 mg Ph. Eur. Cellulose, microcrystalline Filler 233.68 mg Ph. Eur. Magnesium stearate Lubricant 0.32 mg Ph. Eur. Silica, colloidal anhydrous Glidant 5.60 mg Ph. Eur. Core tablet 560.00 mg Tablet coating Opadry ® II White, consisting of: Dye 20.00 mg In-house Polyvinyl alcohol, Titanium dioxide, Macrogol, Talc Water, purified Solvent 80.00 mg Ph. Eur. Final weight of tablet 580.00 mg

Example 4: In Vivo Pharmacokinetics, Metabolism and Safety

(21) The pharmacokinetics, metabolism and safety of the prolonged-release dosage forms according to examples 3.1 to 3.4 were evaluated as follows.

(22) A dose-escalation study was performed in five consecutive periods (7 days wash-out) in 15 healthy subjects (5 females, 20-25, BMI 19.4-27.6 kg/m2). The racemic analytes were measured using validated LC-MS/MS methods according to Hasan et al., 2017 (Hasan et al., Quantitative chiral and achiral determination of ketamine and its metabolites by LC-MS/MS in human serum, urine and fecal samples, Journal of Pharmaceutical and Biomedical Analysis, 2017, 139, 87-97).

(23) Therefore, the prolonged-release dosage forms according examples 3.1 to 3.4 were orally administered with 240 ml of table water in fasting state. In addition, 5 mg ketamine (in form of ketamine hydrochloride) solution was intravenously administered within 30 min in fasting state.

(24) 4.1 Pharmacokinetics

(25) The pharmacokinetics of ketamine and its metabolites norketamine and hydroxynorketamine were measured and depicted in the following table 1. AUC stands for the area under the curve, C.sub.max stands for the maximum plasma concentration, T.sub.max stands for the time to C.sub.max, F stands for absolute bioavailability, T.sub.1/2 stands for the apparent terminal half-life, AUC.sub.NK/K for the ratio of AUC.sub.NK to AUC.sub.K and AUC.sub.HNK/K for the ratio of AUC.sub.HNK to AUC.sub.K.

(26) TABLE-US-00008 TABLE 1 Pharmacokinetic characteristics of ketamine after intravenous infusion (30 min) of 5 mg ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.4 5 mg i.v. 10 mg p.o. 20 mg p.o. 40 mg p.o. 80 mg p.o. AUC.sup.1 ng × h/ml 52.3 ± 12.2 13.4 ± 13.3.sup.  33.5 ± 35.8 63.5 ± 42.6 .sup.  124 ± 72.9  AUC.sub.n-Ket/  1.79 ± 0.557 21.6 ± 14.2.sup.#  .sup. 16.9 ± 8.58.sup.#* 14.9 ± 8.50.sup.#* 14.0 ± 6.50.sup.#*.sup.† AUC.sub.Ket AUC.sub.HNK/ 0.334 ± 0.128 7.33 ± 7.05.sup.#  .sup. 19.8 ± 16.4.sup.#* 14.4 ± 8.99.sup.#* 16.2 ± 7.93.sup.#*.sup.‡ AUC.sub.Ket AUC.sub.DHNK/ 0.446 ± 0.157 7.00 ± 6.19.sup.# .sup. 6.65 ± 5.52.sup.# .sup. 4.46 ± 3.19.sup.#*.sup.† 3.68 ± 2.11.sup.#*.sup.† AUC.sub.Ket C.sub.max ng/ml 29.9 ± 8.48 1.63 ± 1.33.sup.  3.70 ± 3.93 6.66 ± 4.25 .sup.  11.8 ± 6.56   T.sub.max h — 5.34 ± 1.18.sup.   5.70 ± 0.649 5.87 ± 0.915.sup.  .sup. 6.27 ± 0.594*.sup.† F % — 12.3 ± 10.7.sup.   15.3 ± 14.4* 14.9 ± 8.94*.sup.  14.6 ± 7.56*.sup.  V.sub.ss l/kg 6.58 ± 3.07 — — — — T.sub.1/2 h 5.89 ± 2.61 4.96 ± 1.25.sup.   6.74 ± 2.02* 7.21 ± 1.56.sup.#* 7.68 ± 1.43.sup.#*.sup.† CL/F l/min  1.67 ± 0.380 22.3 ± 16.1.sup.#  .sup. 17.9 ± 11.4.sup.#* 16.3 ± 11.1.sup.#* 15.0 ± 8.93.sup.#*.sup.  CL.sub.R ml/min 33.6 ± 36.5 78.9 ± 32.2.sup.#  .sup. 70.2 ± 30.3.sup.#* 67.3 ± 28.0.sup.#  61.7 ± 23.3.sup.#*.sup.  CL.sub.M ml/min  268 ± 75.6 — — — — CL.sub.M, Nor Ket ml/min 34.6 ± 14.4 — — — — CL.sub.M, HNK ml/min 45.5 ± 8.65 — — — — CL.sub.M, DHNK ml/min  188 ± 68.1 — — — — CL.sub.intestinal ml/min 0.046 ± 0.097 — — — — A.sub.e, urine μg 93.4 ± 71.6 44.8 ± 16.3.sup.  96.6 ± 39.3 209 ± 92.0 .sup.  394 ± 1 66  A.sub.e, urine % 1.87 ± 1.43 0.448 ± 0.163.sup.# .sup. 0.483 ± 0.196.sup.# 0.524 ± 0.230.sup.#* 0.493 ± 0.208.sup.#   A.sub.e, feces μg 0.160 ± 0.343 131 ± 118.sup.  335 ± 401 557 ± 465 .sup.  2050 ± 1770   A.sub.e, feces % 0.003 ± 0.007 1.31 ± 1.18.sup.# .sup. 1.68 ± 2.01.sup.# 1.39 ± 1.16.sup.#  2.56 ± 2.21.sup.#*.sup.‡ MRT h 4.68 ± 2.01 10.2 ± 1.41.sup.# .sup. 11.2 ± 1.61.sup.# 11.8 ± 1.27.sup.#* .sup. 12.6 ± 1.10.sup.#*.sup.†‡ MAT h — 6.16 ± 1.40.sup.  7.11 ± 1.27 7.67 ± 1.16*.sup.  8.45 ± 1.02*.sup.†‡ p < 0.05 (Wilcoxon test); .sup.#vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg p.o. .sup.1if T.sub.last = 60 h (24 h for 5 mg iv) then AUC.sub.0-∝, else AUC.sub.0-60 h(24 h)

(27) TABLE-US-00009 TABLE 2 Pharmacokinetic characteristics of norketamine after intravenous infusion (30 min) of 5 mg ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.4 5 mg i.v. 10 mg p.o. 20 mg p.o. 40 mg p.o. 80 mg p.o. AUC.sup.1 ng × h/ml 95.0 ± 21.0  195 ± 68.7 392 ± 151 722 ± 188 1460 ± 404  AUC.sub.HNK/ 0.194 ± 0.093 0.342 ± 0.238  1.07 ± 0.594 0.953 ± 0.310 1.14 ± 0.328 AUC.sub.n-Ket C.sub.max ng/ml 12.4 ± 2.67 15.8 ± 4.75 30.9 ± 10.1 54.9 ± 11.7 102 ± 24.3  T.sub.max h 0.967 ± 0.303 .sup. 4.87 ± 1.01.sup.#  .sup. 5.27 ± 0.923.sup.#    5.80 ± 0.414.sup.#*.sup.†   .sup. 6.27 ± 0.458.sup.#*.sup.†‡ T.sub.1/2 h 7.83 ± 1.46 8.11 ± 1.71 8.28 ± 1.52 8.06 ± 1.05 7.96 ± 0.920 A.sub.e, urine μg 93.6 ± 23.9  173 ± 36.4 352 ± 120 664 ± 182 1280 ± 409  A.sub.e, urine %  1.99 ± 0.507  1.83 ± 0.387  1.87 ± 0.636  1.76 ± 0.483 .sup. 1.70 ± 0.543.sup.#† A.sub.e, feces μg 2.16 ± 1.95 5.02 ± 3.97 9.55 ± 5.66 19.3 ± 17.8 39.4 ± 21.9  A.sub.e, feces % 0.046 ± 0.041 0.053 ± 0.042 0.051 ± 0.030 0.051 ± 0.047 0.052 ± 0.029  p < 0.05 (Wilcoxon test); .sup.#vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg p.o. .sup.1if T.sub.last = 60 h (24 h for 5 mg iv) then AUC.sub.0-∝, else AUC.sub.0-60 h(24 h)

(28) TABLE-US-00010 TABLE 3 Pharmacokinetic characteristics of hydroxynorketamine after intravenous infusion (30 min) of 5 mg ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.4 5 mg i.v. 10 mg p.o. 20 mg p.o. 40 mg p.o. 80 mg p.o. AUC.sup.1 ng × h/ml 17.8 ± 7.97 61.8 ± 34.5 380 ± 185 657 ± 185 1610 ± 482  C.sub.max ng/ml  1.32 ± 0.505 2.75 ± 1.15 20.3 ± 11.0 32.6 ± 9.38 75.5 ± 19.6 T.sub.max h 3.57 ± 1.18 .sup. 8.00 ± 1.73.sup.# .sup. 8.00 ± 1.70.sup.# .sup. 8.47 ± 2.77.sup.# .sup. 8.40 ± 1.50.sup.# T.sub.1/2 h 7.92 ± 2.81 13.2 ± 7.77 9.23 ± 1.95 8.90 ± 1.42 9.27 ± 1.49 A.sub.e, urine μg  145 ± 45.8  265 ± 70.1 540 ± 202 1100 ± 491  2270 ± 952  A.sub.e, urine %  2.90 ± 0.916  2.65 ± 0.701 2.70 ± 1.01 2.74 ± 1.23 2.84 ± 1.19 p < 0.05 (Wilcoxon test); .sup.#vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg p.o. .sup.1if T.sub.last = 60 h (24 h for 5 mg iv) then AUC.sub.0-∝, else AUC.sub.0-60 h(24 h)

(29) TABLE-US-00011 TABLE 4 Pharmacokinetic characteristics (as sum of R- and S-form) of dehydroxynorketamine after intravenous infusion (30 min) of 5 mg ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.4 5 mg i.v. 10 mg p.o. 20 mg p.o. 40 mg p.o. 80 mg p.o. AUC.sup.1 ng × h/ml 21.9 ± 3.88 50.7 ± 12.5  120 ± 44.2 182 ± 19.6 .sup.   331 ± 62.5 C.sub.max ng/ml  2.75 ± 0.776 4.04 ± 1.12 8.94 ± 3.31 12.4 ± 2.74 .sup.  20.1 ± 4.12 T.sub.max h  1.80 ± 0.528  .sup. 4.80 ± 0.411.sup.#  .sup. 5.57 ± 0.998.sup.#* 5.83 ± 1.21.sup.#*   6.50 ± 1.24.sup.#*.sup.† T.sub.1/2 h 5.96 ± 1.85 .sup. 8.20 ± 2.14.sup.# .sup. 8.93 ± 2.72.sup.# 9.43 ± 1.56.sup.#* .sup. 8.90 ± 1.14.sup.# A.sub.e, urine μg 516 ± 110 1040 ± 268  2210 ± 573  3630 ± 869 .sup.  7280 ± 1559 A.sub.e, urine % 10.3 ± 2.20 10.4 ± 2.68 11.0 ± 2.86 9.08 ± 2.17.sup.†  .sup. 9.09 ± 1.95.sup.#† p < 0.05 (Wilcoxon test); .sup.#vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg p.o. .sup.1if T.sub.last = 60 h (24 h for 5 mg iv) then AUC.sub.0-∝, else AUC.sub.0-60 h(24 h)

(30) TABLE-US-00012 TABLE 5 Pharmacokinetic characteristics of (±)-ketamine after intravenous infusion (30 min) of 5 mg (±)-ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.4 5 mg i.v. 10 mg p.o. 20 mg p.o. 40 mg p.o. 80 mg p.o. AUC (ng × h/ml) 52.3 ± 12.2 13.4 ± 13.3 33.5 ± 35.8  63.5 ± 42.6 .sup.  124 ± 72.9  C.sub.max (ng/ml) 29.9 ± 8.48 1.63 ± 1.33 3.70 ± 3.93  6.66 ± 4.25 .sup.  11.8 ± 6.56   T.sub.max (h) — 5.34 ± 1.18 5.70 ± 0.649 5.87 ± 0.915.sup.  .sup. 6.27 ± 0.594*.sup.† F (%) — 12.3 ± 10.7 15.3 ± 14.4* 14.9 ± 8.94*.sup.  14.6 ± 7.56*.sup.  T.sub.1/2 (h) 5.89 ± 2.61 4.96 ± 1.25 6.74 ± 2.02* 7.21 ± 1.56.sup.#* 7.68 ± 1.43.sup.#*.sup.† AUC.sub.NK/K  1.79 ± 0.557 .sup. 21.6 ± 14.2.sup.# .sup. 16.9 ± 8.58.sup.#* 14.9 ± 8.50.sup.#* 14.0 ± 6.50.sup.#*.sup.† AUC.sub.HNK/K 0.334 ± 0.128 .sup. 7.33 ± 7.05.sup.# .sup. 19.8 ± 16.4.sup.#* 14.4 ± 8.99.sup.#* 16.2 ± 7.93.sup.#*.sup.‡ p < 0.05.sup.# vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg p.o. (Wilcoxon)

(31) The maximum concentration (C.sub.max) and the time of maximum concentration (T.sub.max) were obtained directly from the measured concentration-time curves.

(32) The area under the concentrations-time curve (AUC) was calculated with the measured data points from the time of administration until the last quantifiable concentration by the trapezoidal formula. The AUC was assessed up to the last sampling time above the limit of quantification and is extrapolated to infinity to obtain the AUC values.

(33) Apparent Terminal half-life (T.sub.1/2) was calculated by the following equation
T.sub.1/2=ln 2/λ.sub.z.

(34) The terminal elimination rate constant (λ.sub.z) was evaluated from the terminal slope by log-linear regression analysis.

(35) The absolute bioavailability (F) was calculated by the following equation
F.sub.abs=AUC.sub.oral/AUC.sub.iv×dose.sub.iv/dose.sub.oral.
4.2 Safety

(36) An Adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not have necessarily a causal relationship with this treatment. An adverse event (AE) therefore can be any unfavorable and unintended sign including an abnormal laboratory (or vital, ECG etc.) finding, symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

(37) A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, or is life-threatening, or requires hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect

(38) Important medical reactions that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes listed in the definition above should also be considered serious.

(39) Examples of such events are intensive treatment in an emergency unit or at home for allergic bronchospasm, blood dyscrasia or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

(40) The term “life threatening”, in the definition, refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

(41) Hospitalization for rehabilitation or surgery already planned before the start of the study period is not a serious AE. Such an event meets the definition of “no case”.

(42) An AE/SAE, the nature or severity of which is not consistent with the applicable product information (investigator's brochure, local product information sheet) is an Unexpected AE/SAE. Unexpected serious adverse reactions, which are suspected to be related to an investigational medicinal product, are called SUSARs (suspected unexpected serious adverse reaction).

(43) Adverse events (AE) were detected both by a standardized questionnaire on tolerability and by querying the subjects at the scheduled times. Furthermore, the subjects were asked to report any AE spontaneously. 26 AEs occurred during the entire study; 10 AEs in Treatment A, 7 AEs in Treatment B, 1 AE in Treatment C, 2 AEs in Treatment D and 6 AEs in Treatment E. 7 AEs were considered by the clinical investigators to be not or unlikely related. 4 AEs were considered to be possibly related to the study medication and 11 to be probably related.

(44) Dizziness (8 AEs), headache (4 AEs) and palpitations (3 AEs) belonged to the most frequent adverse events.

(45) The results are depicted in the following table.

(46) TABLE-US-00013 TABLE 6 Number and percent of subjects reporting adverse events by system organ class (SOC), preferred term (PT) and treatments for adverse events judged to be certainly, probably or possibly related to the study medication Treatment B Treatment E Treatment A ketamine 10 mg PR ketamine 80 mg PR SOC PT ketamine 5 mg i.v. tablets tablets nervous system disorders dizziness  6 (40%) 1 (7%) — cardiac disorders palpitation 1 (7%) 1 (7%) 1 (7%) nervous system disorders heaviness of head — 1 (7%) — gastrointestinal disorders nausea — 1 (7%) — skin and subcutaneous tissue disorder sweating/cold sweat — 1 (7%) — cardiac disorder tachycardia 1 (7%) — — general disorder and administration site weakness — 1 (7%) — condition