Title of Invention	A PRIMARY PACKAGE AND A PROCESS THEREOF
Abstract	"A PRIMARY PACKAGE AND A PROCESS THEREOF" A primary package, such as a vial, bottle, cartridge or pre-filled syringe, containing an aqueous solution for parenteral administration comprising a low molecular weight peptide-based thrombin inhibitor or a salt thereof, having a pH in the range 3 to 8, the primary package being sealed with a rubber stopper or plunger containing bromobutyl rubber.

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FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] 'A PRIMARY PACKAGE AND A PROCESS THEREOF" ASTRAZENECA AB, a Swedish company, of S-151 85 Sodertalje, Sweden, The following specification particularly describes the invention and the manner in which it is to be performed: Field of the invention The present invention relates to solutions of low molecular weight thrombin inhibitors stored in primary packages containing rubber components, such as vials, bottles, cartridges and prefilled syringes. The invention also relates to the medical use of such stored thrombin inhibitor solutions. Background of the invention Solutions for parenmeral use of pharmaceutically active substances are normally stored in primary packages such as, vials, bottles, cartridges or in prefilled syringes. The primary packages are sealed by a rubber stopper or plunger. A commonly used rubber material contains chlorobutyl. Solutions of low molecular weight thrombin inhibitors stored in vials, bottles, cartridges and prefilled syringes sealed by a stopper or plunger containing chlorobutyl rubber exhibits increased degradation, leading to shortened time of storage. Disclosure of the invention It has now surprisingly been found that by using rubber material containing bromobutyl instead of chlorobutyl, the stability of the low molecular weight thrombin inhibitors in solution can be considerably improved. The present invention provides a primary package, such as a vial, a bottle, a cartridge or a prefilled syringe containing a solution of a low molecular weight thrombin inhibitor for parenmeral injection, sealed by a rubber stopper or plunger containing bromobutyl rubber instead of chlorobutyl rubber. The present invention further provides a medical use of such thrombin inhibitor, or salts of such thrombin inhibitor, solutions kept in a primary package as mentioned above sealed by bromobutyl stoppers or plungers. The present invention further provides an aqueous solution for parenteral administration comprising a low molecular weight peptide-based thrombin inhibitor or a salt thereof, having a pH in the range 3 to 8, preferably a pH about 5 and stored in a primary package, such as a vial, a bottle, a cartridge or a prefilled syringe, sealed by a rubber stopper or plunger containing bromobutyl. Thrombin inhibitors referred to in this application are low molecular weight peptide-based thrombin inhibitors. The term "low molecular weight peptide-based thrombin inhibitors" will be well understood by one skilled in the art to include thrombin inhibitors with one to four peptide linkages, and/or with a molecular weight below 1000, and includes those described generically and, more preferably, specifically in the review paper by Claesson in Blood Coagul. Fibrin. (1994) 5, 411, as well as those disclosed in US Patent No. 4,346,078; International Patent Applications WO 97/23499, WO 97/02284, W097/46577, WO 98/01422, WO 93/05069, W093/11152, WO 95/23609, WO95/35309, WO 96/25426, WO 94/29336, WO WO 93/18060 and WO 95/01168; and European Patent Applications 623 596, 648 780, 468 231, 559 046, 641 779, 185 390, 526 877, 542 525,195 212, 362 002, 364 344, 530 167, 293 881, 686 642, 669 317 and 601 459. Preferred low molecular weight peptide-based thrombin inhibitors include those known collectively as the "gatrans". Particular gatrans which may be mentioned include HOOC-CH2(R)Cha-Pic-Nag-H (known as inogatran; see International Patent Application WO 93/11152 and the list of abbreviations therein) and HOOC-CH2-(R)Cgl-Aze-Pab-H (known as melagatran; see International Patent Application WO 94/29336 and the list of abbreviations therein). The preferred low molecular weight peptide-based thrombin inhibitor to be kept in glass vials or syringes is selected from the group consisting of inogatran, (Glycine, N-[2-[2-[[[3- [(aminoimino-methyl) amino]propyl]amino] carbony1]-1-piperidinyl]-l-(cyclohexy lmethyl)-2-oxoethyl]-, [2R-[2S]]-), melagatran, (Glycine, N-[2-[2-[[[[4 (aminoiminomethyl)phenyl]-methyl]amino] carbonyl]-l-azetidinyl]-l-cyclohexyl-2-oxoethyl]-, [2R-[2S]]-) and compound A, (Glycine, N-[l-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]-phenyl]methyl]amino]carbonyl]-l-azetidinyl]-2-oxoethyl]-, ethyl ester, [S-(R*, S*)]-). In one embodiment of the invention the thrombin inhibitor (preferably melagatran) solutions for parentheral injection is a water solution and are kept in primary packages such as vials, bottles, cartridges or prefilled syringes having a rubber stopper or plunger containing bromobutyl. In another embodiment of the invention; the thrombin inhibitor for parentheral injection is in a water solution with an addition of hydroxy-propyl-p-cyclodextrin (HPpCD). The concentration of the thrombin inhibitor is in the range 0.001-100 mg/ml, preferably 2.5-20 mg/ml. Working Example Analytical technique Liquid Chromatography (LC), for all analysis The following equipment and parameters were used at the analysis of melagatran in solution. Flowrate l.Oml/min Wavelength 237 nm Injection volume 20 μl Analytical column Waters Symmetry C8,150 x 3.9 mm Guard column Waters Symmetry C8, 22x3.9 mm Mobile phase 20 % (v/v) acetonitrile in phosphate buffer, pH 2.0 with 4.6 mM octanesulphonic acid. EVALUATION Results in tables are presented as total degradation of melagatran. This means that all by¬products are included and presented as area% of melagatran. Example 1. This example shows a comparison of melagatran in HPpCD-solution in prefilled syringes (1.0 ml) having rubber plungers containing bromobutyl and chlorobutyl, respectively. The syringes were stored at 4,25 and 50 °C for up to 6 months. The melagatran solution was in direct contact with the different rubber materials. MANUFATURING OF SAMPLES Melagatran, 2.5 mg/ml, in HPβCD water solution (40 % w/w), pH about 5 Batch HF 839-2601 Melagatran 442.1 mg HPpCD 80.0 g HC1, 1 M qs NaOH, 1 M qs water for injection to 200 g final weight (density 1.145 g/ml) Melagatran was dissolved in water in a separate beaker and adjusted to pH 5.06. HPpCD powder was mixed with this solution together with water. The final solution was mixed with a magnetic stirrer until the substance was completely dissolved and pH was finally adjusted to 5.02, and the solution was filtrated with a 0.22 urn sterile filter. Melagatran, 10 mg/ml, in HPpCD water solution (40 % wAv), pH about 5 Batch HF 839-2602 Melagatran 1.77 mg HPPCD 80.0 g HC1,1 M qs NaOH, 1 M qs water for injection to 200 g final weight (density 1.145 g/ml) Melagatran was dissolved in water in a separate beaker and adjusted to pH 4.88. HPpCD powder was mixed with this solution together with water. The final solution was mixed with a magnetic stirrer until the substance was completely dissolved and pH was finally adjusted to 5.0, and the solution was filtrated with a 0.22 urn sterile filter. FILLING OF SYRINGES (1.0 ml) Sample Al (HF 839-2613) 10 rag/ml 0.5 ml of HF 839-2602 was filled in 1 ml HYPAK® syringes from Becton Dickinson with a black plunger material (PH 701/50 from The West Company) containing chlorobutyl rubber. Sample Bl (HF 839-2614) 10 mg/ml 0.5 ml of HF 839-2602 was filled in 1 ml HYPAK® syringes from Becton Dickinson with a grey plunger material (PH 4416/50 from The West Company) containing bromobutyl rubber. Sample CI (HF 839-2615) 2.5 mg/ml 0.5 ml of HF 839-2601 was filled in 1 ml HYPAK® syringes from Becton Dickinson with , a grey plunger material (PH 4416/50 from The West Company) containing bromobutyl rubber. Sample Dl (HF 839-2616) 10 mg/ml 0.5 ml of HF 839-2602 was filled in 1 ml HYPAK® syringes from Becton Dickinson with a black plunger material (PH 701/50 from The West Company) containing chlorobutyl rubber. RESULTS OF STABILITY STUDIES Sample Al (HF 839-2613) 10 mg/ml - Chlorobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 0 5.2 . 1.2 1 5.2 4 1.0 1 5.3 50 7.4 3 5.1 4 1.2 3 5.1 25 4.5 3 5.2 50 14.9 6 5.1 4 1.2 6 5.1 25 3.7 Sample Bl (HF 839-2614) 10 mg/ml - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 0 5.2 - 1.1 1 5.2 4 1.0 1 5.2 50 6.4' 3 5.1 4 1.2 3 5.1 25 2.4 3 5.2 50 12.8 6 5.1 4 1.1 6 5.1 25 3.1 Sample CI (HF 839-2615) 2.5 mg/ml - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 0 5.3 - 1.2 1 5.4 4 1.1 1 5.3 50 7.2 3 5.3 4 1.3 3 5.3 25 3.9 3 5.2 50 14.2 6 5.2 4 1.2 6 5.2 25 5.7 Sample Dl (HF 839-2616) 10 mg/ml - Chlorobutyl rubber Storage time (months) PH Temperature TO Total degradation (area % of melagatran) 0 5.3 - 1.2 1 5.4 4 1.2 1 53 50 8.6 3 5.3 4 1.2. 3 5.3 25 3.1 3 5.2 50 17.4 6 5.2 4 1.4 6 5.2 25 9.9 Conclusion Rubber plungers containing chlorobutyl result in a more pronounced degradation compared to rubber plungers containing bromobutyl. This is true for high concentrations as well as low concentrations of melagatran in aqueous solutions. The most pronounced difference was seen between plungers of chlorobutyl rubber and bromobutyl rubber when the dose of melagatran in aqueous solution was as low as 2.5 mg/ml. Example 2. This example is a comparison of melagatran in a water solution of HPPCD and melagatran in a water solution of NaCl. Both solutions are in direct contact with rubber plungers containing bromobutyl. 3 plungers of the quality FM 257 (from Helvoet Pharma N.V.) were placed in each 3 ml glass vial together with 1 ml solution of melagatran (NaCl water solution and HPpCD water solution, respectively). Reference samples, that is melagatran in NaCl water solution and in HPβCD water solution having no contact with plunger material. The reference samples were treated in the same way as the other samples. The vials were stored at 50 °C for up to 3 months. Compared to the study of Example 1 the ratio between solution exposed plunger surface and the quantity of melagatran solution is 16 times higher. MANUFATURTNG OF SAMPLES Melagatran, 7.5 mg/ml, in HPpCD water solution (40 % w/w), pH about 5. Batch HF 839-2679 Melagatran 928.8 mg HPPCD 55.0 g HC1,1 M qs NaOH, 1 M qs water for injection 137.4 g (density 1.145 g/ml) Melagatran and HPβCD were dissolved in water and adjusted to pH 4.96. The final solution was diluted with water to final weight and sterile filtrated with 0.45 urn filter. Melagatran, 7.5 mg/ml, in NaCl water solution, pH about 5. Batch HF 839-2680 Melagatran 1315.5 g NaCl 1.441 g HC1, 1 M qs NaOH, 1 M qs water for injection to 170 (density 1.0 g/ml) Melagatran and NaCl were dissolved in water and adjusted to pH 5.03. The final solution was diluted with water to final weight and sterile filtrated with 0.22 μm filter. FILLING OF VIALS Sample A2 (HF 839-2682) 7.5 mg/ml in NaCl 1.0 ml of HF 839-2680 was filled in 3 ml vials together with 3 black unsilicomzed plungers (FM 257 from Helvoet Pharma N. V.) containing bromobutyl rubber. Sample B2 (HF 839-2683) 7.5 mg/ml in NaCl 1.0 ml of HF 839-2680 was filled in 3 ml vials together with 3 black siliconized plungers (FM 257 from Helvoet Pharma N. V.) containing bromobutyl rubber. Sample C2 (HF 839-2684) 7.5 mg/ml in NaCl 1.0 ml of HF 839-2680 was filled in 3 ml vials together with 3 grey siliconized plungers (FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber. Sample D2 (HF 839-2688) 7.5 mg/ml in NaCl 1.0 ml of HF 839-2680 was filled in 3 ml vials (Reference). Sample E2 (HF 839-2689) 7.5 mg/ml in HPβCD 1.0 ml of HF 839-2679 was filled in 3 ml vials together with 3 black unsilicomzed plungers (FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber. Sample F2 (HF 839-2690) 7.5 mg/ml in HPPCD 1.0 ml of HF 839-2679 was filled in 3 ml vials together with 3 black siliconized plungers (FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber. Sample G2 (HF 839-2691) 7.5 mg/ml in HPβCD 1.0 ml of HF 839-2679 was filled in 3 ml vials together with 3 grey siliconized plungers (FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber. Sample H2 (HF 839-2695) 7.5 mg/ml in HPpCD 1.0 ml of HF 839-2679 was filled in 3 ml vials (Reference). RESULTS OF STABILITY STUDIES Sample A2 (HF 839-2682) 7.5 mg/ml in NaCl - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 1 5.9 50 4.2 3 6.0 50 9.3 Sample B2 (HF 839-2683) 7.5 mg/ml in NaCl - Bromobutyl rubber Storage time (months) pH Temperature Total degradation (area % of melagatran) 1 5.8 50 4.0 3 6.0 50 8.7 Sample C2 (HF 839-2684) 7.5 mg/ml in NaCl - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 1 5.8 50 3.7 3 5.8 50 7.9 Sample D2 (HF 839-2688) 7.5 mg/ml in NaCl - Reference Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 1 5.2 4 1.4 3 5.3 4 1.4 1 5.4 50 3.4 3 5.6 50 6.8 Sample E2 (HF 839-2689) 7.5 mg/ml in HPPCD - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % melagatran) 1 5.5 50 5.5 3 5.6 50 11.3 Sample F2 (HF 839-2690) 7.5 mg/ml in HPPCD - Bromobutyl rubber Storage time (months) pH Temperature (°C) Total degradation (area % of melagatran) 1 5.4 50 5.4 3 5.5 50 11.3 Sample G2 (HF 839-2691) 7.5 mg/ml in HPpCD - Bromobutyl rubber _____ Storage time pH Temperature Total degradation (months) (°C) (area % of melagatran) 1 5_4 50 5.4 3 5.5 50 10.3 Sample H2 (HF 839-2695) 7.5 mg/ml in HPpCD - Reference Storage time (months) PH Temperature (°C) Total degradation (area % of meiagatran) I 5.2 4 1.5 3 5.3 4 1.7 1 5.3 50 5.7: 3 5.4 50 10.7 Conclusion Meiagatran in a water solution of NaCl exhibits a somewhat lower degradation compared to meiagatran in a water solution of HPpCD. This is true both for solutions in contact with plunger material (FM 257 bromobutyl) 8%* compared to 11%*, and solutions in absence of plunger material (reference) 7%* compared to 11%*. *; is total degradation in area% of meiagatran Example 3. This example shows a comparison of different kinds of stopper and plunger materials containing either bromobutyl rubber or chlorobutyl rubber in contact with a meiagatran solution (NaCl, pH 5). Meiagatran solution was filled in glass vials (3 ml) together with stoppers and plungers of different brands. 5 different rubber materials were used in the study. There were 3 different bromobutyl and 2 different chlorobutyl rubbers. As reference, NaCl water solution of meiagatran was stored without any contact with stopper or plunger material. The ratio between exposed plunger or stopper surface and melagatran in water solution is higher than in Example 1. A calculation has been made of exposed area of each tested plunger or stopper material. In the study the area ratio is 10-15 times higher compared to the area represented in Example 1. The vials were studied up to 19 days at a temperature of 50°C. MANUFACTURING OF SAMPLES Melagatran, 5 mg/ml, in isotonic NaCl solution, pH about 5. Batch HF 839-2719 Melagatran 10.0 mg NaCl 17.6 g HCL 1 M qs NaOH, 1 M qs water for injection To 2000 g final weight (density 1.0 g/ml) Melagatran and NaCl were dissolved in water and pH adjusted to 4.95 The solution was diluted to final weight with water. FILLING OF VIALS The total contact surface between the rubber material and the solution was enhanced in different ways and different extent. One way was by putting pieces of vial'stopper material into each vial. For sample A3, the stopper material was divided into eight equal parts, and two parts in each vial (total of 2/8). Another way to enhance the contact surface was to put 2-3 plungers in each vial. For sample E3, three plungers were put in each vial. In samples A3 to F3, the contact surface was increased of 10-15 times compared to the normal contact surface between plunger and solution in a 1 ml syringe (used in Example 1). Sample A3 (HF 839-2727) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in a 3 ml vial together with two 1/8 parts of a 10 ml vial stopper (FM 50 from Helvoet Pharma N.V.) containing chlorobutyl rubber. Sample B3 (HF 839-2728) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in 3 ml vial together with 2 grey plungers (PH 4023/50 from The West Company) containing bromobutyl rubber. Sample C3 (HF 839-2729) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in 3 ml vial together with 2 black plungers (PH 701/50 from The West Company) containing chlorobutyl rubber. Sample D3 (HF 839-2730) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in 3 ml vial together with 2 grey plungers (W 4416/50 from The West Company) containing bromobutyl rubber. Sample E3 (HF 839-2731) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in 3 ml vial together with 3 black plungers (FM 257 from Helvoet Pharma N.V.) containing bromobutyl rubber. Sample F3 (HF 839-2732) 5 mg/ml in NaCl 1.5 ml of HF 839-2719 was filled in 3 ml vial (Reference). RESULTS OF STABILITY STUDIES Sample A3 (HF 839-2727) 5 mg/ml in NaCl - Chlorobutyl rubber Storage time (days) pH Temperature ' (°C) Total degradation ' (area % of melagatran) 11 -5.0 50 8.0 19 -5.0 50 11.8 Sample B3 (HF 839-2728) 5 mg/ml in NaCl - Bromobutyl rubber Storage time (days) pH Temperature (°C) Total degradation (area % of melagatran) 11 -5.0 50 0.9 19 -5.0 50 1.4 Sample C3 (HF 839-2729) 5 mg/ml in NaCl - Chlorobutyl rubber Storage time (days) pH Temperature (°C) Total degradation (area % of melagatran) 11 -5.0 50 1.5 19 -5.0 50 2.4 Sample D3 (HF 839-2730) 5 mg/ml in NaCl - Bromobutyl rubber Storage time (days) pH Temperature (°C) Total degradation (area % of melagatran) 11 -5.0 50 1.3 19 -5.0 50 1.6 Sample E3 (HF 839-2731) 5 mg/ml in NaCl - Bromobutyl rubber Storage time (days) pH Temperature (oC) Total degradation (area % of melagatran) 11 -5.0 50 1.2 19 -5.0 50 1.4 I Sample F3 (HF 839-2732) 5 mg/ml in NaCI - Reference Storage time (days) pH Temperature (oC) Total degradation (area % of melagatran) 11 -5.0 50 0.6 19 -5.0 50 1.0 Conclusion All three bromobutyl rubber materials demonstrate lower melagatran degradation compared to the two chlorobutyl rubber materials. Summary conclusion It is shown in Example 1 that, for water solutions containing melagatran stored in HYPAK® syringes (from Becton Dickinson), improved stability is demonstrated using plungers containing bromobutyl rubber compared to the corresponding plungers containing chlorobutyl rubber. It is shown in Example 2 that, for water solutions of melagatran stored in glass vials, improved stability is demonstrated using a NaCl water solution compared to a HPβCD water solution. This is true for melagatran in solution with and without contact of plungers containing bromobutyl rubber. WE CLAIM: 1. A primary package, such as a vial, bottle, cartridge or pre-filled syringe, containing an aqueous solution for parenteral administration comprising a low molecular weight peptide-based thrombin inhibitor or a salt thereof, having a pH in the range 3 to 8, the primary package being sealed with a rubber stopper or plunger containing bromobutyl rubber. 2. A primary package as claimed in claim 1, wherein the solution is a NaCl solution 3. A primary package as claimed in any of the preceding claims, wherein the solution also comprises hydroxy-propyl-β-cyclodextrin. 4. A primary package as claimed in any of the preceding claims, wherein the concentration of the thrombin inhibitor in the solution is in the range 0.001-100 mg/ml, preferably 2.5-20 mg/ml. 5. A primary package as claimed in any of the preceding claims, wherein the pH of the solution is in the range 3-8. 6. A primary package as claimed in claim 5, wherein the pH of the solution is 5. 7. A primary package as claimed in any of the preceding claims, wherein the thrombin inhibitor is melagatran. 8. A primary package as claimed in any of the preceding claims, wherein the thrombin inhibitor in the solution is inogatran. 9. A primary package as claimed in any of the preceding claims, wherein the thrombin inhibitor in the solution is compound A (Glycine, N- [l-cyclohexyl-2-[2-[2-[[[[4-[(hydroxyimino)aminomethyl]-phenyl]methyl]- amino]carbonyl]-l-azetidinyl]-2-oxoethyl]-, ethyl ester, [S-R*, S*)]-). 10. A primary package as claimed in any of the preceding claims, wherein the bromobutyl rubber material consists of, or correspond to, the quality PH 4023/53. 11. A primary package as claimed in any of claims 1-9, wherein the bromobutyl rubber material consists of, or correspond to, the quality W 4416/50. 12. A primary package as claimed in any of claims 1-9, wherein the bromobutyl rubber material consists of, or correspond to, the quality FM 257. 13. A process for the manufacture of a primary package as claimed in claim 1 comprising the steps of dissolving a low molecular weight peptide-based thrombin inhibitor in an aqueous solution, adjusting the pH of the solution to be in the range 3 to 8, optionally adding a cyclodextrin substance, sterile filtering the solution and filling it on a primary package which is then sealed with a rubber stopper or plunger containing bromobutyl rubber. Dated this 14th day of February, 2001 (RANJNA MEHTA DUTT) OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

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