Argatroban formulation comprising an acid as solubilizer

[0001] The present invention relates to a new pharmaceutical preparation of 1- [5 [(aminoiminomethyl) amino] -1-oxo-2 - [[(1,2,3,4-tetrahydro-3-methyl] -8-quinolinyl) sulfonyl] acid hydrate amino] pentyl] -4-methyl-2-piperidinecarboxylic acid commonly known by the generic name "argatroban". "Argatroban" is a synthetic direct thrombin inhibitor derived from L-arginine and is useful as an anticoagulant.

[0002] Argatroban is considered to be poorly or very slightly soluble in water according to the classification of solutes USP (United States Pharmacopeia), has a solubility of approximately 0.8 to 0.9 mg / ml. It is also sensitive to both light and heat, and if not stabilized, it tends to break down. Argatroban is commercially available in concentrated form in aseptically filled vial containing 100 mg argatroban, 750 mg D-sorbitol and 1000 mg dehydrated alcohol per ml. When this formulation is administered to a patient, it is diluted to a concentration of 1.0 mg / ml in an admixed diluent solution containing an osmotic agent such as sodium chloride or dextrose (cf. US Patent No. 5,214,052).

[0003] Other preparations of argatroban have been described in US Patent Nos. 5,679,690 and 6,087,375, European Patent Applications 0,565,897 A1 and 0,621,036 A1 and in WO 2005/009361 A2.

[0004] EP-A-0.608,831 discloses an anti-thrombin composition in the form of an emulsion that contains a solvent, diluent, emulsifier and N-arylsulfonyl-L-argininamide such as argatroban. [0005] EP-A-0,669,131 discloses a concentrated aqueous solution containing argatroban, micellogenic agent and lipid substance.

[0006] EP-A-0.608,828 discloses an anti-thrombin composition in the form of a lipid emulsion that ₂ contains unsaturated fatty acid, emulsifiers and N²-arylsulfonyl-L-argininamide such as argatroban.

[0007] US-5,506,241 describes a method for preventing fibrin production in the anterior chamber (eyeball), which comprises administering a preparation containing argatroban to that chamber.

SUMMARY OF THE INVENTION [0008] The present invention provides an aqueous, stable, sterile pharmaceutical composition of a thrombin inhibitor that is suitable for parenteral administration, essentially free of dehydrated alcohol, which has a pH between 4.5 and 5.5 and which contains 0.1 to 10 mg / ml in solution 1- [5 - [(aminoiminomethyl) amino] -1-oxo-2 - [[(1,2,3,4-tetrahydro-3-methyl-8-quinolinyl sulfonyl] amino] pentyl] -4-methyl acid hydrate -2-piperidinecarboxylic (argatroban) and acid to

EP 1948133 B1 to solubilize argatroban. This composition may further optionally contain a buffering agent to help maintain pH and an osmotic regulating agent for improving the infusion properties. The composition is stable during storage (under both light and heat conditions), suitable for aseptic filling and thermal sterilization, and contains argatroban in a concentration range from ready to use to a concentrate requiring dilution before administration. In a further aspect of the present invention there is provided a method of producing the aforesaid argatroban formulation in an airtight container such as an ampoule, vial, syringe or infusion bag, and autoclaving for a sufficient period of time to render the composition sterile.

SUMMARY OF THE DRAWINGS [0009] Figure 1 is a graphical image of the effect of pH on argatroban content as a function of time (weeks) when stored at 55 ° C.

[0010] Figure 2 is a graphical image of solution stability for 1 mg / ml argatroban injection under various thermal conditions as a function of time.

DETAILED DESCRIPTION OF THE INVENTION [0011] The present invention provides a sterile, stable composition for parenteral administration, containing argatroban with improved water solubility and optionally a pharmaceutically acceptable buffering agent and an osmotic regulating agent to regulate the tonicity of the solution. The composition is packaged in a sealed container that can be either aseptically filled or, preferably, heat sterilized to reduce the microbial load of the formulation. The composition of the present invention is resistant to hydrolytic degradation and other adverse chemical reactions, and when properly packaged, for example with an aluminum outer bag, to photolytic degradation.

[0012] The improved solubility of argatroban in the aqueous solution was achieved by the addition of acid. The acids will usually be diluted, i.e., approximately from 0.01 to 3 N. Without limiting any theory, it is believed that the acid (which may be either organic or inorganic) forms an "ionic liquid" or a salt solution of in situ argatroban. This refers to the ionic liquid and salt counterion, where the ions are poorly or accidentally ordered and / or coordinated. Ionic liquid / saline solution in-situ may include ions with a delocalized charge, or resonance in a drug molecule that is stabilized by its counterion. As a result, stable argatroban solutions having solubilities in the range of 0.1 to 10 mg / ml, more typically 0.8 to 10 mg / ml are possible, despite being essentially free of solvent or additional solubilizing and / or stabilizing agents such as ethanol, saccharides, surfactants, long chain fatty acids, cyclodextrin derivatives, caffeine. The solution is thermodynamically stable at room temperature for at least 24 months, substantially without significant degradation, and remains within the appropriate pH range.

[0013] Table I provides a summary of the improved solubility of argatroban in dilute acids.

Table I

<td colspan="3">Solubility of argatroban in dilute acids at room temperature</td>

<td>Diluted acids¹</td><td>Visual dissolution assessment²</td><td>Quantity (mg / ml)³</td>

<td>Phosphoric acid</td><td>Easily soluble</td><td> &gt; 10.08</td>

<td>Acetic acid</td><td>Very soluble</td><td> &gt; 11.5</td>

<td>Tartaric acid</td><td>Easily soluble</td><td> &gt; 10.4</td>

<td>Citric acid</td><td>Moderately soluble</td><td> &gt; 9.79</td>

<td>Formic acid</td><td>Very soluble</td><td> &gt; 10.08</td>

<td>Maleic acid</td><td>Moderately soluble</td><td> &gt; 9.32</td>

<td>Hydrochloric acid</td><td>Moderately soluble</td><td> &gt; 10.1</td>

<td colspan="3">¹ The molarity of the acids used was ~ 1-3 N 2 Classification according to Remington's Pharmaceutical Science, 20th edition 3 The amount of argatroban was determined by HPLC</td>

[0014] The term "stable" as used in the context of this application means remaining in a condition that is suitable for administration to a patient. The formulations of the present invention are stable when kept at room temperature for at least 24 months, and are generally stable in room temperature for 24 to 36 months.

[0015] The term "sterile" composition, when used in the context of this application, means a composition that has been brought to a sterile state and which has not subsequently been exposed to microbial contamination, that is, the container containing the sterile composition has not been tampered with. Sterile compositions are generally made by pharmaceutical manufacturers in accordance with current Good Manufacturing Practice ("cGMP") regulations according to US Food and Drug

Administration.

[0016] The product may take the form of a sterile, stable, ready-to-use infusion preparation. This prevents the inconvenience of diluting the concentrated parenteral low volume argatroban preparation in the diluent for infusion preparation prior to infusion, and also eliminates the risk of microbial contamination during aseptic use and any potential error in calculation or dilution. Such preparations that are not prepared from the concentrate will be substantially free of the saccharide component, e.g. D-sorbitol, and the dehydrated alcohol component, e.g. dehydrated ethanol. The product may also be in the form of a concentrated preparation, which must be diluted before administration.

[0017] The sterile, stable, aqueous pharmaceutical composition according to the present invention is suitable for parenteral administration to a patient. For example, the composition may be administered in the form of a bolus injection or intravenous infusion. Suitable routes for parenteral administration include intravenous, subcutaneous, intradermal, intramuscular, intra-articular and intrathecal administration. The ready-to-use formulation according to the invention is preferably administered as an intravenous infusion.

[0018] Suitable containers according to the present invention are those known in the art. These include the form of a vial, syringe, infusion bag, bottle and ampoule. The containers can be made of glass or of polymeric materials. Ready-to-use preparations are usually packaged in vials, syringes, infusion bags and bottles, while concentrated preparations are usually packaged in ampoules.

[0019] The composition of the present invention may be lyophilized using known techniques and then reconstituted prior to administration. Some acids in the composition, such as acetic acid, may be volatile and partially lost during lyophilization. In such cases, they must be replenished in the reconstituted solution.

[0020] The effect of pH on argatroban degradation was studied in five aqueous buffer solutions at 55 ° C. All buffer solutions were prepared in water for injection according to USP buffer solutions standards. Five buffer solutions with pH 2.01.5.0, 7.4, 8.02 and 11.05 were prepared. 1 mg / ml argatroban was accurately weighed for each level and transferred to a calibrated flask. Buffer solution was added to the flask and mixed until completely dissolved, then diluted to the appropriate volume. Samples of all five solutions were stored in brown glass (to protect from light) and kept at 55 ° C. Samples were taken at pre-determined intervals and then analyzed for pH, strength and physical appearance of the solutions.

[0021] Drug concentration was determined using a high performance liquid chromatography (HPLC) method. The data obtained is presented as the logarithm of the drug concentration as a function of time with the assumption that the reaction rate is apparently first order (k observed). The rate of decomposition of argatroban at an elevated temperature of 55 ° C was monitored as a function of various pH values, and an illustrative illustration is shown in Figure 1. k observed was calculated from the slopes of the linear regression line, and the maximum changes in the decay rate occurred at both low and high pH values ​​(pH 2.0 and 11.05). The lowest k_zaobserwabout_inand_nand in this study it is visible in the range from pH 5.0 to about pH 8.0 suggesting that the pH of the composition should be controlled to ensure maximum stability. The results indicate that the pH should be in the range between 3.5 and 8.5, preferably between 4.5 and 6.5, more preferably about 4.5 to 5.5. The pH can be adjusted as is known in the art by the addition of sodium hydroxide or acetic acid.

[0022] The ready-to-use injection of argatroban was tested under stress to predict the shelf life of the product during storage in an aqueous medium. Solutions of the argatroban composition after autoclaving at 121 ° C for 20 minutes with minimal degradation were stored at 25 ° C, 40 ° C and 55 ° C (protected from

EP 1948133 B1) for a period of six months. The pH, strength, solid particles and physical appearance of the solutions were determined. Drug concentration was determined using the high performance liquid chromatography (HPLC) method. Data obtained from this study indicate that the stabilizing effect was maximized at pH 5.0 ± 0.5 and that the total conversion of degradants over the test period at 40 ° C is less than 1%. Regression and extrapolation of the obtained stability data suggests the stability of the aqueous composition not less than 24 months at room temperature (25 ° C). Figure 2 is a graph of solution stability for 1 mg / ml injection of argatroban versus time under various thermal conditions.

[0023] Furthermore, it has been found that when the argatroban composition of the present invention is stored in some types of containers, no buffering agent is needed because the argatroban composition is intrinsically stable. Such suitable containers are those whose surfaces in contact with the argatroban composition do not contain leaching substances, which are usually alkaline. One such suitable container is the IntraVia® flexible plastic container from Baxter Healthcare Corporation. The composition's pH values ​​when no buffering agent is used will range from about 4.5 to 5.5.

[0024] Argatroban is present in the present composition in an amount ranging from 0.1 to 10 mg / ml. Ready-to-use preparations may contain 0.5 to 10 mg / ml, more typically about 1 mg / ml argatroban. [0025] The acids used to solubilize argatroban can be organic or inorganic. Such suitable acids include; phosphoric acid, acetic acid, tartaric acid, citric acid, formic acid, malic acid, hydrochloric acid and mixtures thereof. They are usually used in solution in concentrations ranging from 0.01 to 3 N, depending on the degree of ionization and association or stability of the counterion in the aqueous environment. The preferred acid is acetic acid, and is present in an amount in the range of 0.5 to 6 mg / ml.

[0026] Suitable physiologically acceptable buffering agents include acetate, glutamate, citrate, tartrate, benzoate, lactate, malate, gluconate, phosphate and glycine, with acetate being preferred. A preferred buffering system contains a combination of sodium acetate and acetic acid. Buffering agents are present in the composition at a concentration that depends on the concentration of argatroban. The concentration will usually be in the range of 0.05 to 200 mM, and 10 to 100 mM for preparations containing 0.5 to 10 mg / ml argatroban.

[0027] Suitable osmotic regulating agents, if used, are compatible with the pH requirements of the present formulation and include one or more of: sodium chloride, calcium chloride, potassium chloride, dextrose and sodium lactate. Sodium chloride and dextrose are preferred.

The formulations of the present invention may contain from 1 to 100 mg / ml of osmotic regulating agent; preferably from 4 to 60 mg / ml sodium chloride, more preferably from 4 to 10 mg / ml sodium chloride; or dextrose with a content not exceeding 5% (by weight), usually in an amount in the range from 25 to 60 mg / ml.

[0028] The compositions of the present invention may be prepared in the form of a low volume parenteral dose (SVP) and a high volume parenteral dose (LVP). Dosage forms can be kept in any suitable container. suitable

Containers include, for example: glass or polymer vials, ampoules, syringes or infusion bags ranging in size from 1 ml to 500 ml. Ready-to-use SVP solutions are usually filled into 1 to 100 ml ampoules or vials. In addition, syringes can be used as ready-to-use SVP containers that are sold as "pre-filled syringes." LVP forms can be contained in infusion bags or bottles.

[0029] The polymeric containers are preferably flexible and may or may not contain polyvinyl chloride (PVC). Preferred containers do not contain PVC, as disclosed in US Patents. 5,849,843 and 5,998,019. In addition, polymeric containers with a moisture barrier, such as an additional packaging system, may be provided to prevent water loss during storage and to further protect the stability of the formulation. A preferred moisture barrier is the aluminum outer bag, which also protects the preparation against photolytic degradation.

[0030] Procedures for filling containers with compositions of the invention and their subsequent processing are known in the art. These procedures are also used to make sterile pharmaceutical medicinal products that are often required for health care. Such processing techniques advantageously use a sterilization process to destroy or eliminate any microorganisms that may be present in argatroban preparations after manufacture. For example, final thermal sterilization can be used to destroy all viable microorganisms in a final, sealed container of an argatroban preparation. The autoclave is widely used for the final thermal sterilization of medicinal products in their final packaging.

[0031] Typical autoclave cycles in the pharmaceutical industry to achieve final sterilization of the final product take 15 minutes at 121 ° C. The argatroban composition of the present invention may be autoclaved at a temperature in the range of 115 to 130 ° C for a period of time in the range of 5 to 40 minutes with acceptable stability. The autoclave is preferably carried out in a temperature range of 119 to 122 ° C for a period of time in the range of 10 to 36 minutes.

[0032] Alternatively, the sterile pharmaceutical compositions of the present invention may be prepared using aseptic processing techniques. Aseptic filling is usually used in the manufacture of medicinal products that are not resistant to thermal sterilization, but in which all ingredients are sterile. Sterility is maintained through the use of sterile materials and a controlled working environment. All containers and devices are sterilized, preferably by thermal sterilization, before filling. The container (e.g., vial, ampoule, infusion bag, bottle or syringe) is then filled under antiseptic conditions.

[0033] The following non-limiting examples further illustrate the invention. In each case, a 1 mg / ml formulation was prepared.

EXAMPLE 1 [0034]

EP 1948133 B1

<td>argatroban</td><td>1 mg</td>

<td>Acetic acid, USP</td><td>0.546 mg</td>

<td>Sodium acetate trihydrate, USP</td><td>2.8 mg</td>

<td>NaCL, Osmotic USP regulating agent</td><td>5.9 mg</td>

<td>Acetic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 2 [0035]

<td>argatroban</td><td>5 mg</td>

<td>Acetic acid, USP</td><td>0.546 mg</td>

<td>NaCL, Osmotic USP regulating agent</td><td>5.9 mg</td>

<td>Acetic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 3 [0036]

<td>argatroban</td><td>1 mg</td>

<td>Phosphoric acid, USP</td><td>8.5 mg</td>

<td>Sodium phosphate</td><td>1.8 mg</td>

<td>NaCL, Osmotic USP regulating agent</td><td>5.9 mg</td>

<td>Acetic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EP 1948133 B1

EXAMPLE 4 [0037]

<td>argatroban</td><td>10 mg</td>

<td>Hydrochloric acid</td><td>0.146 mg</td>

<td>NaCl, Osmic USP regulating agent</td><td>5.9 mg</td>

<td>HCl or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 5.

[0038]

<td>argatroban</td><td>1 mg</td>

<td>Tartaric acid, USP</td><td>12.3 mg</td>

<td>NaCl, Osmic USP regulating agent</td><td>5.9 mg</td>

<td>Tartaric acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 6 [0039]

EP 1948133 B1

<td>argatroban</td><td>5 mg</td>

<td>Citric acid, USP</td><td>15 mg</td>

<td>Sodium Citrate</td><td>1.2 mg</td>

<td>NaCI, Osmotic USP regulating agent</td><td>5.9 mg</td>

<td>Citric acid, or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 7 [0040]

<td>argatroban</td><td>1 mg</td>

<td>Acetic acid, USP</td><td>0.546 mg</td>

<td>Sodium acetate trihydrate, USP</td><td>2.8 mg</td>

<td>Dextrose, USP osmotic regulating agent</td><td>50 mg</td>

<td>Acetic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EXAMPLE 8 [0041]

<td>argatroban</td><td>5 mg</td>

<td>Acetic acid, USP</td><td>0.546 mg</td>

<td>Sodium acetate trihydrate, USP</td><td>2.8 mg</td>

<td>(No osmotic regulating agent)</td><td></td>

<td>Acetic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

EP 1948133 B1

EXAMPLE 9 [0042]

<td>argatroban</td><td>5 mg</td>

<td>Formic acid, USP</td><td>3.6 mg</td>

<td>NaCl, Osmic USP regulating agent</td><td>5.9 mg</td>

<td>Formic acid or NaOH</td><td>To set the required pH</td>

<td>Water for injection, USP</td><td>qs</td>

<td>Autoclave cycle = 121 ° C for 2 to 20 minutes</td><td></td>

PROCEDURE [0043] Apparatus and glass for joining, filtration and filling are properly washed and depyrogenized. The filtration set, filling tube set and other parts of the apparatus are sterilized.

[0044] Eighty percent (80%) of the final volume of cool water for injection was collected in a calibrated mixing tank. Sodium chloride was added to the tank and the solution was stirred until the sodium chloride dissolved. Then sodium acetate was added to the tank and mixed until all the excipients were dissolved. The tank was made up to 90% of the final volume with water for injection and mixed. Approximately 1.08 grams of acetic acid was added to 2 liters of water to form an argatroban suspension solution. Argatroban was weighed into 2 liters of acidified water to produce a suspension solution. Then this suspension was added to the mixing container and the solution was mixed. The solution was then adjusted to pH 5.5 using 1 N sodium hydroxide or acetic acid if necessary. The solution was made up to the final volume with water for injection and mixed.

[0045] Next, a 250 ml solution was filled with PVC-free flexible bags (IntraVia® flexible plastic container (PL 2408-3 PVC-free multilayer plastic film) with one standard PL 146.RTM PVC membrane tube, one tube with a multilayer plastic coextruded delivery port, PL 2409-3, with the PL 141 PVC one-way closure (feed port protection), available from Baxter Healthcare Corporation). These bags are sealed in aluminum foil outer packaging. The products are then placed in an autoclave sterilizer and sterilized at 121 ° C for 20 minutes.

EP 1948133 B1