Patent ID: 12208061

DESCRIPTION OF PREFERRED EMBODIMENTS

Aztreonam has the chemical name (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid, has the structural formula

and a molar mass of 435.433 g/mol.

Aztreonam is known to exist in several polymorphic forms, including the alpha (α), beta (β), delta (δ) and gamma (γ) crystal forms, which are suitable for practicing the present invention. Among these polymorphic forms the j-form is anhydrous, substantially non-hygroscopic, and more stable.

The β-form of aztreonam is preferred for constitution as an injectable solution, or for inhalation, and is packaged in a manually activatable, dual chamber package having a solids chamber (a first chamber) and a liquid chamber (a second chamber).

Preferably, the packaging, i.e., a dual-chamber syringe, a dual chamber pouch, and the like, provides an oxygen barrier to the contents within and also a pH protective interior coating.

A first or solids chamber can contain only sterile β-aztreonam powder, or β-aztreonam powder together with solid solubilizing and stabilizing excipients. A bulking agent such as a disaccharide, e.g., sucrose, lactose, trehalose, and the like may be present as well. A second or liquid chamber can contain a physiologically acceptable carrier for β-aztreonam. The carrier can be sterile water, an aqueous solution of one or more of the aforementioned excipients, an aqueous solution of an organic or inorganic acid that can form a pharmacologically compatible base addition salt with β-aztreonam, or a water-soluble organic solvent or cosolvent such as propylene glycol, glycerin, polyethylene glycol 300, polyethylene glycol 400, and the like, and mixtures thereof. If the injectable formulation is an organic formulation, a surfactant such as pegylated castor oil (Cremophor EL) or a hydrogenated castor oil with varying amounts of ethylene oxide can be present as well.

An additional organic or inorganic acid can also be added to the constituted β-aztreonam solution, if desired, to adjust or stabilize the final pH of the injectable or inhalable product.

The carrier solution, if aqueous at least in part, can also contain a buffer, preferably a phosphate buffer, for enhancing β-aztreonam solubility and for maintaining the constituted solution at a pH value in the range of about 4.5 to about 7.5, preferably about 5.5 to about 7.5, so as to assure complete dissolution of β-aztreonam present over the anticipated product temperature range.

Suitable organic acids are oxalic acid, maleic acid, acetic acid, succinic acid, citric acid, and the like, as well as the basic amino acids such as arginine, lysine, histidine, and mixtures thereof, e.g., a mixture of L-arginine and L-lysine, a mixture of L-arginine and L-histidine, and a mixture of L-lysine and L-histidine.

Suitable inorganic acids are hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, and the like.

If the aqueous solution present in the liquid chamber contains a basic amino acid, the aqueous solution can also contain an amount of the corresponding basic amino acid hydrochloride, e.g., arginine hydrochloride, lysine hydrochloride, histidine hydrochloride, to gain a “salting in” effect and further enhance solubility.

A suitable phosphate buffer consists of a mixture of monobasic potassium phosphate and dibasic sodium phosphate, and the like.

In another embodiment of the invention the solids chamber can contain not only the β-aztreonam powder but also the aforementioned solid excipients in dry powder form, and the liquid chamber contains only solvent in an amount sufficient to dissolve the compounds present in the solids chamber.

Referring to the drawings,FIG.1illustrates a dual chamber mixing syringe embodiment in which syringe10is provided with a hollow syringe body12having inner wall14, distal discharge end portion16, and proximal piston rod receiving end portion18. Inner wall14defines a bypass region, such as groove20, at a midportion of hollow syringe body12.

First piston22in hollow syringe body12together with distal discharge end portion16defines a first chamber34which also includes the bypass region. Discharge end portion terminates in a dispensing nozzle28which can have a male Luer configuration adapted to receive a female Luer fitting of a cannula. Dispensing nozzle28is shown fitted with sealing cap38.

Second piston24is situated in hollow syringe body12in proximal piston rod receiving end portion18and together with first piston22defines a second chamber36.

First chamber34is the solids chamber and contains sterile, anhydrous β-aztreonam either alone or together with the aforesaid optional constituents in dry powder form. Second chamber36is the liquid chamber and contains solvent32for the solids30in first chamber34. The solvent can be a saline solution or sterile water suitable for injection. The solvent can also include a water-soluble, physiologically compatible organic solvent or cosolvent for β-aztreonam. A β-lactamase inhibitor, e.g., avibactam, can be included as well, if desired.

The solvent can also be a solution in water of one or more of the optional solid constituents or excipients discussed hereinabove. In either case, the active ingredient, β-aztreonam, is maintained as an anhydrous powder until such time when second piston24is urged axially toward first piston22by depressing piston rod26and moves first piston22past groove20, thereby introducing physiologically compatible solvent32into first chamber34and combining solvent32with β-aztreonam powder30in first chamber34. Dissolution of powder30is achieved by shaking the syringe after the solvent has been combined with the β-aztreonam until a clear solution can be seen in the first chamber. The clear solution produced in the foregoing manner is then ready to be dispensed via dispensing nozzle28by continued movement of pistons22and24toward dispensing nozzle28.

Pistons22and24must, of course, be compatible with the pH range of chamber contents before as well as after constitution of the β-aztreonam solution.

FIGS.2and3illustrate a second embodiment which utilizes a two-chamber flexible pouch40having front sheet42and back sheet44arranged in opposing face-to-face relationship relative to one another and joined together along a top edge46, a bottom edge48, first side edge50and second side edge52to define a sealed pouch with an interior space54. Frangible seal56partitions interior space54into first chamber64and second chamber66. First chamber64serves as the solids chamber and second chamber66serves as the liquid chamber which contains a solvent for the solids in first chamber64. Second chamber66is provided with dispensing nozzle60sealed by pierceable sealing membrane62. Components70of first chamber64can be the same as those discussed hereinabove for first chamber34in hollow syringe body12. Likewise, the contents72of second chamber66can be the same as those discussed hereinabove for second chamber36in hollow syringe body12.

To combine the contents of both chambers prior to use, frangible seal56is breached by urging the liquid in second chamber66against frangible seal56.

Preferred material of construction for pouch40is a thermoplastic film or sheet such as polyethylene film or sheet, polyvinylchloride film or sheet, ethylenevinyl acetate film or sheet, PL2040 plastic sheet, and the like material compatible with the contents of the pouch.

Table A, below, sets forth preferred sterile β-aztreonam packages that embody the invention.

TABLE APreferred Sterile β-Aztreonam PackagesChamber1 (solids)2 (liquid)DualWFIL-L-PreferredVolume, mlExampleSterileChamberq.s.Arginine,Lysine,Na3 PO4,Na2HPO4,NaH2PO4,AdministrationChamberChamberNumberβ-AztreonamDeviceto mlmgmgmgmgmgRoute12175mgSyringe3—53———Inhalation532500mgSyringe3421————I.M.-I.V.5331.0gSyringe3211529——140I.M.-I.V.5341.0gSyringe3—705——70I.M.-I.V.5351.0gPouch50780———140I.V.125062.0gSyringe8780671——280I.M.-I.V.12872.0gSyringe3—1410——140I.M.-I.V.12382.0gPouch501560———280I.V.125091.0gSyringe5——380——I.M.-I.V.56102.0gSyringe10—1410—1010I.M.-I.V.1210NOTESSterile β-aztreonam is the preferred crystalline form but other sterile polymorphic forms (i.e., α, γ, δ) can be usedPhosphate buffers may be substituted with other organic or inorganic buffersArginine and Lysine ratios can be modified to optimize solubility profilePhosphate buffer ratios can be modified to achieve desired pH intervalWFI = sterile water for injection

Example 11: Stability of Constituted Solutions of Aztreonam

Stability of β-aztreonam solutions containing 1-arginine or 1-lysine and constituted with sterile water-for-injection was evaluated by storing the constituted solutions in a 30 milliliter glass vial at 25° C. for 48 hours. The stored solutions were sampled at zero, 3, 6, 12, 24, 36 and 48 hours storage. The evaluated solutions are listed in Table B, below.

TABLE BConstituted Solutionsβ-Aztreonam(AZT)L-ArginineL-LysineWaterSolutions(mg)(mg)(mg)(mL)AZT 2G + ARG +20001600—5050 mLAZT 1G + ARG +1000800—5050 mLAZT 2G + LYS +2000—13445050 mLAZT 1G + LYS +1000—6725050 mLAZT 1G + LYS +1000—67233 mLAZACTAM ®120001560—502G + 50 mLAZACTAM ®11000780—501G + 50 mLAZACTAM ®11000780—31G + 3 mL1AZACTAM ® is an intravenous aztreonam solution commercially available from Bristol-Myers Squibb, Princeton, NJ, USA. In addition to aztreonam the solution contains 700 mg Dextrose Hydrous, USP and 780 mg of arginine per one gram of aztreonam present.

The pH value of the stored solutions was determined using Mettler Toledo Five Easy pH meter with a combined electrode. The solutions were tested without dilution. The pH measurement results are reported in Table C, below.

TABLE CpH MeasurementsTime of Measurement, hrsSolutionst0t6t12t24t36t48AZT 1G + ARGsol 50 mL5.35.35.35.45.55.3AZT 1G + LYSsol 50 mL5.25.35.25.35.45.2AZACTAM ® 1G + 50 mL5.05.05.05.15.25.1AZT 2G + ARGsol 50 mL6.86.86.76.76.56.3AZT 2G + LYSsol 50 mL5.65.65.55.75.75.6AZACTAM ® 2G + 50 mL5.15.15.15.25.35.1AZT 1G + LYSsol 3 mL5.05.05.05.15.25.1AZACTAM ® 1G + 3 mL5.05.05.05.15.25.1

Degradation of aztreonam during storage was determined using a Waters Alliance HPLC system. Samples were diluted at appropriate concentrations in accordance with analytical method validation.Detector: UV at 254 nmColumn Length: 100×4.6 mmStationary Phase: C18Eluent: Phosphate Buffer, pH 3/Methanol 85/15Flow Rate: 1 ml/min, isocratic @ room temperature
The noted aztreonam degradation results are reported in Table D, below.

TABLE DDegradation of β-Aztreonam Solutions% β-Aztreonam @ Time ofMeasurement (t)Solutionst0t6t12t24t36t48AZT 1G + ARGsol 50 mL10099.697.997.496.293.7AZT 1G + LYSsol 50 mL10096.995.397.093.692.7AZACTAM ® 1G + 50 mL10098.199.597.795.993.2AZT 2G + ARGsol 50 mL100101.197.698.397.094.4AZT 2G + LYSsol 50 mL10097.799.095.395.392.0AZACTAM ® 2G + 50 mL10097.997.899.095.592.5AZT 1G + LYSsol 3 mL100100.3100.5100.297.596AZACTAM ® 1G + 3 mL100101.6100.299.096.694.0

The foregoing data demonstrate the feasibility of separate compartment packaging of aztreonam powder and liquid excipients for constituting an injectable aztreonam composition.

The discussion above and the drawings are intended to be illustrative but not limiting. Still other variants within the spirit and scope of the present invention are possible and will readily present themselves to one skilled in the art.