IE20100322A1 - A pharmaceutical formulation comprising procarbazine hydrochloride - Google Patents

Abstract

A pharmaceutical capsule contains only procarbazine hydrochloride and a mixture of coprocessed corn starch and pregelatinised starch in a weight ratio of about 1:2. The capsule total weight is approximately 250mg and the fill weight is approximately 180mg.

Description

The invention relates to a pharmaceutical formulation comprising procarbazine hydrochloride.

Procarbazine is a hydrazine derivative antineoplastic agent. It is chemically described as n-(lmethylethy 1)-4-[(2-methylhydrazino) methyl] benzamide monohydrochloride, and is used for treating stage III and IV Hodgkin’s disease.

The information available on the currently marketed capsule formulation of procarbazine hydrochloride suggests that the formulation comprises procarbazine hydrochloride, com starch (a filler), mannitol (a granulating agent), talc (a lubricant and glidant) in gelatine capsule shells. This product is marketed under the Trade Mark Matulane.

There is a need for an improved formulation of procarbazine hydrochloride which will provide increased benefits for patients.

Statements of Invention According to the invention there is provided a capsule containing only procarbazine hydrochloride and a mixture of co-processed com starch and pregelatinised starch.

In the manufacture of oral solid dose pharmaceutical products, excipients suchs as fillers, granulating agents, binders, lubricants and glidants are commonly employed. However, we have surprisingly found that the replacement of these components by a co-processed starch containing com starch and pregelatinised starch in a capsule formulation containing Procarbazine results in a product with excellent homogeneity of content, dissolution rate and impurity profile. The improvement in impurity profile is partially unexpected and important. Furthermore the resulting product can be readily manufactured and remains stable with lower impurity levels present. An additional benefit is that the product does not contain mannitol. Mannitol is a sugar alcohol that is derived from a sugar by reduction. The absence of mannitol in tbe capsule formulation of the invention may provide additional benefits to patients who suffer from diabetes.

IE 1 Ο Ο 3 2 2 E1RGO1 In one embodiment the total weight of the capsule is from 220 to 280mg and the fill weight is from 162 to 198mg.

In one embodiment the capsule has a total weight of approximately 250mg and a fill weight of 5 approximately 180mg.

In one case the weight ratio of the procarbazine hydrochloride to the mixture of co-processed com starch and pregelatinised starch is approximately 1:2.

In one embodiment the capsule contains approximately 120mg of the mixture of co-processed com starch and pregelatinised starch.

In one embodiment the capsule contains approximately 58mg of procarbazine hydrochloride.

The invention also provides a hard gelatine capsule having a total weight of approximately 250mg and containing only procarbazine hydrochloride and a mixture of co-processed com starch and pregelatinised starch in a weight ratio of approximately 1:2.

Brief Description of the Drawings The invention will be more clearly understood from the following description of an embodiment thereof, given by way of example only, with reference to the accompanying drawings, in which: Fig. 1 illustrates dissolution release profiles for two different capsule formulations; and Fig. 2 illustrates dissolution release profiles for two different capsule formulations.

Detailed Description Example 1 -- Capsule formulation according to the invention A hard gelatine capsule size 2 (capsule empty shell weight approximately 64mg) was filled with procarbazine hydrochloride and a co-processed mixture of com starch and pregelatinised starch.

The total capsule weight was approximately 250mg and contained approximately 58mg of IE 1 0 0 3 2 2 EIRGOI procarbazine hydrochloride (equivalent to approximately 50 mg of procarbazine) and approximately 122mg of the starch mixture. The weight ratio of procarbazine hydrochloride to the mixture co-processed com starch and pregelatinised starch is 2.09:1.

Starcap 1500 is a non-compendial co-processed excipient mixture which is produced from two 5 compendial grade excipients (com starch and pregelatinised starch) using purified water in the manufacturing process.

We have surprisingly found that the inclusion of Starcap 1500 in the formulation of the invention performed equally as well as the established formulation which contains several excipients.

The appearance of the procarbazine capsules of the invention compared to the commercial 50 mg capsules is outlined in Table 1.

Parameter Procarbazine capsules Procarbazine Hydrochloride Capsules, USP 50 mg (New) Procarbazine 50 mg Capsules ( Marketed) Shape Elongated Elongated Color Yellow Yellow Length 17.7 mm 17.2mm Capsule size 2 2 Total Capsule weight 248.6 mg 402 mg We have found that the capsules of the invention provided greater levels of blend uniformity. In this case, approximately a 250 mg capsule weight was sufficient to hold 50 mg of procarbazine compared to the capsule weight of 402 mg to cater for 50 mg of procarbazine in the known formulation.

Example 2 - Dissolution We have found that there are comparable release profiles between a batch (DT040) of capsules according to the invention and the Reference Listed Brand Drug (RLD). The dissolution profile IE 1 0 0 3 2 2 EIRGOl shows that batch DT040 achieved a release of 110.7% after 60 minutes while the RLD achieved a release of 105.4% after 60 minutes.

Table 2: Dissolution data for trial batch DT040 Vs Commercial Lot No 04222A Time/min DT040 04222A Mean (it = 6) % RSD Mean (n = 3) % RSD 0 0 - 0 - 10 102.0 1.60 86.9 15.44 20 107.3 0.54 99.5 5.76 30 107.7 2.31 106.9 10.73 45 109.6 0.63 105.4 3.69 60 110.7 0.76 105.4 3.69 This data is graphically presented in Fig. 1.

In recent years, FDA (US Food and Drug Administration) has placed more emphasis on a dissolution profile comparison, as under appropriate test conditions, a dissolution profile can characterize the product more precisely than a single point dissolution test. In dissolution profile comparisons, especially to assure similarity in product performance, regulatory interest is in knowing how similar the two curves are, and to have a measure which is more sensitive to large differences at any particular time point. For this reason, the F2 comparison has been the focus in the US Agency guidance’s. The factor F2 measures the closeness between the two profiles and when the two profiles are identical, F2 = 100. An average difference of 10% at all measured time-points results in a F2 value of 50. The FDA has set a public standard of F2 value between 50 and 100 to indicate similarity between two dissolution profiles.

An F2 similarity factor of 59 was calculated (F2 between 50 and 100 indicates that the release profiles are similar). The dissolution profile of DT040 was similar to the RLD lot # 04222A.

Example 3 - Manufacture of large scale batch Method of manufacture 1. The procarbazine hydrochloride was premixed with approximately half of the dispensed StarCap 1500, passed through a screen and collected in an Intermediate Bulk Container IE 1 0 0 3 2 2 EIRGOl 2. The screen was flushed with the remaining StarCap 1500 and collected. 3. The contents of the Intermediate Bulk Container were blended until the contents are uniform.

Capsules were filled to a target fill weight of 180mg and encapsulated. The capsules produced were assigned the batch number SOO 14.

Table 3: Composition of batch number S0014 (Batch Size: 22.5kg) Component mg/capsule % w/w (filled) Procarbazine Hydrochloride 58.24 32.4 StarCap 1500 121.76 67.6 Hard Gelatin capsules 64.0 N/A Table 4: Dissolution profile of batch S0014 Time (mins) Vessel Number Mean % RSD 1 2 3 4 5 6 7 8 9 10 11 12 0 0 0 0 0 0 0 0.0 0.0 0.0 0.0 0.0 0.0 0 - 10 83.7 89.4 87.7 92.1 88.5 102.2 93.9 88.6 96.0 97.6 96.5 92.5 92.4 5.56 20 92.1 96.4 95.1 100.1 97,5 106.8 98.6 92.9 99.6 102.5 103.4 98.0 98.6 4.33 30 97.0 100.0 99.5 101.5 98.9 106.4 100.3 96.0 101.1 104.2 102.5 98.6 100.5 2.91 45 100.0 101.1 101.3 102.3 99.9 105.8 100.5 96.9 102.3 105.4 103.4 99.1 101.5 2.52 60 100.0 102.2 103.3 101.8 100.8 106.4 102.1 99.2 103.8 104.9 104.3 101.0 102.5 2.09 Table 5: Dissolution data for batch Lot # SOO 14 Vs RLD 50mg, Lot # B070087 under USP conditions (900 mis water at 37°C - 50rpm - paddles) S0014 B070087 Minutes Mean (n = 12) % RSD Mean (n = 12) % RSD 0 0 - 0 - 10 92.4 5.56 75.3 11.48 20 98.6 4.33 94.8 4.09 30 100.5 2.91 97.2 3.18 45 101.5 2.52 98.2 2.46 60 102.5 2.09 99.0 2.52 IE 1 0 0 3 2 2 EIRG01 This data is presented graphically in Fig. 2.

Dissolution performed as per USP compendial conditions, as described in above as shown, there were comparable release profiles between batch S0014 and the RLD batch B070087 under USP conditions. The dissolution profile shows that batch S0014 achieved a release of 102.5% after 60 minutes while the RLD achieved a release of 99.0% after 60 minutes. An F2 similarity factor of 54 was calculated; an F2 between 50 and 100 indicates that the release profiles are similar.

During processing, 10 unit dose samples were taken from the final blend and evaluated for homogeneity. Lot No SOO 14 was comprehensively characterized with respect to particle size, hardness range, capsule press speed and uniformity of dose.

These results are favourable when compared to the data generated for RLD batch B070087 reference product.

Table 6: Assay data (SOO 14 and Matulane® B070087) % Assay S0014 Matulane® B070087 101.8 99.8 Table 7: Related substances data (S0014 and Matulane® B070087) S0014 Matulane® ΒΘ70087 % Largest Unidentified Impurity 0.08 1.00 % Impurity B 0.04 N/A % Total impurities 0.17 1.58 Surprisingly significantly better initial impurity profiles for the capsule formulation according to the invention (Total Impurities: 0.17%) versus the established formulation 1.58%). This is particulariy important because greater levels of impurities offer increased risks of side effects to IE 1 Ο Ο 3 2 2 EIRGO1 the patient after administration of the medicine. However these risks are reduced in the invention because there are significantly lower levels of impurites present.

Blend Uniformity In order to verify the appropriate blend time of 20 minutes at 15 rpm, ten unit dose blend 5 samples from batch S0014 were taken from several blender locations and evaluated for homogeneity. The data is presented in table 8 below.

Table 8: Blend uniformity results after 10 minutes blending (Batch S0014) Sample % Procarbazine (After 10 minutes') % Procarbazine (After 20 minutes') 1 99.7% 97.8% 2 100.0% 100.6% 3 101.2% 98.1% 4 101.5% 100.9% 5 100.7% 100.4% 6 101.4% 101.7% 7 100.9% 96.9% 8 100.4% 100.0% 9 98.9% 97.3% 10 101.1% 99.1% Mean 100.6% 99.3% RSD 0.8% 1.7% Minimum 98.9% 96.9% Maximum 101.5% 101.7% It can be seen from the resulting blend data, that the manufacturing process exhibits excellent homogeneity during processing. All results after 10 and 20 minutes blending were within ± 10% of the mean and the %RSD is below 5.0%.

The batch, S0014, was also evaluated for content uniformity using stratified in process unit dose sampling based on the proposal in FDA Draft Guidance for Industry “Powder Blends and Finished Dosage Unity- Stratified In-Process Dosage Unit Sampling and Assessment” In this IE 1 0 0322 E1RGO1 case; three capsules were evaluated for content uniformity at 20 different locations throughout the manufacturing run. The data are presented in the table below.

Table 9: Uniformity of content (Stratified testing) - S0014 Sample A B C Average 1 100.7% 97.8% 101.8% 100.1% 2 103.1% 102.3% 103.5% 103.0% 3 102.8% 101.3% 101.1% 101.7% 4 102.2% 101.3% 101.7% 101.7% 5 101.2% 103.2% 101.3% 101.9% 6 103.5% 101.4% 101.2% 102.0% 7 103.5% 102.8% 101.9% 102.7% 8 102.0% 102.6% 100.6% 101.7% 9 100.9% 103.2% 102.1% 102.1% 10 102.4% 98.3% 99.5% 100.1% 11 106.9% 103.0% 103.0% 104.3% 12 100.9% 102.3% 103.7% 102.3% 13 104.2% 101.9% 100.2% 102.1% 14 100.3% 100.9% 99.8% 100.3% 15 101.8% 104.1% 102.0% 102.6% 16 106.9% 104.9% 102,8% 104.9% 17 104.2% 103.5% 101.7% 103.2% 18 100.7% 100.4% 101.5% 100.9% 19 101.3% 102.9% 101.9% 102.0% 20 100.6% 101.5% 102.0% 101.4% Mean (%) 102.1% Minimum (%) 100.1% Maximum (%) 104.9% %RSD 1.2% The %RSD of the individual stratified sample data is below 4.0% and each location mean is within 90.0 - 110.0 % of the target potency. Furthermore, all individual results are within 75.0%> to 125.0% of the target potency. As a result, the stratified content uniformity meet the “readily pass criteria” of the FDA draft guidance.

The invention is not limited to the embodiments hereinbefore described which may be varied in detail.

Claims (13)

Claims

1. A pharmaceutical capsule containing only procarbazine hydrochloride and a mixture of co-processed com starch and pregelatinised starch.

2. A capsule as claimed in claim 1 wherein the total weight of the capsule is from 220 to 280mg and the fill weight is from 162 to 198mg.

3. A capsule as claimed in claim 1 or 2 wherein the capsule has a total weight of 10 approximately 250mg and a fill weight of approximately 180 mg

4. A capsule as claimed in any of claims 1 to 3 wherein the weight ratio of the procarbazine hydrochloride to the mixture of co-processed com starch and pregelatinised starch is approximately 1:2.

5. A capsule as claimed in any of claims 1 to 4 containing approximately 120mg of the mixture of co-processed com starch and pregelatinised starch.

6. A capsule as claimed in any of claims 1 to 5 containing approximately 58mg of 20 procarbazine hydrochloride.

7. A hard gelatine capsule having a total weight of approximately 250mg, a fill weight of 180 mg and containing only procarbazine hydrochloride and a mixture of co-processed com starch and pregelatinised starch in a weight ratio of approximately 1:2.

8. A capsule substantially as hereinbefore described. IE 1 0 0 3 2 2 1/1 Figure 1: Release profile for DT040 versus 04222A Brand BQ70087 S0014 Figure 2: Release profile for Lot # S0014 Vs Matulane® 50mg, Lot # B070087 The following amended page 20th May 2011 1 of the Specification was filed on IE 1 0 03 2 2 EIRG01 “A pharmaceutical formulation comprising procarbazine hydrochloride” Introduction The invention relates to a pharmaceutical formulation comprising procarbazine hydrochloride. Procarbazine is a hydrazine derivative antineoplastic agent. It is chemically described as n-(lmethylethyl)-4-[(2-methylhydrazino) methyl] benzamide monohydrochloride, and is used for treating stage III and IV Hodgkin’s disease.

9. 10 The information available on the currently marketed capsule formulation of procarbazine hydrochloride suggests that the formulation comprises procarbazine hydrochloride, corn starch (a filler), mannitol (a granulating agent), talc (a lubricant and glidant) in gelatine capsule shells. This product is marketed under the Trade Mark Matulane.

10. 15 There is a need for an improved formulation of procarbazine hydrochloride which will provide increased benefits for patients. Statements of Invention According to the invention there is provided a capsule containing only procarbazine

11. 20 hydrochloride and a mixture of co-processed corn starch and pregelatinised starch. In the manufacture of oral solid dose pharmaceutical products, excipients suchs as fillers, granulating agents, binders, lubricants and glidants are commonly employed. However, we have surprisingly found that the replacement of these components by a co-processed starch containing

12. 25 com starch and pregelatinised starch in a capsule formulation containing Procarbazine results in r a product with excellent homogeneity of content, dissolution rate and impurity profile. The improvement in impurity profile is partially unexpected and important. Furthermore the resulting product can be readily manufactured and remains stable with lower impurity levels present. An additional benefit is that the product does not contain mannitol. Mannitol is a sugar

13. 30 alcohol that is derived fiom a sugar by reduction. The absence of mannitol in the capsule formulation of the invention may provide additional benefits to patients who suffer fiom diabetes.