Oral Dosage Forms of Ketamine

Abstract

The present invention relates to an oral dosage form for administration of ketamine and a method of preparing an oral dosage form for administration of ketamine, preferably once or twice a day.

Claims

1. An oral dosage form comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the dosage form provides an in vitro release of ketamine, when measured according to the USP Basket Method I in 0.1M HCl at 37° C. at 100 rpm of 0 to 40% after 2 hours, of 10 to 70% after 4 hours, of 30 to 85% after 6 hours and of 45 to 100% after 8 hours.

2. A modified release oral dosage form comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, wherein the ratio of the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37° C. in a aqueous solution containing 20% by volume of ethanol to the amount of ketamine released after 1 hour of in-vitro dissolution of the dosage form at 37° C. in an ethanol-free aqueous solution is less than about 2:1, when measured according to the USP 1 Basket Method in 0.1M HCl at 100 rpm.

3. The oral dosage form according to claim 1, wherein the dosage form is a matrix controlled release dosage form, an osmotic controlled release dosage form or a multi particulate controlled release dosage form.

4. The oral dosage form according to claim 1, wherein the dosage form comprises pellets containing a core comprising ketamine or a pharmaceutically acceptable salt or solvate thereof, and a release control layer comprising a release control substance coated upon the core.

5. The oral dosage form according to claim 4, wherein the pellets are contained in an external phase of at least one pharmaceutically acceptable excipient.

6. The oral dosage form according to claim 4, wherein the core comprises a layer comprising ketamine coated on an inert core.

7. The oral dosage form according to claim 4, wherein the release control substance is a water insoluble polymer, preferably an alkyl cellulose and more preferably ethylcellulose.

8. The oral dosage form according to claim 5, wherein the external phase comprises carboxymethyl cellulose, optionally in the form of a salt, as a pharmaceutically acceptable excipient.

9. The oral dosage form according to claim 1 which is a tablet.

10. The oral dosage form according to claim 1, wherein the ketamine salt is ketamine hydrochloride and wherein the amount comprised in the oral dosage form is in the range of from 5 to 400 mg ketamine hydrochloride.

11. The oral dosage form according to claim 1, wherein the dosage form is administered once or twice daily.

12. The oral dosage form according to claim 1 which is a multi-particulate tablet, wherein the tablet comprises i) ketamine-containing cores comprising 1 to 30 wt. % inert beads, 1 to 40 wt. % ketamine, in particular ketamine hydrochloride, 0.01 to 10 wt. % binder, and 0 to 10 wt. % glidant, ii) a release-control layer coated on each ketamine-containing core, comprising 1 to 40 wt. % release-control substance, 0.01 to 10 wt % pore builder, 0.01 to 10 wt. % plasticizer, 0 to 15 wt. % glidant, and iii) an external phase comprising 20 to 85 wt. % filler, 0 to 3 wt. % lubricant and 0 to 5 wt. % glidant, wherein all wt. % are based on the total weight of the tablet.

13. The oral dosage form according to claim 1, wherein the administration of a single oral dosage form leads in-vivo to a C.sub.max of ketamine of 1 to 150 ng/ml and to a AUC.sub.0-∞ of 5 to 1000 h.Math.ng/ml.

14. The oral dosage form according to claim 1, wherein T.sub.max of ketamine is 3 to 9 h.

15. The oral dosage form according to claim 1 having an absolute bioavailability F.sub.abs of 5 to 25%.

16. A method for the treatment of neuropathic pain, said method comprising administering the oral dosage of claim 1 to a patient in need thereof.

17. The method of claim 16 for use in the treatment of patients suffering from spinal cord injury, multiple sclerosis, cancer, immune mediated disorders, metabolic conditions such as diabetes, herpes zoster infection, HIV-related neuropathies, or nutritional deficiencies.

18. A method for preparing an oral dosage form according to claim 1, comprising: a) coating inert cores with a layer comprising ketamine or a pharmaceutically acceptable salt or solvent thereof, b) coating the coated inert cores with a release-control layer comprising the release-controlling substance, thus forming pellets, c) mixing the pellets with at least one pharmaceutically acceptable excipient, d) forming a tablet from the mixture comprising the pellets and the at least one pharmaceutically acceptable excipient.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0151] FIG. 1 shows the dissolution profiles of a 20 mg containing ketamine hydrochloride tablet in 0.1M HCl and of a 20 mg containing ketamine hydrochloride tablet in HCl/EtOH 80:20;

[0152] FIG. 2a shows the geometric mean curves of (±)-ketamine after i.v. infusion of 5 mg (within 0.5 h) and oral administration of 10, 20, 40 and 80 mg ketamine modified release tablets according to the invention;

[0153] FIG. 2b shows the geometric mean curves of (±)-norketamine after i.v. infusion of 5 mg (within 0.5 h) and oral administration of 10, 20, 40 and 80 mg ketamine modified release tablets according to the invention.

EXAMPLES

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

[0154]

TABLE-US-00001 Ketamine HCl  20.00 mg Hydrogenated castor oil  92.74 mg Microcrystalline cellulose  35.00 mg Aerosil 200  1.50 mg Magnesium stearate  0.76 mg Total tablet 150.00 mg

[0155] Ketamine HCl, hydrogenated castor oil, microcrystalline cellulose and Aerosil 200 are sieved through a 600 μm sieve and mixed for 10 minutes.

[0156] 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.

Example 2: Preparation of Multi-Particulate Tablets Containing 20 mg Ketamine Hydrochloride

[0157] Step 1:

[0158] A spraying solution is prepared from the following ingredients:

TABLE-US-00002 Hypromellose  3.00 kg Ketamine hydrochloride 20.00 kg Sugar spheres  8.00 kg Ethanol 96% q.s. Water, purified q.s.

[0159] A spraying suspension is prepared by successively dissolving hypromellose and ketamine hydrochloride in a mixture of purified water and ethanol.

[0160] 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).

[0161] Step 2:

[0162] A coating suspension is prepared from the following ingredients:

TABLE-US-00003 Ethylcellulose 14.54 kg Hydroxypropyl cellulose  4.00 kg Triethyl citrate  3.27 kg Talc  1.45 kg Ethanol 96% q.s Water, purified q.s

[0163] Hydroxypropyl cellulose is dissolved in water. Ethylcellulose and ethanol are then added to the solution. Finally, triethyl citrate and talc are added and the solution is continuously stirred.

[0164] The coated sugar spheres from Step 1 are filled into a fluid-bed processor and preheated. The coated solution prepared as indicated above is sprayed onto the coated sugar spheres. The pellets obtained thereby as then sieved to remove the agglomerates.

[0165] Step 3:

[0166] The following ingredients are dry mixed to a blend:

TABLE-US-00004 Pellets from Step 2 54.26 kg Carmellose sodium 46.00 kg Microcrystalline cellulose 55.49 kg Colloidal anhydrous silica  1.50 kg Magnesium stearate  0.75 kg

[0167] The resulting dry blend is then compressed to tablets.

[0168] Step 4 (Optional):

[0169] A tablet coating suspension is made from the following ingredients:

TABLE-US-00005 Opadry ® II White 1.20 kg Water, purified q.s

[0170] 31.6 kg tablets are film coated with the tablet coating suspension.

[0171] The dissolution profiles of the 20 mg tablets are in accordance with the present invention, as apparent from FIG. 1. The dissolution profiles were measured using the USP 1 Basket Method at 37° C., 1000 ml 100 rpm in 0.1M HCl and HCl/EtOH 80:20.

Example 3: In Vivo Pharmacokinetics

[0172] A comparative bioavailability study of ketamine and norketamine after single dose administration of ketamine (in form of ketamine hydrochloride) 10, 20, 40 and 80 mg modified release tablets according to the invention in fasting state and 5 mg ketamine (in form of ketamine hydrochloride) solution for infusion was carried out. In the study, the C.sub.max, F.sub.abs, AUC.sub.0-∞ and T.sub.max as described above are determined in vivo in healthy subjects.

[0173] The modified release tablets have been produced in analogy to Example 2.

[0174] Objectives

[0175] Single dose, open label, five-treatment, five-period, consecutive study with at least 7 days wash-out between the study periods.

[0176] In the first treatment all subjects received a single dose of 5 mg (±)-ketamine solution for infusion within 30 min intravenously in fasting state.

[0177] The orally administered single doses of (±)-ketamine modified release tablets were given in consecutively increasing doses of 10, 20, 40 and 80 mg with 240 ml of table water in fasting state.

[0178] (±)-Ketamine and (±)-norketamine were measured in serum, urine and feces

[0179] Number of Subjects, Main Criteria for Inclusion [0180] 15 analyzed [0181] age: 18-45 years [0182] sex: male and female [0183] ethnic origin: Caucasian [0184] body mass index: >18.5 kg/m.sup.2 and <30 kg/m.sup.2 [0185] good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which were judged by the clinical investigator not to differ in a clinical relevant way from the normal state [0186] heart frequency between 50 and 90 bpm [0187] blood pressure between 140 and 100 systolic and 90 and 60 diastolic [0188] written informed consent

[0189] Sampling [0190] Blood: blank, 0.167, 0.333, 0.5, 0.667, 0.833, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after intravenous administration and blank, 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 12, 16, 24, 36, 48, 60 h after oral administration [0191] Urine: 0-24 h, 24-48 h and 48-72 h [0192] Feces: 0-120 h

[0193] Drug Assay

[0194] Validated achiral LC-MS/MS method for (±)-ketamine and (±)-norketamine, performed in a laboratory certified according to GLP (Good Laboratory Practice)

[0195] Pharmacokinetic Results

[0196] The results are summarized in the following tables, wherein AUC.sub.0-∞ stands for the area under the curve from zero extrapolated to infinity, C.sub.max stands for the maximum plasma concentration, T.sub.max stands for the time to C.sub.max, F.sub.abs stands for absolute bioavailability, T.sub.1/2 stands for the apparent terminal half-life.

TABLE-US-00006 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 5 mg i.v. 10 mg 20 mg 40 mg 80 mg AUC.sub.0-∞ ng × h/ml 59.9 ± 13.2 13.5 ± 9.73 27.1 ± 21.9 75.6 ± 48.3  178 ± 145 C.sub.max ng/ml 33.7 ± 9.74 1.48 ± 0.901 3.25 ± 2.29 7.64 ± 4.69 16.7 ± 13.4 T.sub.max h — 4.87 ± 1.22 5.87 ± 0.64* 6.00 ± 0.76* 6.07 ± 0.26* F.sub.abs % — 11.5 ± 8.09 11.0 ± 8.57 15.9 ± 9.53*.sup.† 17.9 ± 12.3*.sup.† T.sub.1/2 h 6.99 ± 5.22 7.39 ± 4.86 6.09 ± 4.98 8.44 ± 1.54.sup.#† 8.89 ± 1.42.sup.#† .sup.#vs. 5 mg i.v., *vs. 10 mg, .sup.†vs 20 mg

TABLE-US-00007 TABLE 2 Pharmacokinetics of (±)-norketamine after intravenous infusion (30 min) of 5 mg (±)-ketamine and oral administration of 10, 20, 40 and 80 mg ketamine PR tablets 5 mg 10 mg 20 mg 40 mg 80 mg AUC.sub.0-∞ ng × h/ml 87.7 ± 24.1  162 ± 39.7  339 ± 100  653 ± 164  1620 ± 731 C.sub.max ng/ml 11.4 ± 2.85 13.4 ± 2.92 27.6 ± 6.62 48.7 ± 10.4   113 ± 53.0 T.sub.max h 0.93 ± 0.32 4.72 ± 1.02 5.33 ± 0.77* 5.67 ± 0.52*  6.10 ± 0.60*.sup.†‡ T.sub.1/2 h 8.01 ± 2.35 7.38 ± 1.63 7.74 ± 3.09 8.25 ± 2.70.sup.†  8.48 ± 1.56* *vs. 10 mg, .sup.†vs 20 mg, .sup.‡vs. 40 mg, p < 0.05 (Wilcoxon test)

[0197] The maximum concentration (C.sub.max) and the time of maximum concentration (T.sub.max) were obtained directly from the measured concentration-time curves.

[0198] The area under the concentrations-time curve (AUC0-t) 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.sub.0-∞ values.

[0199] Apparent Terminal half-life (T.sub.1/2) was calculated by the following equation T.sub.1/2=ln 2/λ.sub.z. The terminal elimination rate constant (λ.sub.z) was evaluated from the terminal slope by log-linear regression analysis.

[0200] The absolute bioavailability (F.sub.abs) was calculated by the following equation F.sub.abs=AUC.sub.oral/AUC.sub.iv×dose.sub.iv/dose.sub.oral.