Patent ID: 12239615

EXAMPLES

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

Ketamine HCl20.00mgKollidon ® SR78.50mgAerosil 2001.00mgMagnesium stearate0.50mgTotal tablet100.00mg

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

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

Step 1:

A spraying solution is prepared from the following ingredients:

Hypromellose22.5gKetamine hydrochloride150.0gEthanol 96%q.s.Water, purifiedq.s.

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].

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).

Step 2:

A coating suspension is prepared from the following ingredients:

Ethylcellulose54.0gHydroxypropyl cellulose5.4gPropylene glycol10.8gTalc5.4gEthanol 96%q.sWater, purifiedq.s

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.

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.

Step 3:

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

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

Example 3.1 Prolonged-Release Tablet Containing 10 mg Ketamine Hydrochloride

ComponentFunctionAmount/UnitQuality Standard#Active PelletsKetamine hydrochlorideDrug substance10.00mgPh. Eur.Sugar spheres (250-355 μm)Carrier4.00mgPh. Eur.HypromelloseBinder1.50mgPh. Eur.Ethanol 96%Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate I15.50mgRetard CoatingEthylcelluloseRetarding6.50mgPh. Eur.polymerHydroxypropylcellulosePore builder1.45mgPh. Eur.Propylene glycolPlasticizer1.95mgPh. Eur.TalcGlidant0.65mgPh. Eur.Ethanol (96%)Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate II26.05mgFinal BlendingCarmellose sodiumFiller28.00mgPh. Eur.Cellulose, microcrystallineFiller15.21mgPh. Eur.Magnesium stearateLubricant0.04mgPh. Eur.Silica, colloidal anhydrousGlidant0.70mgPh. Eur.Core tablet70.00mgTablet coatingOpadry ® II White, consisting of:Dye3.00mgIn-housePolyvinyl alcohol, Titanium dioxide,Macrogol, TalcWater, purifiedSolventq.sPh. Eur.Final weight of tablet73.00mg

Example 3.2 Prolonged-Release Tablet Containing 20 mg Ketamine Hydrochloride

ComponentFunctionAmount/UnitQuality Standard#Active PelletsKetamine hydrochlorideDrug substance20.00mgPh. Eur.Sugar spheres (250-355 μm)Carrier8.00mgPh. Eur.HypromelloseBinder3.00mgPh. Eur.Ethanol 96%Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate I31.00mgRetard CoatingEthylcelluloseRetarding13.00mgPh. Eur.polymerHydroxypropylcellulosePore builder2.90mgPh. Eur.Propylene glycolPlasticizer3.90mgPh. Eur.TalcGlidant1.30mgPh. Eur.Ethanol (96%)Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate II52.10mgFinal BlendingCarmellose sodiumFiller56.00mgPh. Eur.Cellulose, microcrystallineFiller30.42mgPh. Eur.Magnesium stearateLubricant0.08mgPh. Eur.Silica, colloidal anhydrousGlidant1.40mgPh. Eur.Core tablet140.00mgTablet coatingOpadry ® II White, consisting of:Dye5.40mgIn-housePolyvinyl alcohol, Titanium dioxide,Macrogol, TalcOpadry ® II Yellow, consistingDye0.60mgIn-houseof:Polyvinyl alcohol, Iron oxideyellow, Macrogol, TalcWater, purified*Solvent24.00mgPh. Eur.Final weight of tablet146.00mg

Example 3.3 Prolonged-Release Tablet Containing 40 mg Ketamine Hydrochloride

ComponentFunctionAmount/UnitQuality Standard#Active PelletsKetamine hydrochlorideDrug substance40.00mgPh. Eur.Sugar spheres (250-355 μm)Carrier16.00mgPh. Eur.HypromelloseBinder6.00mgPh. Eur.Ethanol 96%Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate I62.00mgRetard CoatingEthylcelluloseRetarding26.00mgPh. Eur.polymerHydroxypropylcellulosePore builder5.80mgPh. Eur.Propylene glycolPlasticizer7.80mgPh. Eur.TalcGlidant2.60mgPh. Eur.Ethanol (96%)Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate II104.20mgFinal BlendingCarmellose sodiumFiller112.00mgPh. Eur.Cellulose, microcrystallineFiller60.84mgPh. Eur.Magnesium stearateLubricant0.16mgPh. Eur.Silica, colloidal anhydrousGlidant2.80mgPh. Eur.Core tablet280.00mgTablet coatingOpadry ® II White, consisting of:Dye11.40mgIn-housePolyvinyl alcohol, Titanium dioxide,Macrogol, TalcOpadry ® II Red, consisting of:Dye0.60mgIn-housePolyvinyl alcohol, Iron oxide,Macrogol, TalcWater, purifiedSolvent48.00mgPh. Eur.Final weight of tablet292.00mg

Example 3.4 Prolonged-Release Tablet Containing 80 mg Ketamine Hydrochloride

ComponentFunctionAmount/UnitQuality Standard#Active PelletsKetamine hydrochlorideDrug substance80.00mgPh. Eur.Sugar spheres (250-355 μm)Carrier32.00mgPh. Eur.HypromelloseBinder12.00mgPh. Eur.Ethanol 96%Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate I124.00mgRetard CoatingEthylcelluloseRetarding52.00mgPh. Eur.polymerHydroxypropylcellulosePore builder11.60mgPh. Eur.Propylene glycolPlasticizer15.60mgPh. Eur.TalcGlidant5.20mgPh. Eur.Ethanol (96%)Solventq.sPh. Eur.Water, purifiedSolventq.sPh. Eur.Intermediate II208.40mgFinal BlendingCarmellose sodiumFiller112.00mgPh. Eur.Cellulose, microcrystallineFiller233.68mgPh. Eur.Magnesium stearateLubricant0.32mgPh. Eur.Silica, colloidal anhydrousGlidant5.60mgPh. Eur.Core tablet560.00mgTablet coatingOpadry ® II White, consisting of:Dye20.00mgIn-housePolyvinyl alcohol, Titanium dioxide,Macrogol, TalcWater, purifiedSolvent80.00mgPh. Eur.Final weight of tablet580.00mg

Example 4: In Vivo Pharmacokinetics, Metabolism and Safety

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

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 e: 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).

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.

4.1 Pharmacokinetics

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. Cmax, stands for the maximum plasma concentration, Tmaxstands for the time to Cmax, F stands for absolute bioavailability, T1/2stands for the apparent terminal half-life, AUCNK/Kfor the ratio of AUCNKto AUCKand AUCHNK/Kfor the ratio of AUCHNKto AUCK.

TABLE 1Pharmacokinetic characteristics of ketamine after intravenous infusion (30 min) of 5 mg ketamine andoral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.45 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC1ng × h/ml52.3 ± 12.213.4 ± 13.333.5 ± 35.863.5 ± 42.6124 ± 72.9AUCn-Ket/1.79 ± 0.55721.6 ± 14.2#16.9 ± 8.58#*14.9 ± 8.50#*14.0 ± 6.50#*†AUCKetAUCHNK/0.334 ± 0.1287.33 ± 7.05#19.8 ± 16.4#*14.4 ± 8.99#*16.2 ± 7.93#*‡AUCKetAUCDHNK/0.446 ± 0.1577.00 ± 6.19#6.65 ± 5.52#4.46 ± 3.19#*†3.68 ± 2.11#*†AUCKetCmaxng/ml29.9 ± 8.481.63 ± 1.333.70 ± 3.936.66 ± 4.2511.8 ± 6.56Tmaxh—5.34 ± 1.185.70 ± 0.6495.87 ± 0.9156.27 ± 0.594*†F%—12.3 ± 10.715.3 ± 14.4*14.9 ± 8.94*14.6 ± 7.56*Vssl/kg6.58 ± 3.07————T1/2h5.89 ± 2.614.96 ± 1.256.74 ± 2.02*7.21 ± 1.56#*7.68 ± 1.43#*†CL/Fl/min1.67 ± 0.38022.3 ± 16.1#17.9 ± 11.4#*16.3 ± 11.1#*15.0 ± 8.93#*CLRml/min33.6 ± 36.578.9 ± 32.2#70.2 ± 30.3#*67.3 ± 28.0#61.7 ± 23.3#*CLMml/min268 ± 75.6————CLM, Nor Ketml/min34.6 ± 14.4————CLM, HNKml/min45.5 ± 8.65————CLM, DHNKml/min188 ± 68.1————CLintestinalml/min0.046 ± 0.097————Ae, urineμg93.4 ± 71.644.8 ± 16.396.6 ± 39.3209 ± 92.0394 ± 166Ae, urine%1.87 ± 1.430.448 ± 0.163#0.483 ± 0.196#0.524 ± 0.230#*0.493 ± 0.208#Ae, fecesμg0.160 ± 0.343131 ± 118335 ± 401557 ± 4652050 ± 1770Ae, feces%0.003 ± 0.0071.31 ± 1.18#1.68 ± 2.01#1.39 ± 1.16#2.56 ± 2.21#*‡MRTh4.68 ± 2.0110.2 ± 1.41#11.2 ± 1.61#11.8 ± 1.27#*12.6 ± 1.10#*†‡MATh—6.16 ± 1.407.11 ± 1.277.67 ± 1.16*8.45 ± 1.02*†‡p < 0.05 (Wilcoxon test);#vs. 5 mg i.v.,*vs. 10 mg,†vs 20 mg,‡vs. 40 mg p.o.1if Tlast= 60 h (24 h for 5 mg iv) then AUC0-∞, else AUC0-60 h(24 h)

TABLE 2Pharmacokinetic characteristics of norketamine after intravenous infusion (30 min) of 5 mg ketamineand oral administration of 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.45 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC1ng × h/ml95.0 ± 21.0195 ± 68.7392 ± 151722 ± 1881460 ± 404AUCHNK/AUCn-Ket0.194 ± 0.0930.342 ± 0.2381.07 ± 0.5940.953 ± 0.3101.14 ± 0.328Cmaxng/ml12.4 ± 2.6715.8 ± 4.7530.9 ± 10.154.9 ± 11.7102 ± 24.3Tmaxh0.967 ± 0.3034.87 ± 1.01#5.27 ± 0.923#5.80 ± 0.414#*†6.27 ± 0.458#*†‡T1/2h7.83 ± 1.468.11 ± 1.718.28 ± 1.528.06 ± 1.057.96 ± 0.920Ae, urineμg93.6 ± 23.9173 ± 36.4352 ± 120664 ± 1821280 ± 409Ae, urine%1.99 ± 0.5071.83 ± 0.3871.87 ± 0.6361.76 ± 0.4831.70 ± 0.543#†Ae, fecesμg2.16 ± 1.955.02 ± 3.979.55 ± 5.6619.3 ± 17.839.4 ± 21.9Ae, feces%0.046 ± 0.0410.053 ± 0.0420.051 ± 0.0300.051 ± 0.0470.052 ± 0.029p < 0.05 (Wilcoxon test);#vs. 5 mg i.v.,*vs. 10 mg,†vs 20 mg,‡vs. 40 mg p.o.1if Tlast= 60 h (24 h for 5 mg iv) then AUC0-∞, else AUC0-60 h(24 h)

TABLE 3Pharmacokinetic characteristics of hydroxynorketamine after intravenousinfusion (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 3.45 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC1ng × h/ml17.8 ± 7.9761.8 ± 34.5380 ± 185657 ± 1851610 ± 482Cmaxng/ml1.32 ± 0.5052.75 ± 1.1520.3 ± 11.032.6 ± 9.3875.5 ± 19.6Tmaxh3.57 ± 1.188.00 ± 1.73#8.00 ± 1.70#8.47 ± 2.77#8.40 ± 1.50#T1/2h7.92 ± 2.8113.2 ± 7.779.23 ± 1.958.90 ± 1.429.27 ± 1.49Ae, urineμg145 ± 45.8265 ± 70.1540 ± 2021100 ± 4912270 ± 952Ae, urine%2.90 ± 0.9162.65 ± 0.7012.70 ± 1.012.74 ± 1.232.84 ± 1.19p < 0.05 (Wilcoxon test);#vs. 5 mg i.v.,*vs. 10 mg,†vs 20 mg,‡vs. 40 mg p.o.1if Tlast= 60 h (24 h for 5 mg iv) then AUC0-∞, else AUC0-60 h(24 h)

TABLE 4Pharmacokinetic characteristics (as sum of R- and S-form) of dehydroxynorketamineafter intravenous infusion (30 min) of 5 mg ketamine and oral administrationof 10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.45 mg i.v.10 mg p.o.20 mg p.o.40 mg p.o.80 mg p.o.AUC1ng × h/ml21.9 ± 3.8850.7 ± 12.5120 ± 44.2182 ± 19.6331 ± 62.5Cmaxng/ml2.75 ± 0.7764.04 ± 1.128.94 ± 3.3112.4 ± 2.7420.1 ± 4.12Tmaxh1.80 ± 0.5284.80 ± 0.411#5.57 ± 0.998#*5.83 ± 1.21#*6.50 ± 1.24#*†T1/2h5.96 ± 1.858.20 ± 2.14#8.93 ± 2.72#9.43 ± 1.56#*8.90 ± 1.14#Ae, urineμg516 ± 1101040 ± 2682210 ± 5733630 ± 8697280 ± 1559Ae, urine%10.3 ± 2.2010.4 ± 2.6811.0 ± 2.869.08 ± 2.17†9.09 ± 1.95#†p < 0.05 (Wilcoxon test);#vs. 5 mg i.v.,*vs. 10 mg,†vs 20 mg,‡vs. 40 mg p.o.1if Tlast= 60 h (24 h for 5 mg iv) then AUC0-∞, else AUC0-60 h(24 h)

TABLE 5Pharmacokinetic characteristics of (±)-ketamine after intravenousinfusion (30 min) of 5 mg (±)-ketamine and oral administration of10, 20, 40 and 80 mg ketamine PR tablets according to examples 3.1 to 3.45 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 ± 12.213.4 ± 13.333.5 ± 35.863.5 ± 42.6124 ± 72.9Cmax(ng/ml)29.9 ± 8.481.63 ± 1.333.70 ± 3.936.66 ± 4.2511.8 ± 6.56Tmax(h)—5.34 ± 1.185.70 ± 0.6495.87 ± 0.9156.27 ± 0.594*†F (%)—12.3 ± 10.715.3 ± 14.4*14.9 ± 8.94*14.6 ± 7.56*T1/2(h)5.89 ± 2.614.96 ± 1.256.74 ± 2.02*7.21 ± 1.56#*7.68 ± 1.43#*†AUCNK/K1.79 ± 0.55721.6 ± 14.2#16.9 ± 8.58#*14.9 ± 8.50#*14.0 ± 6.50#*†AUCHNK/K0.334 ± 0.1287.33 ± 7.05#19.8 ± 16.4#*14.4 ± 8.99#*16.2 ± 7.93#*‡p < 0.05#vs. 5 mg i.v.,*vs. 10 mg,†vs 20 mg,‡vs. 40 mg p.o. (Wilcoxon)

The maximum concentration (Cmax) and the time of maximum concentration (Tmax) were obtained directly from the measured concentration-time curves.

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.

Apparent Terminal half-life (T1/2) was calculated by the following equation

T1/2=ln2/λz. The terminal elimination rate constant (λz) was evaluated from the terminal slope by log-linear regression analysis.

The absolute bioavailability (F) was calculated by the following equation
Fabs=AUCoral/AUCiv×doseiv/doseoral.

4.2 Safety

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.

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

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.

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.

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.

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”.

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).

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.

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

The results are depicted in the following table.

TABLE 6Number and percent of subjects reporting adverse events by system organ class (SOC), preferred term (PT) andtreatments for adverse events judged to be certainly, probably or possibly related to the study medicationTreatment BTreatment ETreatment Aketamine 10 mg PRketamine 80 mg PRSOCPTketamine 5 mg i.v.tabletstabletsnervous system disordersdizziness6 (40%)1 (7%)—cardiac disorderspalpitation1 (7%)1 (7%)1 (7%)nervous system disordersheaviness of head—1 (7%)—gastrointestinal disordersnausea—1 (7%)—skin end subcutaneoussweating/cold sweat—1 (7%)—tissue disorderscardiac disorderstachycardia1 (7%)——general disorders andweakness—1 (7%)—administration sitecondition