Patent Application
20080063704
Table 1: Composition of the proprietary medical product
Table 2: Stability Specification and routine tests for Gabapentin Capsules
Table 3: Details of batches put on stability
Table 4: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 25° C.±2° C./60%±5% RH
Table 5: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 30° C±2° C./60%±5% RH
Table 6: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/100) stored at 40° C.±2° C./ 75%±5% RH
Table 7: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 25° C.±2° C./60%±5% RH
Table 8: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 30° C.±2° C./60%±5% RH
Table 9: Stability of Gabapentin Capsules 100 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/100) stored at 40° C.±2° C./75%±5% RH
Table 10: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/300) stored at 25° C.±2° C./60%±5% RH
Table 11: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/300) stored at 30° C.±2° C./60%±5% RH
Table 12: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/300) stored at 30° C.±2° C./60%±5% RH
Table 13: Stability of Gabapentin Capsules 300 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/300) stored at 25° C.±2° C./ 60%±5% RH
Table 14: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/400) stored at 25° C.±2° C./60%±5% RH
Table 15: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I/400) stored at 30° C.±2° C./60%±5% RH
Table 16: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-I1/400) stored at 40° C.±2° C./75%±5% RH
Table 17: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/400) stored at 25° C.±2° C./60%±5% RH
Table 18: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II1/400) stored at 30° C.±2 ° C./60%±5% RH
Table 19: Stability of Gabapentin Capsules 400 mg stored in PVC/PVdC/Aluminium packs (Batch Number GBC-II/400) stored at 40° C.±2° C./75%±5% RH
Table 20: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 25° C.±2° C. /60%±5% RH
Table 21: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 30° C.±2° C./60%±5% RH
Table 22: Stability of Neurontin® Capsules 400 mg stored in PVC/PVdC/Aluminium packs stored at 40° C.±2° C./75%±5% RH
Table 23: Excipients used in the pre-formulation studies
Table 24: Trial blends for pre-formulation studies.
Table 25: Pre-formulation studies, Batch Number: GD
Table 26: Pre-formulation studies, Batch Number: GD2
Table 27: Pre-formulation studies, Batch Number: GD3
Table 28: Pre-formulation studies, Batch Number: GD4
Table 29: Pre-formulation studies, Batch Number: GD5
Table 30: Pre-formulation studies, Batch Number: GD6
Table 31: Pre-formulation studies, Batch Number: GD7
Table 32: Pre-formulation studies, Batch Number: GL1
Table 33: Pre-formulation studies, Batch Number: GL2
Table 34: Pre-formulation studies, Batch Number: GL3
Table 35: Pre-formulation studies, Batch Number: GS1
Table 36: Pre-formulation studies, Blend I
Table 37: Pre-formulation studies, Blend II
Table 38: Pre-formulation studies, Neurontin® Capsules 400 mg, Batch Number: 015077
Table 39: Pre-formulation studies, Drug Substance, Gabapentin Lot number: R 90562
The invention shall now be described further by way of exemplification.
HPLC Assay for Related Substances
Chromatographic Conditions
YMC—ODS—AQ, 5 μm, 250 mm×4.6 or equivalent
Ambient
0.025 M Potassium Phosphate Monobasic (pH 6.0): Methanol (70:30)
UV at 210 nm
10 ml/minute
50 μl
10 minutes or as appropriate for Standard Solution
15 minutes or as appropriate for Resolution Solution
70 minutes or as appropriate for Lactam Marker, Test Solution and Diluent Solutions.
Water:methanol (70:30)
0.025M potassium phosphate, monobasic (KH2PO4) buffer solution pH 6.0: Weight about 6.8 g of potassium phosphate, monobasic (KH2PO4) and dissolve in about 1800 ml of water. Adjust pH of the solution to 6.0 (±0.05) using 1 N Sodium Hydroxide solution. Add sufficient water to make 2000 ml and mix well.
Mobile Phase: Mix 1400 ml of 0.025 M potassium phosphate, monobasic (KH2PO4) buffer solution pH 6.0 with 600 ml methanol, filter and degas.
Weigh 20 intact capsules. Empty the capsules as completely as possible into a suitable container. Clean and weigh the empty capsule shells and determine the average capsule filled weight. Mix thoroughly the combined contents of the capsules.
Weigh accurately amount of powder equivalent to 600 mg Gabapentin into a 50 ml volumetric flask. Add about 30 ml of mobile phase and sonicate for 10 minutes with intermittent shaking to disperse the powder. Shake for 30 minutes. Dilute to volume with mobile phase and mix well. Filter the solution.
Stock Standard Solution
Weigh accurately about 25 mg Gabapentin R.S. and transfer to 50 ml volumetric flask. Add to it about 25 ml mobile phase. Sonicate to dissolve, make up the volume with mobile phase.
Working Standard Solution
Pipette out 6 ml of the solution from Standard Stock Solution into 50 ml volumetric Flask. Dilute to volume with mobile phase and mix well.
Resolution stock solution (C.A.M)
Weigh accurately about 12.5 mg of C.A.M., dissolved and dilute to 25 ml with methanol
Note: Store under refrigeration for future use. The solution may be used as long as a peak due to C.A.M. is clearly visible in the chromatogram.
Pipette out 6 ml of Standard Stock Solution and 6 ml of C.A.M. Stock Solution and dilute to 50 ml with mobile phase.
Lactam stock solution
Weigh accurately about 12.5 mg lactam, dissolve and dilute to 25 ml with methanol.
Note: Store under refrigeration for future use. The solution nay be used as long as the lactam peak is clearly seen.
Pipette 6 ml of Lactam Stock solution and dilute to 50 ml with mobile phase.
Weigh accurately about 25 mg of methyl parabens and dissolve and dilute to 50 ml with mobile phase. Pipette 5 ml of solution into a 50 ml volumetric flask and make up to volume with mobile phase. Further pipette 5 ml and dilute to 50 ml with mobile phase.
System suitability test solution: Inject 50 μl of Resolution Solution into the equilibrated chromatograph. Calculate the system suitability requirements. Gabapentin peak has retention time of about 6 minutes. C.A.M. has retention time of about 10 minutes
The resolution between Gabapentin and C. A. M. peaks is NLT 4.5
The tailing factor (T), determined from the Gabapentin peak is NMT 2.0%. Perform 6 replicate injections of 50 μl of Working Standard Solution. The System precision is acceptable if the RSD of 6 replicate standard injections is NMT 5.0%
Separately inject 50 μl of the mobile phase, Standard Solution, lactam marker solution, Methyl Parabens marker solution and Test Solutions into the Chromatograph. Measure the responses of the major peaks.
Calculate the content of impurity lactam: single largest individual/unidentified impurity/degradant and total impurities/degradant.
Note: Identify the peak due to methyl parabens based upon the retention time in the chromatogram of the Methtyl Parabens marker solution. Disregard any peak occurring in the test solution at the same RRT as the Methyl Parabens peak.
A. Impurity 1: lactam {cyclohexanespiro (4,5) decane-2,3-butyrolactam}
B. Single Largest Individual Unidentified Impurities/Degradant
C. Total other impurities/degradants:
Sum the peak areas of all unidentified impurities.
D. % Total Impurities/degradant:
=% lactam+% total other impurities/degradants
Exemplary medicinal products containing gabapentin are disclosed in Table 1. Table 1 relates to gabapentin formulations containing active doses at 100, 200 and 400 mg. In hard gelatine capsules. Excipients include microcrystalline cellulose as the sole diluent and magnesium stearate as a lubricant. Table 1 additionally sets out capsule shell constituents and also constituents of the printing ink.
Stability data for the formulations of Table 1 at a range of temperatures (20° C. to 40° C.) and durations is provided in Tables 4 through 18.
Composition of Proprietary Medicinal Product
Stability Tests on the Finished Product
Quality Specification for the proposed shelf-life
The Stability specification for Gabapentin Capsules 100 mg, 300 mg and 400 mg is presented in Table 2
E. coli - absent
E. coli - absent
E. coli - absent
(1)To be tested on initial, 6, 24 and 36 months.
Active drug substance used for the manufacture of the above batches was supplied from Teva. All batches were manufactured at Nicholas Piramal (Pithampur) Limited, India.
The above stability batches were packed into white opaque PVC/PVdC/Aluminium blister strips. These blister strips were cartooned prior to being placed on test.
Stability samples were stored at 25° C.±2° C./60%±5% RH and 30° C.±2° C./60%±5% RH and were tested at initial, 3, 6, 12, 18 and 24 and 36 month time points and 3, 6, 12, 18 and 24 month time points respectively.
Stability samples were stored at 40° C.±2° C./75%±5% RH and were tested at initial, 1 month, 2 months, 3 months and 6 months time points.
The analytical methods for all the tests used in the stability studies are the same as proposed for routine batch analysis and are known to persons skilled in the art. The methodology for, related substances and assay has been validated and are suitable for stability purposes.
The assay and related substances methods used throughout the stability studies are stability indicating.
The stability data is for 6 months for all strengths at accelerated conditions and for 36 months at 25° C.±2° C./60%±5% RH and 24 months at 30° C.±2° C./60%±5% RH. The results of physical testing of the stability batches packed in PVC/PVdC/Aluminium blister packs is shown in Tables 4 to 19.
Throughout the period of study under all the conditions 25° C.±2° C./60%5% RH, 30° C.±2° C./60%±5% RH and 40° C.±2° C./75%±5% RH, no significant changes were noted in the appearance or disintegration time of any of the samples on test. It is noted none of the stability batches have the markings proposed for marketing, however this does not affect the stability profile.
The percentage water content by KF had shown an increase after one month study in the test samples for 300 and 400 mg strengths.
However, at the end of the second month, once again a similar trend was observed and investigation was initiated as per the SOP for out of specification. The result of the investigation indicated that the test was performed after 6-7 hours of removal of the powder blend from the capsule. The exposure to atmosphere could have resulted in higher values. The statement to the effect that KF should be done on fresh samples only has been included in the method of analysis.
The amount of all the secondary peaks obtained was calculated with respect to Gabapentin diluted standard. In the determination of the amount of known impurity i.e. lactam, the higher response of this impurity (RRF=21 relative to gabapentin) was accounted for in the calculation. From Tables 4 to 19, it may be noted that the value for lactam is well below 0.2% up to 3 months interval for all the strengths. However, at the sixth month interval, the values obtained were slightly above 0.2%.
One unknown impurity at a RRT of about 6.0 was noted under accelerated conditions (40° C.±2° C./75%±5% RH) at the end of one month. Investigation was taken up with respect to the identification and characterisation of this impurity and it was found to be due to the preservative, methyl parabens, present in the capsule shells. The methodology was therefore revised to include preparation of a methyl parabens marker solution and to disregard any peaks occurring in the test samples at the same retention time as the marker.
Total impurities were found to be within the shelf life limits proposed.
No significant changes were observed in the dissolution results of any of the samples under test.
Up to 36 months data at 25° C.2±° C./60%±5% RH, 24 months data at 30° C.±2° C./60%±5% RH and 6 months at 40° C.±2° C./75%±5% RH are available for all strengths of capsules. The data are within specification limits for all the batches.
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
E. coli - absent
Gabapentin capsules packed into PVC/PVdC/Aluminium blister pack have been shown to be physically and chemically stable for 36 months when stored at 25° C./50%±5% RH, 24 months when stored at 30° C.±2° C./60%±5% H and for 6 months when stored at 40° C.±2° C./75%±5% H.
The stability data generated supports the following:
Proposed product shelf-life: 36 months when packed in blister packs.
Labelled storage conditions: none.
Further exemplary medicinal products containing the gabapentin active are disclosed in Tables 23 and 24.
Exemplary trial blends for 400 mg formulations are disclosed e.g. in Table 24.
Tables 25 through 39 show stability data for these further exemplary formulations.
A capsule formulation was needed which would be linear for all three strengths.
The excipients used in the preformulation studies and the coding are shown in Table 23.
Two trial blends (Blend I and Blend II) having the composition as shown in Table 24 were also evaluated as per the protocol for pre-formulation trials.
All the ingredients were passed through 20 mesh screen and blended together. The results of all the pre-formulation compatibility studies are given in Tables 25 to 39, including comparative results for the drug substance (Table 39) and UK reference product (Table 38) as controls.
Aim: To carry out preformulation excipient compatibility studies for Gabapentin capsules
Gabapentin drug substance
Samples retained at 4° C.
Individual Excipients
Dibasic calcium phosphate
Tribasic calcium phosphate
Calcium sulphate
Mannitol
Microcrystalline cellulose
Starch IP
Lactose
Magnesium stearate
Steric acid
Colloidal silicon dioxide-to confirm the reported incompatibility
Sodium lauryl sulphate
Gabapentin
Binary mixtures to be evaluated (with and without water as necessary):
1. Drug and diluents (1:0.5)
2. Drug and lubricants(1:0.1)
3. Drug and solubilizer (1:0.001)
4. Proposed formulation from the in vitro formulation trials to confirm the extent of interactions and identify suitably stable formulations.
5. Other combinations as appropriate
Significant degradation is defined as
1. >0.5% w/w formation of lactam degradation product at conditions up to 40° C./75% RH.
2. Formation of other degradants at levels >0.1% w/w.
3. Greater relative instability of mixture or formulation to Gabapentin drug substance and Neurotonin capsules.
Where humidity controls are not available a defined amount of water may be added to the samples. Storage of samples was in petridishes and in stoppered glass vials.
The following tests were performed at each interval:
1. Appearance
2. HPLC assay (as for HPLC related substances assay but calibrated for gabapentin resolution rather than for related substances)
The following tests were performed at 14 and 28 day intervals.
1. Appearance
2. HPLC assay
3. HPLC assay for related substances
4. Water (to determine the hygroscopicity of the proposed formulations.
DSC was carried out on initial and end point stability samples.
Similar stability profile to Neurotonin capsules, similar stability profile to Gabapentin drug substance, lactam levels <0.5% w/w at 25° C. /60% RH and 40° C./75% RH after 28 days, dissolution of the proposed formulation is >80% (Q) in 20 minutes at 25° C. C/60% RH and 40° C./75% RH after 28 days.
The excipient compatibility study reveals that commonly used pharmaceutical excipients are compatible with gabapentin. The excipients studied do not adversely affect the stability of gabapentin when stored at 25° C./60% RH and 40° C./75% RH.
While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0400993.2 | Jan 2004 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US05/01423 | 1/15/2005 | WO | 00 | 9/11/2007 |
